Natural products in atherosclerosis therapy by targeting PPARs: a review focusing on lipid metabolism and inflammation

Inflammation and dyslipidemia are critical inducing factors of atherosclerosis. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and control the expression of multiple genes that are involved in lipid metabolism and inflammatory responses. However, synthesized PPAR agonists exhibit contrary therapeutic effects and various side effects in atherosclerosis therapy. Natural products are structural diversity and have a good safety. Recent studies find that natural herbs and compounds exhibit attractive therapeutic effects on atherosclerosis by alleviating hyperlipidemia and inflammation through modulation of PPARs. Importantly, the preparation of natural products generally causes significantly lower environmental pollution compared to that of synthesized chemical compounds. Therefore, it is interesting to discover novel PPAR modulator and develop alternative strategies for atherosclerosis therapy based on natural herbs and compounds. This article reviews recent findings, mainly from the year of 2020 to present, about the roles of natural herbs and compounds in regulation of PPARs and their therapeutic effects on atherosclerosis. This article provides alternative strategies and theoretical basis for atherosclerosis therapy using natural herbs and compounds by targeting PPARs, and offers valuable information for researchers that are interested in developing novel PPAR modulators.


Introduction
Cardiovascular disease (CVD) has become the number one cause of human death due to changes in lifestyle, especially highfat and high-caloric diet, and aging of population.It is estimated that approximately 170,000 people die from CVD each year (1).Of note, atherosclerosis is an important cause of CVD events (2).In the year of 2020, nearly 2 billion people suffered from carotid atherosclerosis in the world including 270 million people in China (3,4).Atherosclerosis is a chronic inflammatory and degenerative process that primarily occurs in large-and mediumsized arteries.This disease is characterized by accumulation of fatty and fibrous materials and calcium minerals in the intima layer of arteries (5,6).
Inflammation drives all phases of atherosclerosis including initiation, metaphase, advanced phase, and rupture or regression (6).Thus, inflammatory factors, such as C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor-α (TNF-α), are consistently elevated in atherosclerosis.Furthermore, receptors and other molecules involved in inflammation, such as toll-like receptor (TLR), particularly, TLR2 and TLR4, are augmented in human atherosclerotic plaques (7,8).Dyslipidemia, characterized by high levels of total cholesterol (TC) and triglyceride (TG) and low levels of high-density lipoprotein (HDL) cholesterol (HDL-c), is equally or even more dangerous for the onset and development of atherosclerosis.It is acknowledged that low-density lipoprotein (LDL) cholesterol (LDL-c) or LDL particles and hypertriglyceridemia or TG-rich lipoproteins are leading inducing factors of atherosclerosis (9,10).
Peroxisome proliferator-activated receptors (PPARs) are recognized as promoters of peroxisome proliferation more than 40 years ago (11).Due to their various functions, research on PPARs has grown exponentially in recent years.Notably, the distribution and function of PPARs exhibit organ-and cellspecificity.PPARα is chiefly expressed in heart, liver, skeletal muscle, and cardiovascular system; PPARβ/δ is widely distributed in the body; and PPARγ is highly expressed in white adipose tissue (12)(13)(14).The roles of PPARs in physiological and pathological conditions have been reviewed recently by distinct groups (14)(15)(16).Mechanistically, PPARs heterodimerize with retinoid X receptor (RXR) and bind to specific DNA regions of target genes (AGGTCAXAGGTCA, with X being a random nucleotide) that are termed as peroxisome proliferator hormone response elements.Ligand activation triggers conformational changes of PPAR-RXR and finally activate the transcription of target genes.Notably, PPARs regulate multiple genes associated with cellular lipid metabolism and inflammation in cardiovascular system (14).Downregulation of PPARα is found to decrease hepatic de novo lipogenesis, while PPARα agonists restore lipid homeostasis in the liver (17).Mechanistically, PPARα induces the expression of genes involved in fatty acid uptake, conversion, and catabolism through β-oxidation pathway, leading to reductions in fatty acid and TG synthesis and hepatic very low-density lipoprotein production.Similar to PPARα, PPARβ activates carnitine palmitoyl transferase (CPT), which facilitates fatty acid transport across mitochondrial membrane and the subsequent β-oxidation (18).Furthermore, PPARβ activation enhances energy expenditure through upregulation of heat-producing enzymes including uncoupling protein 1 and 3 in brown adipose tissue, thereby protecting against obesity and fatty liver.On the contrary, PPARγ agonists, such as rosiglitazone, cannot decrease TG and fatty acid levels.Mechanistically, PPARγ increases glucose utilization, thereby decreasing glucose-fatty acid cycle and the subsequent upregulation of the genes involved in fatty acid synthesis and uptake (19).
In a previous article, we reviewed PPARs' regulation and their roles in atherosclerosis as well as synthesized PPAR agonists and antagonists (14).Although synthetic PPAR modulators exhibit attractive potential in atherosclerosis therapy, these compounds induce various side effects and show contrary therapeutic effects in different participants and animal models.Notably, phytochemical compounds show therapeutic effects in different diseases by modulation of PPARs (24, 25), and they are considered as preventive agents for metabolic syndrome including nonalcoholic fatty liver disease (NAFLD) by targeting PPARs (26,27).Given multiple diseases, particularly NAFLD, diabetes, obesity, and fibrosis, are closely associated with the onset and development of atherosclerosis (28)(29)(30)(31)(32), compounds with the activities of ameliorating the above diseases are useful for atherosclerosis therapy.Importantly, the majority of natural products exhibit good therapeutic efficacy and safety compared to synthetic medications (15,33).These properties suggest that natural products are potential candidate molecules for atherosclerosis therapy.This article reviews the roles of natural herbs and compounds in treatment of atherosclerosis through activation of PPARs by focusing on lipid metabolism and inflammation.Recent literatures, mainly from 2020 to present, published in PubMed, Web of Science, and Google Scholar were screened out using traditional Chinese medicine (TCM), flavonoid, acid, alkaloid, terpenoid, phenolic compound, and carbohydrate in combination with PPAR as key words.

TCM prescription and lipid metabolism
TCMs have been used for treatment of metabolic disorders and CVDs for hundreds of years.Recent studies have demonstrated that TCMs ameliorate hyperlipidemia and atherosclerosis through modulation of PPARs (Figure 1).Huo-Xue-Qu-Yu formula (HXQY, 活血祛瘀方) ameliorates lipid profiles including apolipoprotein (Apo) B and ApoA1 in rats with NAFLD via upregulating the expression of PPARα and CPT-1 in the liver, thereby improving symptoms of NAFLD (34).Similarly, heartprotecting musk pill (麝香护心丸) is found to attenuate atherosclerosis partially via activating PPARα/CPT-1α signaling pathway in ApoE-deficient mice (35).TCM believes that "phlegm stasis interjunction (痰瘀互结)" is an important inducing factor in the occurrence and development of atherosclerosis.Dan-Lou prescription (丹蒌方) has been demonstrated to reduce phlegm, repair diseased blood vessels, and eliminate hyperlipidemia, thus ameliorating atherosclerosis.Notably, this prescription enhances cholesterol efflux by activating PPARα/ATP-binding cassette transporter (ABC) A1 signaling pathway (36).
In addition to activating PPARα signaling, many TCM prescriptions stimulate PPARγ-liver X receptor (LXR) α-ABCA1/ABCG1 signaling pathways, thereby ameliorating lipid profiles and atherosclerosis through upregulation of reverse Mechanisms of action of TCM prescriptions and natural bioactive molecules in atherosclerosis therapy by targeting peroxisome proliferator-activated receptors (PPARs).TCM prescriptions and natural bioactive molecules including flavonoids, natural acids, alkaloids, terpenoids, and phenolic compounds mainly decreases lipid accumulation by activating AMP-activated protein kinase (AMPK) and the subsequent signaling pathways including PPARα/carnitine palmitoyl transferase (CPT)-1 and acyl-CoA oxidase 1 (ACOX1)-mediated fatty acid β-oxidation in liver and PPARγ/liver X receptor (LXR) α/ATP-binding cassette transporter (ABC) A1/ABCG1-mediated cholesterol efflux from macrophages to apolipoprotein (Apo) A1 and high-density lipoprotein (HDL) particles, thereby decreasing foam cell formation.Moreover, some TCM prescriptions and natural molecules may decrease cluster of differentiation (CD) 36-mediated lipid absorption via suppressing PPARγ, thereby reducing lipid accumulation in macrophages.Notably, TCM prescriptions and natural molecules primarily ameliorate inflammation by suppressing mitogen-activated protein kinase (MAPK)/ nuclear factor kappa B (NK-κB) and phosphoinositide-3 kinase (PI3K)/protein kinase B (AKT/PKB)/NK-κB signaling pathways through activation of PPARγ.Furthermore, these natural compounds can inhibit Toll-like receptor (TLR)4/myeloid differentiation factor 88 (MyD88)/NF-κB signaling pathway and promote macrophage shift to an anti-inflammatory M2 type through activation of PPARα.Notably, natural compounds may stimulate PPARγ coactivator (PGC)-1β-estrogen related receptor α to activate PPARβ/PPARγ signaling pathways and enhance protein kinase A (PKA)/AMPK signaling pathway to upregulate PPARα in the liver.Except for NF-κB, nuclear transcription factor activator protein 1 (AP-1) is involved in the modulatory effects of PPARs on anti-inflammation.These beneficial effects of TCMs are supposed to retard the development of atherosclerosis.IKK: inhibitor of nuclear factor κB kinase subunit; IL: interleukin; TNF-α: tumor necrosis factor α.
3 Natural compounds in regulation of PPARs

Flavonoids in regulation of PPARs
Plants-derived flavonoids have been demonstrated to improve lipid metabolism and inflammation by modulating PPAR signaling pathways (Figures 1, 2).These natural flavonoids provide a new therapeutic direction for treatment of atherosclerosis.The anti-inflammatory and anti-allergic potential as well as the basic structure of some dietary flavonoids have been reviewed recently by Rakha et al. (52).Moreover, the CVDprotecting effects of myricetin have been summarized in the literature (53).

Flavonoids and lipid metabolism
Citrus flavonoids play an important role in treatment of dyslipidemia and atherosclerosis.The roles of Citrus fruitsderived compounds in modulation of metabolic diseases have been reviewed recently by Aslan et al. (54).Nobiletin is an active component of citrus peel.This molecule increases the expression of PPARγ but not PPARα.Furthermore, it activates AMPK, thus promoting the expression of ABC transporters including ABCA1 and ABCG1.Notably, the LXRα-PPARγ loop amplifies its action (55).Rosa rugosa Thunb-and Rosa davurica Pall.fruits-derived flavonoids upregulate the expression of PPARα and its downstream genes that are involved in lipid metabolism (56,57).Genestein improves lipid metabolism by upregulating PPARα and activating estrogen receptor β-AKT-mammalian target of rapamycin (mTOR) signaling pathway (58).Hesperidin decreases TG levels by enhancing PPARα and suppressing PPARγ and other lipogenic genes including SREBP-1, fatty acid synthesis (FAS), and stearoyl-CoA desaturase; it reduces TC by suppressing cholesterol absorption through downregulation of fatty acid binding protein (FABP) and retinol binding protein (59).

Natural acids and lipid metabolism
The structure of some bioactive natural acids and their mechanisms of action are shown in Figures 1, 3. The widely distributed chlorogenic acid and caffeine acid are demonstrated to benefit health and cardiovascular system (77).The anti-obesity properties of chlorogenic acid have been recently reviewed by Kumar et al. (78).Notably, chlorogenic acid and caffeine acid may act synergistically on reducing lipid deposition in macrophages via inhibiting PPARγ signaling pathway (77).Furthermore, 5-aminolevulinic acid-mediated sonodynamic therapy improves cholesterol efflux via activating PPARγ-LXRα-ABCA1/ABCG1 signaling pathways, enhancing efferocytosis and cholesterol efflux, and eventually ameliorating atherosclerosis (79).
Oleic acid prevents intracellular lipid accumulation in human macrophages through modulation of PPARs and down-regulation of ApoB48 receptor, suggesting the role of monounsaturated fatty acid in regulation of postprandial TG-rich lipoprotein/ApoB48 receptor axis (80).Dodecahexaenoic acid (DHA) ameliorates postprandial hyperlipidemia potentially by upregulating PPARα and the genes involved in fatty acid β-oxidation and downregulating TG and ApoB secretion (81).Furthermore, ω-3 polyunsaturated fatty acids (PUFAs) attenuate hepatic steatosis through upregulation of PPARα/CPT-1α signaling pathway (82).Supplement of DHA-rich fish oil increases PPARγ activity in peripheral blood mononuclear cells of the participants (83).However, administration of DHA rapidly increases the production of cyclic adenosine monophosphate inside cilia, and finally activates PPARγ to initiate adipogenesis in preadipocytes (84).
Hydroxypentaenoic acid reduces LDL-c levels and increases HDL-c levels in atherosclerotic animal models, leading to reductions in aortic atherosclerotic plaques (85)(86)(87).Mechanistically, this molecule acts as a PPAR ligand and elevates LXRs-ABCA1/ABCG1 signaling pathways (85,88).Similarly, 12-Hydroxyeicosapentaenoic acid reduces foam cell formation and atherosclerosis via activation of PPARγ-ABCA1/ABCG1 signaling pathways (89, 90).8-hydroxyeicosapentaenoic acid is a pan PPAR activator and has beneficial effects against dyslipidemia and atherosclerosis (86).However, medium-chain structured lipids ameliorate high-fat diet-induced atherosclerosis potentially by reducing the expression of PPARγ (91).It seems that carbon number of fatty acids plays a role in regulation of PPARγ.
Sea cucumber saponins reduce lipogenesis and promote fatty acid β-oxidation via inhibiting SREBP-1c and enhancing the expression of PPARα and ACOX1, respectively, thereby improving lipid deposition in rodents (134)(135)(136)(137).In combination with eicosapentaenoic acid-enriched phospholipids, sea cucumber saponins further reduce hepatic TG partially by enhancing the expression of PPARα as reviewed by Lin et al. (137).Interestingly, sea cucumber saponin treatment induces changes of lipid metabolism-related genes including PPARα in rhythm, suggesting saponin may modulate lipid metabolism by regulating the clock genes, such as CLOCK and BMAL1 (137,138).The major bioactive component of saponin, echinoside A, also regulates the expression of some key genes that are involved in lipid metabolism in a diurnal manner (139).The marine-derived PPAR activators have been reviewed recently by D'Aniello et al. (140).

Terpenoids and inflammation
PPARγ plays a vital role in anti-inflammatory mechanisms of action of terpenoids (Figure 1).Saponin notoginsenoside Fc ameliorates inflammatory response in high glucose-induced endothelial cell injury partly by activation of PPARγ (141).Stevioside attenuates inflammation by upregulating PPARγ, thereby activating PI3K/AKT signaling pathway in a middle cerebral artery occlusion/reperfusion rat model (142).

Phenolic compounds and lipid metabolism
Phenolic compounds are widely distributed bioactive compounds, they are found to exert lipid-modulatory and antiinflammatory functions by regulating PPARs (Figures 1, 6).Resveratrol ameliorates hepatocyte steatosis via activating protein kinase A/AMPK/PPARα signaling pathway (149).It abolishes intestinal fatty acid and monoglyceride accumulation via activation of PPARα/PPARγ and their downstream ABCA1 and ABCG1 transporters in atherosclerotic mice (150).Furthermore, it is found to promote fatty acid β-oxidation by enhancing Ellagic acid has anti-atherogenic and cardioprotective properties, suggesting its role in atherosclerosis therapy (154).Mechanistically, ellagic acid regulates the genes that are mainly correlated with PPAR signaling pathway, thereby ameliorating lipid metabolism (155).Hydroxytyrosol, a polyphenol, decreases the expression of FAS, SREBP-1c, and PPARγ, ameliorating TC and TG levels and hepatic steatosis in ethanol-induced HepG2 cells (156).In addition, methyl brevifolincarboxylate, a polyphenolic compound, improves hepatic lipid accumulation through upregulation of AMPKα/PPARα signaling pathway and the target genes of PPARα including CPT-1 and ACOX1 in free fatty acid-treated hepatocytes (157).Sesamol, a phenolic compound derived from sesame oil, activates PPAR signaling pathway, leading to enhanced fatty acid oxidation, cholesterol efflux, and catabolism, thus accelerating lipid consumption and reducing intracellular lipid accumulation in HepG2 cells (158).

Carbohydrates in regulation of PPARs
Polysaccharides are a kind of carbohydrate polymers that are generally consisted of more than ten monosaccharides through glycosidic linkages in linear or branched chains.Given polysaccharides generally have low toxicity and various biological activities, such as antioxidant, anti-inflammatory, and antiatherosclerosis, some polysaccharides have been used in medical and biochemical areas as reviewed by different groups (137, 167- Structure of some bioactive phenolic compounds with potential anti-atherosclerotic effects. ). Notably, carbohydrates are found to exert their function via activating PPAR signaling pathways (Figure 7).

Carbohydrates and lipid metabolism
Different groups have demonstrated that brown seaweed fucoidans attenuate hyperlipidemia and atherosclerosis by modulating PPARs in different animal models (170).For instance, Kjellmaniella crassifolia-derived fucoidan ameliorates hyperlipidemia by improving PPARα-mediated fatty acid β-oxidation in Wistar rats (171).Similarly, Saccharina sculperaderived fucoidans improve hyperlipidemia potentially by enhancing the gene expression of PPARα and PPARγ in Wistar rats (172).Cladosiphon okamuranus-derived fucoidan improves hyperlipidemia and atherosclerosis partially by elevating the expression of PPARα and inhibiting SREBP-1 (173).Except for PPARα, PPARγ activation also stimulates LXR/ABC transporter signaling pathways, thereby accelerating lipid transport and excretion (14).However, Ascophyllum nodosum-derived fucoidan is found to inhibit the expression of PPARγ and elevate the expression of PPARα, thereby attenuating hyperlipidemia and atherosclerosis in ApoE-deficient mice (174).
Besides brown seaweeds, sea cucumber-derived polysaccharides improve lipid metabolism in different models (137).For instance, Isostihopus badionotus-derived fucosylated chondroitin sulfate (4,300 Da) exhibits a hypolipidemic effect in mice partially by down-regulating the expression of FAS and PPARγ (175).Acaudina molpadioides-derived fucoidan inhibits adipocyte proliferation and differentiation via enhancing Wnt/β-Catenin signaling pathway and suppressing the expression of SREBP-1c and PPARγ (176,177).Glycosaminoglycans isolated from sea cucumber Holothuria leucospilota are found to ameliorate hyperlipidemia in male BALB/c mice by improving the expression of PPARα and ameliorating gut microbiota (137,178).
Polysaccharides isolated from plants and fungi also exhibit powerful lipid-lowering effects as reviewed recently by distinct groups (179,180).Cyclocarya paliurus-, Saussurea involucrata-, Astragalus membranaceus-, and Cordyceps militaris-derived polysaccharides exert therapeutic effects in hyperlipidemic rats partially via upregulating PPARα/CPT signaling pathway Mechanisms of action of carbohydrates in atherosclerosis therapy.Carbohydrates prevent against lipid accumulation by enhancing PPARα/PPARγliver X receptor (LXR)-ABC transporter and PPARα-mediated fatty acid β-oxidation.Alternatively, some polysaccharides alleviate lipid accumulation by suppressing fatty acid synthesis-related genes including PPARγ, fatty acid synthase, and sterol response element-binding protein (SREBP)-1c potentially through up-regulation of AMP-activated protein kinase (AMPK) in the liver.Furthermore, they inhibit phosphoinositide-3 kinase (PI3K)/ protein kinase B (AKT/PKB)/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NK-κB) signaling pathways to suppress inflammation.In the small intestine, carbohydrates decrease cholesterol absorption and increase cholesterol excretion by decreasing the level of Niemann-Pick C1-like 1 protein and enhancing the LXR/ABCG5/8 signaling pathway, respectively.Moreover, carbohydrates suppress inflammation by inhibiting Toll-like receptor (TLR)/myeloid differentiation factor 88 (MyD88)/NF-κB and modulating PPARγ/NK-κB signaling pathway.(191).D-mannose promotes fatty acid oxidation via enhancing PPARα (192).Our group demonstrates that N-acetylneuraminic acid reduces TC and particularly TG partially by enhancing PPARα in ApoE-deficient mice (193,194).Aging enhances the expression of SREBP-1c and decreases the expression of PPARα.Interestingly, oral intake of trehalose reverses these changes in aged liver, suggesting trehalose decreases lipogenesis and boosts fatty acid β-oxidation (195).Fructose is considered as a lipogenic nutrient.It suppresses transcriptional activity of PPARα and its target gene CPT-1α, potentially via modulating PGC-1α acetylation and CPT-1α acetylation (196).

Concluding remarks and future directions
TCMs, especially TCM prescriptions, and natural compounds including flavonoids, acids, alkaloids, terpenoids, phenolic compounds, and carbohydrates are effective in suppression of dyslipidemia and inflammatory responses with good safety by targeting PPARs, thereby retarding the progression of atherosclerosis.Notably, these natural molecules exhibit equivalent effects compared to chemically synthetic compounds but the former exhibit less harmful side effects (15).Furthermore, TCMs have been used for atherosclerosis therapy for hundreds of years in Asia, especially in China.Importantly, several natural compounds, such as anthocyanins, resveratrol, hesperidin, quercetin, epicatechin, and genistein, have been promoted to clinical trials (71).In this study, we also listed some clinical trials However, the research in this field has several limitations.First, although prescription/formula is a characteristic of TCM, it is necessary to clarify the key active ingredients and their mechanisms of action to enable TCM to enter the international market.In this aspect, artemisinin is a very good example.Secondly, seldom natural compounds have been applied in clinic.It seems that researchers are impelled to explore modified natural compounds to improve their novelty, bioavailability, and commercial value of interested molecules.These chemical modifications are sure to induce further environmental pollution.Therefore, researchers need to balance the beneficial and harmful aspects during drug discovery.Thirdly, as the distribution and action of PPARs show tissue-specificity, it is interesting to investigate the combined effects of interested compounds based on their pharmacokinetic characteristics and tissue distribution.Fourth, both activation and inactivation of PPARβ and particularly PPARγ may achieve similar therapeutic effects, suggesting some complex regulatory mechanisms are involved in PPARs' therapy of atherosclerosis.For instance, PPARγ activation is demonstrated to suppress inflammation via inhibiting NF-κB signaling pathway and decrease lipid accumulation via enhancing RCT through upregulation of LXRs-ABCA1/G1 signaling pathways; while PPARγ inactivation is indicated to decrease lipogenesis and CD36-mediated lipid uptake, thereby suppressing lipid accumulation and hyperlipidemia-induced inflammation.To elucidate the detailed mechanisms of action of an interested compound, it is necessary to investigated the above-mentioned mechanisms in one study in Ameliorates dyslipidemia, lowers plasma ceramide 16:0 and ceramide 18:0, and increases HDL-c, ApoA-I, and cholesterol efflux capacity potentially by activation of PPAR-ABCA1/G1 signaling pathways (206,207).
Hesperidin 49 patients with metabolic syndrome; twice daily for a total of 500 mg for 12 weeks.
Decreases fasting glucose level, TG, blood pressure and inflammatory factors including TNF-α potentially by activation of PPARs (208).
Flaxseed power and/or hesperidin 98 patients with metabolic syndrome; flaxseed powder 30 g daily, or hesperidin 1 g daily, or a combination for 12 weeks.
Decreases systolic blood pressure, serum TG and insulin potentially by activating PPARα and regulating ApoB100 secretion (210).
Genistein 45 participants with homeostasis model assessment index >2.5 and body mass index ≥30 and ≤40 kg/m 2 ; 50 mg daily for 2 months.
Increases β-oxidation and decreases inflammatory symptoms and insulin resistance potentially by modulating gut microbiota and activating AMPK-PPARs signaling pathway (211).
Decreases LDL-c and TG in carriers of PPARγ polymorphisms, suggesting genetic-driven personalization of cardiovascular interventions (212).
DHA-rich fish oil Fifty patients with type 2 diabetes mellitus aged 30-70 years; 2,400 mg/d for 8 weeks.
Conjugated linoleic acid 15 healthy human; 90 g daily for 2 or 4 weeks.
Colchicine 4,745 patients recruited within 30 days after a myocardial infarction; 0.5 mg daily.
Decreases TC levels and may increase HDL-c (216).
Decreases inflammatory factors and increases antioxidant activities (218).
Decreases body weight, body mass index, and potentially TG (221).
Lycium barbarum polysaccharide 50 patients with non-alcohol fatty liver disease; twice daily for a total of 0.6 g for 3 months.
Results are not available at present (222).
Polysaccharide peptide of Ganoderma lucidum 37 high risk and 34 stable angina patients; three times daily for a total of 0.75 g for 90 days.
Decreases atherosclerosis potentially by decreasing circulating endothelial cells and endothelial progenitor cells, and oxidation as well as malondialdehyde contents (223).

FIGURE 5
FIGURE 5Structure of some bioactive terpenoids with potential anti-atherosclerotic effects.

FIGURE 7
FIGURE 7 (189,190) esculenta alleviates obesity and liver injury mainly by restoringFirmicutes/Bacteroidetes ratio and increasing SCFA production.However, it decreases hepatic gene expression including PPARα and PPARγ(185).Similarly, Liriope spicata var.prolifera-andPlatycodon grandiflorus-derived polysaccharides exhibit strong lipid-lowering and hepatoprotective effects potentially by downregulating the expressions of PPARγ in vivo(186).Interestingly, P. grandiflorus-derived polysaccharides may control PPAR signaling by increasing the production of SCFAs including acetate, propionate, and butyrate in the gut through upregulation of SCFAs-producing gut bacteria(187).Similarly, Pueraria lobata-and Pueraria thomsonii-derived polysaccharides show therapeutic effects in type 2 diabetes mellitus through regulation of PPAR signaling pathway.Mechanistically, P. lobata-derived polysaccharides increase the abundance of Romboutsia bacteria to reduce serum concentration of taurocholic acid, thereby regulating the PPAR signaling pathway, such as inhibiting PPARγ.P. thomsonii-derived polysaccharides reduce the abundance of Klebsiella bacteria to decrease the serum levels of uric acid, thereby regulating PPAR signaling pathway to exert a therapeutic effect on insulin resistance(188).Lycium barbarum polysaccharide and Astragalus polysaccharide ameliorate lipid disorders by decreasing the gene expression of PPARγ, CD36, and FAS, and ameliorating gut microbiota(189,190).Moreover, C. militaris-derived polysaccharide CM3-SII is demonstrated to inhibit the level of Niemann-Pick C1-like 1 protein, suggesting this polysaccharide may decrease cholesterol absorption (184).

Table 1 .
Collectively, natural compounds are useful for atherosclerosis therapy by regulation of PPARs.

TABLE 1
Clinical trials related to anti-atherosclerotic effects of natural medicines.
Last but not least, rodents have distinct lipid profiles and lifestyles compared to our human, it is necessary to explore humanized models for drug screening in future to improve the potential translation of interested compounds.