Flavonoids in herbal medicine -
With the development of medical information technology, flavonoids derived from herbal medicines have received more and more attention due to their significant efficacy and high safety Li et al.
Flavonoids are mainly found in vacuoles of plants and are a secondary metabolite with abundant content. The main function of flavonoids is to protect plants against pathogens and UV radiation, and to participate in pollination by being recognized by pollinators Pandey and Rizvi, Previous studies have shown that flavonoids have unique antioxidant activity due to their ability to provide hydrogen atoms or electrons, which can directly remove reactive oxygen species, thereby limiting the effects of oxidative stress Li et al.
In addition, a large number of literature studies have shown that flavonoids derived from herbal medicines also have a significant effect on AS.
Notably, flavonoids derived from herbal medicines also have been shown to regulate endothelial cell dysfunction during AS development Yamagata, Therefore, based on the above explanation, we can propose that flavonoids derived from herbal medicines can inhibit oxidative stress, thereby inhibiting the occurrence of endothelial dysfunction.
Endothelial cells, as a unique type of epithelial cells, are distributed in a monolayer of blood vessels and constitute the vascular endothelium that maintains vascular homeostasis Krüger-Genge et al.
The vascular endothelium is a semipermeable barrier between plasma and vascular tissue that extends along the entire circulatory system. Due to its unique location, endothelial cells can not only undergo metabolic exchange with plasma and interstitial fluid, but also interact with cells in the blood vessel wall Yamaoka-Tojo, In addition, changes in blood composition and blood flow also have a great influence on the function of endothelial cells, among which mechanical transduction due to shear stress is considered to be the most important factor Mitra et al.
eNOS promotes nitric oxide NO production by converting L-arginine to L-citrulline and NO Förstermann and Munzel, ; Xu et al. As all we known, NO is an important vasoactive substance Figure 1.
NO can diffuse into vascular smooth muscle cells VSMC , promote vasodilation by stimulating soluble guanyl cyclase and increasing cyclic guanosine monophosphate cGMP , and has an antiproliferative effect on VSMC Jin and Loscalzo, In the circulatory system, NO can also inhibit the adhesion and aggregation of platelets and exert anti-inflammatory properties.
In addition, molecules represented by hydrogen sulfide H 2 S , carbon monoxide, and arachidonic acid metabolites can also mediate vasodilation by inducing endothelium-derived hyperpolarization Shimokawa, Under physiological conditions, in addition to vasodilation, endothelial cells can also mediate vasoconstriction by releasing a variety of vasoconstrictor molecules such as thromboxane A2 TXA2 , angiotensin Ang II and endothelin ET Ley et al.
Besides this, endothelial cells also can regulate platelet activity, coagulation cascade and fibrinolysis system. However, these functions of endothelial cells can be disrupted to varying degrees by diseases, including hyperlipidemia, diabetes, and heart failure Tuñón et al.
Apparently, aging and genetic changes can also induce endothelial cell dysfunction. FIGURE 1. Shear stress helps endothelial cells maintain homeostasis in a healthy state Ang II, angiotensin II; eNOS, endothelial NO synthase; ET, endothelin; TXA2, thromboxane A2; VSMC, vascular smooth muscle cells.
Inflammation, oxidative stress and autophagy are considered as important cellular events that affect endothelial function. Previous studies have shown that lipids in endothelial cells can be transported to autophagic vesicles for lysosome-mediated degradation after ox-LDL stimulation.
At the same time, ER stress is triggered in endothelial cells and further induces autophagy Torisu et al. In addition, endothelial cells can also regulate autophagic flux through different transcription factors when shear stress is changed Hua et al.
Therefore, autophagy has also been proposed as an effective tool to alleviate endothelial dysfunction. Since inflammation is an important factor in inducing endothelial dysfunction, its role in AS cannot be ignored.
There are many ways to induce endothelial inflammation. For example, lipopolysaccharide release from the blood promotes inflammation by increasing the expression of interferon-induced proteins and tetrapeptide repeats in endothelial cells Wang et al.
Insulin can increase Ang-II expression through the p38 MAPK-cFOS pathway and enhance inflammation in a paracrine manner Chandel et al. In addition, excessive ROS can also induce endothelial dysfunction by enhancing inflammatory response Zeng et al. When endothelial injury occurs in blood vessels, white blood cells will combine with fibrin tissue to form fibrin network, which plays a role in the repair of endothelial injury Ley et al.
Unfortunately, when the body suffers from a wide range of pathological damage, vascular endothelial cells are continuously damaged and stimulated, and the repair effect is ineffective. Under these conditions, the endothelial cells undergo a phenotypic shift, the balance between vasodilator and vasoconstrictor is disrupted, and the arterial structure is destroyed Incalza et al.
As an early event of AS, endothelial cell dysfunction plays a role in the development of AS Figure 2. After the occurrence of endothelial cell dysfunction, the vascular barrier function is weakened, and the low-density lipoprotein cholesterol LDL-C in the blood is more likely to accumulate in the intima and undergo oxidation reaction, and then produce oxidized low-density lipoprotein ox-LDL Gao et al.
The injured endothelial cells will release monocyte chemoattractant protein-1 MCP-1 , intercellular cell adhesion molecule-1 ICAM-1 , vascular cell adhesion molecule-1 VCAM-1 and so on to induce monocyte and macrophages to adhere to the vessel wall Clapp et al.
Subsequently, macrophage colony stimulating factor M-CSF and granulocyte macrophage colony stimulating factor GM-CSF stimulate mononuclear macrophages to differentiate into macrophages, which will take up ox-LDL to generate foam cells and further aggravate AS Trus et al.
As an important component of vascular composition, VSMC will switch from a contractile to a synthetic phenotype after endothelial cell injury. Similarly, VSMC also undergo abnormal proliferation and migration induced by chemokines and matrix metalloproteinases MMP , which destroys the stability of plaques.
In the intima, VSMC not only uptake ox-LDL to generate foam cells, but also secrete extracellular matrix components to form fibrous caps Liang et al. FIGURE 2. Endothelial dysfunction contributes to the development of atherosclerosis GM-CSF: granulocyte macrophage colony stimulating factor; ICAM-1, intercellular cell adhesion molecule-1; LDL-C, low-density lipoprotein cholesterol; MCP-1, monocyte chemoattractant protein-1; M-CSF, macrophage colony stimulating factor; ox-LDL, oxidized low-density lipoprotein; VCAM-1, vascular cell adhesion molecule As mentioned above, factors such as hyperlipidemia, diabetes, heart failure, aging, and genetics may contribute to the development of endothelial dysfunction.
Among these factors, we can find the presence of oxidative stress and ox-LDL. At present, many studies believe that excessive reactive oxygen species ROS can induce oxidative stress on the one hand, and aggravate the oxidative modification of LDL on the other hand.
Subsequently, oxidative stress interacts with ox-LDL to jointly promote the occurrence of endothelial dysfunction. ROS is an endogenous and important mediator involved in various biological processes of the organism and can serve as a second messenger in cell signaling. Because ROS can easily acquire or loss electrons, it is widely involved in redox reactions.
However, when the content of ROS exceeds limitation, it will disrupt the redox balance in the body, which in turn leads to the occurrence of oxidative stress, thereby affecting all aspects of physiological functions Kattoor et al. Nowadays, the ROS family includes many small molecules and ions, such as superoxide, hydroxyl radicals, hydrogen peroxide and so on.
It is well known that almost all cells in blood vessels can produce ROS, and its generation mechanism mainly includes NADPH oxidase NOX , xanthine oxidase, mitochondrial respiratory chain and NOS Figure 3 Goszcz et al. As a membrane-binding enzyme complex, NOX is the only family of enzymes whose main function is to produce ROS.
When the body has hypertension, diabetes or high cholesterol, it is easy to increase the expression of NOX and thus increase the content of ROS in the body Balaban et al.
Existing studies have shown that the congeners of NOX are expressed in various types of vascular cells, but the difference in their content cannot be ignored. For example, NOX2, NOX4, and NOX5 are predominantly expressed in EC, whereas NOX1 and NOX4 are predominantly expressed in VSMC.
At the same time, different NOX have different effects on AS. For example, downregulation of NOX1, NOX2, and NOX5 can inhibit AS, while NOX-4 has a cardioprotective effect possibly due to the fact that NOX4 mainly produces H 2 O 2 Guzik et al.
Xanthine oxidase is another important enzymatic source of ROS and is mainly present in EC. In addition, xanthine oxidase can also elevate LOX-1 and CD in macrophages and VSMCS, disrupt intracellular lipid metabolism, and increase the risk of AS Kattoor et al.
Mitochondria, as an important organelle within the cells, is an important source of energy required for cellular activities. This process is recognized as the main way to generate ROS. Normally, ROS generated by this process can be removed by various oxidoreductases to maintain homeostasis.
Under pathological conditions, the disruption of this balance will lead to excessive accumulation of ROS and further induce ROS leakage Peoples et al. NOS has three distinct isoforms, namely, neuronal NOS nNOS , inducible NOS iNOS and endothelial NOS eNOS. Among them, eNOS is most closely associated with AS.
Notably, although eNOS could produce NO in the presence of tetrahydrobiopterin BH4 to scour oxygen radicals and thus exert anti-atherosclerosis effect, it has been shown in previous studies that overexpression of eNOS may also promote the development of AS.
The possible mechanism lies in the decoupling of eNOS caused by excessive BH4 depletion Ozaki et al. This hypothesis has been confirmed by a recent study. nNOS can exert a synergistic effect with eNOS in anti-atherosclerosis by regulating vascular tone Capettini et al. It was shown that excessive ROS-induced oxidative stress can directly affect intracellular biomacromolecules to cause damage.
ROS and its oxidation products can act as signal transduction molecules to activate related pathways, damage endothelial cells, and promote the development of AS.
As one of the oxidation products, ox-LDL is thought to play a major role in lipid metabolic disorders. LDL-related modifications include oxidation, deacetylation, glycosylation and aggregation, among which the oxidation of LDL is closely related to AS Nègre-Salvayre et al.
ROS can oxidise a variety of polyunsaturated lipids in blood vessels, and the by-products formed can react with apolipoprotein B and damage its function. Subsequently, modified ApoB retards LDL removal and prolongs the exposure of lipids and apoB to ROS attack, which further enhances LDL oxidation Negre-Salvayre et al.
When endothelial cells are exposed to oxidative stress for a long time, their structure and function are continuously damaged, which also leads to the continuous oxidation of LDL to form ox-LDL Stocker and Keaney, However, after numerous studies on the oxidation mechanism of LDL, it has been found that ox-LDL is heterogeneous, and different concentrations of ox-LDL also have a dual effect on vascular cells.
For example, low concentrations of ox-LDL can induce cell migration and proliferation, and create a pro-inflammatory environment for AS, while high concentrations of ox-LDL can promote apoptosis Dandapat et al. Excessive ROS can cause endothelial cell apoptosis through several major pathways. Firstly, ROS can not only activate nuclear factor kappa-B NF-κB through redox factor-1 Ref-1 , but also directly activate NF-κB.
Subsequently, activated NF-κB translocates into the nucleus where it binds to the apoptosis-related gene c-Myc, promoting gene transcription and inducing apoptosis. The p38 pathway and c-Jun N-terminal kinase pathways are also strongly associated with ROS-induced apoptosis Haghi Aminjan et al.
et al. Notably, excessive ROS causes lipid peroxidation, damages the inner mitochondrial membrane, and ultimately induces both endogenous and exogenous endothelial cell apoptosis Sinha et al. In addition, the generated ox-LDL disrupts the structure of actin filaments upon contact with endothelial cells, causing disruption of the cytoskeleton, which in turn alters endothelial cell permeability.
The increased permeability of endothelial cells makes it easier for lipids to pass through the cells, further aggravating the development of AS Chouinard et al.
Ox-LDL can enter endothelial cells through a variety of cell-surface expressed scavenger receptors, the most typical of which are LOX-1 and CD36 Nègre-Salvayre et al.
LOX-1 is the main receptor for ox-LDL uptake by endothelial cells. As a multifunctional receptor, CD36 recognizes oxidized phospholipids and other ligands in addition to ox-LDL. When ox-LDL binds to CD36, MAPK, NF-κB and Toll-like receptors TLR are activated, which enhance the local response Park et al.
Flavonoids are a class of secondary metabolites widely found in plants and fungi. Their characteristic structure mainly contains 15 carbon atoms.
Flavonoids can be subdivided according to their structure into anthocyanins, flavonoids, flavanones, flavonols, anthoxanthins, and isoflavonoids. Because flavonoids have hydroxyl groups in their structure, they can play an antioxidant role both in vivo and in vitro. In this review, we searched the relevant literature on flavonoids inhibiting oxidative stress to treat endothelial dysfunction in AS, and selected some important compounds to elaborate.
Quercetin is a natural polyhydroxy flavonoid found in a variety of plants such as Bupleurum chinense DC, Bupleurum scorzonerifolium Willd Apiaceae , mulberry leaves, Crataegus pinnatifida Bunge, and C. pinnatifida var. Major N. It is a plant secondary metabolite with antioxidant activity Zhi et al.
In the past decades, quercetin has been widely used in clinical practice for various diseases due to its superior activity, including cancer, arthritis, neurodegenerative diseases and cardiovascular diseases Wang et al.
There are numerous studies on quercetin in the treatment of AS. In vivo and in vitro studies have shown that quercetin exerts multiple effects on various processes of AS development, including foam cell formation, lipid metabolism, monocyte migration, and endothelial cell dysfunction.
Firstly, intragastric administration of quercetin ameliorated arterial lipid deposition in high-fat diet fed ApoE mice. In ox-LDL-induced human umbilical vein endothelial cells HUVECs , quercetin reduced intracellular ROS and increased mitochondrial membrane potential. At the same time, apoptosis and senescence induced by ox-LDL were also alleviated, lipid droplet deposition was reduced, and cell morphology was improved.
By exploring the underlying mechanism, p53 and mTOR signaling pathways were found to be involved in the pharmacological mechanism of quercetin Jiang et al.
Naringenin, a flavonoid extracted from the pericarp of Citrus reticulata Blanco, is a trihydroxy flavanone. It can be found in past reports that naringenin exerts antioxidant activity directly through free radical scavenging activity, and has the ability to induce endogenous antioxidant system Hernández-Aquino and Muriel, The comparison of the antioxidant capacity of naringenin with that of quercetin has been controversial in some studies.
It was reported that naringenin equivalent antioxidant activity was 1. However, in the study of Cavia-Saiz et al. Therefore, further studies are needed to compare the antioxidant capacity of naringenin with other flavonoids. However, it was no doubt about the role of naringenin in protecting endothelial dysfunction in AS.
In previous experiments, naringenin was found to inhibit AS by ameliorating dyslipidemia, and subsequently it was found to protect mitochondrial membrane potential to ameliorate ischemic damage Mulvihill et al.
Therefore, in the study of Li et al. RNA-seq transcriptome analysis and experimental validation showed that naringenin significantly restored the expression of Sirt1, AMPKα and eNOS.
In addition, knockdown of Sirt1 and AMPKα by siRNA almost abolished this protective effect Li et al. Naringenin could significantly inhibit the damage of arterial wall and protect endothelial function after treatment, and its mechanism was consistent with the results in vitro Li et al.
Carthamus tinctorius L. has been used as a traditional medicinal plant for thousands years. According to Kaibao Materia Medica, the dried flowers of C.
tinctorius L. can promote blood circulation and relieve pain. So far, C. has been developed as Danhong injection, safflower injection and other preparations for the treatment of coronary heart disease and angina pectoris.
Hydroxysafflor yellow A is an important active component of C. tinctorius L Xue et al. In recent years, hydroxysafflor yellow A has been shown to protect endothelial cells by inhibiting inflammation and apoptosis.
First, Ji et al. This phenomenon was further illustrated in the experiments of Xie et al. Meanwhile, hydroxysafflor yellow A reduced ROS generation and restored intracellular redox balance by increasing intracellular superoxide dismutase SOD in H 2 O 2 -induced HUVECs Xie et al.
In addition, in ox-LDL-induced HUVECs, hydroxysafflor yellow A could upregulate VDAC2 or inhibit apoptosis through AMPK signaling, in which VDAC2 could exert an anti-apoptotic effect by interfering with Bak-mediated apoptosis Ye et al.
Genistein is a natural isoflavone first obtained from Genista tinctoria L. It is mainly derived from Euchresta japonica Hook. ex Regel, Sophora japonica L. and so on. Currently, methanol, ethanol, acetonitrile and other organic solvents are used to extract genistein.
Meanwhile, the chemical synthesis of genistein is simple and feasible Spagnuolo et al. The structure of genistein is similar to that of endogenous estrogen, so it can bind to estrogen receptors and exert estrogen-like effects after being absorbed by the body. In addition, as a typical flavonoid, it is connected with multiple hydroxyl groups on the phenyl ring, which makes it have excellent antioxidant effects and can be applied to the treatment of cardiovascular diseases, diabetes, depression and other diseases Borrás et al.
In endothelial dysfunction, genistein can effectively inhibit ROS and malondialdehyde MDA in cells, and restore the four oxidoreductases activities including superoxide dismutase SOD , catalase CAT , glutathione GSH and glutathione peroxidase GPx.
In this way, the redox balance of endothelial cells is maintained Zhang et al. Genistein can downregulate the expression of MiRa in ox-LDL-induced HUVES, thereby promoting the expression of sirtuin In addition, sirtuin-1 is known to exert antioxidant activity by activating fxo3a in previous studies.
However, after genistein treatment, the expression of fxo3a was significantly increased Zhang et al. Baicalein, also known as 5, 6, 7-trihydroxyflavone, is a well-recognized natural flavonoid with antioxidant and anti-inflammatory activities.
Baicalein is the most abundant component in the root of Scutellaria baicalensis S. baicalensis Georgi, a traditional Chinese medicine also known as Huangqin in Chinese Huang et al. In a previous study, it was shown that baicalein inhibited IL-1β-induced ICAM-1 expression in HUVECs, suggesting that baicalein could protect endothelial cell function Kimura et al.
In a recent study, ox-LDL was used to induce apoptosis in HUVECs and baicalein was preincubated before induction. It was showed that baicalein effectively inhibited the generation of intracellular ROS and the release of cytochrome C from mitochondria, and increased mitochondrial membrane potential.
The expression of pro-apoptotic protein BAX was downregulated, while the expression of anti-apoptotic protein Bcl-2 was upregulated. In addition, the bioavailability of NO was also improved Chan et al.
Subsequently, it was also shown that baicalein pretreatment could inhibit the binding ability of ox-LDL by reducing the expression of LOX-1, thereby inhibiting the generation of ROS.
In addition, baicalein inhibited the protein expression of NADPH oxidase and increased the phosphorylation level of AMPK, thereby inhibiting the activation of protein kinase C PKC -α and PKC-β Tsai et al.
Luteolin is a common flavonoid, which is usually found in the form of glycosylated in celery, green pepper, Perilla frutescens L. Luteolin possesses the antioxidant properties, as well as anti-inflammatory ability.
Therefore, it also has a good advantage in the treatment of AS Prasher et al. Up to now, the antioxidant activity of luteolin has been fully confirmed. It can exert efficacy in all stages of AS, such as VSMC migration and proliferation, cell adhesion molecule secretion and endothelial cell dysfunction Luo et al.
When endothelial cells are dysfunctional, luteolin can inhibit the generation of intracellular ROS, while the phosphorylation of p38MAPK and nuclear translocation of NF-kB induced by ox-LDL are reversed. At the same time, the mRNA levels of ICAM-1, VCAM-1, selectin, MMP-1, MMP-2, and MMP-9 are also downregulated by luteolin Yi et al.
In another study, this conclusion was further developed. Ultimately, luteolin restored the redox balance in endothelial cells, that is, the contents of GSH and SOD were restored and LDH was decreased Xia et al. Erigeron breviscapus Vant.
The modern pharmacological studies have shown that the main active substance is scutellarin. Previous studies have found that scutellarin not only prevents cerebral ischemia by inhibiting inflammatory response, but also improves liver damage by inhibiting oxidative stress Yuan et al.
In addition, scutellarin also plays a role in endothelial dysfunction through its antioxidant effect in AS. Scutellarin scavenged excess ROS and increased the bioavailability of NO in HAECs induced by either angiotensin II or H 2 O 2.
The contents of oxidoreductases, including SOD, GPx, CAT and Nox, could be restored to varying degrees after treatment with scutellarin.
After treating with scutellarin, the mRNA levels of mammalian sterilelike kinases 1 Mst1 , Yes-associated protein YAP and FOXO3A were significantly downregulated, as well as the protein levels of p-Mst1, p-YAP and nuclear translocation of FOXO3A. The specific indicators are referred to Table 1.
TABLE 1. Natural flavonoids derived from herbal medicines are potential anti-AS agents by inhibiting oxidative stress in endothelial cells. et Kir. In nature, acacetin mostly exists in the form of free or glycosides, and has pharmacological activities on cancer, obesity, diabetes, etc Wu et al.
In recent years, acacetin has been found to have a protective effect on endothelial dysfunction in AS, which has attracted extensive attention from the scientific community.
In vivo study believed that acacetin significantly accelerated lipid metabolism in AS mice and reduced the levels of inflammatory factors in plasma Han et al.
In vitro experiment confirmed that acacetin could protect mitochondrial function, reverse mitochondrial depolarization, and inhibit the excessive production of ROS and MDA in HUVECs induced by high glucose. In addition, the study has shown that acacetin may restore the antioxidant function of endothelial cells by promoting the phosphorylation of Nrf2, the degradation of Keap1 and the expression of methionine sulfite reductase Wu et al.
Artemisia princeps Pampanini has been widely used as a medicinal plant in Asia over the last thousands of years. In modern times, due to the rapid development of modern pharmacology, eupatilin has been found to have a wider range of pharmacological activities Lim et al.
For example, eupatilin has therapeutic potential in diseases such as oncology, allergy, and inflammation Park, ; Jeong et al.
In AS, eupatilin has been shown to inhibit the proliferation and migration of human aortic smooth muscle cells.
The oxidative stress as well as inflammatory responses occurring in endothelial cells could also be inhibited by eupatilin. In addition, Yu et al. has been confirmed that eupatilin could effectively reduce the ROS content in TNF-α-induced HUVECs, inhibit the expression of VCAM-1 and ICAM-1, and thus reduce the adhesion ability of U cells to endothelial cells.
The mechanism by which eupatilin exerted its therapeutic effect was closely related to MAPK-NF-ĸB. The phosphorylation of NF-kB p65 and MAPK was significantly inhibited by eupatilin. From the foregoing, it is known that the preceding flavonoid compounds can protect the cells from oxidative stress damage by restoring the antioxidant capacity of endothelial cells.
However, glabridin extracted from the root of Glycyrrhiza glabra licorice could attenuate the oxidative stress injury to endothelial cells by inhibiting the oxidative sensitivity of LDL. However, the degree of LDL oxidation was significantly reduced after glabridin treatment, and glabridin inhibited the formation of lipid peroxides and cholesterol linoleic acid hydroperoxides CLOOH Belinky et al.
This protective effect of glabridin provides a novel form of protection for flavonoids. The protective effects of other flavonoid compounds on endothelial cells are shown in Table 1.
In this review, we summarized the pathogenesis of endothelial dysfunction in AS, and then selected representative flavonoids with anti-oxidative stress effects for relevant elaboration.
After summarizing, we have found that flavonoids from natural herbal medicines not only inhibit oxidative stress, but also have anti-inflammatory and anti-adhesion effects in the treatment of endothelial dysfunction.
This result is consistent with the multi-level and multi-target advantages of traditional Chinese medicine. In modern clinical practice, it has been demonstrated that flavonoids can be used to reduce the incidence of AS.
First of all, epidemiological investigations have shown that increasing the intake of flavonoids in daily diet can effectively reduce the risk of AS Lagiou et al. Subsequently, more and more evidence has shown that the intake anthocyanins, tea the main components are flavanols , etc.
However, after in-depth understanding, flavonoids from natural herbal medicines also have certain limitations and problems that need to be solved urgently. Firstly, most of the models used in the existing studies are in vitro models. Flavonoids have been shown to exert protective effects on endothelial cells in experiments, but it is not clear whether this protective effect will change with the transformation of drug structure due to complex changes after drug entry into the body.
Secondly, although some researchers have confirmed the protective effect of flavonoids on AS from in vivo and in vitro experiments, there is no relevant clinical data to support.
At the same time, the toxicity and safety of drugs are also essential before the development of drugs. The oncogenic activity of quercetin remains controversial. However, it is generally believed that quercetin is safe when used under the intended conditions, and caution should be taken when taking quercetin in high doses or for a long time.
Therefore, the safety and toxicity of flavonoids should be considered before they are used in clinical practice, and more work needs to be done. Finally, because the flavonoid compounds have more phenolic hydroxyl groups in their structure, it makes their structure unstable.
Therefore, it is necessary to consider how to solve the problem of drug stability before developing flavonoid compounds into drugs.
Looking at the existing flavonoid drug development, it can be found that the research on the treatment of endothelial dysfunction in AS is still relatively basic, and has not yet considered what kind of preparation the flavonoid is made into, or how it is administered.
The development of flavonoids into modern formulations such as nanoparticles may change the instability of the compounds, which can also become the future development direction of flavonoids for the treatment of endothelial dysfunction.
In summary, flavonoid compounds hold great promise in the treatment of endothelial dysfunction in AS, but further exploration is needed. All authors made a significant contribution to the work reported, whether that is in the conception, execution, acquisition of data, analysis and interpretation.
R-LL and L-YW took part in drafting, revising and critically reviewing the article; H-XD, DQ, and QZ gave final approval of the version to be published; L-SH and X-PL have agreed on the journal to which the article has been submitted and agree to be accountable for all aspects of the work.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
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Förstermann, U. Endothelial nitric oxide synthase in vascular disease: From marvel to menace. NO level was determined with the Griess reagent [ 20 ], which quantifies nitrite, one of the stable reaction products. Briefly, the supernatant was mixed with an equal volume of Griess reagent 0.
After standing for 5 min at room temperature, the absorbance was measured at nm using a Bio-Rad microplate reader. The remaining supernatant was removed from each well for the TNF-α assay by ELISA. Cell viability was assessed using a modified MTT assay [ 21 ].
After further 4 h incubation at 37°C, μL of DMSO was added to each well to solubilise the deposited formazan. The optical density of each well was measured at nm by a microplate reader. A sandwich ELISA method was used as described previously [ 22 ] to determine the TNF-α concentration.
The capture antibody was used with 0. TNF-α was detected using a biotinylated secondary antibody and an avidin peroxidase conjugate with TMB as the detection reagent.
After 30 min, the reaction was stopped by 2 M sulfuric acid and the absorbance was measured at nm. The results were expressed as mean ± standard deviation SD , calculated from duplicate determinations and the linear relationship was visually determined.
The significance of differences among groups of data were determined with one-way analysis of variance ANOVA by using statistical software SPSS The yield of the water extracts The total phenolic and flavonoid contents of the extracts was measured using the F-C reagent and aluminium chloride methods, respectively.
The highest phenolic content was found in C. bonariensis H argyi H7: brevicornum H vulgaris H9: grandiflora H 5. In the other herbs the total phenolic content ranged The flavonoid content varied greatly from 9.
The highest flavonoid content was found in A. genistelloides H1: alba H8: A : Hot water extracts. B : Ethanol extracts. The flavonoid content of the herbs was in the range The highest flavonoid content was found in L. gracile H alkekengi H2: baicalensis H militaris H Phenolics and flavonoids neutralize free radicals by donating a hydrogen atom or an electron, and chelate metal ions [ 24 ].
The antioxidant activities of the water and ethanol extracts in this study were evaluated using an antioxidant assay for scavenging activity with S.
cerevisiae , a DPPH free radical scavenging assay, an assay assessing the iron II chelating ability, and a FRAP assay. Most of the water and ethanol extracts fourteen samples out of fifteen displayed significant antioxidant activity as measured by the DPPH method.
The results from the antioxidant assay suggested that the water extracts showed higher activity than the ethanol extracts in general.
The percentage inhibitions of the free radical DPPH were in the range 7. chinensis H5 , T. capilipes H6 and P. The highest inhibition of DPPH activity was found in the ethanol extract of L. The free radical scavenging activities were very low in the ethanol extracts of C.
militaris H 4. grandiflora H 2. The herbs displayed antioxidant activities owing to a combination of their total phenolic and flavonoid content as reported in other studies [ 6 , 10 ].
Iron is the chief peroxidant and is able to generate lipid peroxidation through the Fenton reaction or by accelerating the dissociation of lipid hydroperoxides to their respective peroxy and alkoxy radicals [ 25 ].
The water extracts of A. argyi H7 , P. vulgaris H9 , L. gracile H10 and E. brevicornum H14 exhibited The highest percentage chelating capacity of the ethanol extracts was found in L.
Seu calvatia H4: capilipes H6: Flavonoid and phenolic compounds are known to act as antioxidants, radical scavengers and metal chelators [ 27 ]. These extracts have appreciable amounts of flavonoid and phenolic compounds that may contribute to their chelating ability.
A wide variation was observed. The water extract of P. vulgaris H9 showed the highest FRAP CPE grandiflora H13 showed the lowest FRAP CPE 2. The FRAP of the ethanol extracts was in the range 3. FRAP was significant in some of the water and ethanol extracts owing to the presence of phenolic and flavonoid compounds and a similar trend is observed for many other plant extracts that have been studied [ 28 ].
The reducing properties are generally associated with compounds that can donate hydrogen atoms to free radicals and convert them into stable non-reactive molecules [ 29 ].
NO is an important intracellular and intercellular regulator of multiple biological functions, including macrophage-mediated cytotoxicity, neurotransmission and smooth muscle relaxation [ 30 , 31 ]. Overexpression of NO has been associated with oxidative stress [ 32 , 33 ] and with the pathophysiology of various diseases such as arthritis, diabetes, autoimmune disease and chronic inflammation [ 34 , 35 ].
It has also been shown that the production of TNF-α is crucial for the synergistic induction of NO synthesis in IFN-γ- and LPS-stimulated macrophages [ 36 , 37 ]. The cell toxicity of the plant extracts was determined by MTT assay.
vulgaris H9 and E. brevicornum H Therefore the water extracts of these plants exhibited low toxicity. The role of TNF-α production was suggested for the antitumor activity of phenols and flavonoids [ 38 ], but the underlying mechanisms by which different flavonoid and phenolic compounds affect TNF-α and NO production are to be investigated.
Effect of water extracts of herbs on LPS-stimulated macrophage production of NO and TNF-α, and cell viability. A : Cell viability. B : NO production. C : TNF-α production.
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Flavlnoids Medicine volume 7Article number: Uerbal Cite African Mango seed capsules article. Nedicine details. This study aims to determine the relationship between the antioxidant Flavonoidw Flavonoids in herbal medicine activities of meedicine thirteen herbs and two fungi extracts, and their total phenolic and flavonoid Insulin pump site rotation. Antioxidant Flaovnoids were evaluated by four assays: an antioxidant activity assay using Saccharomyces cerevisiaea DPPH 2, 2-diphenylpicrylhydrazyl assay to assess free radical scavenging, an assay assessing ferrous ions or iron II chelating ability, and a ferric reducing antioxidant power FRAP assay. Total phenolic and flavonoid contents were determined using the Folin-Ciocalteu and aluminium chloride methods, respectively. Anti-inflammatory activities were determined by measuring the inhibition of nitric oxide and TNF-α production in lipopolysaccharide- and interferon-γ-activated JA. Their cytotoxicities against macrophages were determined by MTT assay. Flavonoids are compounds found in many ln products, including Flavonouds, citrus fruits, Flavonoids in herbal medicine vegetables. They have antioxidant properties and may Flavonoids in herbal medicine your risk Flavnooids heart attack or medicind. Flavonoids are Manage muscle soreness compounds found naturally in many Flavonoidw and vegetables. There are six different types of flavonoids found in food, and each kind is broken down by your body in a different way. Flavonoids are rich in antioxidant activity and can help your body ward off everyday toxins. Including more flavonoids in your diet is a great way to help your body stay healthy and potentially decrease your risk of some chronic health conditions. Many plant products contain dietary flavonoids.
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