Antiatherogenic Effects Research Articles

Ganoderma Triterpenoids Exert Antiatherogenic Effects in Mice by Alleviating Disturbed Flow-Induced Oxidative Stress and Inflammation.

Ganoderma mushrooms, used in traditional Chinese medicine to promote health and longevity, have become widely accepted as herbal supplements. Ganoderma lucidum (GL), a commonly seen ganoderma species, is commercially cultivated under controlled conditions for more consistent chemical composition. The medicinal properties of GL are attributable to its antioxidant and anti-inflammatory activities. We intended to assess the effect of GL in atherosclerosis, an arterial condition associated with chronic oxidative stress and inflammation, using a carotid-artery-ligation mouse model. Flow turbulence created in the ligated artery induces oxidative stress and neointimal hyperplasia, a feature of early atherogenesis. Daily oral GL prevented neointimal thickening 2 weeks after ligation. Moreover, the ganoderma triterpenoid (GT) crude extract isolated from GL abolished ligation-induced neointima formation. Mechanistically, endothelial dysfunction was observed 3 days after ligation before any structural changes could be detected. GTs alleviated the oxidative stress and restored the atheroresistent status of endothelium by inhibiting the induction of a series of atherogenic factors, including endothelin-1, von Willebrand factor, and monocyte chemoattractant protein-1 after 3-day ligation. The anti-inflammatory activity of GTs was tested in cultured human umbilical vein endothelial cells (HUVECs) exposed to disturbed flow in an in vitro perfusion system. GTs abolished the induction of proinflammatory VCAM-1, TNF-α, and IL-6 by oscillatory shear stress. Moreover, the antioxidant activity of GTs was tested in HUVECs against the insult of H2O2. GTs dissipated the cellular superoxide accumulation imposed by H2O2, thereby mitigating H2O2-induced cell damage and proatherogenic response. Our results revealed the atheroprotective properties of ganoderma mushrooms and identified triterpenoids as the critical constituents for those effects. GTs prevent atherogenesis by eliminating disturbed flow-induced oxidative stress and inflammation.

COMBINED HORMONAL CONTRACEPTION AND NOT ONLY…

Chlormadinone acetate-containing combined contraceptives are well researched, they have a high degree of reliability during prolonged use in different modes. They have a protective anti-atherogenic properties and is offset by the risk for cardiovascular system, because the existing data indicate that the risk of thromboembolism against the background of chlormadinone preparation is minimal to date among all COCs and is comparable with the «first-generation» progestins, like levonorgestrel. The undeniable advantage of CMA-containing COC is a neutral impact on carbohydrate metabolism and blood coagulation system. CMA COCs have anti-atherogenic effect, which makes them “the drugs of choice” in patients with sclerocystic ovaries, metabolic syndrome and systemic diseases associated with hypercoagulability.Russian scholars and Western specialists who studied the effect of CMA-containing combination drug, allow us to recommend COC Belara® to assign not only with the contraceptive purpose, but also as a product for the stability of the menstrual cycle, as the drug of choice in the hyperpolimenorrhea, al’go – and dysmenorrhea, hyperandrogenism, expressed in the form of acne, hirsutism, oily seborrhea, decrease in sexual activity because of dyspareunia, as well as to anxiolytic and sedative effect in PMS.

In vivo antimutagenic and antiatherogenic effects of the (1 → 3)(1 → 6)-β-d- glucan botryosphaeran

The antimutagenic effect of botryosphaeran, an exocellular (1 → 3)(1 → 6)-β-d-glucan, from the ascomyceteous and plant-borne endophytic fungus, Botryosphaeria rhodina MAMB-05, was evaluated in young (6–8 weeks) and elderly (18 months) Swiss albino mice of both genders. The hypolipidemic, hypoglycemic and antiatherogenic potential was also evaluated in 18-month old male LDL receptor knockout (LDLr−/−) mice. Administration of botryosphaeran by gavage (doses: 7.5, 15, 30 mg/kg b.w./day) in a 30-day pretreatment protocol (young mice), or 15-day protocol (older mice), did not cause genotoxicity as assessed by the micronucleus test in peripheral blood (PB) and bone marrow cells (BMCs). Furthermore, there was no cytotoxic effect of this β-d-glucan in the treatments. A lower frequency of micronuclei was observed in BMCs from young and old mice that received botryosphaeran, indicating its antimutagenic effect. Botryosphaeran (30 mg/kg b.w./day) promoted 102.22% (young) and 103.45% (elderly) reductions in cyclophosphamide-induced damage in male mice. Botryosphaeran also exerted chemoprotective effects in LDLr−/− and wild-type (C57BL/6) mice. Botryosphaeran treatment for 15 days at a dose of 30 mg/kg b.w./day improved the lipidic profile (reductions of 53.8–84.3%), and decreased aortic lipid deposition (32.8%) in the LDLr−/− atherosclerotic mice. The results indicate botryosphaeran has relevant biologic effects, making it a promising candidate for the development of new therapeutic agents.

Lipid-lowering and antiatherogenic effects of Vitex megapotamica (Spreng.) Moldenke in a mice experimental model

Ethnopharmacological relevanceVitex megapotamica (Spreng.) Moldenke is a deciduous tree, native of South America. Its leaves are traditionally used to treat cardiovascular diseases. This activity is related to the presence of flavonoids, the major compounds of the crude extract. Aim of the studyThis study investigated the effects of the oral administration of crude extract and standardized fractions from V. megapotamica leaves on lipid profile and on the formation of atherosclerotic plaque in C57BL/6 LDLr-KO mice treated with high-fat diet (HFD). Materials and methodsMale C57BL/6 LDLr-KO mice were fed with HFD (cholesterol, 1.25%) for 30 days. They were treated with hydroethanolic extract (500 or 1000mg/kg/day) or fractions (125 or 250mg/kg/day). After 30 days of treatment, it was evaluated the serum lipid profile, atherogenic index, and atherosclerotic plaque. ResultsAll doses of the hydroethanolic extract reduced significantly the levels of total cholesterol, triglycerides, LDL-c and the atherogenic index. The n-butanolic fraction also reduced significantly the levels of total cholesterol, triglycerides, LDL-c and the atherogenic index, at all doses, with exception for the triglycerides, which only the lower dose was effective. The residual fraction reduced significantly the levels of total cholesterol, LDL-c and the atherogenic index, at all doses, with exception for the atherogenic index, which only the higher dose was effective. The atherosclerotic plaque formation was impaired only by the lower dose of the hydroethanolic extract. ConclusionsOverall, our data suggest that V. megapotamica has potential for the treatment of dyslipidemias.

Naringenin induces laxative effects by upregulating the expression levels of c-Kit and SCF, as well as those of aquaporin 3 in mice with loperamide-induced constipation.

Constipation is a common affliction which causes discomfort and affects the quality of life of affected individuals. Naringenin (NAR), a natural flavonoid widely found in citrus fruits and tomatoes, has been reported to exhibit various pharmacological effects, such as anti-inflammatory, anti-atherogenic, anti-mutagenic, hepatoprotective and anticancer effects. Increasing evidence has indicated that NAR has potential for use in the treatment of constipation. Thus, the aim of this study was to evaluate the laxative effects of NAR in mice with loperamide-induced (Lop-induced) constipation. The data indicated that NAR relieved Lop-induced constipation in mice based on the changes of fecal parameters (numbers, weight and water content), the intestinal charcoal transit ratio and the histological alteration. ELISA revealed that NAR regulated the production levels of gastrointestinal metabolic components, such as motilin (MTL), gastrin (Gas), endothelin (ET), substance P (SP), acetylcholinesterase (AChE) and vasoactive intestinal peptide (VIP) in serum. The expression levels of enteric nerve-related factors, glial cell line-derived neurotrophic factor (GDNF), transient receptor potential vanilloid 1 (TRPV1), nitric oxide synthase (NOS), c-Kit, stem cell factor (SCF) and aquaporin 3 (AQP3) were examined by western blot analysis and RT-PCR analysis. The results of this study suggest that NAR relieves Lop-induced constipation by increasing the levels of interstitial cells of Cajal markers (c-Kit and SCF), as well as AQP3. Thus, NAR may be effective as a candidate in patients suffering from lifestyle-induced constipation.

Flaxseed: its bioactive components and their cardiovascular benefits.

Cardiovascular disease remains the leading cause of mortality and morbidity worldwide. The inclusion of functional foods and natural health products in the diet are gaining increasing recognition as integral components of lifestyle changes in the fight against cardiovascular disease. Several preclinical and clinical studies have shown the beneficial cardiovascular effects of dietary supplementation with flaxseed. The cardiovascular effects of dietary flaxseed have included an antihypertensive action, antiatherogenic effects, a lowering of cholesterol, an anti-inflammatory action, and an inhibition of arrhythmias. Its enrichment in the ω-3 fatty acid α-linolenic acid and the antioxidant lignan secoisolariciresinol diglucoside as well as its high fiber content have been implicated primarily in these beneficial cardiovascular actions. Although not as well recognized, flaxseed is also composed of other potential bioactive compounds such as proteins, cyclolinopeptides, and cyanogenic glycosides, which may also produce biological actions. These compounds could also be responsible for the cardiovascular effects of flaxseed. This article will not only summarize the cardiovascular effects of dietary supplementation with flaxseed but also review its bioactive compounds in terms of their properties, biological effects, and proposed mechanisms of action. It will also discuss promising research directions for the future to identify additional health-related benefits of dietary flaxseed.

Irisin Alleviates Advanced Glycation End Products-Induced Inflammation and Endothelial Dysfunction via Inhibiting ROS-NLRP3 Inflammasome Signaling.

The activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome have been implicated in the initiation or progression of atherosclerosis. Recent research showed that irisin, a newly discovered adipomiokine, alleviates endothelial dysfunction in type 2 diabetes partially via reducing oxidative/nitrative stresses, suggesting that irisin may be a promising candidate for the treatment of vascular complications of diabetes. However, the association between irisin and NLRP3 inflammasome in the pathogenesis of atherosclerosis remains unclear. In the present study, we cultured human umbilical vein endothelial cells (HUVECs) in advanced glycation end products (AGEs) medium; exogenous irisin (0.01, 0.1, 1μg/ml) were used as an intervention reagent. siRNA and adenoviral vector were constructed to realize silencing and over-expression of NLRP3 gene. Our data showed that irisin significantly reversed AGEs-induced oxidative stress and NLRP3 inflammasome signaling activation (p<0.05), and increased the endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production in a dose-dependent manner (p<0.05). siRNA-mediated knockdown NLRP3 facilitated the irisin-mediated anti-inflammatory and antiatherogenic effects (p<0.05). However, these irisin-mediated effects were reversed by over-expression NLRP3 (p<0.05). Taken together, our results reveal that irisin alleviates AGEs-induced inflammation and endothelial dysfunction via inhibiting ROS-NLRP3 inflammasome signaling, suggest a likely mechanism for irisin-induced therapeutic effect in vascular complications of diabetes.

166 - 23-Hydroxy Ursolic Acid Protects Atherosclerosis-prone Mice from Monocyte Dysfunction

We showed that ursolic acid (UA), a pentacyclic triterpenoid with anti-inflammatory properties, reduces atherosclerotic lesion size and improves kidney function in diabetic mice. We proposed that the atheroprotective effects of UA are due to its ability to protect monocytes against metabolic stress-induced dysfunction or “priming”, i.e. the hyper-responsiveness to chemokine-induced cell adhesion and migration. Based on structure-function analyses of UA’s naturally occurring analogs, we identified and synthesized a compound, 23-hydroxy ursolic acid (23-OHUA), with a structural feature that we predicted to enhance both bioavailability and the protective effects of UA against monocyte dysfunction in vitro and in dyslipidemia atherosclerosis-prone mice. 23-OHUA protected monocytes from metabolic priming and dysfunction with a similar efficacy to UA. Both phytochemicals protected monocytes from metabolic stress by preventing the degradation of MAPK phosphatase-1 (MKP-1), a master regulator of monocyte chemotaxis and macrophage function. To test the efficacy of 23-OHUA in protecting mice against monocyte dysfunction and atherogenesis, we fed atherosclerosis-prone LDLR-/- mice a high fat diet (HFD) or a HFD supplemented with either 0.05% UA or 0.05% 23-OHUA. Monocytes were primed and hyper-sensitive to chemokines as early as 6 weeks after initiating HFD-feeding as shown by our in vivo chemotaxis assay. After 20 weeks, mice fed 23-OHUA showed 11% less weight gain compared to HFD-fed control mice and 40% reduced atherosclerotic plaque formation. Both dietary UA and 23-OHUA reduced metabolic priming and prevented the decrease in MKP-1 activity, suggesting that both compounds exert their anti-inflammatory, anti-obesogenic and anti-atherogenic effects through a novel but common mechanism involving the protection of blood monocytes against metabolic stress-induced priming and dysfunction. Our results suggest 23-OHUA and UA are viable candidates for dietary supplements for the prevention of chronic inflammatory diseases associated with metabolic disorders.

Screening for adiponectin receptor agonists and their metabolites in urine and dried blood spots

AdipoRon and 112254 represent two known synthetic adiponectin receptor (adipoR) agonists. Although AdipoRon is the more potent compound, both have physiological properties that are similar to adiponectin - an adipokine with antidiabetic and antiatherogenic effects. Several transcriptional regulators are activated by adipoR-agonists leading to increased mitochondrial DNA content in vitro, an effect that can be abused by athletes for performance enhancing purposes. In the context of preventive anti-doping research, detection of AdipoRon and 112254 in routine doping control specimens would be valuable. Here, we describe our process for incorporating AdipoRon and 112254 into routine doping control methods involving urine and dried blood spot (DBS) analysis. Method validation including evaluation of specificity, limit of detection, identification capability, carryover, matrix interference, recovery, interday and intraday precision and linearity to standards provided by WADA. For identification in human urine, a liquid chromatography-tandem mass spectrometry-based testing approach was implemented for both adipoR agonists and two respective phase-I metabolites. Recovery of 85–104%, satisfactory limits of detection (i.e., 0.5–1ng/mL), and imprecision values over three days at three concentration levels of <19% demonstrated the assay’s fitness-for-purpose. For identification from DBS a liquid chromatography-high-resolution/high-accuracy tandem mass spectrometry with online solid-phase extraction was implemented for AdipoRon and 112254. Here also, acceptable recoveries (i.e., 22–33%), limits of detection of 5–10ng/mL, and imprecision values over three days at three concentration levels of <23%, were demonstrated. Hence, two methods for doping control screening from urine and DBS were established and shown to be fit-for-purpose for routine use.

Atorvastatin accelerates clearance of lipoprotein remnants generated by activated brown fat to further reduce hypercholesterolemia and atherosclerosis

Background and aimsActivation of brown adipose tissue (BAT) reduces both hyperlipidemia and atherosclerosis by increasing the uptake of triglyceride-derived fatty acids by BAT, accompanied by formation and clearance of lipoprotein remnants. We tested the hypothesis that the hepatic uptake of lipoprotein remnants generated by BAT activation would be accelerated by concomitant statin treatment, thereby further reducing hypercholesterolemia and atherosclerosis. MethodsAPOE*3-Leiden.CETP mice were fed a Western-type diet and treated without or with the selective β3-adrenergic receptor (AR) agonist CL316,243 that activates BAT, atorvastatin (statin) or both. Resultsβ3-AR agonism increased energy expenditure as a result of an increased fat oxidation by activated BAT, which was not further enhanced by statin addition. Accordingly, statin treatment neither influenced the increased uptake of triglyceride-derived fatty acids from triglyceride-rich lipoprotein-like particles by BAT nor further lowered plasma triglyceride levels induced by β3-AR agonism. Statin treatment increased the hepatic uptake of the formed cholesterol-enriched remnants generated by β3-AR agonism. Consequently, statin treatment further lowered plasma cholesterol levels. Importantly, statin, in addition to β3-AR agonism, also further reduced the atherosclerotic lesion size as compared to β3-AR agonism alone, without altering lesion severity and composition. ConclusionsStatin treatment accelerates the hepatic uptake of remnants generated by BAT activation, thereby increasing the lipid-lowering and anti-atherogenic effects of BAT activation in an additive fashion. We postulate that, in clinical practice, combining statin treatment with BAT activation is a promising new avenue to combat hyperlipidemia and cardiovascular disease.

Genetic Depletion or Hyperresponsiveness of Natural Killer Cells Do Not Affect Atherosclerosis Development.

Chronic inflammation is central in the development of atherosclerosis. Both innate and adaptive immunities are involved. Although several studies have evaluated the functions of natural killer (NK) cells in experimental animal models of atherosclerosis, it is not yet clear whether NK cells behave as protective or proatherogenic effectors. One of the main caveats of previous studies was the lack of specificity in targeting loss or gain of function of NK cells. We used 2 selective genetic approaches to investigate the role of NK cells in atherosclerosis: (1) Ncr1iCre/+R26lsl-DTA/+ mice in which NK cells were depleted and (2) Noé mice in which NK cells are hyperresponsive. No difference in atherosclerotic lesion size was found in Ldlr-/- (low-density lipoprotein receptor null) mice transplanted with bone marrow (BM) cells from Ncr1iCreR26Rlsl-DTA , Noé, or wild-type mice. Also, no difference was observed in plaque composition in terms of collagen content, macrophage infiltration, or the immune profile, although Noé chimera had more IFN (interferon)-γ-producing NK cells, compared with wild-type mice. Then, we investigated the NK-cell selectivity of anti-asialoganglioside M1 antiserum, which was previously used to conclude the proatherogenicity of NK cells. Anti-asialoganglioside M1 treatment decreased atherosclerosis in both Ldlr-/- mice transplanted with Ncr1iCreR26Rlsl-DTA or wild-type bone marrow, indicating that its antiatherogenic effects are unrelated to NK-cell depletion, but to CD8+ T and NKT cells. Finally, to determine whether NK cells could contribute to the disease in conditions of pathological NK-cell overactivation, we treated irradiated Ldlr-/- mice reconstituted with either wild-type or Ncr1iCreR26Rlsl-DTA bone marrow with the viral mimic polyinosinic:polycytidylic acid and found a significant reduction of plaque size in NK-cell-deficient chimeric mice. Our findings, using state-of-the-art mouse models, demonstrate that NK cells have no direct effect on the natural development of hypercholesterolemia-induced atherosclerosis, but may play a role when an additional systemic NK-cell overactivation occurs.

Chemoinformatic Database Building and in Silico Hit-Identification of Potential Multi-Targeting Bioactive Compounds Extracted from Mushroom Species.

Mushrooms are widely-consumed fungi which contain natural compounds that can be used both for their nutritive and medicinal properties, i.e., taking advantage of their antimicrobial, antiviral, antitumor, anti-allergic, immunomodulation, anti-inflammatory, anti-atherogenic, hypoglycemic, hepatoprotective and antioxidant effects. Currently, scientific interest in natural compounds extracted from the fungal species is increasing because these compounds are also known to have pharmacological/biological activity. Unfortunately, however, their mechanisms of action are often unknown, not well understood or have not been investigated in their entirety. Given the poly-pharmacological properties of bioactive fungal compounds, it was decided to carry out a multi-targeted approach to predict possible interactions occurring among bioactive natural fungal extracts and several macromolecular targets that are therapeutically interesting, i.e., proteins, enzymes and nucleic acids. A chemical database of compounds extracted from both edible and no-edible mushrooms was created. This database was virtually screened against 43 macromolecular targets downloaded from the Protein Data Bank website. The aim of this work is to provide a molecular description of the main interactions involving ligand/multi-target recognition in order to understand the polypharmacological profile of the most interesting fungal extracts and to suggest a design strategy of new multi-target agents.

Chebulinic acid inhibits smooth muscle cell migration by suppressing PDGF-R\u03b2 phosphorylation and inhibiting matrix metalloproteinase-2 expression

Excessive migration of vascular smooth muscle cells (VSMCs) after vascular injury contributes to the development of occlusive vascular disease. Inhibition of VSMC migration is a validated therapeutic modality for occlusive vascular diseases, such as atherosclerosis and restenosis. We investigated the inhibitory effect of chebulinic acid (CBA) on cell migration and matrix metalloproteinase (MMP)-2 activation in platelet-derived growth factor (PDGF)-BB-induced mouse and human VSMCs. CBA significantly inhibited PDGF-BB-induced migration in mouse and human VSMCs, without inducing cell death. Additionally, CBA significantly blocked PDGF-BB-induced phosphorylation of the PDGF receptor (PDGF-R), Akt, and extracellular signal-regulated kinase (ERK)1/2 by inhibiting the activation of the PDGF-BB signalling pathway. In both mouse and human VSMCs, CBA inhibited PDGF-induced MMP-2 mRNA and protein expression as well as the proteolytic activity of MMP-2. Moreover, CBA suppressed sprout outgrowth formation of VSMCs from endothelium-removed aortic rings as well as neointima formation following rat carotid balloon injury. Taken together, our findings indicated that CBA inhibits VSMC migration by decreasing MMP-2 expression through PDGF-R and the ERK1/2 and Akt pathways. Our data may improve the understanding of the antiatherogenic effects of CBA in VSMCs.

Biofunctional Polymer-Lipid Hybrid High-Density Lipoprotein-Mimicking Nanoparticles Loading Anti-miR155 for Combined Antiatherogenic Effects on Macrophages.

A biofunctional polymer-lipid hybrid high-density lipoprotein-mimicking nanoparticle (HNP) loading anti-miR155 was constructed for combined antiatherogenic effects on macrophages. The HNP consisted of an anti-miR155 core condensed by acid-labile polyethylenimine (acid-labile PEI) polymers and a lipid bilayer coat that was decorated with apolipoprotein A-1, termed acid-labile PEI/HNP. The acid-labile PEI was synthesized with low-molecular-weight PEI and glutaraldehyde to reduce the cytotoxicity and facilitate nucleic acids escaping from acidic endolysosomes. The increased silencing efficiency of acid-labile PEI/HNP was ascribed to the clathrin-mediated endocytosis and successful endolysosomal escape. Decreased intracellular reactive oxygen species production and DiI-oxLDL uptake revealed the antioxidant activities of both anti-miR155 and HNP. Cholesterol efflux assay indicated the potential of HNP in reverse cholesterol transport. Collectively, the acid-labile PEI/HNP not only realized the efficacy of anti-miR155 in macrophages but also exerted the antiatherosclerotic biofunction of HNP.

Anti-atherogenic and anti-lipidemic effects of vanadium in high fat diet rabbits – An histological and biochemical study

Anti-atherogenic and anti-lipidemic effects of vanadium in high fat diet rabbits – An histological and biochemical study

AMPK activation enhances the anti-atherogenic effects of high density lipoproteins in apoE−/− mice

HDL plays crucial roles at multiple stages of the pathogenesis of atherosclerosis. AMP-activated protein kinase (AMPK) is a therapeutic candidate for the treatment of cardiovascular disease. However, the effect of AMPK activation on HDL functionality has not been established in vivo. We assessed the effects of pharmacological AMPK activation using A-769662, AICAR, metformin, and IMM-H007 on the atheroprotective functions of HDL in apoE-deficient (apoE−/−) mice fed with a high-fat diet. After administration, there were no changes in serum lipid levels among the groups. However, mice treated with AMPK activators showed significantly enhanced reverse cholesterol transport in vivo and in vitro. AMPK activation also increased the expression of ABCA1 and ABCG1 in macrophages and scavenger receptor class B type I and LCAT in the liver. HDL from AMPK activation mice exhibited lower HDL inflammatory index and myeloperoxidase activity and higher paraoxonase 1 activity than HDL from untreated mice, implying superior antioxidant and anti-inflammatory capacities. Pharmacological AMPK activation also induced polarization of macrophages to the M2 state and reduced plasma lipid peroxidation, inflammatory cytokine production, and atherosclerotic plaque formation in apoE−/− mice. These observations suggest that pharmacological AMPK activation enhances the anti-atherogenic properties of HDL in vivo. This likely represents a key mechanism by which AMPK activation attenuates atherosclerosis.

Statin treatment potentiates the lipid-lowering and anti-atherogenic effect of bat activation by accelerating lipoprotein remnant clearance

Statin treatment potentiates the lipid-lowering and anti-atherogenic effect of bat activation by accelerating lipoprotein remnant clearance

Effect of Certain Oral Anti Diabetic Drugs on Coagulation Cascade in Diabetes Mellitus

Thrombotic events in diabetics contribute for almost 65-80% of cardiovascular events. Diabetes affects the platelet, the coagulation factors and fibrinolytic system leading to a state of hypercoagulation and hypofibrinolysis resulting in to thrombosis. Oral drugs commonly used in management of type II diabetes mellitus are antidiabetics like metformin, PPAR- γ agonist and DPP-4 inhibitor. They rarely produce hypoglycemia. Metformin has been proved to prevent release of mtDNA from arachidonic acid stimulated platelets, reduce membrane damage and mitochondrial ROS production in the platelets. Similarly processes like platelet adhesion, activation and aggregation on collagen coated surfaces which initiate thrombosis are prevented by metformin. PPAR- γ agonists like pioglitazone and rosiglitazone have anti atherogenic effect. They decrease the expression of inflammatory markers and affect the coagulation markers like factor VII: C and inhibit platelet activation. Pioglitazone also reduces the VLDL, triglycerides and increases HDL which further contributes in attenuation of atherosclerosis. DPP-4 inhibitors, which are relatively newer class of antidiabetics, having minimum potential for hypoglycemia induction, due to their novel mechanism of action. Studies have proved that long term use of DPP-4 inhibitors have reduced cardiac mortality by their lipid lowering action, increased release of NO from endothelium and inhibition of TNF- α, PAI-1 and VCAM expression. Increased levels of stromal cell derived factor - 1α helps to maintain endothelial homeostasis and vascular repair. Decreased oxidative stress, inhibition of inflammatory genes like IL- 6, IL-12, TNF- α provide additional benefit. Destabilization of vasculo-atherosclerotic plaque is prevented by DPP-4 inhibitors. Thus these oral antidiabetics drugs offer many benefits beyond blood glucose control which prevent atherosclerosis, inhibits hypercoagulable state and enhances fibrinolysis which translates into decreased cardiac complications in diabetes

Effect of Euterpe oleracea Mart. (Açaí) Oil on Dyslipidemia Caused by Cocos nucifera L. Saturated Fat in Wistar Rats.

Dyslipidemia is caused by disturbances in lipid metabolism that lead to chronic elevations of serum lipids, especially low-density lipoprotein (LDL)-cholesterol and triglycerides, increasing the risk of metabolic syndrome, obesity, diabetes, atherogenic processes, and cardiovascular diseases. The oil from the fruits of Euterpe oleracea (OFEO) is rich in unsaturated fatty acids with potential for treating alterations in lipid metabolism. In this study, we aimed to investigate the effect of OFEO on hyperlipidemia induced by Cocos nucifera L. saturated fat (GSC) in Wistar rats. Chromatographic profile showed that unsaturated fatty acids account for 66.08% in OFEO, predominately oleic acid (54.30%), and saturated fatty acids (palmitic acid 31.6%) account for 33.92%. GSC-induced dyslipidemia resulted in an increase in total cholesterol, LDL-cholesterol, triglycerides, glucose, and liver and abdominal fat, as well as atherogenic processes in the thoracic aorta. OFEO treatment did not reduce hypertriglyceridemia, but did reduce total cholesterol and LDL-cholesterol, thus contributing to the antiatherogenic action of OFEO. OFEO treatment inhibited the formation of atheromatous plaques in the vascular endothelium of the treated rats, as well as those who were treated with simvastatin. The results obtained suggest that OFEO has an antiatherogenic effect in a rat model of dyslipidemia.

Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr-/- Mice.

The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands are employed to functionalize the NPs to improve targeting to the atherosclerotic plaque, and formulation parameters such as the length of the polyethylene glycol (PEG) coating molecules are systematically optimized. In vitro studies indicate that the GW-encapsulated NPs upregulate the LXR target genes and downregulate proinflammatory mediator in macrophages. The Col IV-targeted NPs encapsulating GW (Col IV-GW-NPs) successfully reaches atherosclerotic lesions when administered for 5 weeks to mice with preexisting lesions, substantially reducing macrophage content (≈30%) compared to the PBS group, which is with greater efficacy versus nontargeting NPs encapsulating GW (GW-NPs) (≈18%). In addition, mice administered the Col IV-GW-NPs do not demonstrate increased hepatic lipid biosynthesis or hyperlipidemia during the treatment period, unlike mice injected with the free GW. These findings suggest a new form of LXR-based therapeutics capable of enhanced delivery of the LXR agonist to atherosclerotic lesions without altering hepatic lipid metabolism.