Anti-atherosclerotic Properties Research Articles

Cardioprotective potential of oleuropein, hydroxytyrosol, oleocanthal and their combination: unravelling complementary effects on acute myocardial infarction and metabolic syndrome

Abstract Background/Introduction Clinical studies have established the role of olive products in primary and secondary prevention of cardiovascular (CV) disease, but the single compounds or compound combinations responsible for the protective effects are still under investigation. Purpose We sought to explore and compare the cardioprotective potential of Oleuropein (OL), Hydroxytyrosol (HT), Oleocanthal (OC) and Oleanolic Acid (OA) and three combinational treatments after chronic oral administration in mice subjected to Ischemia/Reperfusion Injury (IRI) in the presence of metabolic syndrome (MS) and verify the effect of combination in a proof-of-concept clinical study in Chronic Coronary Artery Syndrome (CCAS) patients. Methods First, we explored the IRI-limiting potential of 6-weeks daily oral treatment with OL (20.6 mg/kg), HT (5.9 mg/kg), OC (11.6 mg/kg), OA (17.4 mg/kg) or vehicle (DMSO 5%) in healthy C57Bl6 mice. At week 6, myocardial ischemia/reperfusion (30 minutes/2 hours) was induced and infarct size was measured. Next, MS was established by 14 weeks of Western diet and the isolated compounds were administered for the last 6 weeks. At week 14, IRI was surgically induced, and infarct size was determined. Basic MS parameters (fasting blood glucose, plasma cholesterol, body weight and blood pressure) were recorded at baseline, weeks 8 and 14. According to the exerted benefits, three combinational treatments were designed and tested on the MS model of IRI. The underlying cardioprotective mechanism was investigated on the mixture with preponderant CV benefits (OL-HT-OC, Combo 2). ApoE-/- mice fed with Western diet for 12 weeks were treated with Combo 2 orally for the last 4 weeks and aortic atherosclerotic lesion extent was determined to detect possible antiatherosclerotic effects. After multi-organ toxicity evaluation, a Combo 2-based supplement was administered in CCAS patients for evaluation of cardiac function, inflammation and oxidative stress biomarkers. Results OL, OC and OA, but not HT, significantly reduced infarct size in vivo both in healthy and MS mice. OL was the only compound to reduce hyperglycemia, while OA significantly reduced plasma cholesterol. All mixtures (Combo 1: OL-HT-OA, Combo 2: OL-HT-OC, Combo 3: OL-HT-OC-OA) were cardioprotective, but only Combo 2 prevented MS progression by limiting hyperglycemia. Combo 2 protection against IRI was attributed to apoptosis suppression (reduced Bax/BcL-xL ratio) and increased expression of the antioxidant enzymes Superoxide Dismutase and Catalase in the ischemic myocardium. Combo 2 treatment also reduced atherosclerotic lesion extent. In our proof-of-concept clinical study, Combo 2 treatment ameliorated cardiac, vascular and endothelial function in CCAS patients. Conclusions Combinational treatment with OL-HT-OC exerts potent cardioprotective, antihyperglycemic and antiatherosclerotic properties in vivo, with remarkable and clinically translatable CV benefits in high-risk patients.

Endothelial insulin-like growth factor-1 signaling regulates vascular barrier function and atherogenesis

Abstract Background Progressive deposition of cholesterol in the arterial wall characterizes atherosclerosis, which underpins most cases of myocardial infarction and stroke. Insulin-like growth factor-1 (IGF-1) is a hormone that regulates systemic growth and metabolism and possesses anti-atherosclerotic properties. However, the role of IGF-1 in the endothelium remains unexplored. Purpose To study the effect of increased endothelial IGF-1 receptor (IGF-1R) expression on atherogenesis using in vivo and in vitro models. Methods We generated atherosclerosis prone ApoE-/- transgenic mice with endothelium restricted overexpression of human IGF-1R (hIGFREO-ApoE-/-) or signalling defective K1003R mutant IGF-1R (mIGFREO-ApoE-/-). ApoE-/- littermates were controls. Following 12 weeks of western diet, we assessed atherosclerosis, systemic metabolism, leukocyte homeostasis and vascular permeability using histology, flow cytometry, metabolic testing, bone marrow transplantation and in vivo perfusion with either VE-Cadherin, Evans blue or BODIPY-LDL. For in vitro studies, human umbilical vein endothelial cells were transduced with custom-made lentivirus particles allowing doxycyline-inducible wild-type or mutant K1003R IGF-1R overexpression; with transduced cells not exposed to doxycycline as controls. Confluent cells were exposed to 100mM hydrogen peroxide to model the permeability-inducing conditions observed in atherosclerosis. In vitro, we assessed junctional proteins, FITC-dextran permeability and transcellular BODIPY-LDL uptake. Results We show that mice with endothelial overexpression of IGF-1R have less atherosclerosis, arterial cholesterol uptake, and vascular leakage of multiple organs. Conversely, mice with endothelial overexpression of signalling defective IGF-1R did not exhibit these phenomena. We found no differences in systemic metabolism or growth. In complementary in vitro studies, overexpressing wildtype IGF-1R altered the localization of some tight junction proteins (VE-Cadherin and Claudin 5) and reduced leakage across human endothelial monolayers; this was not observed with signalling defective IGF-1R. Moreover, it reduced endothelial cell internalization of cholesterol-rich lipoproteins and increased the association of these particles with clathrin, but not caveolin-1, both of which participate in vesicular uptake of lipoproteins. Conclusion Overall, our findings indicate that endothelial IGF-1 signalling modulates both para- and trans-cellular vascular barrier function. This is particularly relevant to the phenomenon of atherosclerosis and suggests that increased vascular IGF-1 signalling reduces atherosclerosis. Beyond this, our data are potentially relevant to many disease processes associated with altered vascular barrier function. This discovery could lead to novel therapeutics to normalise vascular barrier function.

Isoliquiritigenin mitigates intervertebral disc degeneration induced by oxidative stress and mitochondrial impairment through a PPARγ-dependent pathway

ObjectivesOxidative stress, mitochondrial dysfunction, and apoptosis play significant roles in the degradation of extracellular matrix (ECM) in nucleus pulposus cells (NPCs), ultimately contributing to intervertebral disc degeneration (IVDD). This study investigates the potential of isoliquiritigenin (ISL), a natural extract known for its antioxidant, anti-inflammatory, and anti-atherosclerotic properties, to alleviate IVDD. MethodsThe viability of NPCs treated with ISL and tert-butyl hydroperoxide (TBHP) was assessed using the CCK-8 assay. Various techniques, including Western blot, qRT-PCR, immunofluorescence (IF), and immunohistochemistry, were employed to measure the expression of ECM components, oxidative stress markers, and apoptosis-related proteins. Mitochondrial function was evaluated through Western blot and IF analyses. Network pharmacology predicted ISL targets, and the expression levels of PPARγ were assessed using the aforementioned methods. The role of PPARγ in the therapeutic effects of ISL on IVDD was examined through siRNA knockdown. The therapeutic impact of ISL on puncture-induced IVDD in rats was evaluated using X-ray, MRI, and histological staining techniques. ResultsIn vitro, ISL reduced oxidative stress in NPCs, restored mitochondrial function, inhibited apoptosis, and improved the ECM phenotype. In vivo, ISL slowed the progression of IVDD in a rat model. Further analysis revealed that ISL enhances PPARγ activity and promotes its expression by direct binding, contributing to the delay of IVDD progression. ConclusionThis study demonstrates that ISL effectively treats puncture-induced IVDD in rats by inhibiting oxidative stress, restoring mitochondrial function, and reducing NPC apoptosis through a PPARγ-dependent mechanism. By balancing ECM synthesis and degradation, ISL presents a novel therapeutic approach for IVDD and identifies a promising target for treatment.

Dipsacoside B Attenuates Atherosclerosis by Promoting Autophagy to Inhibit Macrophage Lipid Accumulation.

Atherosclerosis is a chronic inflammatory disease characterized by lipid accumulation and foam cell formation in the arterial wall. Promoting macrophage autophagy has emerged as a promising therapeutic strategy against atherosclerosis. Dipsacoside B (DB) is an oleanane-type pentacyclic triterpenoid saponin extracted from Lonicerae flos with potential anti-atherosclerotic properties. In this study, we investigated the effects of DB on atherosclerosis progression in ApoE-/- mice fed a high-fat diet and explored the underlying mechanisms in oxidized low-density lipoprotein (ox-LDL)-induced foam cells. DB treatment significantly reduced atherosclerotic lesion size, improved plaque stability, and regulated lipid metabolism without impairing liver and kidney function in ApoE-/- mice. In vitro studies revealed that DB dose-dependently inhibited ox-LDL internalization and intracellular lipid accumulation in RAW264.7 macrophages. Mechanistically, DB induced autophagy, as evidenced by increased autophagosome formation and upregulated expression of autophagy markers LC3-II and p62 both in vivo and in vitro. Inhibition of autophagy by chloroquine abolished the antiatherosclerotic and pro-autophagic effects of DB. Furthermore, DB treatment increased LC3-II and p62 mRNA levels, suggesting transcriptional regulation of autophagy. Collectively, our findings demonstrate that DB exerts anti-atherosclerotic effects by inhibiting foam cell formation via autophagy induction, providing new insights into the pharmacological actions of DB and its potential as a therapeutic agent against atherosclerosis.

Tetramethylpyrazine and paeoniflorin combination (TMP-PF) alleviates atherosclerosis progress by reducing hyperlipemia and inhibiting plaque angiogenesis via the NR4A1/VEGFR2 pathway

Atherosclerosis remains a great threat to human health worldwide. Previous studies found that tetramethylpyrazine (TMP) and paeoniflorin (PF) combination (TMP-PF) exerts anti-atherosclerotic effects in vitro. However, whether TMP-PF improves atherosclerosis in vivo needs further exploration. The present study aims to assess the anti-atherosclerotic properties of TMP-PF in ApoE-/- mice and explore the related molecule mechanisms. Results showed that TMP and high-dose TMP-PF decreased serum triglyceride and low-density lipoprotein cholesterol levels, suppressed vascular endothelial growth factor receptor 2 (VEGFR2) and nuclear receptor subfamily 4 group A member 1 (NR4A1) expression in aortic tissues, inhibited plaque angiogenesis, reduced plaque areas, and alleviated atherosclerosis in ApoE-/- mice. Also, TMP-PF exhibited a better modulation effect than TMP or PF alone. However, NR4A1 agonist abolished the anti-atherosclerotic effects of TMP-PF. In conclusion, TMP-PF was first found to alleviate atherosclerosis progression by reducing hyperlipemia and inhibiting plaque angiogenesis via the NR4A1/VEGFR2 pathway, indicating that TMP-PF had a positive effect on reducing hyperlipemia and attenuating atherosclerosis development.

Cardioprotective potential of oleuropein, hydroxytyrosol, oleocanthal and their combination: Unravelling complementary effects on acute myocardial infarction and metabolic syndrome

Clinical studies have previously established the role of olive products in cardiovascular disease (CVD) prevention, whilst the identification of the responsible constituents for the beneficial effects is still pending. We sought to assess and compare the cardioprotective potential of oleuropein (OL), hydroxytyrosol (HT), oleocanthal (OC) and oleanolic Acid (OA), regarding Ischemia/Reperfusion Injury (IRI) and CVD risk factors alleviation. The scope of the study was to design a potent and safe combinatorial therapy for high-cardiovascular-risk patients on a bench-to-bedside approach. We evaluated the IRI-limiting potential of 6-weeks treatment with OL, HT, OC or OA at nutritional doses, in healthy and metabolic syndrome (MS)-burdened mice. Three combinatorial regimens were designed and the mixture with preponderant benefits (OL-HT-OC, Combo 2), including infarct sparing and antiglycemic potency, compared to the isolated compounds, was further investigated for its anti-atherosclerotic effects. In vivo experiments revealed that the combination regimen of Combo 2 presented the most favorable effects in limiting infarct size and hyperglycemia, which was selected to be further investigated in the clinical setting in Chronic Coronary Artery Syndrome (CCAS) patients. Cardiac function, inflammation markers and oxidative stress were assessed at baseline and after 4 weeks of treatment with the OL-HT-OC supplement in the clinical study. We found that OL, OC and OA significantly reduced infarct size in vivo compared to Controls. OL exhibited antihyperglycemic properties and OA attenuated hypercholesterolemia. OL-HT-OA, OL-HT-OC and OL-HT-OC-OA combination regimens were cardioprotective, whereas only OL-HT-OC mitigated hyperglycemia. Combo 2 cardioprotection was attributed to apoptosis suppression, enhanced antioxidant effects and upregulation of antioxidant enzymes. Additionally, it reduced atherosclerotic plaque extent in vivo. OL-HT-OC supplement ameliorated cardiac, vascular and endothelial function in the small-scale clinical study. Conclusively, OL-HT-OC combination therapy exerts potent cardioprotective, antihyperglycemic and anti-atherosclerotic properties in vivo, with remarkable and clinically translatable cardiovascular benefits in high-risk patients.

Production of Bioactive Peptides from Microalgae and Their Biological Properties Related to Cardiovascular Disease

Microalgae are a substantial group of unicellular prokaryotic and eukaryotic marine organisms. Due to their high protein content of 50–70%, microalgae have the potential to become a sustainable alternative protein source, as well as aiding in the development of bioactive peptide-based nutraceuticals. A series of major steps are involved in the production of peptides from microalgae, which include the disruption of the microalgal cell wall, the hydrolysis of proteins, and the extraction or isolation of peptides derived from hydrolysis. Physical methods of cell wall disruptions are favored due to the ability to obtain high-quality protein fractions for peptide production. Bioactive peptides are protein fragments of two to twenty amino acid residues that have a beneficial impact on the physiological functions or conditions of human health. Strong scientific evidence exists for the in vitro antioxidant, antihypertensive, and anti-atherosclerotic properties of microalgal peptides. This review is aimed at summarizing the methods of producing microalgal peptides, and their role and mechanisms in improving cardiovascular health. The review reveals that the validation of the physiological benefits of the microalgal peptides in relation to cardiovascular disease, using human clinical trials, is required.

Promotion of Raf-1/ASK1 complex formation by corylin inhibits cell apoptosis in myocardial ischemia/reperfusion injury

Effective treatment of myocardial ischemia–reperfusion (MIR) injury remains an unmet clinical need. Cardiomyocyte apoptosis is common at this stage and poses a significant risk. Corylin, a flavonoid compound extracted from Psoralea corylifolia L., has been shown to have anti-inflammatory, anticancer, and antiatherosclerotic properties. However, whether and how corylin affects MIR injury remain unclear. In this study, we explored the mechanism of corylin as a potent therapeutic agent for MI/R injury, using a left anterior descending (LAD) coronary artery ligation and oxygen–glucose deprivation and reperfusion (OGD/R) model in vivo and in vitro. TUNEL, Annexin-V/PI double staining,Ki67 immunohistochemistry, western blot analysis, and immunofluorescence were used to validate cell apoptosis level and Raf-1/ASK1 complex activity. The interaction between corylin and Raf-1/ASK1 complex was detected using molecular docking, corylin-Raf-1 binding assays, and coimmunoprecipitation (Co-IP). Moreover, TTC staining, echocardiography, HE staining, Masson trichrome staining and serological testing were performed to assess the cardioprotective effects of corylin in vivo. These findings showed that corylin reduces MIR injury-induced cardiomyocyte apoptosis and improves cardiac function. Mechanistically, corylin can interact with Raf-1 and promote the formation of the Raf-1/ASK1 complex, thus inhibiting cardiomyocyte apoptosis. In conclusion, our results demonstrate that corylin ameliorated cardiac dysfunction after MIR injury by reducing myocardial apoptosis.

HEALTH PROMISING NUTRITIONAL MILLETS (KSHUDRA DHANYA) FOR CARDIOVASCULAR DISEASES AND ITS MODIFIABLE RISK FACTORS: AN EV-IDENCE-BASED OVERVIEW.

Cardiovascular disease is a leading cause of death worldwide in today's era along with rising risk factors such as diabetes, hypertension, dyslipidemia, malnutrition, etc. Acharyas treats Diet as 'Mahabhaishajya' (the superior medicine). Shuka Dhanya Varga (group of Cereals) is reviewed for their properties for Santarpanottha (allevia-tion of heart diseases by excessively nourishing bodily tissues), heart diseases, and other modified risk factors. This review aims to concisely outline the nutritional essentials and therapeutic characteristics of millets for car-diovascular diseases and the alteration of risk factors associated with heart health. In this review, we have tried to summarize the essential nutrition and therapeutic properties of millets for cardiovascular diseases and modi-fied risk factors for heart diseases. Millets offer numerous health benefits, including the reduction of cardiovas-cular disease and its associated risk factors contributing to mortality. Millets serve as a great source of essential nutrients and trace elements, playing a pivotal role as catalysts in supporting the optimal functioning of the car-diovascular system. Moreover, trace elements provided by millets help the cardiovascular system primarily function as catalysts and are a good source. This comprehensive review draws from various authentic sources, including Ayurvedic texts, medical books, and published articles from reputable scientific sources like PubMed, Google Scholar, and Sci-ence Direct. This article reviews the various authentic sources from Ayurveda texts, medical books, and pub-lished articles from scientific sources such as PubMed, Google Scholar, Science Direct, etc. The primary focus of this review is extensive research on the benefits of nutrition, the balance of Ayurvedic Doshas (fundamental elements), and a comprehensive evaluation of therapeutic properties. Essentially, the principles are adopted from value-added research of nutritional benefits and research along with Ayurveda dosha balancing and centred re-view of therapeutic properties. The evidence-based review of research shows that Kshudra Dhanya (millets) have been proven for anti-atherosclerotic, anti-hypertensive, hypoglycemic, and anti-dyslipidemia properties.

The Theoretical Substantiation of the Targeted Search for New DPP4 Inhibitors. Computational Studies of Potential Candidates

Growing evidence suggests that dipeptidyl peptidase 4 (DPP4) inhibitors, in addition to their role in improving glycemic control, help to reduce endothelial dysfunction and have hypolipidemic, anti-atherosclerotic, antitumor, antiviral, and neurotropic properties. This multi-target property may be one of the reasons for repurposing therapeutic treatment strategies with existing agents and the basis for finding new agents to inhibit this target. Based on the structural prerequisites and the evolutionary path of creating DPP4 inhibitors, an inhibitory (R)-β-aminoamide base was used as the basis for constructing potential candidates. It contained a substituted piperazine-2-one derivative and (S)-pyrrolidine-2-carbonitrile fragment, as well as phenyl and diphenyl rings, which were additionally saturated with substituents of various electronic structures, in position 4 of the β-aminoamide chain. The construction of the molecules was carried out taking into account the correspondence of chiral centers to combinations of chiral chains at the DPP4 binding site to possibly prevent a decrease in the inhibitory activity. In silico assessment of the “drug-likeness” and pharmacokinetic profile of the group of compounds studied showed that it had favorable characteristics and could be recommended for further molecular docking in order to predict the likely inhibition of the catalytic activity of DPP4. According to the results of docking, molecules with a moderate and high affinity were found. A detailed analysis of the resulting complexes showed that only nine compounds had a binding mode similar to classical inhibitors. According to the calculated array of values and analysis of the results of docking among the derivatives tested, a hit compound was found as a promising DPP4 inhibitor.

The Anti-Atherosclerotic Effects of Endothelin Receptor Antagonist, Bosentan, in Combination with Atorvastatin-An Experimental Study.

Bosentan, an endothelin receptor antagonist (ERA), has potential anti-atherosclerotic properties. We investigated the complementary effects of bosentan and atorvastatin on the progression and composition of the atherosclerotic lesions in diabetic mice. Forty-eight male ApoE-/- mice were fed high-fat diet (HFD) for 14 weeks. At week 8, diabetes was induced with streptozotocin, and mice were randomized into four groups: (1) control/COG: no intervention; (2) ΒOG: bosentan 100 mg/kg/day per os; (3) ATG: atorvastatin 20 mg/kg/day per os; and (4) BO + ATG: combined administration of bosentan and atorvastatin. The intra-plaque contents of collagen, elastin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), matrix metalloproteinases (MMP-2, -3, -9), and TIMP-1 were determined. The percentage of lumen stenosis was significantly lower across all treated groups: BOG: 19.5 ± 2.2%, ATG: 12.8 ± 4.8%, and BO + ATG: 9.1 ± 2.7% compared to controls (24.6 ± 4.8%, p < 0.001). The administration of both atorvastatin and bosentan resulted in significantly higher collagen content and thicker fibrous cap versus COG (p < 0.01). All intervention groups showed lower relative intra-plaque concentrations of MCP-1, MMP-3, and MMP-9 and a higher TIMP-1concentration compared to COG (p < 0.001). Importantly, latter parameters presented lower levels when bosentan was combined with atorvastatin compared to COG (p < 0.05). Bosentan treatment in diabetic, atherosclerotic ApoE-/- mice delayed the atherosclerosis progression and enhanced plaques' stability, showing modest but additive effects with atorvastatin, which are promising in atherosclerotic cardiovascular diseases.

Associations between Serum Kallistatin Levels and Markers of Glucose Homeostasis, Inflammation, and Lipoprotein Metabolism in Patients with Type 2 Diabetes and Nondiabetic Obesity.

Kallistatin is an endogenous serine proteinase inhibitor with various functions, including antioxidative, anti-inflammatory, and anti-atherosclerotic properties. To date, associations between kallistatin and lipoprotein subfractions are poorly investigated. In this study, we enrolled 62 obese patients with type 2 diabetes (T2D), 106 nondiabetic obese (NDO) subjects matched in gender, age, and body mass index, as well as 49 gender- and age-matched healthy, normal-weight controls. Serum kallistatin levels were measured with ELISA, and lipoprotein subfractions were analyzed using Lipoprint® (Quantimetrix Corp., Redondo Beach, CA, USA) gel electrophoresis. Kallistatin concentrations were significantly higher in T2D patients compared to NDO and control groups. We found significant positive correlations between very-low-density lipoprotein (VLDL), small high-density lipoprotein (HDL) subfractions, glucose, hemoglobin A1c (HbA1c), betatrophin, and kallistatin, while negative correlations were detected between mean low-density lipoprotein (LDL) size, large and intermediate HDL subfractions, and kallistatin in the whole study population. The best predictor of kallistatin was HbA1c in T2D patients, high-sensitivity C-reactive protein (hsCRP) and betatrophin in NDO patients, and hsCRP in controls. Our results indicate that kallistatin expression might be induced by persistent hyperglycemia in T2D, while in nondiabetic subjects, its production might be associated with systemic inflammation. The correlation of kallistatin with lipid subfractions may suggest its putative role in atherogenesis.

Hive Products: Composition, Pharmacological Properties, and Therapeutic Applications.

Beekeeping provides products with nutraceutical and pharmaceutical characteristics. These products are characterized by abundance of bioactive compounds. For different reasons, honey, royal jelly, propolis, venom, and pollen are beneficial to humans and animals and could be used as therapeutics. The pharmacological action of these products is related to many of their constituents. The main bioactive components of honey include oligosaccharides, methylglyoxal, royal jelly proteins (MRJPs), and phenolics compounds. Royal jelly contains jelleins, royalisin peptides, MRJPs, and derivatives of hydroxy-decenoic acid, particularly 10-hydroxy-2-decenoic acid (10-HDA), which possess antibacterial, anti-inflammatory, immunomodulatory, neuromodulatory, metabolic syndrome-preventing, and anti-aging properties. Propolis has a plethora of activities that are referable to compounds such as caffeic acid phenethyl ester. Peptides found in bee venom include phospholipase A2, apamin, and melittin. In addition to being vitamin-rich, bee pollen also includes unsaturated fatty acids, sterols, and phenolics compounds that express antiatherosclerotic, antidiabetic, and anti-inflammatory properties. Therefore, the constituents of hive products are particular and different. All of these constituents have been investigated for their properties in numerous research studies. This review aims to provide a thorough screening of the bioactive chemicals found in honeybee products and their beneficial biological effects. The manuscript may provide impetus to the branch of unconventional medicine that goes by the name of apitherapy.

Aortic Injury Induced by Benzo(a)pyrene and Atherogenic Diet Increased Hepatic FGF21 Expression in C57BL/6J Mice.

Benzo(a)pyrene (BaP), an environmental toxicant and endocrine disruptor, has been shown to exacerbate atherosclerosis when combined with a high-fat diet. Fibroblast Growth Factor-21 (FGF21), a novel hormone with anti-atherosclerotic properties, is associated with the presence of atherosclerosis and reduces plaque formation in experimental animals. The present study aimed to investigate the chronic effect of BaP injection on hepatic FGF21 expression, as an anti-atherosclerotic hormone, in mice fed with or without an atherogenic diet (AtD). Eighteen C57BL/6J male mice (6 weeks) were randomly divided into six groups based on the dosage and diet. Blood samples were collected, and serum cholesterol, triglyceride, HDL-C, LDL-C, and glucose levels were measured. FGF21 expression was assessed by quantitative real-time PCR. Atherosclerotic lesions in mice were studied with Oil Red O (ORO) staining. Benzo(a)pyrene causes a significant increase in liver FGF21 expression in a dose-dependent manner, and BaP co-exposure with AtD leads to a further increase in FGF21 expression. Additionally, the addition of BaP to AtD significantly increased the serum glucose, cholesterol, and LDL-C levels and accelerated the formation of atherosclerotic lesions. Besides, our findings showed that there is a significant positive correlation between FGF21 expression and glucose, cholesterol, LDL-C, and ORO-positive areas. Our findings revealed that BaP increases the expression of endogenous FGF21 in treated animals as a compensatory response to protect the heart from atherosclerosis induced by BaP and AtD.

The natural polyphenol fisetin in atherosclerosis prevention: a mechanistic review.

The incidence and mortality rate of atherosclerotic cardiovascular disease (ASCVD) is increasing yearly worldwide. Recently, a growing body of evidence has unveiled the anti-atherosclerotic properties of fisetin, a natural polyphenol compound. In this article, we reviewed the pharmacologic actions of fisetin on experimental atherosclerosis and its protective effects on disease-relevant cell types such as endothelial cells, macrophages, vascular smooth muscle cells, and platelets. Based on its profound cardiovascular actions, fisetin holds potential for clinical translation and could be developed as a potential therapeutic option for atherosclerosis and its related complications. Large-scale randomized clinical trials are warranted to ascertain the safety and efficacy of fisetin in patients with or high risk for ASCVD.

Myo-inositol supplementation in obese patients with non-alcoholic fatty liver disease: Assessment of sirtuin-1 pathway, atherogenic and hematological parameters

BackgroundNon-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease, is closely associated with higher risks of atherosclerosis through a number of molecular cascades such as the sirtuin-1 (SIRT-1) pathway. Myo-inositol as a precursor isomer of cyclohexanehexols exerts anti-hyperlipidemic and anti-obesity features in metabolic disorders. The current study aimed to assess the effects of myo-inositol supplementation on genes expression of the SIRT-1 pathway, atherogenic indices, and hematological parameters in obese patients with NAFLD. MethodsThis double-blinded randomized clinical trial was conducted on 44 obese patients with ultrasound proven- NAFLD who received dietary recommendations and were randomly allocated into either myo-inositol (4 g/day) or placebo (maltodextrin 4 g/day) receiving groups for 8 weeks. At baseline and the end of the study mRNA expression levels of SIRT-1 pathway genes in peripheral blood mononuclear cells (PBMCs), complete blood cell count, lipid profile, and atherogenic indices were assessed. Inter-group differences were determined using analysis of covariance (by adjusting for the potential confounders) at the end of the trial. ResultsAt the end of the trial mRNA expression levels of low-density- lipoprotein receptor (LDLR) (only in myo-inositol group) and endothelial nitric oxide synthase (eNOS) (in both groups) significantly increased, compared with steady-state levels (p = 0.004 and p = 0.001, respectively). Moreover, myo-inositol supplementation significantly inhibited lectin-like oxidized- low-density lipoprotein receptor-1 (LOX-1) expression compared with the placebo group (p = 0.045). Slight improvements in Cholesterol-related atherogenic indices and hematological parameters were also observed in myo-inositol group, compared with baseline values (p < 0.05). ConclusionMyo-inositol supplementation could slightly activate SIRT-1 pathway and thereby exert marginal anti-atherosclerotic properties in obese patients with NAFLD.

Anti-Atherosclerotic Properties of Aronia melanocarpa Extracts Influenced by Their Chemical Composition Associated with the Ripening Stage of the Berries.

The high content of bioactive compounds in Aronia melanocarpa fruit offers health benefits. In this study, the anti-atherosclerotic effect of Aronia extracts was assessed. The impact on the level of adhesion molecules and the inflammatory response of human umbilical vein endothelial cells (HUVECs) was shown in relation to the chemical composition and the stage of ripening of the fruits. Samples were collected between May (green, unripe) and October (red, overripe) on two farms in Poland, which differed in climate. The content of chlorogenic acids, anthocyanins, and carbohydrates in the extracts was determined using HPLC-DAD/RI. The surface expression of ICAM-1 and VCAM-1 in HUVECs was determined by flow cytometry. The mRNA levels of VCAM-1, ICAM-1, IL-6, and MCP-1 were assessed using the quantitative real-time PCR method. The farms' geographical location was associated with the quantity of active compounds in berries and their anti-atherosclerotic properties. Confirmed activity for green fruits was linked to their high chlorogenic acid content.

The role of nanosystems in the delivery of glucose-lowering drugs for the preemption and treatment of diabetes-associated atherosclerosis.

Diabetes is one of the most prevalent diseases worldwide. In recent decades, type-2 diabetes has become increasingly common, particularly in younger individuals. Diabetes leads to many vascular complications, including atherosclerosis. Atherosclerosis is a cardiovascular disease characterized by lipid-rich plaques within the vasculature. Plaques develop over time, restricting blood flow, and can, therefore, be the underlying cause of major adverse cardiovascular events, including myocardial infarction and stroke. Diabetes and atherosclerosis are intrinsically linked. Diabetes is a metabolic syndrome that accelerates atherosclerosis and increases the risk of developing other comorbidities, such as diabetes-associated atherosclerosis (DAA). Gold standard antidiabetic medications focus on attenuating hyperglycemia. Though recent evidence suggests that glucose-lowering drugs may have broader applications, beyond diabetes management. This review mainly evaluates the role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as liraglutide and semaglutide in DAA. These drugs mimic gut hormones (incretins), which inhibit glucagon secretion while stimulating insulin secretion, thus improving insulin sensitivity. This facilitates delayed gastric emptying and increased patient satiety; hence, they are also indicated for the treatment of obesity. GLP-1 RAs have significant cardioprotective effects, including decreasing low-density lipoprotein (LDL) cholesterol and triglycerides levels. Liraglutide and semaglutide have specifically been shown to decrease cardiovascular risk. Liraglutide has displayed a myriad of antiatherosclerotic properties, with the potential to induce plaque regression. This review aims to address how glucose-lowering medications can be applied to treat diseases other than diabetes. We specifically focus on how nanomedicines can be used for the site-specific delivery of antidiabetic medicines for the treatment of diabetes-associated atherosclerosis.

Naringenin Inhibits Acid Sphingomyelinase-Mediated Membrane Raft Clustering to Reduce NADPH Oxidase Activation and Vascular Inflammation.

Macrophage inflammation and oxidative stress promote atherosclerosis progression. Naringenin is a naturally occurring flavonoid with antiatherosclerotic properties. Here, we elucidated the effects of naringenin on monocyte/macrophage endothelial infiltration and vascular inflammation. We found naringenin inhibited oxidized low-density lipoprotein (oxLDL)-induced pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α toward an M2 macrophage phenotype and inhibited oxLDL-induced TLR4 (Toll-like receptor 4) membrane translocation and downstream NF-κB transcriptional activity. Results from flow cytometric analysis showed that naringenin reduced monocyte/macrophage infiltration in the aorta of high-fat-diet-treated ApoE-deficient mice. The aortic cytokine levels were also inhibited in naringenin-treated mice. Further, we found that naringenin reduced lipid raft clustering and acid sphingomyelinase (ASMase) membrane gathering and inhibited the TLR4 and NADPH oxidase subunit p47phox membrane recruitment, which reduced the inflammatory response. Recombinant ASMase treatment or overexpression of ASMase abolished the naringenin function and activated macrophage and vascular inflammation. We conclude that naringenin inhibits ASMase-mediated lipid raft redox signaling to attenuate macrophage activation and vascular inflammation.

Formulation and evaluation of nanobiotherapeutics of Terminalia arjuna through plant tissue culture for atherosclerosis

Abstract Background The study seeks to investigate the therapeutic potential of Terminalia arjuna callus in addressing atherosclerosis. In order to get maximum beneficial phytoconstituents from Terminalia arjuna, it is recommended to harvest the bark from Arjuna trees that are at least 15 years old and a gap of minimum 2 years should be kept before harvesting bark from the same plant. The callus culture technique was employed to expedite the process. The callus culture extract was subsequently converted into a nanosuspension with the aim of improving the efficacy of its phytoconstituents. It was then subjected to a comprehensive series of in vitro and in vivo evaluations to ascertain its potential for treatment of atherosclerosis. Results Liquid chromatography–mass spectrometry analysis of the callus extract confirmed the presence of flavonoids and terpenoids, known for their antioxidant and anti-inflammatory activities. Some terpenoids were even absent in Arjuna tree naturally. TEM images validated successful entrapment of the extract within the nanoparticles. In vitro analysis for antilipase and antioxidant assay confirmed the antiatherosclerotic potential of the extract. In vivo tests on rat blood serum demonstrated a significant reduction in total cholesterol, low-density lipoprotein, triglycerides, high-density lipoprotein, and very low-density lipoprotein. Histopathological analysis of rat aortas showed additional confirmation of antiatherosclerotic action. Conclusion In conclusion, the study highlights the potential of nanosuspension derived from Terminalia arjuna callus extract as a comprehensive therapeutic strategy for atherosclerosis treatment. The research highlights antioxidant, anti-inflammatory, and antiatherosclerotic properties of the callus, hinting at its viability as a potential treatment for atherosclerosis. This interdisciplinary investigation emphasizes the promising role of traditional medicinal plants within modern medical paradigms.