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Roles of Reactive Oxygen Species in Vascular Complications of Diabetes: Therapeutic Properties of Medicinal Plants and Food

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Oxygen 2022, 2(3), 246-268;
Submission received: 5 June 2022 / Revised: 29 June 2022 / Accepted: 30 June 2022 / Published: 2 July 2022
(This article belongs to the Special Issue Review Papers in Oxygen)


The rising prevalence of chronic metabolic disorders, such as obesity and type 2 diabetes, most notably associated with cardiovascular diseases, has emerged as a major global health concern. Reactive oxygen species (ROS) play physiological functions by maintaining normal cellular redox signaling. By contrast, a disturbed balance occurring between ROS production and detoxification of reactive intermediates results in excessive oxidative stress. Oxidative stress is a critical mediator of endothelial dysfunction in obesity and diabetes. Under a hyperglycemic condition, the antioxidant enzymes are downregulated, resulting in an increased generation of ROS. Increases in ROS lead to impairment of endothelium-dependent vasodilatations by reducing NO bioavailability. Chronic treatments with antioxidants were reported to prevent the development of endothelial dysfunction in diabetic patients and animals; however, the beneficial effects of antioxidant treatment in combating vascular complications in diabetes remain controversial as antioxidants do not always reverse endothelial dysfunction in clinical settings. In this review, we summarize the latest progress in research focused on the role of ROS in vascular complications of diabetes and the antioxidant properties of bioactive compounds from medicinal plants and food in animal experiments and clinical studies to provide insights for the development of therapeutic strategies.

1. Introduction

Diabetes is a chronic metabolic disease with high prevalence all over the world. According to statistics from the International Diabetes Federation (IDF), an estimated 10.5% of people around the world were suffering from diabetes in 2021. It is predicted that by 2024, the number of diabetic patients will rise to 783 million. Type 1 diabetes is an autoimmune condition in which the pancreas is attacked to lose the ability to produce insulin in the body. More than 90% of diabetes cases are type 2 diabetes which is closely linked to unhealthy living styles such as physical inactivity as well as a high-fat and high-carbohydrate diet. Hyperglycemia and hyperlipidemia are widely considered to contribute to vascular dysfunction, leading to the occurrence of cardiovascular disease. Cardiovascular disease is one of the most severe complications of diabetes and the major cause of death in diabetic patients. People with diabetes have twice the risk of cardiovascular disease than people without diabetes. According to the statistics from 2007 to 2017, cardiovascular disease accounted for half of all deaths from type 2 diabetes [1]. Cardiovascular disease includes macrovascular and microvascular complications such as coronary heart disease, peripheral artery disease, stroke, nephropathy, diabetic retinopathy, and cardiac autonomic neuropathy [2]. In diabetes, excess reactive oxygen species (ROS) play a critical role in the occurrence and development of cardiovascular disease [3]. Elevated glucose and free fatty acids (FFAs) contribute to the release of ROS from mitochondrial electron chain, NADPH oxidases, xanthine oxidase, arachidonic acid, and uncoupling of NOS, and so on [4,5]. The accumulation of ROS reduces NO bioavailability and induces intracellular inflammation and apoptosis, which mediate the occurrence of cardiovascular disease [6]. Numerous studies have shown that suppressing oxidative stress helps improve diabetes-associated cardiovascular disease [4,7,8]. Therefore, antioxidant therapy is the hot spot of medical research in this area.
Many different antioxidants such as vitamin C and E, α-lipoic acid, glutathione, vitamin A and the carotenoids, vitamin B and folic acid, coenzyme Q10 (CoQ10), estrogen, probucol, chelation of iron and minerals were demonstrated to have a positive effect in diabetic animal models and in vitro experiments [8,9,10,11]. Although previous studies reported that some antioxidants play a positive role in the cardiovascular events of diabetic patients, most studies have shown that antioxidants have limitations or no effect in the clinical trials of diabetic cardiovascular disease [12,13,14,15]. In addition, the minimum effective dose of antioxidants is ambiguous in the human body; and importantly, a high-dose, redundant or continuous supplement of antioxidants may increase health risks in some cases [10,16,17]. For example, vitamin E may have a potential harm to hemorrhagic stroke as suggested in a long-term trial of male physicians; and β-carotene was associated with lung cancer incidence in smokers [17,18]. Antioxidants are also prone to be oxidated during preservation, which can have adverse effects on treatment [19,20]. Antioxidants generally have no significant therapeutic effect on advanced cardiovascular disease [8,21]. To date, there are no clinically approved antioxidants that can effectively treat diabetic cardiovascular disease [10].
Medicinal plants and food are commonly recommended as sources of natural antioxidants to reduce the risk of cardiovascular diseases, and their efficacy has been proven in clinical trials [22,23,24,25,26]. According to NIH, compared with artificial antioxidants, the antioxidant ingredients in natural plants and food are not a single compound but might work together to achieve antioxidant activity. The overall cost of cardiovascular disease therapy is increasing, which puts pressure on society and medical resources. Nowadays, people have paid more attention to natural products. This review aims to provide insights into the development of diabetes-related vascular therapeutic strategies based on the antioxidant properties of bioactive compounds from medicinal plants and food.

2. Involvement of Oxidative Stress in the Pathogenesis of Diabetes-Associated Vascular Dysfunction

ROS play a critical role in the development, growth, differentiation, and proliferation of multicellular organisms; and as crucial transduction molecules to regulate critical metabolic and regulatory pathways in cells [27,28]. In cellular metabolism, ROS are co-products that are mainly produced by mitochondria [29]. The overproduction or lesser elimination of ROS attributed to an imbalance between oxidants and antioxidants can cause oxidative stress, potentially leading to cell damage [30,31].
Endothelial cells (ECs) and smooth muscle cells (VSMCs) are two primary cell types in the blood vessel playing essential roles in maintaining vascular homeostasis. The endothelium is not only acting as a selectively permeable barrier, but also regulates the vascular tone and structural basis. The vascular endothelium is constructed by a monolayer of ECs that lines the entire inner surface of the blood vessel [32]. The endothelium plays crucial physiological functions, including sustaining vascular tone, repairing vessel inflammation, modulating the growth of blood vessels, and regulating aggregation and coagulation of platelet [33]. The ECs sense and respond to the stimuli from blood flow to induce contraction or relaxation from VSMCs by producing vasoactive substances, such as NO (vasodilator) or angiotensin II (Ang II, vasoconstrictor) [34]. Furthermore, physiological levels of ROS are essential for signal delivery that maintains vascular homeostasis. Almost every cell type in the blood vessel wall can produce ROS and is regulated by ROS [35,36]. A low concentration of H2O2 plays a significant role in the normal function of ECs as an endothelium-derived hyperpolarizing factor to induce vasodilatation [37]. The balance between ROS production and elimination is also necessary for activating the signaling pathways that participate in the normal function of the endothelium [38]; however, under the condition of diabetes mellitus, redox homeostasis is altered, contributing to the pathogenesis of endothelial dysfunction [39]. ECs can reduce the production of ROS in VSMCs by thioredoxin upregulation, which is functionally associated with growth inhibition, indicating that ECs protect VSMCs from oxidative stress and thus maintain vascular integrity [40].

3. ROS Production in Diabetes

ROS generation can either form exogenous or intracellular through many different sources. Usually, the generation and elimination of ROS are dependent on enzymatic and non-enzymatic pathways. The formation of superoxide anion (O2•−), which is the precursor of most other ROS, is produced by the univalent reduction of oxygen [41]. The production of O2•− is mediated by enzymes, including NADPH oxidases and xanthine oxidase or the redox-reactive compounds such as the semi-ubiquinone compound of the mitochondrial electron transport chain [42,43]. As the O2•− itself can affect vascular function, the generation of other types of ROS is also associated with it. Hydrogen peroxide (H2O2) is the production of O2•− dismutation mediated by superoxide dismutase (SOD) [41]. Partially reducing H2O2 can form hydroxide ions and hydroxyl radicals (OH) by reducing transition metals, or entirely reducing to H2O by catalase and glutathione peroxidase (GPx). When H2O2 is metabolized by myeloperoxidase (MPO), it generates hypochlorous acid. Almost all vascular cells can produce O2•− and H2O2 [44].
Diabetes is a high-risk factor of vascular dysfunction, and chronic diabetes complications include microvascular and macrovascular diseases [45]. In addition, cardiovascular disease is the primary cause of mortality in diabetes [46]. ROS contribute to the developing processes of diabetes-related cardiovascular disease. Hyperglycemia is the characteristics of diabetes, increasing generation of ROS and oxidative stress involved in vascular dysfunction [47]. Different models that induced hyperglycemia for studying diabetes complications result in oxidative stress [48,49,50,51]. There are many possible mechanisms by which hyperglycemia increases ROS production. A widely accepted pathway is diacylglycerol (DAG)-protein kinase C (PKC)-and NADPH oxidase pathway activated by hyperglycemia and eventually result in the acumination of ROS [52,53,54]. Multiple pathways can induce increased levels of DAG under hyperglycemia conditions. For example, by activating phospholipase C (PLC) and phospholipase D (PLD), both can act on phosphatidylcholine (PC) and phosphatidylinositol bisphosphate (PIP2) to trigger the generation of DAG [55,56]. PKC isoforms can be divided into different families, some of which can be activated by DAG (α, βI, βII, γ, δ, ε, η, and θ) [52,57]. PKC then activates NADPH-oxidase to stimulate ROS production. NAPDH is the cofactor of glutathione (GSH) reductase (GR). High glucose can enhance the activity of NADPH oxidase which increases expend of NADPH and decreases the generation of GSH, resulting in damage of ECs [58,59]. Under hyperglycemia, glucose generates pyruvate through the glycolysis pathway, and provides an increased amount of hydrogen donors (NADH and FADH2) through the tricarboxylic acid cycle to the mitochondrial respiratory chain, promoting the production of ROS, especially O2•− [60]. The enzymatic antioxidative system of mitochondria includes SOD and GPx. SOD catalyzes dismutation of O2•− to H2O2 and O2, while GPx reduces H2O2 to H2O under the synergism of glutathione-S-transferase (GST) to block the cell damage from O2•−; however, excessive blood glucose can bind to the lysine, which is the active center of SOD, and lower the activity of SOD by glycation [61]. The reaction reducing monosaccharides under the catalysis of transition metal ions, such as Fe3+ and Cu2+, is known as glucose autoxidation and results in the increased production of ROS [62]. The active polyol pathway in diabetes promotes ROS generation by depleting NADPH and GSH during the conversion of sorbitol to fructose; and increased accumulation of fructose also augments oxidative stress via nonezymatic glycation forming advanced glycation end-products (AGEs) [63].
Hyperlipidemia is highly associated with the risk of vascular dysfunction in diabetes, where the increase in circulating low-density lipoproteins (LDLs) is one of the major vascular risk factors [64]. O2•− can induce the oxidation of LDLs and promote vascular inflammation through increasing monocyte/macrophage infiltration into the vessel wall, subsequently leading to foam cell formation [65,66]. In ECs, eNOS can produce a large amount of ROS through uncoupling L-arginine from NO. In addition, adding LDLs or oxidated LDLs (oxLDLs) leads to the decrease of the eNOS cofactor tetrahydrobiopterin (BH4) by BH4 oxidation to form 7,8-dihydrobiopterin (BH2) and results in increased ROS production [67]. NADPH oxidase is one of the most important regulators in ROS production in ECs. The activation of NADPH oxidase requires the assembly of different subunits into lipid rafts, which need a specific content of lipid components [68]. The pathological changes in raft composition and structure affect the production of ROS. For example, the reduction of free cholesterol decreases ROS production [69,70].
Nitric oxide (NO) is an endothelium-derived relaxing factor biosynthesized from L-arginine, oxygen, and NADPH [71]. NO produced in ECs prevents ECs apoptosis and neutrophil and platelet adhesion to the vessel wall, which can also penetrate VSMCs to regulate vascular tone and proliferation, mediate flow-induced adaptive vascular modeling, and regulate platelet-derived growth factors [72]. The eNOS is expressed in blood vessels and is an essential enzyme in the cardiovascular system catalyzing the formation of NO [73]. The activity of eNOS is regulated by multiple sites, where the most studied site is the activation site Ser1177 [74]. Activating eNOS by phosphorylating Ser1177 can increase NO production in response to vascular stimuli. NO bioavailability is reduced by oxidative stress. Vessel under prolonged exposure to hyperglycemia generates O2•−, which can act on NO to form peroxynitrite (ONOO); and such reactive nitrogen species (RNS) with reduced NO availability contribute to vascular dysfunction in diabetes [75]. In addition, hyperglycemia blunts phosphorylation of eNOS at Ser1177 to diminish the activity of eNOS and enhances eNOS uncoupling, leading to further accumulation of ROS [76,77]. The mechanisms of ROS generation in diabetes-related to vascular dysfunction were summarized in Figure 1. Besides, a decrease of antioxidant enzymes as well as an increase of ROS and RNS in rupture of redox homeostasis in diabetes were listed in Table 1.

4. ROS-Induced Vascular Dysfunction

4.1. Lipid Peroxidation

The increased generation of ROS under diabetes mellitus can induce lipid peroxidation. Cell membrane or organelle membrane is especially sensitive to ROS damage due to its content of high polyunsaturated fatty acids. The process of lipid peroxidation is the oxidative degradation of lipid and the accumulation of peroxidation products is one of the main risk factors of vascular dysfunction [78]. The internalization of LDL in the intima of blood vessel enhances the permeability of endothelium and increases the expression of adhesion molecules; and the aggregated LDLs at the extracellular matrix can be oxidized by ROS to form oxLDLs which could promote the development of plaques [79]. The markers of lipid peroxidation include malonaldehyde (MDA), hydroxynonenal (HNE), and 8-isoprostaglandin F2⍺ [80,81]. 8-isoprostaglandin F2⍺ showed multiple activities to induce vascular dysfunction, including plateles adhesion and aggregation activities as well as vasoconstriction activities. Growing evidence has suggested that oxysterols, which are lipid peroxidation products of cholesterol, are involved in the pathology of diabetes mellitus [82]. Oxysterols were found elevated in the brains in the rodent diabetic models and in the blood of diabetic patients [83]. Increased levels of oxysterols were also found in the plasma and vascular walls of patients with cardiovascular diseases, particularly in atherosclerotic lesions; and can induce cell death, oxidative and inflammatory activities, and phospholipidosis [84]. Macrophages absorb excessive oxysterols in the presence of high peripheral cholesterol level and thereby converse to an inflammatory phenotype. The accumulation of these cholesterol-laden immune cells on blood vessel walls contributes to vascular dysfunction and atherosclerosis [85].

4.2. Protein Carbonylation

Protein carbonylation is one of the most detrimental oxidative protein modifications which cannot be reversed easily [86]. It is also regarded as a crucial biomarker of oxidative stress-related diseases [87]. Under metal ion catalysis, especially Fe3+ and Cu2+, ROS can directly oxidize amino acid residue on the protein side-chain to introduce a carbonyl group, which leads to loss of catalytic or structural function of the influenced proteins [88]. It is investigated that carbonylation of actin leads to changes in cytoskeleton dynamics and damage of barrier function of blood vessels [89].

4.3. Glycation

Glycation is also called non-enzymatic glycosylation which is a process of attachment of sugars, generally glucose, fructose, and their derivatives, to protein or lipid [90]. AGEs are glycated proteins or lipids formed after exposure to sugars. AGEs are widely studied in different diseases including vascular complications in diabetes. The amount of AGEs raised under diabetes mellitus is related to hyperglycemia and oxidative stress [91]. The proposed mechanism of AGEs-associated vascular dysfunction includes stimulation of inflammatory response by increasing the release of pro-inflammatory cytokines, promoting the progression of plaque, and enhancing oxidative stress in blood vessels [92,93,94].

5. Interaction of Oxidative Stress with Various Signaling Pathways

5.1. Keap1-Nrf2-ARE Signaling

Nuclear factor erythroid 2-like 2 (Nrf2) responses to oxidative stress and plays an essential role in preventing endothelium damage and protecting vascular function [95]. Kelch-like ECH-associated protein 1 (Keap1)-Nrf2-antioxidant response element (ARE) signaling pathway participates in the intracellular redox homeostasis of ECs. Nrf2 is the transcription activator that binds to ARE elements in the promoter regions of target genes. Keap1 is not only the negative repressor of Nrf2 but also modulates Nrf2 ubiquitination. Under the normal physiological conditions, Nrf2 is sequestered in the cytosol and maintains at a low concentration; however, the multiple cysteine residues of Keap1 sense the redox state, and it modulates the ubiquitarian level of Nrf2. Under oxidative stress, the chemical modifications of Keap1 relieve Nrf2 from Keap1-directed degradation and translocate it into the nucleus. The binding of Nrf2 to ARE result in the transcription of downstream target genes [96]. In ECs, Nrf2 can be activated by ROS level and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway [97]. A single-cell sequencing shows that Nrf2 is the key regulating factor of VSMCs transformation [98]. Nrf2 activation suppresses AngII-induced NOX-1/NOX-1/NOX-4 and mitochondrial ROS level, thereby postponing vascular remodeling [99].

5.2. NF-κB Signaling

NF-κB proteins are a transcription factor family critical in inflammation and immunology [100]. ROS and NF-κB signaling pathways can interact in multiple ways. H2O2 can affect the activation of the NF-κB pathway by inhibiting the phosphorylation and degradation of IκBα [101,102,103]; however, the findings on IKK are controversial. Some studies indicated that ROS, especially H2O2, can activate IKK in specific cell types whilst some showed that H2O2 suppresses IKK [101,102,104]. The activation of the NF-κB signaling pathway leads to the upregulated expression of NF-κB-dependent genes, such as adhesion molecules, cytokines, and growth factors. It has also been demonstrated that the NF-κB is involved in regulating NADPH oxidase subunit p22phox in VSMCs [105].

5.3. PI3K/Akt/AMPK Signaling

The PI3K-Akt signaling pathway plays a critical role in the transduction of mitogenic signals of VSMCs and the proliferative dysfunction of ECs [106,107,108]. ROS not only activates PI3K to enhance its downstream signaling but also deactivates its phosphatase and tension homolog (PTEN) and then negatively regulates the synthesis of phosphatidylinositol 3,4,5-triphosphate (PIP3), which leads to the inhibition of Akt activation [109]. Akt can significantly enhance the phosphorylation of eNOS. Overexpression of Akt can increase the resting diameter of the blood vessel and blood flow; however, suppressing Akt weakens the EC-dependent vascular relaxation induced by acetylcholine [110]. The endothelial migration induced by vascular endothelial growth factor (VEGF) is also mediated via the PI3K-Akt signaling pathway [111]. Activation of AMP-activated protein kinase (AMPK) is reported to exhibit vascular protective effects [112]. The activity of AMPK can be regulated by multiple stimuli, including low ATP levels, hypoxia, shear stress, exercise, etc. The activation of AMPK leads to the phosphorylation and activation of eNOS [113].

5.4. MAPK Signaling

The Mitogen-activated protein kinases (MAPK, or ERK) pathway, also known as the Ras-Raf-MEK-ERK pathway, includes many proteins, such as MAPK, which is activated by growth neurotrophic factors. There are more than three MAPKs families that have been characterized: p38 MAPKs, c-Jun N-terminal kinases (JNKs), and extracellular signal-regulated kinase (ERKs) [114,115]. The MAPK pathway participates in multiple fundamental cellular processes, including proliferation, differentiation, motility, stress response, apoptosis, and survival. For example, the phosphorylation of MEK and ERK shed the junction protein of VE-cadherin, which results in the opening of junctions and elevation of paracellular permeability [116]. Studies have already shown that ROS induce the activation of MAPK pathways through various routes [117]. H2O2 can activate MAPK pathways by the activation of growth factor receptors [118]; or by oxidative modification of intracellular kinases [119]. By inactivating and degrading the MAPK phosphatases (MKPs) through oxidation, ROS can also activate MAPK [120].

5.5. ER Stress

Endoplasmic reticulum (ER) stress has been illustrated to be associated with cardiovascular disease [121]. Three ER stress-sensing proteins, PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol requiring enzyme 1 (IRE1) are activated to induce downstream signaling cascade. More and more studies have investigated the cross-talk between oxidative stress and ER stress. ROS can directly attack the free sulfhydryl groups that are necessary to maintain protein folding, inducing oxidative modification of proteins and triggering ER stress due to the prolonged accumulation of unfolded or misfolded proteins in the ER lumen. At the same time, the expression of glucose-regulated protein 78 (GRP78) increases significantly and unbind from the ER stress-sensing proteins, which results in the activation of ER stress [122]. Studies have already shown that hyperglycemia-induced ER stress can lead to endothelial dysfunction and elevated ROS which can be reversed by ER stress alleviators; nevertheless, ROS scavengers cannot suppress ER stress [123,124].

5.6. Apoptosis

In ECs, the endogenous production of ROS is related to different pro-inflammatory and pro-atherosclerotic factors such as Ang II, oxLDL, or TNF-⍺, all associated with the apoptosis of cells [125]. The induction of DNA damage by a high concentration of ROS can activate p53 which downregulates Bcl-2 and upregulates Bax [126,127,128]; however, the reaction of VSMCs to ROS seems to be different from ECs. Ang II and PDGF-induced ROS generation can promote the proliferation and cell growth in VSMCs [129,130,131].
The aforementioned signaling pathways affecting ROS production in diabetes were summarized in a schematic diagram (Figure 2).

6. Antioxidative Effects of Medicinal Plants in Experimental Settings

In order to keep readers abreast of the latest progress in the research on antioxidant effects of medicinal plants and food, we summarized the latest progress in research on antioxidative activity since 2018.

6.1. Salvia miltiorrhiza

Until now, in some countries such as China, India, and Brazil, phytotherapy is still widely used to improve people’s health and even treat diseases [132]. Salvia miltiorrhiza Bunge, whose root is called DanShen in Chinese medicine, is a golden herbal medicine to treat cardiovascular diseases. Tanshiones and phenolics are considered to be the main bioactive ingredients [133]. A recent study showed that Salvia miltiorrhiza Bunge reduced high glucose-induced ROS generation in VSMCs and high-fat diet (HFD)-induced diabetic mice by inhibiting KLF10 expression and upregulating HO-1 [134]. In H9c2 cell and doxorubicin-induced heart failure Wistar rats, its aqueous extract suppressed oxidative stress through the Nrf2/HO-1 signaling cascade and further reduced ROS-dependent apoptosis by amending the ERK/p53/Bcl-xL/caspase-3 signaling pathways [135]; moreover, a similar result of Tanshinone I was attributed to its modulation of Nrf2/MAPK signaling in Nrf2−/− mice [136].

6.2. Panax notoginseng and Panax ginseng

Panax notoginseng, another popular traditional Chinese medicine, has been demonstrated potential antioxidant effects. Its ethanolic extract and total saponin (PNS) activated the AMPK/eNOS pathway to restore acetylcholine-induced endothelium-dependent relaxation in mouse aortas ex vivo and inhibited oxidative stress in high glucose-induced HUVECs and aortas from HFD-induced diabetic mice [137]. PNS protected HUVECs from AGE-induced injury by upregulating the expression of SIRT1 and increasing the SOD level [138]. Keap-1/Nrf2/HO-1 pathway mediated antioxidant activity of 20(S)-Rg3 and 20(R)-Rg3 in H9C2 cells [139]. Similar functions were presented in Panax ginseng C.A. Mey; its root, also known as ginseng, has been used to maintain cardiovascular health in Korea and China [140]. Ginsenoside compound K prevented ox-LDL-induced HUVECs injury by the inhibition of NF-κB/p38/JNK pathways [141]. At the same time, these effects also involved the activation of the Nrf2/HO-1 pathway [142,143]. Even in healthy model rats, ginseng extract increased vasodilation by reducing the level of lysophosphatidylcholine (LPC) that is related to atherosclerosis-induced tissue damage [144].

6.3. Chuanxiong

Ligustrazine (also known as tetra methylpyrazine) is an alkaloid that has been isolated from Chuanxiong (Ligusticum chuanxiong hort), and it was reported as a protective ingredient against homocysteine-induced oxidation in HUVECs through improving mitochondrial dysfunction [145]. In addition, Ligustrazine activated PI3K/Akt/eNOS signaling and increased NO release to protect HAECs from damage by oxygen-glucose deprivation, alleviating cerebral ischemia-reperfusion injury in rats [146].

6.4. Astragalus

Astragaloside IV(AsⅣ) is the main bioactive component of Astragalus, a dry rhizome of Astragalus membranaceus, which improves blood circulation, metabolism, and cardiovascular function [147,148]. AsIV reversed upregulated expression of P2X7R and p-p38 MAPK as well as increased the levels of eNOS and NO in glucose-stimulated RAECs and STZ-stimulated SD rats, showing the potential to improve endothelial dysfunction [149]. The same effects of AsIV in RAECs could be achieved by increasing Akt phosphorylation at Ser473, eNOS dephosphorylation at Thr495, and eNOS mRNA expression [150]. In an earlier study (2016), Xu et al. reported that AsⅣ rose the levels of BH4 and NO, and decreased the generation of anions and ONOO in rats with the isoproterenol (Iso)-induced vascular dysfunction, accompanied by inhibition of myocardial hypertrophy in rats [151].

6.5. Carhamus tinctorius L.

Dried flowers (Honghua) and seeds of Carhamus tinctorius L. are often used to improve gynecological diseases and have good oxidation resistance [152]. The ethanol extract of flowers of C. tinctorius retarded TNF α-stimulated intracellular ROS generation by activating Nrf2/HO-1/CO signaling in HUVECs, followed by inhibiting p65 NF-κB nuclear translocation [153]. In 2K-1C hypertensive rats, the ethanolic extract of C. tinctorius suppressed the Ang II-AT1R-NADPH oxidase pathway to reduce O2 production in renovascular hypertension while inhibiting aortic gp91phox overexpression as well as increasing NO bioavailability [154].

6.6. Ginkgo biloba L.

With a reputation as “living fossil”, Ginkgo biloba L. has a great variety of biological activities such as anticancer, antioxidant, and improvement of cognitive function [155]. Ginkgolide B, a natural product from Ginkgo biloba L., targeted NOX-4, LOX-1, MCP-1, ICAM-1, and VCAM-1 to abrogate ox-LDL-induced oxidative damage in HUVECs [156,157]. As an HO-1 activator, Ginkgo biloba extract improved vascular repairment by activating PI3K/Akt/eNOS signaling in endothelial progenitor cells [158].

6.7. Coptis chinensi

Coptisine, an isoquinoline alkaloid from Coptis chinensis Franch. Is well known for its excellent antibacterial properties and revealed the potential to improve diabetes and cardiovascular disease in vivo and in vitro [159,160,161]. Coptisine protected endothelium-dependent relaxation in diabetic mice by activating AMPK signaling, further increasing phosphorylation of eNOS and inhibiting ER stress [162]. More antioxidant studies of medicinal plants in cardiovascular disease are supplemented in Table 2.

7. In Vitro and In Vivo Studies of Food

7.1. Berries

Berries are rich in polyphenols, flavonoids, vitamins, fiber, and minerals [174]. A trial sequence analysis reported berries as a nutraceutical or functional food to prevent and control cardiovascular disease [175]. Blueberry anthocyanins upregulated PI3K/Akt/eNOS/PPARγ signaling pathway to protect HUVECs from high glucose-induced oxidative stress and dysfunction, decreasing the levels of ACE, XO-1, and LDL [176]. Aboonabi et al. (2020) reported a similar result for berry anthocyanins in diabetic human aortic endothelial cells with inhibition of IκB-α and caspase-1 activation [177]. Elderberry extract increased A23187-stimulated eNOS activity in EA.hy926 cells. 20beta-hydroxyursolic acid, a special dihydroxy triterpenoid, was regarded to be a potential active compound of elderberry [178]. Saskatoon Berry which contains anthocyanins and phenolic acids improved cardiovascular function and modulated glucose metabolism in HFD-induced diabetic rats [179].

7.2. Cucurbitaceous Vegetables

Common vegetables of the Cucurbitaceae family include squash, bitter gourd, and cucumber. In bitter gourd, Charantin has been proven to improve blood glucose and blood lipids [180,181]. Meanwhile, Cucurbitaceous vegetables play an enormous role in alleviating oxidative stress-mediated disorders, which are attributed to their nutrient composition: cucurbitacins, carotenoids, phytosterols, antioxidative polyphenols and polyunsaturated fatty acids, etc. [182]. Cucurbitacin I upregulated the expression of NRF-1, PPARα, ERRα, and PGC-1-β to protect H2O2-treated H9c2 from mitochondrial dysfunction-induced oxidative stress [183]. The ethanol extract of bitter gourd increased GPx, MDA, and CAT levels. It also avoided the degeneration of the internal elastic lamina of the aorta, showing anti-atherosclerotic potential in cholesterol-fed rats [184]. Recently, pumpkin seed protein was reported to offset high glucose-induced hypertension and hyperlipidemia in rats with metabolic syndrome, which is beneficial for preventing and treating cardiovascular diseases [185]. Cucumis sativus aqueous fraction enhanced NO bioavailability and ICAM-1 expression to inhibit Ang II-induced oxidative stress in HMEC-1 and improved endothelial function [186].

7.3. Cruciferous Vegetables

Common cruciferous vegetables include cauliflower, kale, horseradish, radishes, etc., which contain a variety of nutrients such as carotene, vitamins, folic acid, glucosinolate, and minerals [187]. Earlier studies reported that glucosinolate and its secondary metabolite, Indole-3-carbinol (I3C), have antioxidant and anticancer abilities by increasing Nrf2 nuclear translocation, which induced the expression of downstream antioxidant genes and detoxifying enzymes [188,189]. Recently, Prado et al. reported that I3C increased NO bioavailability and Hsp70 expression to improve hypertension and ischemia-reperfusion arrhythmias in vivo and ex vivo [190]. I3C and its derivate 3,3,′-diindolylmethane inhibited cytokines, ROS production, and thrombus formation [191]. In addition, the benefits of cruciferous vegetables are not limited to being attributed to glucosinolates as the mixtures of compounds mentioned above (such as vitamins K1 and carotene) also play a key antioxidant role [187,192].

7.4. Other Food

Okra (Malvaceae) shows antidiabetic properties that include anti-oxidation, anti-inflammatory, and blood glucose and lipid regulation [193,194]. Okra seed extract reduced TNFα-stimulated VCAM-1 and SELE expression and protected HMEC-1 from H2O2 injury, which might be attributed to high concentrations of quercetin 3-O-(malonyl)-glucose, quercetin Cortex-3-O-glucose-xylose and kaempferol-3-O-glucose [195]. In LDLr-KO mice, okra alleviated atherosclerotic lesion development of the aorta [196]. Dietary lycopene presents in fruits and vegetables such as tomatoes, carrots, watermelon, papaya, and guava, has been extensively studied for its role in cardiovascular disease [197]. Lycopene improved endothelium-dependent vasodilation, through increasing NO bioavailability and reducing mitochondrial damage [197]. In a recent study, lycopene ameliorated atherosclerosis in ApoE−/− mice with a decrease in HNF-1α and NPC1L1 expression [198]. Tea and red wine are considered beverages with antioxidant activity [199]. Green tea extract and epigallocatechin gallate prevented bisphenol A-induced vascular toxicity by reducing MDA levels in aorta and inhibiting HUVECs apoptosis [200]. Red wine polyphenols prolonged the lifespan of SR-B1 KO/ApoER61h/h mice (a model of lethal ischemic heart disease) by reducing atherosclerosis and decreasing MDA level in plasma [201]. On the other hand, resveratrol improved endothelial function by activating the PI3K/Akt/eNOs/PPARγ pathway in HFD-induced diabetic mice, accompanied by up-regulation of PPARδ [202]. In the general diet, arachidonic acid from chicken, milk, fish, and beef is beneficial for improving cardiovascular function, such as anti-atherosclerosis, regulating blood pressure, and maintaining vasodilation [203]. Omega3 and omega6 are polyunsaturated fatty acids that reported to increase NO availability more than arachidonic acid in HUVECs [204]. Therefore, foods rich in omega3 and omega6 such as salmon, are also beneficial for improving cardiovascular disease [205,206]. Antioxidant studies of functional food and their bioactive compounds in cardiovascular disease are supplemented in Table 3.

8. Clinical Applications of Antioxidant Treatment

Salvia miltiorrhiza (Danshen) and its compound preparations are widely used in the clinical treatment of angina pectoris, coronary heart disease, ischemic stroke, and diabetes-related cardiovascular diseases [24]. Compound Danshen dripping pills (CDDPs) is commonly used for the treatment of coronary heart disease and angina pectoris in clinical practice in China, consisting of Salvia miltiorrhiza, Panax notoginseng, and borneol [207]. It is the first traditional Chinese medicine preparation compound that completed the FDA Phase III clinical trial. In a meta-analysis involving 2574 patients with coronary heart disease, compared with percutaneous coronary intervention (PCI) alone, CDDPs combined with PCI more effectively improved blood lipid indexes, vascular endothelial function, inflammation, and cardiac function [208]. Danhong injection (DHI), a Sino Food and Drug Administration (SFDA) approved Chinese traditional medicine, is composed of the water-soluble complex from Danshen and Honghua [209]. A network meta-analysis that compared five Danshen preparations (Danshen injection, Salvianolate injection, compound Danshen injection, and Sodium Tanshinone IIA Sulfonate injection) for clinical improvement (4458 patients) and electrocardiographic improvement (3049 patients) reported that Danhong injection was more effective in treating coronary heart disease than other Danshen preparations [210]. Previously, the hydrophilic extract of Danshen was reported to reduce the levels of VCAM-1, vWF, and oxLDL and increase the activity of antioxidant enzymes (SOD, PONase, GSSG-R) in 62 diabetic patients with a history of coronary heart disease [211,212]. Based on the pharmacological research mentioned above, Panax notoginseng preparation was also applied to clinical cardiovascular disease and diabetes therapy in China [213]. Particularly Xuesaitong, which is mainly composed of Panax notoginseng saponins (PNS), is a commonly used botanical medicine for the treatment of cardiovascular diseases and diabetic complications [214,215]. Extensive sample data showed that oral administration of PNS improved angina frequency, duration, blood lipids, and cardiac function in patients with unstable angina (UA) [216]. Furthermore, another meta-study of 1828 patients showed that combined use of Panax notoginseng increased the efficacy of conventional drugs in the treatment of UA [217]. It is worth mentioning that coronary artery disease, diabetes, and obesity are the main causes of UA [218]; however, the roles of natural products in the human body are limited. For example, Ginseng effectively ameliorated oxidative stress and vascular diseases in diabetes in vitro and in vivo [219]. In a randomized controlled trial, combined administration of Korean red Ginseng and American Ginseng improved blood pressure in patients with type 2 diabetes but did not affect vascular stiffness or endothelial function [220]. Clinical applications of antioxidant treatment with medicinal plants in cardiovascular disease are supplemented in Table 4.

9. Conclusions and Future Perspectives

Among the causes of disability and death of diabetics, the most prominent part is the sequelae of vascular dysfunction in various parts of the body. Under the pathological of diabetes, the imbalance between ROS generation and elimination would play a critical role in vascular dysfunction. The progressing injury of ECs and VSMCs would eventually lead to diabetic complications, such as hypertension and atherosclerosis. Therefore, antioxidant treatment against vascular complications in diabetes is worth studying, and compounds from medicinal plants and food are widely studied in this field. Studies showed that the antioxidant effects of natural compounds are synergistic and complicated in many cases, of which the underlying mechanisms still need further study. Foods such as berries, cruciferous vegetables and okra, or drinks such as red wine that people can uptake daily were shown to ameliorate vascular dysfunction. Medicinal plants such as Salvia miltiorrhiza and Panax notoginseng were also shown to protect against vascular complications in diabetes during the individual or combination treatment with other drugs in clinical studies; it implies that medicinal plants or food can be an adjunct therapy in treatment of vascular complications in diabetes. Some therapeutic effects of medicinal plant treatment are limited or even insignificant. Therefore, clinical trials of medicinal plant treatment on vascular complications in diabetes may need to increase the sample size to better study the efficacy in the human body. The rich resources of bioactive compounds from medicinal plants and food might benefit from reducing the cost and medicinal consumption in the treatment of diabetes and its vascular complications; however, a healthy lifestyle and eating habits are the keys to improving or preventing cardiovascular disease and metabolic syndrome.

Author Contributions

Conceptualization, W.S.C.; writing—original draft preparation, Y.T. and M.S.C.; writing—review and editing, W.S.C.; supervision, W.S.C. All authors have read and agreed to the published version of the manuscript.


This research was funded by University of Macau, grant number MYRG2019-00157-ICMS, and the Science and Technology Development Fund of Macau (FDCT), grant number 0117/2020/A.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Einarson, T.R.; Acs, A.; Ludwig, C.; Panton, U.H. Prevalence of cardiovascular disease in type 2 diabetes: A systematic literature review of scientific evidence from across the world in 2007–2017. Cardiovasc. Diabetol. 2018, 17, 83. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Dal Canto, E.; Ceriello, A.; Rydén, L.; Ferrini, M.; Hansen, T.B.; Schnell, O.; Standl, E.; Beulens, J.W. Diabetes as a cardiovascular risk factor: An overview of global trends of macro and micro vascular complications. Eur. J. Prev. Cardiol. 2019, 26, 25–32. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Wang, M.; Liu, Y.; Liang, Y.; Naruse, K.; Takahashi, K. Systematic Understanding of Pathophysiological Mechanisms of Oxidative Stress-Related Conditions—Diabetes Mellitus, Cardiovascular Diseases, and Ischemia–Reperfusion Injury. Front. Cardiovasc. Med. 2021, 8, 649785. [Google Scholar] [CrossRef] [PubMed]
  4. Kayama, Y.; Raaz, U.; Jagger, A.; Adam, M.; Schellinger, I.N.; Sakamoto, M.; Suzuki, H.; Toyama, K.; Spin, J.M.; Tsao, P.S. Diabetic Cardiovascular Disease Induced by Oxidative Stress. Int. J. Mol. Sci. 2015, 16, 25234–25263. [Google Scholar] [CrossRef] [PubMed]
  5. Battelli, M.G.; Polito, L.; Bolognesi, A. Xanthine oxidoreductase in atherosclerosis pathogenesis: Not only oxidative stress. Atherosclerosis 2014, 237, 562–567. [Google Scholar] [CrossRef] [Green Version]
  6. Paneni, F.; Beckman, J.A.; Creager, M.A.; Cosentino, F. Diabetes and vascular disease: Pathophysiology, clinical consequences, and medical therapy: Part I. Eur. Heart J. 2013, 34, 2436–2443. [Google Scholar] [CrossRef]
  7. Vega-López, S.; Devaraj, S.; Jialal, I. Oxidative Stress and Antioxidant Supplementation in the Management of Diabetic Cardiovascular Disease. J. Investig. Med. 2004, 52, 24–32. [Google Scholar] [CrossRef]
  8. Scott, J.A.; King, G.L. Oxidative stress and antioxidant treatment in diabetes. Ann. N. Y. Acad. Sci. 2004, 1031, 204–213. [Google Scholar] [CrossRef]
  9. Goszcz, K.; Deakin, S.J.; Duthie, G.G.; Stewart, D.; Leslie, S.J.; Megson, I.L. Antioxidants in Cardiovascular Therapy: Panacea or False Hope? Front. Cardiovasc. Med. 2015, 2, 29. [Google Scholar] [CrossRef]
  10. Yoshihara, D.; Fujiwara, N.; Suzuki, K. Antioxidants: Benefits and risks for long-term health. Maturitas 2010, 67, 103–107. [Google Scholar] [CrossRef]
  11. Forman, H.J.; Zhang, H. Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy. Nat. Rev. Drug Discov. 2021, 20, 689–709. [Google Scholar] [CrossRef]
  12. Pruthi, S.; Allison, T.G.; Hensrud, D.D. Vitamin E supplementation in the prevention of coronary heart disease. Mayo Clin. Proc. 2001, 76, 1131–1136. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Shargorodsky, M.; Debby, O.; Matas, Z.; Zimlichman, R. Effect of long-term treatment with antioxidants (vitamin C, vitamin E, coenzyme Q10 and selenium) on arterial compliance, humoral factors and inflammatory markers in patients with multiple cardiovascular risk factors. Nutr. Metab. 2010, 7, 55. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Vivekananthan, D.P.; Penn, M.S.; Sapp, S.K.; Hsu, A.; Topol, E.J. Use of antioxidant vitamins for the prevention of cardiovascular disease: Meta-analysis of randomised trials. Lancet 2003, 361, 2017–2023. [Google Scholar] [CrossRef]
  15. Pellegrino, D. Antioxidants and cardiovascular risk factors. Diseases 2016, 4, 11. [Google Scholar] [CrossRef] [Green Version]
  16. Frei, B. Efficacy of Dietary Antioxidants to Prevent Oxidative Damage and Inhibit Chronic Disease. J. Nutr. 2004, 134, 3196S–3198S. [Google Scholar] [CrossRef]
  17. Sesso, H.D.; Buring, J.E.; Christen, W.G.; Kurth, T.; Belanger, C.; MacFadyen, J.; Bubes, V.; Manson, J.E.; Glynn, R.J.; Gaziano, J.M. Vitamins E and C in the Prevention of Cardiovascular Disease in Men: The Physicians’ Health Study II Randomized Controlled Trial. JAMA 2008, 300, 2123–2133. [Google Scholar] [CrossRef] [Green Version]
  18. De Luca, L.M.; Ross, S.A. Beta-Carotene Increases Lung Cancer Incidence in Cigarette Smokers. Nutr. Rev. 1996, 54, 178–180. [Google Scholar] [CrossRef]
  19. Sotler, R.; Poljšak, B.; Dahmane, R.; Jukić, T.; Pavan Jukić, D.; Rotim, C.; Trebše, P.; Starc, A. Prooxidant activities of antioxidants and their impact on health. Acta Clin. Croat. 2019, 58, 726–736. [Google Scholar] [CrossRef]
  20. Sharifi-Rad, M.; Anil Kumar, N.V.; Zucca, P.; Varoni, E.M.; Dini, L.; Panzarini, E.; Rajkovic, J.; Tsouh Fokou, P.V.; Azzini, E.; Peluso, I.; et al. Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases. Front. Physiol. 2020, 11, 694. [Google Scholar] [CrossRef]
  21. Hodis, H.N.; Mack, W.J.; Dustin, L.; Mahrer, P.R.; Azen, S.P.; Detrano, R.; Selhub, J.; Alaupovic, P.; Liu, C.-R.; Liu, C.-H. High-dose B vitamin supplementation and progression of subclinical atherosclerosis: A randomized controlled trial. Stroke 2009, 40, 730–736. [Google Scholar] [CrossRef] [Green Version]
  22. Wang, S.; Melnyk, J.P.; Tsao, R.; Marcone, M.F. How natural dietary antioxidants in fruits, vegetables and legumes promote vascular health. Food Res. Int. 2011, 44, 14–22. [Google Scholar] [CrossRef]
  23. Wang, B.-Q. Salvia miltiorrhiza: Chemical and pharmacological review of a medicinal plant. J. Med. Plants Res. 2010, 4, 2813–2820. [Google Scholar]
  24. Ren, J.; Fu, L.; Nile, S.H.; Zhang, J.; Kai, G. Salvia miltiorrhiza in Treating Cardiovascular Diseases: A Review on Its Pharmacological and Clinical Applications. Front. Pharmacol. 2019, 10, 753. [Google Scholar] [CrossRef] [PubMed]
  25. Zhang, S.; Chen, C.; Lu, W.; Wei, L. Phytochemistry, pharmacology, and clinical use of Panax notoginseng flowers buds. Phytother. Res. 2018, 32, 2155–2163. [Google Scholar] [CrossRef] [PubMed]
  26. Park, S.K.; Hyun, S.H.; In, G.; Park, C.-K.; Kwak, Y.-S.; Jang, Y.-J.; Kim, B.; Kim, J.-H.; Han, C.-K. The antioxidant activities of Korean Red Ginseng (Panax ginseng) and ginsenosides: A systemic review through in vivo and clinical trials. J. Ginseng Res. 2021, 45, 41–47. [Google Scholar] [CrossRef] [PubMed]
  27. Apel, K.; Hirt, H. Reactive oxygen species: Metabolism, oxidative stress, and signal transduction. Annu. Rev. Plant Biol. 2004, 55, 373–399. [Google Scholar] [CrossRef] [Green Version]
  28. Xia, C.; Meng, Q.; Lin, L.Z.; Rojanasakul, Y.; Wang, X.R.; Jiang, B.H. Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res. 2007, 67, 10823–10830. [Google Scholar] [CrossRef] [Green Version]
  29. Thannickal, V.J.; Fanburg, B.L. Reactive oxygen species in cell signaling. Am. J. Physiol.-Lung Cell. Mol. Physiol. 2000, 279, L1005–L1028. [Google Scholar] [CrossRef] [Green Version]
  30. Sies, H. What is oxidative stress? In Oxidative Stress and Vascular Disease; Springer: Berlin/Heidelberg, Germany, 2000; pp. 1–8. [Google Scholar]
  31. Valko, M.; Leibfritz, D.; Moncol, J.; Cronin, M.T.D.; Mazur, M.; Telser, J. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol. 2007, 39, 44–84. [Google Scholar] [CrossRef]
  32. Sumbria, R.; Fisher, M. Chapter 8—Endothelium. In Primer on Cerebrovascular Diseases, 2nd ed.; Caplan, L.R., Biller, J., Leary, M.C., Lo, E.H., Thomas, A.J., Yenari, M., Zhang, J.H., Eds.; Academic Press: San Diego, CA, USA, 2017; pp. 47–51. [Google Scholar]
  33. Tousoulis, D.; Kampoli, A.-M.; Tentolouris Nikolaos Papageorgiou, C.; Stefanadis, C. The role of nitric oxide on endothelial function. Curr. Vasc. Pharmacol. 2012, 10, 4–18. [Google Scholar] [CrossRef] [PubMed]
  34. Tian, X.-L.; Li, Y. Endothelial Cell Senescence and Age-Related Vascular Diseases. J. Genet. Genom. 2014, 41, 485–495. [Google Scholar] [CrossRef]
  35. Griendling, K.K.; Ushio-Fukai, M. NADH/NADPH Oxidase and Vascular Function. Trends Cardiovasc. Med. 1997, 7, 301–307. [Google Scholar] [CrossRef]
  36. Suzuki, Y.J.; Ford, G.D. Redox regulation of signal transduction in cardiac and smooth muscle. J. Mol. Cell. Cardiol. 1999, 31, 345–353. [Google Scholar] [CrossRef]
  37. Matoba, T.; Shimokawa, H.; Nakashima, M.; Hirakawa, Y.; Mukai, Y.; Hirano, K.; Kanaide, H.; Takeshita, A. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. J. Clin. Investig. 2000, 106, 1521–1530. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Ray, P.D.; Huang, B.-W.; Tsuji, Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell. Signal. 2012, 24, 981–990. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Kaneto, H.; Katakami, N.; Matsuhisa, M.; Matsuoka, T.-a. Role of reactive oxygen species in the progression of type 2 diabetes and atherosclerosis. Mediat. Inflamm. 2010, 2010, 453892. [Google Scholar] [CrossRef] [Green Version]
  40. Xu, S.; He, Y.; Vokurkova, M.; Touyz, R.M. Endothelial cells negatively modulate reactive oxygen species generation in vascular smooth muscle cells: Role of thioredoxin. Hypertension 2009, 54, 427–433. [Google Scholar] [CrossRef] [Green Version]
  41. Turrens, J.F. Mitochondrial formation of reactive oxygen species. J. Physiol. 2003, 552, 335–344. [Google Scholar] [CrossRef]
  42. Taniyama, Y.; Griendling, K.K. Reactive oxygen species in the vasculature: Molecular and cellular mechanisms. Hypertension 2003, 42, 1075–1081. [Google Scholar] [CrossRef] [Green Version]
  43. Dröge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 2002, 82, 47–95. [Google Scholar] [CrossRef] [PubMed]
  44. Touyz, R.; Briones, A. Reactive oxygen species and vascular biology: Implications in human hypertension. Hypertens. Res. 2011, 34, 5–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Bagheri, S.C. 14—Medical Conditions. In Clinical Review of Oral and Maxillofacial Surgery; Bagheri, S.C., Jo, C., Eds.; Mosby: Saint Louis, MO, USA, 2008; pp. 363–409. [Google Scholar]
  46. Shintani, T.; Klionsky, D.J. Autophagy in health and disease: A double-edged sword. Science 2004, 306, 990–995. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Rebolledo, O.; Dato, S.A. Postprandial hyperglycemia and hyperlipidemia-generated glycoxidative stress: Its contribution to the pathogenesis of diabetes complications. Eur. Rev. Med. Pharmacol. Sci. 2005, 9, 191. [Google Scholar]
  48. Huynh, K.; Kiriazis, H.; Du, X.-J.; Love, J.E.; Gray, S.P.; Jandeleit-Dahm, K.A.; McMullen, J.R.; Ritchie, R.H. Targeting the upregulation of reactive oxygen species subsequent to hyperglycemia prevents type 1 diabetic cardiomyopathy in mice. Free Radic. Biol. Med. 2013, 60, 307–317. [Google Scholar] [CrossRef]
  49. Zhong, P.; Wu, L.; Qian, Y.; Fang, Q.; Liang, D.; Wang, J.; Zeng, C.; Wang, Y.; Liang, G. Blockage of ROS and NF-κB-mediated inflammation by a new chalcone L6H9 protects cardiomyocytes from hyperglycemia-induced injuries. Biochim. Biophys. Acta (BBA)-Mol. Basis Dis. 2015, 1852, 1230–1241. [Google Scholar] [CrossRef] [Green Version]
  50. Guo, Y.; Zhuang, X.; Huang, Z.; Zou, J.; Yang, D.; Hu, X.; Du, Z.; Wang, L.; Liao, X. Klotho protects the heart from hyperglycemia-induced injury by inactivating ROS and NF-κB-mediated inflammation both in vitro and in vivo. Biochim. Biophys. Acta (BBA)-Mol. Basis Dis. 2018, 1864, 238–251. [Google Scholar] [CrossRef]
  51. Shen, E.; Li, Y.; Li, Y.; Shan, L.; Zhu, H.; Feng, Q.; Arnold, J.M.O.; Peng, T. Rac1 Is Required for Cardiomyocyte Apoptosis During Hyperglycemia. Diabetes 2009, 58, 2386–2395. [Google Scholar] [CrossRef] [Green Version]
  52. Volpe, C.M.O.; Villar-Delfino, P.H.; dos Anjos, P.M.F.; Nogueira-Machado, J.A. Cellular death, reactive oxygen species (ROS) and diabetic complications. Cell Death Dis. 2018, 9, 119. [Google Scholar] [CrossRef]
  53. Inoguchi, T.; Battan, R.; Handler, E.; Sportsman, J.R.; Heath, W.; King, G.L. Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: Differential reversibility to glycemic control by islet cell transplantation. Proc. Natl. Acad. Sci. USA 1992, 89, 11059–11063. [Google Scholar] [CrossRef] [Green Version]
  54. Inoguchi, T.; Xia, P.; Kunisaki, M.; Higashi, S.; Feener, E.P.; King, G.L. Insulin’s effect on protein kinase C and diacylglycerol induced by diabetes and glucose in vascular tissues. Am. J. Physiol.-Endocrinol. Metab. 1994, 267, E369–E379. [Google Scholar] [CrossRef] [PubMed]
  55. Nishizuka, Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 1992, 258, 607–614. [Google Scholar] [CrossRef] [PubMed]
  56. Das Evcimen, N.; King, G.L. The role of protein kinase C activation and the vascular complications of diabetes. Pharmacol. Res. 2007, 55, 498–510. [Google Scholar] [CrossRef]
  57. Yang, C.; Kazanietz, M.G. Divergence and complexities in DAG signaling: Looking beyond PKC. Trends Pharmacol. Sci. 2003, 24, 602–608. [Google Scholar] [CrossRef]
  58. Jansen, F.; Yang, X.; Franklin, B.S.; Hoelscher, M.; Schmitz, T.; Bedorf, J.; Nickenig, G.; Werner, N. High glucose condition increases NADPH oxidase activity in endothelial microparticles that promote vascular inflammation. Cardiovasc. Res. 2013, 98, 94–106. [Google Scholar] [CrossRef] [Green Version]
  59. Winkler, B.S.; DeSantis, N.; Solomon, F. Multiple NADPH-producing pathways control glutathione (GSH) content in retina. Exp. Eye Res. 1986, 43, 829–847. [Google Scholar] [CrossRef]
  60. Cardoso, S.; Correia, S.; Santos, R.; Carvalho, C.; Candeias, E.; Duarte, A.; Plácido, A.; Santos, M.; Moreira, P. Hyperglycemia, hypoglycemia and dementia: Role of mitochondria and uncoupling proteins. Curr. Mol. Med. 2013, 13, 586–601. [Google Scholar] [CrossRef]
  61. Adachi, T.; Ohta, H.; Hayashi, K.; Hirano, K.; Marklund, S.L. The site of nonenzymic glycation of human extracellular-superoxide dismutase in vitro. Free Radic. Biol. Med. 1992, 13, 205–210. [Google Scholar] [CrossRef]
  62. Wolff, S.P.; Dean, R.T. Glucose autoxidation and protein modification. The potential role of ‘autoxidative glycosylation’ in diabetes. Biochem. J. 1987, 245, 243–250. [Google Scholar] [CrossRef]
  63. Yan, L.J. Redox imbalance stress in diabetes mellitus: Role of the polyol pathway. Anim. Model. Exp. Med. 2018, 1, 7–13. [Google Scholar] [CrossRef]
  64. Cox, D.; Cohen, M.L. Effects of oxidized low-density lipoprotein on vascular contraction and relaxation: Clinical and pharmacological implications in atherosclerosis. Pharmacol. Rev. 1996, 48, 3–19. [Google Scholar] [PubMed]
  65. Tsimikas, S. Lipoproteins and oxidation. In Antioxidants and Cardiovascular Disease; Springer: Berlin/Heidelberg, Germany, 2006; pp. 17–48. [Google Scholar]
  66. Peluso, I.; Morabito, G.; Urban, L.; Ioannone, F.; Serafi, M. Oxidative stress in atherosclerosis development: The central role of LDL and oxidative burst. Endocr. Metab. Immune Disord.-Drug Targets (Former. Curr. Drug Targets-Immune Endocr. Metab. Disord.) 2012, 12, 351–360. [Google Scholar] [CrossRef] [PubMed]
  67. Förstermann, U.; Münzel, T. Endothelial nitric oxide synthase in vascular disease: From marvel to menace. Circulation 2006, 113, 1708–1714. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Amiya, E. Interaction of hyperlipidemia and reactive oxygen species: Insights from the lipid-raft platform. World J. Cardiol. 2016, 8, 689–694. [Google Scholar] [CrossRef]
  69. Amiya, E.; Watanabe, M.; Takeda, N.; Saito, T.; Shiga, T.; Hosoya, Y.; Nakao, T.; Imai, Y.; Manabe, I.; Nagai, R.; et al. Angiotensin II Impairs Endothelial Nitric-oxide Synthase Bioavailability under Free Cholesterol-enriched Conditions via Intracellular Free Cholesterol-rich Membrane Microdomains. J. Biol. Chem. 2013, 288, 14497–14509. [Google Scholar] [CrossRef] [Green Version]
  70. Fang, Y.; Mohler III, E.R.; Hsieh, E.; Osman, H.; Hashemi, S.M.; Davies, P.F.; Rothblat, G.H.; Wilensky, R.L.; Levitan, I. Hypercholesterolemia suppresses inwardly rectifying K+ channels in aortic endothelium in vitro and in vivo. Circ. Res. 2006, 98, 1064–1071. [Google Scholar] [CrossRef] [Green Version]
  71. Perez, K.M.; Laughon, M. Sildenafil in Term and Premature Infants: A Systematic Review. Clin. Ther. 2015, 37, 2598–2607.e2591. [Google Scholar] [CrossRef]
  72. Förstermann, U.; Sessa, W.C. Nitric oxide synthases: Regulation and function. Eur. Heart J. 2011, 33, 829–837. [Google Scholar] [CrossRef] [Green Version]
  73. Tsutsui, M. Neuronal nitric oxide synthase as a novel anti-atherogenic factor. J. Atheroscler. Thromb. 2004, 11, 41–48. [Google Scholar] [CrossRef] [Green Version]
  74. Chen, Z.P.; Mitchelhill, K.I.; Michell, B.J.; Stapleton, D.; Rodriguez-Crespo, I.; Witters, L.A.; Power, D.A.; Ortiz de Montellano, P.R.; Kemp, B.E. AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett. 1999, 443, 285–289. [Google Scholar] [CrossRef] [Green Version]
  75. Creager, M.A.; Lüscher, T.F.; of, p.w.t.a.; Cosentino, F.; Beckman, J.A. Diabetes and vascular disease: Pathophysiology, clinical consequences, and medical therapy: Part I. Circulation 2003, 108, 1527–1532. [Google Scholar] [CrossRef] [Green Version]
  76. Du, X.L.; Edelstein, D.; Dimmeler, S.; Ju, Q.; Sui, C.; Brownlee, M. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J. Clin. Investig. 2001, 108, 1341–1348. [Google Scholar] [CrossRef]
  77. Chu, S.; Bohlen, H.G. High concentration of glucose inhibits glomerular endothelial eNOS through a PKC mechanism. Am. J. Physiol.-Ren. Physiol. 2004, 287, F384–F392. [Google Scholar] [CrossRef] [Green Version]
  78. Negre-Salvayre, A.; Auge, N.; Ayala, V.; Basaga, H.; Boada, J.; Brenke, R.; Chapple, S.; Cohen, G.; Feher, J.; Grune, T.; et al. Pathological aspects of lipid peroxidation. Free Radic. Res. 2010, 44, 1125–1171. [Google Scholar] [CrossRef]
  79. Badimon, L.; Storey, R.F.; Vilahur, G. Update on lipids, inflammation and atherothrombosis. Thromb. Haemost. 2011, 105, S34–S42. [Google Scholar] [PubMed]
  80. Gopaul, N.K.; Änggård, E.E.; Mallet, A.I.; Betteridge, D.J.; Wolff, S.P.; Nourooz-Zadeh, J. Plasma 8-epi-PGF2 α levels are elevated in individuals with non-insulin dependent diabetes mellitus. FEBS Lett. 1995, 368, 225–229. [Google Scholar] [CrossRef] [Green Version]
  81. Gaweł, S.; Wardas, M.; Niedworok, E.; Wardas, P. Malondialdehyde (MDA) as a lipid peroxidation marker. Wiad. Lek. 2004, 57, 453–455. [Google Scholar] [PubMed]
  82. Samadi, A.; Sabuncuoglu, S.; Samadi, M.; Isikhan, S.Y.; Chirumbolo, S.; Peana, M.; Lay, I.; Yalcinkaya, A.; Bjorklund, G. A Comprehensive Review on Oxysterols and Related Diseases. Curr. Med. Chem. 2021, 28, 110–136. [Google Scholar] [CrossRef] [PubMed]
  83. Weigel, T.K.; Kulas, J.A.; Ferris, H.A. Oxidized cholesterol species as signaling molecules in the brain: Diabetes and Alzheimer’s disease. Neuronal Signal. 2019, 3, NS20190068. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Vejux, A.; Lizard, G. Cytotoxic effects of oxysterols associated with human diseases: Induction of cell death (apoptosis and/or oncosis), oxidative and inflammatory activities, and phospholipidosis. Mol. Aspects Med. 2009, 30, 153–170. [Google Scholar] [CrossRef]
  85. Chistiakov, D.A.; Bobryshev, Y.V.; Orekhov, A.N. Macrophage-mediated cholesterol handling in atherosclerosis. J. Cell. Mol. Med. 2016, 20, 17–28. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Wong, C.-M.; Marcocci, L.; Das, D.; Wang, X.; Luo, H.; Zungu-Edmondson, M.; Suzuki, Y.J. Mechanism of protein decarbonylation. Free Radic. Biol. Med. 2013, 65, 1126–1133. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Cattaruzza, M.; Hecker, M. Protein carbonylation and decarboylation: A new twist to the complex response of vascular cells to oxidative stress. Circ. Res. 2008, 102, 273–274. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Hecker, M.; Wagner, A.H. Role of protein carbonylation in diabetes. J. Inherit. Metab. Dis. 2018, 41, 29–38. [Google Scholar] [CrossRef]
  89. Dalle-Donne, I.; Rossi, R.; Giustarini, D.; Gagliano, N.; Lusini, L.; Milzani, A.; Di Simplicio, P.; Colombo, R. Actin carbonylation: From a simple marker of protein oxidation to relevant signs of severe functional impairment. Free Radic. Biol. Med. 2001, 31, 1075–1083. [Google Scholar] [CrossRef]
  90. Lima, M.; Baynes, J.W. Glycation. In Encyclopedia of Biological Chemistry, 2nd ed.; Lennarz, W.J., Lane, M.D., Eds.; Academic Press: Waltham, MA, USA, 2013; pp. 405–411. [Google Scholar]
  91. Brownlee, M. The Pathobiology of Diabetic Complications: A Unifying Mechanism. Diabetes 2005, 54, 1615–1625. [Google Scholar] [CrossRef] [Green Version]
  92. Peng, W.H.; Lu, L.; Hu, J.; Yan, X.X.; Zhang, Q.; Zhang, R.Y.; Chen, Q.J.; Shen, W.F. Decreased serum esRAGE level is associated with angiographically determined coronary plaque progression in diabetic patients. Clin. Biochem. 2009, 42, 1252–1259. [Google Scholar] [CrossRef]
  93. Park, L.; Raman, K.G.; Lee, K.J.; Lu, Y.; Ferran, L.J.; Chow, W.S.; Stern, D.; Schmidt, A.M. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat. Med. 1998, 4, 1025–1031. [Google Scholar] [CrossRef]
  94. Yamagishi, S.-i.; Maeda, S.; Matsui, T.; Ueda, S.; Fukami, K.; Okuda, S. Role of advanced glycation end products (AGEs) and oxidative stress in vascular complications in diabetes. Biochim. Biophys. Acta (BBA)-Gen. Subj. 2012, 1820, 663–671. [Google Scholar] [CrossRef]
  95. Chen, B.; Lu, Y.; Chen, Y.; Cheng, J. The role of Nrf2 in oxidative stress-induced endothelial injuries. J. Endocrinol. 2015, 225, R83–R99. [Google Scholar] [CrossRef] [Green Version]
  96. Lu, M.C.; Ji, J.A.; Jiang, Z.Y.; You, Q.D. The Keap1–Nrf2–ARE pathway as a potential preventive and therapeutic target: An update. Med. Res. Rev. 2016, 36, 924–963. [Google Scholar] [CrossRef] [PubMed]
  97. Chen, X.-L.; Varner, S.E.; Rao, A.S.; Grey, J.Y.; Thomas, S.; Cook, C.K.; Wasserman, M.A.; Medford, R.M.; Jaiswal, A.K.; Kunsch, C. Laminar flow induction of antioxidant response element-mediated genes in endothelial cells: A novel anti-inflammatory mechanism. J. Biol. Chem. 2003, 278, 703–711. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Pan, H.; Xue, C.; Auerbach, B.J.; Fan, J.; Bashore, A.C.; Cui, J.; Yang, D.Y.; Trignano, S.B.; Liu, W.; Shi, J. Single-cell genomics reveals a novel cell state during smooth muscle cell phenotypic switching and potential therapeutic targets for atherosclerosis in mouse and human. Circulation 2020, 142, 2060–2075. [Google Scholar] [CrossRef] [PubMed]
  99. He, X.; Deng, J.; Yu, X.-J.; Yang, S.; Yang, Y.; Zang, W.-J. Activation of M3AchR (type 3 muscarinic acetylcholine receptor) and Nrf2 (nuclear factor erythroid 2–related factor 2) signaling by choline alleviates vascular smooth muscle cell phenotypic switching and vascular remodeling. Arterioscler. Thromb. Vasc. Biol. 2020, 40, 2649–2664. [Google Scholar] [CrossRef]
  100. Hayden, M.S.; Ghosh, S. Shared Principles in NF-κB Signaling. Cell 2008, 132, 344–362. [Google Scholar] [CrossRef] [Green Version]
  101. Chen, F.; Yang, R.; Luo, X.; Zhong, S.; LI, Z.; Zeng, T.; Wei, G. Effect of Rosiglitazone on Insulin Resistance and ROS. IKK Signaling Pathway in Vascular Endothelial Cells. Her. Med. 2014, 33, 1420–1423. [Google Scholar] [CrossRef] [Green Version]
  102. Jaspers, I.; Zhang, W.; Fraser, A.; Samet, J.M.; Reed, W. Hydrogen peroxide has opposing effects on IKK activity and I κ B α breakdown in airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 2001, 24, 769–777. [Google Scholar] [CrossRef] [Green Version]
  103. Flohé, L.; Brigelius-Flohé, R.; Saliou, C.; Traber, M.G.; Packer, L. Redox regulation of NF-kappa B activation. Free Radic. Biol. Med. 1997, 22, 1115–1126. [Google Scholar] [CrossRef]
  104. Byun, M.-S.; Jeon, K.-I.; Choi, J.-W.; Shim, J.-Y.; Jue, D.-M. Dual effect of oxidative stress on NF-κB activation in HeLa cells. Exp. Mol. Med. 2002, 34, 332–339. [Google Scholar] [CrossRef]
  105. Manea, A.; Manea, S.; Gafencu, A.; Raicu, M. Regulation of NADPH oxidase subunit p22phox by NF-kB in human aortic smooth muscle cells. Arch. Physiol. Biochem. 2007, 113, 163–172. [Google Scholar] [CrossRef]
  106. Isenovic, E.R.; Kedees, M.H.; Tepavcevic, S.; Milosavljevic, T.; Koricanac, G.; Trpkovic, A.; Marche, P. Role of PI3K/AKT, cPLA2 and ERK1/2 signaling pathways in insulin regulation of vascular smooth muscle cells proliferation. Cardiovasc. Haematol. Disord.-Drug Targets (Former. Curr. Drug Targets-Cardiovasc. Hematol. Disord.) 2009, 9, 172–180. [Google Scholar] [CrossRef] [PubMed]
  107. Varma, S.; Lal, B.K.; Zheng, R.; Breslin, J.W.; Saito, S.; Pappas, P.J.; Hobson, R.W.; Durán, W.N. Hyperglycemia alters PI3k and Akt signaling and leads to endothelial cell proliferative dysfunction. Am. J. Physiol.-Heart Circ. Physiol. 2005, 289, H1744–H1751. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  108. Goncharova, E.A.; Ammit, A.J.; Irani, C.; Carroll, R.G.; Eszterhas, A.J.; Panettieri, R.A.; Krymskaya, V.P. PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 2002, 283, L354–L363. [Google Scholar] [CrossRef] [Green Version]
  109. Leslie, N.R.; Downes, C.P. PTEN: The down side of PI 3-kinase signalling. Cell. Signal. 2002, 14, 285–295. [Google Scholar] [CrossRef]
  110. Xu, B.C.; Long, H.B.; Luo, K.Q. Tert-butylhydroquinone lowers blood pressure in AngII-induced hypertension in mice via proteasome-PTEN-Akt-eNOS pathway. Sci. Rep. 2016, 6, 29589. [Google Scholar] [CrossRef] [Green Version]
  111. Findley, C.M.; Cudmore, M.J.; Ahmed, A.; Kontos, C.D. VEGF Induces Tie2 Shedding via a Phosphoinositide 3-Kinase/Akt–Dependent Pathway to Modulate Tie2 Signaling. Arterioscler. Thromb. Vasc. Biol. 2007, 27, 2619–2626. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Ewart, M.-A.; Kennedy, S. AMPK and vasculoprotection. Pharmacol. Ther. 2011, 131, 242–253. [Google Scholar] [CrossRef]
  113. Rodríguez, C.; Muñoz, M.; Contreras, C.; Prieto, D. AMPK, metabolism, and vascular function. FEBS J. 2021, 288, 3746–3771. [Google Scholar] [CrossRef]
  114. Lewis, T.S.; Shapiro, P.S.; Ahn, N.G. Signal Transduction through MAP Kinase Cascades. In Advances in Cancer Research; Vande Woude, G.F., Klein, G., Eds.; Academic Press: Cambridge, MA, USA, 1998; Volume 74, pp. 49–139. [Google Scholar]
  115. Garrington, T.P.; Johnson, G.L. Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr. Opin. Cell Biol. 1999, 11, 211–218. [Google Scholar] [CrossRef]
  116. Long, Y.-M.; Yang, X.-Z.; Yang, Q.-Q.; Clermont, A.C.; Yin, Y.-G.; Liu, G.-L.; Hu, L.-G.; Liu, Q.; Zhou, Q.-F.; Liu, Q.S.; et al. PM2.5 induces vascular permeability increase through activating MAPK/ERK signaling pathway and ROS generation. J. Hazard. Mater. 2020, 386, 121659. [Google Scholar] [CrossRef]
  117. Grote, K.; Luchtefeld, M.; Schieffer, B. JANUS under stress—Role of JAK/STAT signaling pathway in vascular diseases. Vasc. Pharmacol. 2005, 43, 357–363. [Google Scholar] [CrossRef] [PubMed]
  118. Son, Y.; Cheong, Y.-K.; Kim, N.-H.; Chung, H.-T.; Kang, D.G.; Pae, H.-O. Mitogen-activated protein kinases and reactive oxygen species: How can ROS activate MAPK pathways? J. Signal Transduct. 2011, 2011, 792639. [Google Scholar] [CrossRef] [PubMed]
  119. Tobiume, K.; Matsuzawa, A.; Takahashi, T.; Nishitoh, H.; Morita, K.-i.; Takeda, K.; Minowa, O.; Miyazono, K.; Noda, T.; Ichijo, H. ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep. 2001, 2, 222–228. [Google Scholar] [CrossRef] [PubMed]
  120. Kamata, H.; Honda, S.-i.; Maeda, S.; Chang, L.; Hirata, H.; Karin, M. Reactive oxygen species promote TNFα-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 2005, 120, 649–661. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  121. Zhou, Y.; Murugan, D.D.; Khan, H.; Huang, Y.; Cheang, W.S. Roles and Therapeutic Implications of Endoplasmic Reticulum Stress and Oxidative Stress in Cardiovascular Diseases. Antioxidants 2021, 10, 1167. [Google Scholar] [CrossRef]
  122. Zeeshan, H.M.A.; Lee, G.H.; Kim, H.-R.; Chae, H.-J. Endoplasmic reticulum stress and associated ROS. Int. J. Mol. Sci. 2016, 17, 327. [Google Scholar] [CrossRef] [Green Version]
  123. Lenna, S.; Han, R.; Trojanowska, M. Endoplasmic reticulum stress and endothelial dysfunction. IUBMB Life 2014, 66, 530–537. [Google Scholar] [CrossRef] [Green Version]
  124. Cheang, W.S.; Tian, X.Y.; Wong, W.T.; Lau, C.W.; Lee, S.S.; Chen, Z.Y.; Yao, X.; Wang, N.; Huang, Y. Metformin protects endothelial function in diet-induced obese mice by inhibition of endoplasmic reticulum stress through 5′ adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor delta pathway. Arterioscler. Thromb. Vasc. Biol. 2014, 34, 830–836. [Google Scholar] [CrossRef] [Green Version]
  125. Dimmeler, S.; Zeiher, A.M. Reactive oxygen species and vascular cell apoptosis in response to angiotensin II and pro-atherosclerotic factors. Regul. Pept. 2000, 90, 19–25. [Google Scholar] [CrossRef]
  126. Reed, J.C. Double identity for proteins of the Bcl-2 family. Nature 1997, 387, 773–776. [Google Scholar] [CrossRef]
  127. Guarente, L. Mutant mice live longer. Nature 1999, 402, 243–245. [Google Scholar] [CrossRef] [PubMed]
  128. Miyashita, T.; Krajewski, S.; Krajewska, M.; Wang, H.G.; Lin, H.; Liebermann, D.A.; Hoffman, B.; Reed, J.C. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 1994, 9, 1799–1805. [Google Scholar] [PubMed]
  129. Griendling, K.K.; Harrison, D.G. Dual role of reactive oxygen species in vascular growth. Circ. Res. 1999, 85, 562–563. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  130. Sundaresan, M.; Yu, Z.-X.; Ferrans, V.J.; Irani, K.; Finkel, T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 1995, 270, 296–299. [Google Scholar] [CrossRef] [Green Version]
  131. Finkel, T. Oxygen radicals and signaling. Curr. Opin. Cell Biol. 1998, 10, 248–253. [Google Scholar] [CrossRef]
  132. Lopes, C.M.C.; Lazzarini, J.R.; Soares Júnior, J.M.; Baracat, E.C. Phytotherapy: Yesterday, today, and forever? Rev. Da Assoc. Médica Bras. 2018, 64, 765–768. [Google Scholar] [CrossRef]
  133. Jiang, Z.; Gao, W.; Huang, L. Tanshinones, Critical Pharmacological Components in Salvia miltiorrhiza. Front. Pharmacol. 2019, 10, 202. [Google Scholar] [CrossRef]
  134. Zhou, J.; Zhang, L.; Zheng, B.; Zhang, L.; Qin, Y.; Zhang, X.; Yang, Z.; Nie, Z.; Yang, G.; Yu, J.; et al. Salvia miltiorrhiza bunge exerts anti-oxidative effects through inhibiting KLF10 expression in vascular smooth muscle cells exposed to high glucose. J. Ethnopharmacol. 2020, 262, 113208. [Google Scholar] [CrossRef]
  135. Hung, Y.-C.; Wang, P.-W.; Lin, T.-Y.; Yang, P.-M.; You, J.-S.; Pan, T.-L. Functional redox proteomics reveal that Salvia miltiorrhiza aqueous extract alleviates adriamycin-induced cardiomyopathy via inhibiting ROS-dependent apoptosis. Oxid. Med. Cell. Longev. 2020, 2020, 5136934. [Google Scholar] [CrossRef]
  136. Wu, Y.-T.; Xie, L.-P.; Hua, Y.; Xu, H.-L.; Chen, G.-H.; Han, X.; Tan, Z.-B.; Fan, H.-J.; Chen, H.-M.; Li, J.; et al. Tanshinone I Inhibits Oxidative Stress-Induced Cardiomyocyte Injury by Modulating Nrf2 Signaling. Front. Pharmacol. 2021, 12, 644116. [Google Scholar] [CrossRef]
  137. Zhang, X.; Zhou, C.; Miao, L.; Tan, Y.; Zhou, Y.; Cheong, M.S.; Huang, Y.; Wang, Y.; Yu, H.; Cheang, W.S. Panax Notoginseng Protects against Diabetes-Associated Endothelial Dysfunction: Comparison between Ethanolic Extract and Total Saponin. Oxid. Med. Cell. Longev. 2021, 2021, 4722797. [Google Scholar] [CrossRef] [PubMed]
  138. Bo, Y.; Jian, Z.; Zhi-Jun, S.; Quing, W.; Hua, Z.; Chuan-Wei, L.; Yu-Kang, C. Panax notoginseng saponins alleviates advanced glycation end product-induced apoptosis by upregulating SIRT1 and antioxidant expression levels in HUVECs. Exp. Ther. Med. 2020, 20, 99. [Google Scholar] [CrossRef] [PubMed]
  139. He, B.; Chen, D.; Zhang, X.; Yang, R.; Yang, Y.; Chen, P.; Shen, Z. Oxidative Stress and Ginsenosides: An Update on the Molecular Mechanisms. Oxid. Med. Cell. Longev. 2022, 2022, 9299574. [Google Scholar] [CrossRef] [PubMed]
  140. Zhang, H.; Abid, S.; Ahn, J.C.; Mathiyalagan, R.; Kim, Y.-J.; Yang, D.-C.; Wang, Y. Characteristics of Panax ginseng cultivars in Korea and China. Molecules 2020, 25, 2635. [Google Scholar] [CrossRef]
  141. Lu, S.; Luo, Y.; Zhou, P.; Yang, K.; Sun, G.; Sun, X. Ginsenoside compound K protects human umbilical vein endothelial cells against oxidized low-density lipoprotein-induced injury via inhibition of nuclear factor-κB, p38, and JNK MAPK pathways. J. Ginseng Res. 2019, 43, 95–104. [Google Scholar] [CrossRef]
  142. Carota, G.; Raffaele, M.; Sorrenti, V.; Salerno, L.; Pittalà, V.; Intagliata, S. Ginseng and heme oxygenase-1: The link between an old herb and a new protective system. Fitoterapia 2019, 139, 104370. [Google Scholar] [CrossRef]
  143. Xu, H.; Jiang, Y.; Yu, K.; Zhang, X.; Shi, Y. Effect of Ginsenoside Rh1 on Proliferation, Apoptosis, and Oxidative Stress in Vascular Endothelial Cells by Regulation of the Nuclear Erythroid 2-related Factor-2/Heme Oxygenase-1 Signaling Pathway. J. Cardiovasc. Pharmacol. 2022, 79, 335–341. [Google Scholar] [CrossRef]
  144. Lee, H.-J.; Kim, B.-M.; Lee, S.H.; Sohn, J.-T.; Choi, J.W.; Cho, C.-W.; Hong, H.-D.; Rhee, Y.K.; Kim, H.-J. Ginseng-Induced Changes to Blood Vessel Dilation and the Metabolome of Rats. Nutrients 2020, 12, 2238. [Google Scholar] [CrossRef]
  145. Fan, X.; Wang, E.; He, J.; Zhang, L.; Zeng, X.; Gui, Y.; Sun, Q.; Song, Y.; Yuan, H. Ligustrazine Protects Homocysteine-Induced Apoptosis in Human Umbilical Vein Endothelial Cells by Modulating Mitochondrial Dysfunction. J. Cardiovasc. Transl. Res. 2019, 12, 591–599. [Google Scholar] [CrossRef]
  146. Ding, Y.; Du, J.; Cui, F.; Chen, L.; Li, K. The protective effect of ligustrazine on rats with cerebral ischemia–reperfusion injury via activating PI3K/Akt pathway. Hum. Exp. Toxicol. 2019, 38, 1168–1177. [Google Scholar] [CrossRef]
  147. Ren, S.; Zhang, H.; Mu, Y.; Sun, M.; Liu, P. Pharmacological effects of Astragaloside IV: A literature review. J. Tradit. Chin. Med. 2013, 33, 413–416. [Google Scholar] [CrossRef]
  148. Tan, Y.-Q.; Chen, H.-W.; Li, J. Astragaloside IV: An Effective Drug for the Treatment of Cardiovascular Diseases. Drug Des. Devel. Ther. 2020, 14, 3731–3746. [Google Scholar] [CrossRef] [PubMed]
  149. Leng, B.; Li, C.; Sun, Y.; Zhao, K.; Zhang, L.; Lu, M.-L.; Wang, H.-X. Protective effect of astragaloside IV on high glucose-induced endothelial dysfunction via inhibition of P2X7R dependent P38 MAPK signaling pathway. Oxid. Med. Cell. Longev. 2020, 2020, 5070415. [Google Scholar] [CrossRef] [PubMed]
  150. Lin, X.-P.; Cui, H.-J.; Yang, A.L.; Luo, J.-K.; Tang, T. Astragaloside IV Improves Vasodilatation Function by Regulating the PI3K/Akt/eNOS Signaling Pathway in Rat Aorta Endothelial Cells. J. Vasc. Res. 2018, 55, 169–176. [Google Scholar] [CrossRef]
  151. Xu, C.; Tang, F.; Lu, M.; Yang, J.; Han, R.; Mei, M.; Hu, J.; Zhou, M.; Wang, H. Astragaloside IV improves the isoproterenol-induced vascular dysfunction via attenuating eNOS uncoupling-mediated oxidative stress and inhibiting ROS-NF-κB pathways. Int. Immunopharmacol. 2016, 33, 119–127. [Google Scholar] [CrossRef]
  152. Mani, V.; Lee, S.-K.; Yeo, Y.; Hahn, B.-S. A Metabolic Perspective and Opportunities in Pharmacologically Important Safflower. Metabolites 2020, 10, 253. [Google Scholar] [CrossRef]
  153. Lee, Y.J.; Lee, Y.P.; Seo, C.S.; Choi, E.S.; Han, B.H.; Yoon, J.J.; Jang, S.H.; Jeong, C.G.; Mun, Y.J.; Kang, D.G.; et al. The Modulation of Nrf-2/HO-1 Signaling Axis by Carthamus tinctorius L. Alleviates Vascular Inflammation in Human Umbilical Vein Endothelial Cells. Plants 2021, 10, 2795. [Google Scholar] [CrossRef]
  154. Bunbupha, S.; Wunpathe, C.; Maneesai, P.; Berkban, T.; Kukongviriyapan, U.; Kukongviriyapan, V.; Prachaney, P.; Pakdeechote, P. Carthamus tinctorius L. extract improves hemodynamic and vascular alterations in a rat model of renovascular hypertension through Ang II-AT1R-NADPH oxidase pathway. Ann. Anat.-Anat. Anz. 2018, 216, 82–89. [Google Scholar] [CrossRef]
  155. Liu, X.-G.; Lu, X.; Gao, W.; Li, P.; Yang, H. Structure, synthesis, biosynthesis, and activity of the characteristic compounds from Ginkgo biloba L. Nat. Prod. Rep. 2022, 39, 474–511. [Google Scholar] [CrossRef]
  156. Feng, Z.; Yang, X.; Zhang, L.; Ansari, I.A.; Khan, M.S.; Han, S.; Feng, Y. Ginkgolide B ameliorates oxidized low-density lipoprotein-induced endothelial dysfunction via modulating Lectin-like ox-LDL-receptor-1 and NADPH oxidase 4 expression and inflammatory cascades. Phytother. Res. 2018, 32, 2417–2427. [Google Scholar] [CrossRef]
  157. Wang, G.; Liu, Z.; Li, M.; Li, Y.; Alvi, S.S.; Ansari, I.A.; Khan, M.S. Ginkgolide B Mediated Alleviation of Inflammatory Cascades and Altered Lipid Metabolism in HUVECs via Targeting PCSK-9 Expression and Functionality. BioMed Res. Int. 2019, 2019, 7284767. [Google Scholar] [CrossRef] [PubMed]
  158. Wu, T.-C.; Chen, J.-S.; Wang, C.-H.; Huang, P.-H.; Lin, F.-Y.; Lin, L.-Y.; Lin, S.-J.; Chen, J.-W. Activation of heme oxygenase-1 by Ginkgo biloba extract differentially modulates endothelial and smooth muscle-like progenitor cells for vascular repair. Sci. Rep. 2019, 9, 17316. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  159. Wu, J.; Luo, Y.; Deng, D.; Su, S.; Li, S.; Xiang, L.; Hu, Y.; Wang, P.; Meng, X. Coptisine from Coptis chinensis exerts diverse beneficial properties: A concise review. J. Cell. Mol. Med. 2019, 23, 7946–7960. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  160. Shi, L.-l.; Jia, W.-h.; Zhang, L.; Xu, C.-y.; Chen, X.; Yin, L.; Wang, N.-q.; Fang, L.-h.; Qiang, G.-f.; Yang, X.-y.; et al. Glucose consumption assay discovers coptisine with beneficial effect on diabetic mice. Eur. J. Pharmacol. 2019, 859, 172523. [Google Scholar] [CrossRef] [PubMed]
  161. Feng, M.; Kong, S.-Z.; Wang, Z.-X.; He, K.; Zou, Z.-Y.; Hu, Y.-R.; Ma, H.; Li, X.-G.; Ye, X.-L. The protective effect of coptisine on experimental atherosclerosis ApoE−/− mice is mediated by MAPK/NF-κB-dependent pathway. Biomed. Pharmacother. 2017, 93, 721–729. [Google Scholar] [CrossRef]
  162. Zhou, Y.; Zhou, C.; Zhang, X.; Vong, C.T.; Wang, Y.; Cheang, W.S. Coptisine Attenuates Diabetes—Associated Endothelial Dysfunction through Inhibition of Endoplasmic Reticulum Stress and Oxidative Stress. Molecules 2021, 26, 4210. [Google Scholar] [CrossRef]
  163. Seong, H.R.; Wang, C.; Irfan, M.; Kim, Y.E.; Jung, G.; Park, S.K.; Kim, T.M.; Choi, E.-K.; Rhee, M.H.; Kim, Y.-B. DK-MGAR101, an extract of adventitious roots of mountain ginseng, improves blood circulation by inhibiting endothelial cell injury, platelet aggregation, and thrombus formation. J. Ginseng Res. 2022, in press. [Google Scholar] [CrossRef]
  164. Chen, M.; Zou, W.; Chen, M.; Cao, L.; Ding, J.; Xiao, W.; Hu, G. Ginkgolide K promotes angiogenesis in a middle cerebral artery occlusion mouse model via activating JAK2/STAT3 pathway. Eur. J. Pharmacol. 2018, 833, 221–229. [Google Scholar] [CrossRef]
  165. Kim, G.D. Sirt1-Mediated Anti-Aging Effects of Houttuynia cordata Extract in a High Glucose-Induced Endothelial Cell-Aging Model. Prev. Nutr. Food Sci. 2020, 25, 108–112. [Google Scholar] [CrossRef]
  166. Liu, X.; Cao, K.; Lv, W.; Liu, J.; Gao, J.; Wang, Y.; Qin, C.; Liu, J.; Zang, W.; Liu, J. Aqueous extract of Houttuynia cordata ameliorates aortic endothelial injury during hyperlipidemia via FoxO1 and p38 MAPK pathway. J. Funct. Foods 2019, 62, 103510. [Google Scholar] [CrossRef]
  167. Kim, G.D. SIRT1-Mediated Protective Effect of Aralia elata (Miq.) Seem against High-Glucose-Induced Senescence in Human Umbilical Vein Endothelial Cells. Nutrients 2019, 11, 2625. [Google Scholar] [CrossRef] [Green Version]
  168. Takano, K.; Tatebe, J.; Washizawa, N.; Morita, T. Curcumin Inhibits Age-Related Vascular Changes in Aged Mice Fed a High-Fat Diet. Nutrients 2018, 10, 1476. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  169. Wu, M.; Yang, S.; Wang, S.; Cao, Y.; Zhao, R.; Li, X.; Xing, Y.; Liu, L. Effect of Berberine on Atherosclerosis and Gut Microbiota Modulation and Their Correlation in High-Fat Diet-Fed ApoE−/− Mice. Front. Pharmacol. 2020, 11, 223. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  170. Purnomo, F.A.; Karlowee, V.; Wijayahadi, N.; Setiawan, A.A. The Effect of Black Garlic (Allium sativum Linn) on Cardiac and Aortic Histopathology in Experimental Studies in Obesity Rats. J. Biomed. Transl. Res. 2021, 7, 62–68. [Google Scholar]
  171. Liu, S.; He, Y.; Shi, J.; Liu, L.; Ma, H.; He, L.; Guo, Y. Allicin Attenuates Myocardial Ischemia Reperfusion Injury in Rats by Inhibition of Inflammation and Oxidative Stress. Transplant. Proc. 2019, 51, 2060–2065. [Google Scholar] [CrossRef] [PubMed]
  172. Rachmawati, N.A.; Wasita, B.; Kartikasari, L.R. Basil Leaves (Ocimum sanctum linn.) extract decreases total cholesterol levels in hypercholesterolemia Sprague Dawley rats model. IOP Conf. Ser. Mater. Sci. Eng. 2019, 546, 062020. [Google Scholar] [CrossRef]
  173. Rachmawati, E.; Muhammad, R.F. The ethanolic extract of holy basil leaves (Ocimum sanctum L.) attenuates atherosclerosis in high fat diet fed rabbit. AIP Conf. Proc. 2021, 2353, 030113. [Google Scholar]
  174. Festa, J.; Da Boit, M.; Hussain, A.; Singh, H. Potential Benefits of Berry Anthocyanins on Vascular Function. Mol. Nutr. Food Res. 2021, 65, e2100170. [Google Scholar] [CrossRef]
  175. Luís, Â.; Domingues, F.; Pereira, L. Association between berries intake and cardiovascular diseases risk factors: A systematic review with meta-analysis and trial sequential analysis of randomized controlled trials. Food Funct. 2018, 9, 740–757. [Google Scholar] [CrossRef]
  176. Huang, W.; Hutabarat, R.P.; Chai, Z.; Zheng, T.; Zhang, W.; Li, D. Antioxidant Blueberry Anthocyanins Induce Vasodilation via PI3K/Akt Signaling Pathway in High-Glucose-Induced Human Umbilical Vein Endothelial Cells. Int. J. Mol. Sci. 2020, 21, 1575. [Google Scholar] [CrossRef] [Green Version]
  177. Aboonabi, A.; Singh, I.; Rose’ Meyer, R. Cytoprotective effects of berry anthocyanins against induced oxidative stress and inflammation in primary human diabetic aortic endothelial cells. Chem.-Biol. Interact. 2020, 317, 108940. [Google Scholar] [CrossRef]
  178. Waldbauer, K.; Seiringer, G.; Sykora, C.; Dirsch, V.M.; Zehl, M.; Kopp, B. Evaluation of Apricot, Bilberry, and Elderberry Pomace Constituents and Their Potential To Enhance the Endothelial Nitric Oxide Synthase (eNOS) Activity. ACS Omega 2018, 3, 10545–10553. [Google Scholar] [CrossRef] [PubMed]
  179. du Preez, R.; Wanyonyi, S.; Mouatt, P.; Panchal, S.K.; Brown, L. Saskatoon Berry Amelanchier alnifolia Regulates Glucose Metabolism and Improves Cardiovascular and Liver Signs of Diet-Induced Metabolic Syndrome in Rats. Nutrients 2020, 12, 931. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  180. Akbar, S. Momordica charantia L. (Cucurbitaceae). In Handbook of 200 Medicinal Plants: A Comprehensive Review of Their Traditional Medical Uses and Scientific Justifications; Akbar, S., Ed.; Springer International Publishing: Cham, Switzerland, 2020; pp. 1195–1219. [Google Scholar]
  181. Thomford, K.P.; Thomford, A.K.; Yorke, J.; Yeboah, R.; Appiah, A.A. Momordica charantia L. for hyperlipidaemia: A randomised controlled assessment of the Ghanaian herbal medicinal product MCP-1. J. Herb. Med. 2021, 28, 100453. [Google Scholar] [CrossRef]
  182. Salehi, B.; Quispe, C.; Sharifi-Rad, J.; Giri, L.; Suyal, R.; Jugran, A.K.; Zucca, P.; Rescigno, A.; Peddio, S.; Bobiş, O.; et al. Antioxidant potential of family Cucurbitaceae with special emphasis on Cucurbita genus: A key to alleviate oxidative stress-mediated disorders. Phytother. Res. 2021, 35, 3533–3557. [Google Scholar] [CrossRef]
  183. Yang, D.K.; Kim, S.-J. Cucurbitacin I Protects H9c2 Cardiomyoblasts against H2O2-Induced Oxidative Stress via Protection of Mitochondrial Dysfunction. Oxid. Med. Cell. Longev. 2018, 2018, 3016382. [Google Scholar] [CrossRef] [Green Version]
  184. Innih, S.O.; Eze, I.G.; Omage, K. Evaluation of the haematinic, antioxidant and anti-atherosclerotic potential of Momordica charantia in cholesterol-fed experimental rats. Toxicol. Rep. 2022, 9, 611–618. [Google Scholar] [CrossRef]
  185. Chenni, A.; Cherif, F.Z.H.; Chenni, K.; Elius, E.E.; Pucci, L.; Yahia, D.A. Effects of Pumpkin (Cucurbita pepo L.) Seed Protein on Blood Pressure, Plasma Lipids, Leptin, Adiponectin, and Oxidative Stress in Rats with Fructose-Induced Metabolic Syndrome. Prev. Nutr. Food Sci. 2022, 27, 78–88. [Google Scholar] [CrossRef]
  186. Trejo-Moreno, C.; Méndez-Martínez, M.; Zamilpa, A.; Jiménez-Ferrer, E.; Perez-Garcia, M.D.; Medina-Campos, O.N.; Pedraza-Chaverri, J.; Santana, M.A.; Esquivel-Guadarrama, F.R.; Castillo, A.; et al. Cucumis sativus Aqueous Fraction Inhibits Angiotensin II-Induced Inflammation and Oxidative Stress In Vitro. Nutrients 2018, 10, 276. [Google Scholar] [CrossRef] [Green Version]
  187. Connolly, E.L.; Bondonno, C.P.; Sim, M.; Radavelli-Bagatini, S.; Croft, K.D.; Boyce, M.C.; James, A.P.; Clark, K.; Anokye, R.; Bondonno, N.P.; et al. A randomised controlled crossover trial investigating the short-term effects of different types of vegetables on vascular and metabolic function in middle-aged and older adults with mildly elevated blood pressure: The VEgetableS for vaScular hEaLth (VESSEL) study protocol. Nutr. J. 2020, 19, 41. [Google Scholar] [CrossRef]
  188. Fuentes, F.; Paredes-Gonzalez, X.; Kong, A.-N.T. Dietary Glucosinolates Sulforaphane, Phenethyl Isothiocyanate, Indole-3-Carbinol/3,3′-Diindolylmethane: Antioxidative Stress/Inflammation, Nrf2, Epigenetics/Epigenomics and In Vivo Cancer Chemopreventive Efficacy. Curr. Pharmacol. Rep. 2015, 1, 179–196. [Google Scholar] [CrossRef] [Green Version]
  189. Esteve, M. Mechanisms Underlying Biological Effects of Cruciferous Glucosinolate-Derived Isothiocyanates/Indoles: A Focus on Metabolic Syndrome. Front. Nutr. 2020, 7, 111. [Google Scholar] [CrossRef] [PubMed]
  190. Prado, N.J.; Ramirez, D.; Mazzei, L.; Parra, M.; Casarotto, M.; Calvo, J.P.; Cuello carrión, D.; Ponce Zumino, A.Z.; Diez, E.R.; Camargo, A.; et al. Anti-inflammatory, antioxidant, antihypertensive, and antiarrhythmic effect of indole-3-carbinol, a phytochemical derived from cruciferous vegetables. Heliyon 2022, 8, e08989. [Google Scholar] [CrossRef]
  191. Ampofo, E.; Schmitt, B.M.; Menger, M.D.; Laschke, M.W. Targeting the Microcirculation by Indole-3-carbinol and Its Main Derivate 3,3,′-diindolylmethane: Effects on Angiogenesis, Thrombosis and Inflammation. Mini Rev. Med. Chem. 2018, 18, 962–968. [Google Scholar] [CrossRef] [PubMed]
  192. Lobo, M.; Hounsome, N.; Hounsome, B. Biochemistry of Vegetables: Secondary Metabolites in Vegetables—Terpenoids, Phenolics, Alkaloids, and Sulfur-Containing Compounds. In Handbook of Vegetables and Vegetable Processing; John Wiley & Sons: Hoboken, NJ, USA, 2018; pp. 47–82. [Google Scholar]
  193. Elkhalifa, A.E.O.; Alshammari, E.; Adnan, M.; Alcantara, J.C.; Awadelkareem, A.M.; Eltoum, N.E.; Mehmood, K.; Panda, B.P.; Ashraf, S.A. Okra (Abelmoschus esculentus) as a Potential Dietary Medicine with Nutraceutical Importance for Sustainable Health Applications. Molecules 2021, 26, 696. [Google Scholar] [CrossRef] [PubMed]
  194. Nikpayam, O.; Safaei, E.; Bahreini, N.; Saghafi-Asl, M. The effects of okra (Abelmoschus esculentus L.) products on glycemic control and lipid profile: A comprehensive systematic review. J. Funct. Foods 2021, 87, 104795. [Google Scholar] [CrossRef]
  195. Ong, E.S.; Oh, C.L.Y.; Tan, J.C.W.; Foo, S.Y.; Leo, C.H. Pressurized Hot Water Extraction of Okra Seeds Reveals Antioxidant, Antidiabetic and Vasoprotective Activities. Plants 2021, 10, 1645. [Google Scholar] [CrossRef] [PubMed]
  196. Kone Berethe, R. Cardiovascular Benefits of Okra in Low Density Lipoprotein Knockout Mice. Master’s Thesis, The University of Manitoba, Winnipeg, MB, Canada, 2022. [Google Scholar]
  197. Mozos, I.; Stoian, D.; Caraba, A.; Malainer, C.; Horbańczuk, J.O.; Atanasov, A.G. Lycopene and Vascular Health. Front. Pharmacol. 2018, 9, 521. [Google Scholar] [CrossRef]
  198. Liu, H.; Liu, J.; Liu, Z.; Wang, Q.; Liu, J.; Feng, D.; Zou, J. Lycopene Reduces Cholesterol Absorption and Prevents Atherosclerosis in ApoE−/− Mice by Downregulating HNF-1α and NPC1L1 Expression. J. Agric. Food Chem. 2021, 69, 10114–10120. [Google Scholar] [CrossRef]
  199. Lange, K.W. Tea in cardiovascular health and disease: A critical appraisal of the evidence. Food Sci. Human Wellness 2022, 11, 445–454. [Google Scholar] [CrossRef]
  200. Mohsenzadeh, M.S.; Razavi, B.M.; Imenshahidi, M.; Mohajeri, S.A.; Rameshrad, M.; Hosseinzadeh, H. Evaluation of green tea extract and epigallocatechin gallate effects on bisphenol A-induced vascular toxicity in isolated rat aorta and cytotoxicity in human umbilical vein endothelial cells. Phytother. Res. 2021, 35, 996–1009. [Google Scholar] [CrossRef]
  201. Rivera, K.; Salas-Pérez, F.; Echeverría, G.; Urquiaga, I.; Dicenta, S.; Pérez, D.; de la Cerda, P.; González, L.; Andia, M.E.; Uribe, S.; et al. Red Wine Grape Pomace Attenuates Atherosclerosis and Myocardial Damage and Increases Survival in Association with Improved Plasma Antioxidant Activity in a Murine Model of Lethal Ischemic Heart Disease. Nutrients 2019, 11, 2135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  202. Cheang, W.S.; Wong, W.T.; Wang, L.; Cheng, C.K.; Lau, C.W.; Ma, R.C.W.; Xu, A.; Wang, N.; Huang, Y.; Tian, X.Y. Resveratrol ameliorates endothelial dysfunction in diabetic and obese mice through sirtuin 1 and peroxisome proliferator-activated receptor δ. Pharmacol. Res. 2019, 139, 384–394. [Google Scholar] [CrossRef]
  203. Zhou, Y.; Khan, H.; Xiao, J.; Cheang, W.S. Effects of Arachidonic Acid Metabolites on Cardiovascular Health and Disease. Int. J. Mol. Sci. 2021, 22, 12029. [Google Scholar] [CrossRef] [PubMed]
  204. Sherratt, S.C.R.; Dawoud, H.; Bhatt, D.L.; Malinski, T.; Mason, R.P. Omega-3 and omega-6 fatty acids have distinct effects on endothelial fatty acid content and nitric oxide bioavailability. Prostaglandins Leukot. Essent. Fat. Acids 2021, 173, 102337. [Google Scholar] [CrossRef] [PubMed]
  205. Ponnampalam, E.N.; Sinclair, A.J.; Holman, B.W.B. The Sources, Synthesis and Biological Actions of Omega-3 and Omega-6 Fatty Acids in Red Meat: An Overview. Foods 2021, 10, 1358. [Google Scholar] [CrossRef]
  206. Holen, E.; Araujo, P.; Sissener, N.H.; Rosenlund, G.; Waagbø, R. A comparative study: Difference in omega-6/omega-3 balance and saturated fat in diets for Atlantic salmon (Salmo salar) affect immune-, fat metabolism-, oxidative and apoptotic-gene expression, and eicosanoid secretion in head kidney leukocytes. Fish Shellfish Immunol. 2018, 72, 57–68. [Google Scholar] [CrossRef] [PubMed]
  207. Sun, L.; Zhang, Y.-N. Compound Danshen dripping pills in treating with coronary heart disease: A protocol for systematic review and meta-analysis. Medicine 2022, 101, e28927. [Google Scholar] [CrossRef]
  208. Li, C.; Li, Q.; Xu, J.; Wu, W.; Wu, Y.; Xie, J.; Yang, X. The Efficacy and Safety of Compound Danshen Dripping Pill Combined with Percutaneous Coronary Intervention for Coronary Heart Disease. Evid. Based Complement. Alternat. Med. 2020, 2020, 5067137. [Google Scholar] [CrossRef]
  209. Orgah, J.O.; He, S.; Wang, Y.; Jiang, M.; Wang, Y.; Orgah, E.A.; Duan, Y.; Zhao, B.; Zhang, B.; Han, J.; et al. Pharmacological potential of the combination of Salvia miltiorrhiza (Danshen) and Carthamus tinctorius (Honghua) for diabetes mellitus and its cardiovascular complications. Pharmacol. Res. 2020, 153, 104654. [Google Scholar] [CrossRef]
  210. Zhang, G.-x.; Zhang, Y.-y.; Zhang, X.-x.; Wang, P.-q.; Liu, J.; Liu, Q.; Wang, Z. Different network pharmacology mechanisms of Danshen-based Fangjis in the treatment of stable angina. Acta Pharmacol. Sin. 2018, 39, 952–960. [Google Scholar] [CrossRef]
  211. Qian, S.; Wang, S.; Fan, P.; Huo, D.; Dai, L.; Qian, Q. Effect of Salvia miltiorrhiza hydrophilic extract on the endothelial biomarkers in diabetic patients with chronic artery disease. Phytother. Res. 2012, 26, 1575–1578. [Google Scholar] [CrossRef] [PubMed]
  212. Qian, Q.; Qian, S.; Fan, P.; Huo, D.; Wang, S. Effect of Salvia miltiorrhiza hydrophilic extract on antioxidant enzymes in diabetic patients with chronic heart disease: A randomized controlled trial. Phytother. Res. 2012, 26, 60–66. [Google Scholar] [CrossRef] [PubMed]
  213. Xu, C.; Wang, W.; Wang, B.; Zhang, T.; Cui, X.; Pu, Y.; Li, N. Analytical methods and biological activities of Panax notoginseng saponins recent trends. J. Ethnopharmacol. 2019, 236, 443–465. [Google Scholar] [CrossRef] [PubMed]
  214. Yang, Z.; Shao, Q.; Ge, Z.; Ai, N.; Zhao, X.; Fan, X. A Bioactive Chemical Markers Based Strategy for Quality Assessment of Botanical Drugs: Xuesaitong Injection as a Case Study. Sci. Rep. 2017, 7, 2410. [Google Scholar] [CrossRef] [Green Version]
  215. Xu, L.; Hui, X.; Du, P.; Du, L. Meta-analysis of the curative effect of panax notoginseng saponins in the treatment of diabetic peripheral neuropathy. In Proceedings of the 2021 11th International Conference on Information Technology in Medicine and Education (ITME), Wuyishan, China, 19–21 November 2021; pp. 292–297. [Google Scholar]
  216. Duan, L.; Xiong, X.; Hu, J.; Liu, Y.; Wang, J. Efficacy and safety of oral Panax notoginseng saponins for unstable angina patients: A meta-analysis and systematic review. Phytomedicine 2018, 47, 23–33. [Google Scholar] [CrossRef]
  217. Song, H.; Wang, P.; Liu, J.; Wang, C. Panax notoginseng preparations for unstable angina pectoris: A systematic review and meta-analysis. Phytother. Res. 2017, 31, 1162–1172. [Google Scholar] [CrossRef]
  218. Fava, S.; Azzopardi, J.; Agius-Muscat, H. Outcome of unstable angina in patients with diabetes mellitus. Diabet. Med. 1997, 14, 209–213. [Google Scholar] [CrossRef]
  219. Zhang, H.; Hu, C.; Xue, J.; Jin, D.; Tian, L.; Zhao, D.; Li, X.; Qi, W. Ginseng in vascular dysfunction: A review of therapeutic potentials and molecular mechanisms. Phytother. Res. 2022, 36, 857–872. [Google Scholar] [CrossRef]
  220. Jovanovski, E.; Lea Duvnjak, S.; Komishon, A.; Au-Yeung, F.; Zurbau, A.; Jenkins, A.L.; Sung, M.-K.; Josse, R.; Vuksan, V. Vascular effects of combined enriched Korean Red ginseng (Panax Ginseng) and American ginseng (Panax Quinquefolius) administration in individuals with hypertension and type 2 diabetes: A randomized controlled trial. Complement. Ther. Med. 2020, 49, 102338. [Google Scholar] [CrossRef]
  221. Chen, A.D.; Wang, C.-L.; Qin, Y.; Tian, L.; Chen, L.-B.; Yuan, X.-M.; Ma, L.-X.; Wang, Y.-F.; Sun, J.-R.; Wang, H.-S.; et al. The effect of Danshen extract on lipoprotein-associated phospholipase A2 levels in patients with stable angina pectoris: Study protocol for a randomized controlled trial—The DOLPHIN study. Trials 2017, 18, 606. [Google Scholar] [CrossRef] [Green Version]
Figure 1. The mechanisms of ROS/oxidative stress generation in diabetes mellitus and the effects of ROS release on the vasculature.
Figure 1. The mechanisms of ROS/oxidative stress generation in diabetes mellitus and the effects of ROS release on the vasculature.
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Figure 2. Interaction of oxidative stress with various signaling pathways, leading to vascular dysfunction in diabetes.
Figure 2. Interaction of oxidative stress with various signaling pathways, leading to vascular dysfunction in diabetes.
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Table 1. Decrease of antioxidant enzymes as well as increase of ROS and RNS in rupture of redox homeostasis in diabetes mellitus.
Table 1. Decrease of antioxidant enzymes as well as increase of ROS and RNS in rupture of redox homeostasis in diabetes mellitus.
Decreased Antioxidant EnzymesType of ROS and RNS Increased
Superoxide dismutases (SODs)Superoxide ion (O2•−)
Peroxynitrite (ONOO)
Catalase (CAT)Hydrogen peroxide H2O2
Hydroxyl radical OH•−
Glutathione peroxidase (GPx)
Glutathione-S-transferase (GST)
Myeloperoxidase (MPO)
Table 2. Antioxidant effects of medicinal plants and their bioactive compounds in improving cardiovascular disease in experimental settings. ↑: upregulation; ↓: downregulation.
Table 2. Antioxidant effects of medicinal plants and their bioactive compounds in improving cardiovascular disease in experimental settings. ↑: upregulation; ↓: downregulation.
Medical PlantActive Ingredients/ExtractIn Vivo/In Vitro ModelMolecular MechanismReferences
Salvia miltiorrhiza BungeSalvia miltiorrhiza Bunge extractHG-treated VSMCs and HFD-induced diabetic miceKLF10 ↓
HO-1 ↑
ADR-treated H9c2 cell and
Wistar rats
Tanshinone INrf2−/− miceNrf2/MAPK Signaling[136]
Panax notoginsengPanax notoginseng extract and PNSHFD- induced diabetic mice
ex vivo mice aorta
HG-treated HUVECs
AMPK/eNOS pathway
restore relaxations
SOD levels ↓
20(S)-Rg3 and 20I-Rg3H9C2 cellsKeap-1/Nrf2/HO-1[139]
Panax ginseng C.A. MeyGinsenoside compound Kox-LDL-induced HUVECsNF-κB/p38/JNK pathways[141]
Ginsenoside Rh1ox-LDL-induced VECNrf2/HO-1 pathway[142,143]
Ginseng extractHealthy ratsBlood vessel dilation[144]
Mountain ginseng Roots extract (including Rb1, Rg1, Rg3, Rg5, and Rk1)Sprague-Dawley rats
and H2O2 -RAECs
Survival rate of RAECs ↑
thrombus formation ↓
Ligusticum chuanxiong hortLigustrazineHcy-induced HUVECsMitochondrial dysfunction ↓[145]
MI/R injury in rats
NO release ↑
Astragalus membranaceusAstragaloside IVHG-treated RAECs
STZ SD rats
P2X7R, p-p38 MAPK ↓
eNOS and NO ↑
eNOS mRNA expression
Carhamus tinctorius L.The ethanol extract of flowersTNF α-stimulated HUVECsNrf2/HO-1/CO signaling
2K-1C hypertensive ratsAng II-AT1R-NADPH ↓
Ginkgo biloba L.Ginkgolide BLDL-induced HUVECsNOX-4, LOX-1, MCP-1, ICAM-1, and VCAM-1 ↓[156,157]
Ginkgolide KtMCAO mouse modelJAK2/STAT3
Ginkgo biloba extractEPCsPI3K/Akt/eNOS signaling[158]
Coptis chinensis FranchCoptisineHFD-induced mice
ex vivo mice aorta
AMPK signaling
phosphorylation of eNOs ↑
Houttuynia cordataHouttuynia cordata extractHG-treated ECsSirt1/eNOS
NO ↑
Hyperlipidemia mice and HAEC cultured with PAFoxO1/p38 MAPK pathway
Ginkgo bilobaGinkgolide KtMCAO mouse modelJAK2/STAT3
Aralia ElataAralia Elata extractHG-treated HUVECsSIRT/AMPK
Curcuma longa LinnCurcuminHFD-induced miceHO-1 Enzyme Activity ↑
sirt1 ↑
Coptis chinensis Franch and Cortex phellodendriBerberineApoE−/− miceAtherosclerotic plaque area ↓
Allium sativum LinnAllium sativum Linn Obesity RatsAortic wall thickness ↓[170]
AllicinMI/R injury in ratsThe activity of SOD, CAT, and GPx ↑
p38 MAPK signaling pathway
Ocimum sanctum LinnOcimum sanctum Linn extractSprague-Dawley rats Cholesterol levels ↓[172]
HFD-induced rabbitFatty streaks lesion in the artery wall ↓[173]
Table 3. Antioxidant effects of functional food and their bioactive compounds in improving cardiovascular disease in experimental settings. ↑: upregulation; ↓: downregulation.
Table 3. Antioxidant effects of functional food and their bioactive compounds in improving cardiovascular disease in experimental settings. ↑: upregulation; ↓: downregulation.
Food and NutrientsActive Ingredients/ExtractIn Vivo/In Vitro ModelMolecular MechanismReferences
Berries (polyphenols, flavonoids, vitamins, fiber and minerals)Blueberry anthocyaninsHG-induced HUVECsPI3K/Akt/eNOs/PPARγ signaling pathway
ACE, XO-1 and LDL ↓
Berry anthocyaninsD-HAECIkB-α and caspase-1 activation[177]
Elderberry extract (20beta-hydroxyursolic acid)EA.hy926eNOS activity ↑[178]
Saskatoon Berry extractHFD-induced ratsCardiovascular function ↑
glucose metabolism ↑
Cucurbitaceous vegetables (cucurbitacins, carotenoids, phytosterols, antioxidative polyphenols and polyunsaturated fatty acids, etc.)Cucurbitacin IH2O2-treated H9c2NRF-1, PPARα, ERRα, PGC-1-β ↑[183]
Bitter gourd extractCholesterol-fed ratsGPX and CAT levels ↑[184]
Pumpkin seed proteinHigh-fructose diet rats TC and TG level ↓
the activity of SOD, CAT, and GPx ↑
CucumisAngiotensin II-Induced HMEC-1NO bioavailability ↑
ICAM-1 ↑
Cruciferous vegetable (carotene, vitamins, folic acid and minerals, glucosinolates, etc.)I3C Spontaneously hypertensive rats and Wistar Kyoto ratsNO bioavailability ↑
Hsp70 ↑
Other foodOkraOkra seed extract (quercetin 3-O-(malonyl)-glucose, quercetin Cortex-3-O-glucose-xylose and kaempferol-3-O-glucose)H2O2-induced HMEC-1 VCAM-1, SELE ↓[195]
Okra powderLDLr-KO miceThe extent of atherosclerosis ↓[196]
tomatoes, carrots, watermelon, papaya, and guavaLycopeneApoE−/− miceHNF-1α, NPC1L1 ↓
LDL-C level ↓, HDL-C level ↑
the extent of atherosclerosis ↓
abyssal Fish: salmon, trout, anchovies, sardines;
Flaxseeds, flaxseed oil, walnuts, soybeans
omega3 and omega6HUVECsNO availability ↑[204]
DrinkTea Green tea extract
epigallocatechin gallate
Bisphenol A-induced HUVECsMDA levels ↓[200]
Red wineResveratrolHFD-induced micePI3K/Akt/eNOs/PPARγ pathway[202]
Red wine polyphenolsHFD-induced SR-B1 KO/ApoER61h/h miceMDA level ↓
atherosclerotic plaque area ↓
Table 4. Clinical applications of antioxidant treatment with medicinal plants.
Table 4. Clinical applications of antioxidant treatment with medicinal plants.
PreparationIngredientsDisease Sample CountsReferences
DanshenDuofensuanyan injection and Danshen drop spillDanshen extractstable angina pectoris156 patients[221]
Compound Danshen dripping pills (CDDPs) combined with PCIDanshen, Panax notoginseng and borneolcoronary heart disease2574 patients[208]
Danhong injection (DHI)the water-soluble complex from Danshen and Honghuastable angina4458 patients[210]
Xuesaitong (XST)PNSunstable angina1828 patients[217]
Combined administration of Korean red ginseng and American ginsengKorean red ginseng and American ginsenghypertension and type 2 diabetes80 patients[220]
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Tan, Y.; Cheong, M.S.; Cheang, W.S. Roles of Reactive Oxygen Species in Vascular Complications of Diabetes: Therapeutic Properties of Medicinal Plants and Food. Oxygen 2022, 2, 246-268.

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Tan Y, Cheong MS, Cheang WS. Roles of Reactive Oxygen Species in Vascular Complications of Diabetes: Therapeutic Properties of Medicinal Plants and Food. Oxygen. 2022; 2(3):246-268.

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Tan, Yi, Meng Sam Cheong, and Wai San Cheang. 2022. "Roles of Reactive Oxygen Species in Vascular Complications of Diabetes: Therapeutic Properties of Medicinal Plants and Food" Oxygen 2, no. 3: 246-268.

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