Antiatherogenic Properties Research Articles

Implications for Clinical Practice, Mechanisms, and Efficacy of Ageratum conyzoides Leaf Extracts in Streptozotocin-Induced Diabetes Rats: An Investigation into Their Antidiabetic, Hypolipidemic, and Antiatherogenic Activities

Ageratum conyzoides, a perennial herb native to tropical and subtropical regions, has been utilized in traditional medicine for centuries due to its diverse therapeutic properties. This review consolidates current research on the antidiabetic, hypolipidemic, and antiatherogenic effects of Ageratum conyzoides leaf extracts, specifically in streptozotocin-induced diabetic rat models. The review explores the plant’s potential mechanisms of action, including enhancement of insulin sensitivity, improvement of lipid profiles, and reduction of atherosclerotic plaque formation. Ageratum conyzoides extracts have demonstrated significant antidiabetic effects by lowering blood glucose levels, enhancing insulin secretion, and improving insulin sensitivity. They also exhibit hypolipidemic effects by reducing total cholesterol, LDL cholesterol, and triglycerides, while increasing HDL cholesterol. Additionally, these extracts show antiatherogenic properties by inhibiting plaque formation and reducing oxidative stress, thereby supporting cardiovascular health. The review examines the pharmacokinetics and bioavailability of Ageratum conyzoides bioactive compounds, emphasizing the need for further research to optimize their therapeutic potential. Comparative studies highlight its efficacy relative to other natural remedies and pharmaceuticals, noting its favorable safety profile. The review underscores the importance of integrating Ageratum conyzoides into both traditional and modern medicine practices and explores its role in dietary supplements and functional foods. Ongoing translational research and clinical trials are essential to validate the efficacy and safety of these extracts for broader clinical application. Keywords: Ageratum conyzoides, Leaf Extracts, Streptozotocin, Diabetes, Rats

The plant extract PNS mitigates atherosclerosis via promoting Nrf2-mediated inhibition of ferroptosis through reducing USP2-mediated Keap1 deubiquitination.

Atherosclerosis is the basis of cardiovascular disease. Ferroptosis is a form of programmed cell death characterized by lipid peroxidation, which contributes to atherogenesis. The plant extract PNS (Panax notoginseng saponins), containing the main active ingredients of Panax notoginseng, exhibits anti-atherogenic properties. Herein, we determined whether PNS and its major components could attenuate atherosclerosis by suppressing ferroptosis and revealed the underlying mechanism(s). The anti-atherogenic effects of PNS and their association with inhibition of ferroptosis was determined in apoE-/- mice. In vitro, the anti-ferroptotic effect and mechanism(s) of PNS components were demonstrated in the presence of ferroptosis inducers. Expression of ferroptosis markers and the ubiquitination of Keap1 were evaluated in USP2-/- macrophages. Finally, the anti-atherogenic effect of USP2 knockout was determined by using USP2-/- mice treated with high-fat diet (HFD) and AAV-PCSK9. PNS inhibited ferroptosis and atherosclerosis in vivo. PNS suppressed ferroptosis and ferroptosis-aggravated foam cell formation and inflammation in vitro. Mechanistically, PNS and its components activated Nrf2 by antagonizing Keap1, which was attributed to the inhibition of USP2 expression. USP2 knockout antagonized ferroptosis and ferroptosis-aggravated foam cell formation and inflammation, thus mitigating atherosclerosis. USP2 knockout abolished inhibitory effects of PNS on foam cell formation and inflammation in vitro. PNS reduced USP2-mediated Keap1 de-ubiquitination and promoted Keap1 degradation, thereby activating Nrf2, improving iron metabolism and reducing lipid peroxidation, thus contributing to an anti-atherosclerotic outcome. Our study revealed the mechanism(s) underlying inhibition of ferroptosis and atherosclerosis by PNS.

Monoclonal Antibody chP3R99 Reduces Subendothelial Retention of Atherogenic Lipoproteins in Insulin-Resistant Rats: Acute Treatment Versus Long-Term Protection as an Idiotypic Vaccine for Atherosclerosis.

Atherosclerosis is triggered by the retention of apolipoprotein B-containing lipoproteins by proteoglycans. In addition to low-density lipoprotein, remnant lipoproteins have emerged as pivotal contributors to this pathology, particularly in the context of insulin resistance and diabetes. We have previously reported antiatherogenic properties of a monoclonal antibody (chP3R99) that recognizes sulfated glycosaminoglycans on arterial proteoglycans. Solid-phase assays demonstrated that chP3R99 effectively blocked >50% lipoprotein binding to chondroitin sulfate and vascular extracellular matrix invitro. The preperfusion of chP3R99 (competitive effect) resulted in specific antibody-arterial accumulation and reduced fluorescent lipoprotein retention by ~60% in insulin resistant JCR:LA-cp rats. This competitive reduction was dose dependent (25-250 μg/mL), effectively decreasing deposition of cholesterol associated with lipoproteins. In a 5-week vaccination study in insulin resistant rats with (200 μg subcutaneously, once a week), chP3R99 reduced arterial lipoprotein retention, and was associated with the production of antichondroitin sulfate antibodies (Ab3) able to accumulate in the arteries (dot-blot). Neither the intravenous inoculation of chP3R99 (4.5 mg/kg), nor the immunization with this antibody displayed adverse effects on lipid or glucose metabolism, insulin resistance, liver function, blood cell indices, or inflammation pathways in JCR:LA-cp rats. Both acute (passive) and long-term administration (idiotypic cascade) of chP3R99 antibody reduced low-density lipoprotein and remnant lipoprotein interaction with proteoglycans in an insulin-resistant setting. These findings support the innovative approach of targeting proatherogenic lipoprotein retention by chP3R99 as a passive therapy or as an idiotypic vaccine for atherosclerosis.

Development of Pomegranate Aloe Vera Juice: Pomalo

Abstract: Pomegranate juice is a good source of polyphenols and has good antioxidant potential, whereas, the studies on pomegranate juice have shown that it possesses antiatherogenic, antioxidant, antihypertensive, and anti-inflammatory properties. The literature also reported the major decrease in atherosclerotic lesion region in immune-deficient mice and intima media thickness in cardiac patients on medications, due to consumption of pomegranate juice. Whereas, in patients with type 2 diabetes, a reduction in lipid peroxidation was observed and in hypertensive patients, a systolic blood pressure and serum angiotensin converting enzyme activity was determined. Therefore, the study showed the potential cardioprotective advantages of pomegranate juice and suggests the inclusion of this juice in a diet for a healthy living. the composition of aloe vera and its role in development of functional foods. The colorless and watery gel-like consistency are the characteristics of aloe vera gel that makes it better option for blend beverages. The functional characteristics render aloe vera with broad range of application in the pharmaceutical, cosmetics and food sectors. The presence of antioxidants and hormones (auxins and gibberellins) in aloe vera, are responsible for preventing chronic diseases and wound healing properties by inducing the cell propagation, thus providing anti-inflammatory action, respectively. Saponins and salicylic acid present in it, provides antibacterial and antiseptic activity. The literature also reveals that emidine and aloin are the compounds present in aloe that act as antiviral, antibacterial and analgesic agent. Whereas, it also contains vitamins E, C and minerals such as, copper, selenium and zinc, along with enzyme brady kinase, fatty acids and sugar, essential and non-essential amino acids, 12 anthraquinones phenolic compounds. The most abundant monosaccharide and polysaccharides found in aloe vera are Mannose-6-phosphate, and glucomannans, respectively.

Pistacia lentiscus: Phytochemistry and Antidiabetic Properties.

Pistacia lentiscus L. (P. lentiscus) is an evergreen shrub (Anacardiaceae family) primarily found in the Mediterranean region. The plant has been thoroughly characterized, resulting in a high concentration of bioactive compounds as flavonoids and phenolics. Moreover, P. lentiscus was revealed to possess a great nutritional and industrial importance because of its variety of biological activities, including antibacterial, anti-inflammatory, anti-atherogenic and antioxidant properties. Many of its beneficial health properties and applications date back to antiquity, and the European Medicines Agency officially acknowledged it as an herbal medicinal product. Indeed, it is widely employed in conventional medicine to treat several diseases, including type 2 diabetes (T2D). On this basis, this review aims to summarize and describe the chemical composition of different parts of the plant and highlight the potential of P. lentiscus, focusing on its antidiabetic activities. The plant kingdom is drawing increasing attention because of its complexity of natural molecules in the research of novel bioactive compounds for drug development. In this context, P. lentiscus demonstrated several in vitro and in vivo antidiabetic effects, acting upon many therapeutic T2D targets. Therefore, the information available in this review highlighted the multitarget effects of P. lentiscus and its great potential in T2D treatment.

B cells and atherosclerosis: A HIV perspective.

Atherosclerosis remains a leading cause of cardiovascular disease (CVD) globally, with the complex interplay of inflammation and lipid metabolism at its core. Recent evidence suggests a role of B cells in the pathogenesis of atherosclerosis; however, this relationship remains poorly understood, particularly in the context of HIV. We review the multifaceted functions of B cells in atherosclerosis, with a specific focus on HIV. Unique to atherosclerosis is the pivotal role of natural antibodies, particularly those targeting oxidized epitopes abundant in modified lipoproteins and cellular debris. B cells can exert control over cellular immune responses within atherosclerotic arteries through antigen presentation, chemokine production, cytokine production, and cell-cell interactions, actively participating in local and systemic immune responses. We explore how HIV, characterized by chronic immune activation and dysregulation, influences B cells in the context of atherosclerosis, potentially exacerbating CVD risk in persons with HIV. By examining the proatherogenic and antiatherogenic properties of B cells, we aim to deepen our understanding of how B cells influence atherosclerotic plaque development, especially within the framework of HIV. This research provides a foundation for novel B cell-targeted interventions, with the potential to mitigate inflammation-driven cardiovascular events, offering new perspectives on CVD risk management in PLWH.

Nano-delivery Systems and Therapeutic Applications of Phytodrug Mangiferin.

In order to cure a range of ailments, scientists have investigated a number of bioactive antioxidant compounds produced from natural sources. Mangiferin, a C-glycosyl xanthone-structured yellow polyphenol, is abundant in mangoes and other dietary sources. In-depth examinations found that it is effective in the treatment of a variety of disorders due to its antiviral, anti-inflammatory, antiproliferative, antigenotoxic, antiatherogenic, radioprotective, nephroprotective, antihyperlipidemic, and antidiabetic properties. However, it is recognised that mangiferin's poor bioavailability, volatility, and limited solubility restrict its therapeutic usefulness. Over time, effective solutions to these problems have arisen in the shape of effective delivery methods. The current articles present a summary of the several researches that have updated Mangiferin's biopharmaceutical characteristics. Additionally, strategies for enhancing the bioavailability, stability, and solubility of this phytodrug have been discussed. This review provides detailed information on the development of innovative Mangiferin delivery methods such as nanoparticles, liposomes, micelles, niosomes, microspheres, metal nanoparticles, and complexation, as well as its therapeutic applications in a variety of sectors. This article provides effective guidance for researchers who desire to work on the formulation and development of an effective delivery method for improved magniferin therapeutic effectiveness.

Study of Correlation of Serum Adiponectin Concentration with Different Lipid Profile Components

Adiponectin is a hormone, secreted from adipose tissue. It is inversely correlated with body fat mass. This hormone has also anti-inflammatory and ant-iatherogenic properties. This study was purposed to explore the relationship between serum adiponectin concentration and lipid profile. This cross-sectional analytical study was carried out in the Department of Biochemistry, Bangabandhu Sheikh Mujib Medical University (BSMMU) from March 2016 to February 2017. By non-probability sampling, a total of 156 study subjects were selected from apparently healthy adult individuals attending outpatient department of BSMMU. Serum adiponectin level positively correlated with serum HDL cholesterol (r=0.246, p value 0.002) concentrations and negatively correlated with serum total cholesterol (r=-0.171, p value 0.033) and serum triacylglycerol level (r=-0.3, p value 0.00). So, from this study it can be concluded that adiponectin has an important role in the metabolism of lipid profile components and responsible for controlling the concentration of serum lipid profile components. When adiponectin concentration of blood increases it is responsible for raised serum HDL-C concentration and decreased total cholesterol and triacylglycerol concentration.
 Bangladesh J Med Biochem 2019; 12(1): 6-10

Plasma legumain in familial hypercholesterolemia: associations with statin use and cardiovascular risk markers

Legumain is known to be regulated in atherosclerotic disease and may have both pro- and anti-atherogenic properties. The study aimed to explore legumain in individuals with familial hypercholesterolemia (FH), a population with increased cardiovascular risk. Plasma legumain was measured in 251 subjects with mostly genetically verified FH, of which 166 were adults (≥18 years) and 85 were children and young adults (<18 years) and compared to 96 normolipidemic healthy controls. Plasma legumain was significantly increased in the total FH population compared to controls (median 4.9 versus 3.3 pg/mL, respectively, p < 0.001), whereof adult subjects with FH using statins had higher levels compared to non-statin users (5.7 versus 3.9 pg/mL, respectively, p < 0.001). Children and young adults with FH (p = 0.67) did not have plasma legumain different from controls at the same age. Further, in FH subjects, legumain showed a positive association with apoB, and markers of inflammation and platelet activation (i.e. fibrinogen, NAP2 and RANTES). In the current study, we show that legumain is increased in adult subjects with FH using statins, whereas there was no difference in legumain among children and young adults with FH compared to controls. Legumain was further associated with cardiovascular risk markers in the FH population. However the role of legumain in regulation of cardiovascular risk in these individuals is still to be determined.

Atorvastatin's Therapeutic Potential in Atherosclerosis: Inhibiting TGF-β-Induced Proteoglycan Glycosaminoglycan Chain Elongation through ROS-ERK1/2-Smad2L Signaling Pathway Modulation in Vascular Smooth Muscle Cells.

According to the response-to-retention hypothesis, the inception of atherosclerosis is attributed to the deposition and retention of lipoprotein in the arterial intima, facilitated by altered proteoglycans with hyperelongated glycosaminoglycan (GAG) chains. Recent studies have elucidated a signaling pathway whereby transforming growth factor-β (TGF-β) promotes the expression of genes linked to proteoglycan GAG chain elongation (CHSY1 and CHST11) via reactive oxygen species (ROS) and the downstream phosphorylation of ERK1/2 and Smad2L. Atorvastatin is known to exhibit pleiotropic effects, including antioxidant and anti-inflammatory. The purpose of the present research was to ascertain the influence of atorvastatin on TGF-β-stimulated expression of CHSY1 and CHST11 and associated signaling pathways using an in vitro model. In this experimental study, vascular smooth muscle cells (VSMCs) were pre-incubated with atorvastatin (0.1-10 μM) prior to being stimulated with TGF-β (2 ng/ml). The experiment aimed to evaluate the phosphorylation levels of Smad2C, Smad2L, ERK1/2, the NOX p47phox subunit, ROS production, and the mRNA expression of CHST11 and CHSY1. Our research results indicated that atorvastatin inhibited TGF-β-stimulated CHSY1 and CHST11 mRNA expression. Further experiments showed that atorvastatin diminished TGF-β-stimulated ROS production and weakened TGF-β-stimulated phosphorylation of p47phox, ERK1/2, and Smad2L; however, we observed no effect on the TGF-β- Smad2C pathway. These data suggest that atorvastatin demonstrates anti-atherogenic properties through the modulation of the ROS-ERK1/2-Smad2L signaling pathway. This provides valuable insight into the potential mechanisms by which atorvastatin exerts its pleiotropic effects against atherosclerosis.

Formulation and evaluation of herbal chocolate from Arjuna Bark- treatment of heart disease condition

In the indigenous medical system, Terminalia arjuna is one of the most widely used and advantageous medicinal herbs for the treatment of cardiovascular disorders. This thorough analysis offers the most recent information on the traditional uses, phytochemistry, pharmacological data, toxicological data, clinical efficacy, safety and efficacy of Terminalia arjuna. It also lays out plans for further study and development to substantiate the plant's therapeutic potential through scientific means. A thorough web and library search of numerous indexed and non-indexed journals, some local literature and a variety of publications published on ethnopharmacology, phytochemistry and traditional usage were used to gather information about Terminalia arjuna. Regarding the effectiveness and safety profile of Terminalia arjuna, numerous pre-clinical (2000–2014) and clinical investigations (1990–2014) have also been taken into consideration. The pleiotropic advantages associated with Terminalia arjuna, comprising its anti-atherogenic, hypotensive, inotropic, anti-inflammatory, anti-thrombotic and antioxidant properties, have been demonstrated in numerous in vitro, in vivo and clinical investigations. These effects can be used to treat a variety of cardiovascular problems. There is sample evidence to support the plant's good safety profile when combined with other traditional medications. The precise molecular mechanism of its action, the best way to administer the medication, whether to employ an alcoholic, watery or crude extract, toxicological research and how it interacts with other medications are all poorly understood. This review concludes by emphasizing the significance of Terminalia arjuna, as well as its pleiotropic effects and functional characteristics particularly in relation to cardiovascular disorders. Even though a number of pharmacological research and clinical trials back up its traditional use in treating CVD, more rigorous, state-of-the-art clinical trials with larger sample sizes are necessary to evaluate Terminalia arjuna purported efficacy.

Ethanolic Stem-Bark Extract of Blighia unijugata Possesses Anti-Hyperglycemic and Anti-Hyperlipidemic Activity in a Streptozotocin-Induced Diabetes Model

Introduction: The global rise in the incidence of diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), and its associated complications have become a public health threat. Besides hyperglycemia, hyperlipidemia has been associated with diabetes due to the defect in insulin secretion and/or action. Medicinal plants are being investigated to discover drug alternatives with better efficacies, lesser adverse effects, and cost-effectiveness. This work investigated the anti-hyperglycemic and anti-hyperlipidemic activity of ethanolic stem bark extract of Blighia unijugata (EBU) in streptozotocin (STZ)-induced diabetic Sprague- Dawley (SD) rats.&#x0D; Method: T2DM was induced in male SD rats by a single intraperitoneal injection of STZ (50 mg/kg in 0.1 M citrate buffer, pH 4.5) and confirmed 72 hours later. EBU (100 and 200 mg/kg) and glibenclamide (5 mg/kg) were administered orally to the diabetic rats (n = 5) for 28 days. The effect of the treatments on fasting blood glucose (FBG), lipid profile, atherogenic predictor indices, and body weight were assessed.&#x0D; Results: EBU treatments significantly reduced (p≤0.001) elevated blood glucose, total cholesterol, triglycerides, and Very Low-Density Lipoprotein cholesterol (VLDL-c, p≤0.001) but increased High-Density Lipoprotein cholesterol (HDL, p≤0.05) compared to the diabetic control. Also, all the atherogenic risk predictor indices were significantly reduced (p≤0.001). In addition, EBU treatment mitigated the significant weight loss (p≤0.01) associated with the diabetic state when compared to the normal control.&#x0D; Conclusion: These findings first report the anti-hyperglycemic, anti-hyperlipidemic, and anti-atherogenic properties of the stem bark of ethanolic extract of Blighia unijugata, and can be further studied and used as an anti-diabetic and anti-hyperlipidemic agent.&#x0D; Keywords: Blighia unijugata; hyperglycemia; atherogenic index; hyperlipidemia; diabetes

Pleiotropic functions and clinical importance of circulating HDL-PON1 complex.

High density lipoprotein (HDL) functions are mostly mediated through a complex proteome, particularly its enzymes. HDL can provide a scaffold for the assembly of several proteins that affect each other's function. HDL particles, particularly small, dense HDL3, are rich in paraoxonase 1 (PON1), which is an important enzyme in the functionality of HDL, so the antioxidant and antiatherogenic properties of HDL are largely attributed to this enzyme. There is an increasing need to represent a valid, reproducible, and reliable method to assay HDL function in routine clinical laboratories. In this context, HDL-associated proteins may be key players; notably PON1 activity (its arylesterase activity) may be a proper candidate because its decreased activity can be considered an important risk factor for HDL dysfunctionality. Of note, automated methods have been developed for the measurement of serum PON1 activity that facilitates its assay in large sample numbers. Arylesterase activity is proposed as a preferred activity among the different activities of PON1 for its assay in epidemiological studies. The binding of PON1 to HDL is critical for the maintenance of its activity and it appears apolipoprotein A-I plays an important role in HDL-PON1 interaction as well as in the biochemical and enzymatic properties of PON1. The interrelationships between HDL, PON1, and HDL's other components are complex and incompletely understood. The purpose of this review is to discuss biochemical and clinical evidence considering the interactions of PON1 with HDL and the role of this enzyme as an appropriate biomarker for HDL function as well as a potential therapeutic target.

Antioxidant and Anti-Inflammatory Functions of High-Density Lipoprotein in Type 1 and Type 2 Diabetes.

(1) Background: high-density lipoproteins (HDLs) exhibit antioxidant and anti-inflammatory properties that play an important role in preventing the development of atherosclerotic lesions and possibly also diabetes. In turn, both type 1 diabetes (T1D) and type 2 diabetes (T2D) are susceptible to having deleterious effects on these HDL functions. The objectives of the present review are to expound upon the antioxidant and anti-inflammatory functions of HDLs in both diabetes in the setting of atherosclerotic cardiovascular diseases and discuss the contributions of these HDL functions to the onset of diabetes. (2) Methods: this narrative review is based on the literature available from the PubMed database. (3) Results: several antioxidant functions of HDLs, such as paraoxonase-1 activity, are compromised in T2D, thereby facilitating the pro-atherogenic effects of oxidized low-density lipoproteins. In addition, HDLs exhibit diminished ability to inhibit pro-inflammatory pathways in the vessels of individuals with T2D. Although the literature is less extensive, recent evidence suggests defective antiatherogenic properties of HDL particles in T1D. Lastly, substantial evidence indicates that HDLs play a role in the onset of diabetes by modulating glucose metabolism. (4) Conclusions and perspectives: impaired HDL antioxidant and anti-inflammatory functions present intriguing targets for mitigating cardiovascular risk in individuals with diabetes. Further investigations are needed to clarify the influence of glycaemic control and nephropathy on HDL functionality in patients with T1D. Furthermore, exploring the effects on HDL functionality of novel antidiabetic drugs used in the management of T2D may provide intriguing insights for future research.

Association of adiponectin gene expression with atrial fibrillation in a Pakistani populace

Adiponectin, an adipocytokine produced and secreted by adipose tissue, has anti-diabetic, anti-atherogenic, and anti-inflammatory properties. This case-control study was aimed to assess the expression and serum levels of adiponectin in subject suffereing from atrial fibrillation (AF). The study's subjects (n = 690) were enrolled from the Punjab Institute of Cardiology, Lahore and were grouped into control, AF without Metabolic syndrome (MetS), and AF with MetS groups. Along with the collection of demographic data, an analysis of adiponectin and biochemical parameters were performed. A highly significant difference in serum levels of adiponectin was observed among the control, AF without MetS, and AF with MetS groups (61.61 ± 45.30 ng/ml, 37.20 ± 19.46 ng/ml, 63.78 ± 61.69 ng/ml). The expression analysis of adiponectin was decreased (n-fold = ̴ 0.30) in AF without MetS group as compared to control group (n-fold = ~ 1.16) but increased in AF with MetS group (n-fold = ̴ 6.26). The correlation analysis revealed a highly significant positive relationship between the expression of the adiponectin gene with waist-to-hip ratio (WHR) in AF without MetS group. Whereas, serum adiponectin was negatively related to serum triglycerides (TG) in AF with MetS group. In multiple regression analysis using adiponectin expression as the dependent variable, WHR was a determinant in AF without MetS. Whereas, when serum adiponectin was used as the dependent variable, serum TG was the determinant in group AF with MetS. The present study implicates that decreased expression and serum levels of adiponectin were associated with the development of AF in which WHR and serum TG also contributed towards the onset of atrial fibrillation.

Elevated plasma adiponectin in risk of heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction: observational and mendelian randomization studies

Abstract Background and purpose Adiponectin, an adipocyte-secreted protein-hormone, may play an important protective role in heart failure and associated cardiovascular diseases through insulin-sensitizing, anti-atherogenic, and anti-inflammatory properties. We hypothesized that plasma adiponectin is associated observationally and causal, genetically with risk of heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction. Methods In the Copenhagen General Population Study (CGPS), we examined 30,045 individuals with plasma adiponectin measurements observationally and 96,903 individuals genetically in one-sample Mendelian randomization analyses using five genetic variants. In the HERMES, UK Biobank, The Nord-Trøndelag Health Study (HUNT), deCODE, the Michigan Genomics Initiative (MGI), DiscovEHR, and the AFGen consortia, we performed two-sample Mendelian randomization analyses in up to 1,030,836 individuals using 12 genetic variants. Results In observational analyses, a 1 unit log-transformed higher plasma adiponectin was associated with a hazard ratio of 1.51 (95% confidence interval: 1.37–1.66) for heart failure, 1.63 (1.50–1.78) for atrial fibrillation, 1.21 (1.03–1.41) for aortic valve stenosis, and 1.03 (0.93–1.14) for myocardial infarction; levels above the median was also associated with increased risk of myocardial infarction. Corresponding genetic, causal risk ratios were 0.92 (0.65–1.29), 0.87 (0.68–1.12), 1.55 (0.87–2.76), and 0.93 (0.67–1.30) in one-sample Mendelian randomization analyses, while corresponding causal risk ratios were 0.99 (0.89–1.09), 1.00 (0.92–1.08), 1.01 (0.79–1.28), and 0.99 (0.86–1.13) in two-sample Mendelian randomization analyses, respectively. Conclusion Elevated plasma adiponectin was associated with increased risk of heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction. However, genetic evidence did not support causality for those associations.Observational associationObservational and genetic association

Synergistic effect of Interleukin-1beta and cholesterol efflux capacity on outcomes in acute myocardial infarction patients

Abstract Background Low cholesterol efflux capacity and elevated levels of Interleukin-1ß (IL-1ß) are both associated with residual cardiovascular risk in patients with acute myocardial infarction (MI) and may be used as new biomarkers to identify patients at higher cardiovascular risk. Both pathways are currently evaluated as new therapeutic targets in ongoing clinical trials. Objectives We evaluated potential synergetic effect of cholesterol efflux capacity and IL-1ß on recurrent major cardiovascular events (MACE) at one-year in patients with acute ST-segment elevation MI who underwent primary percutaneous coronary intervention. Methods Cholesterol efflux capacity and IL-1ß were measured among 2012 ST-segment elevation MI patients enrolled in a prospective cohort. The association of these biomarkers with the primary outcome of MACE (MI, Stroke, or cardiovascular death) was evaluated at one-year follow-up using a multivariate-cox proportional regression analysis. In addition, in-vitro analysis of anti-atherogenic properties of HDL particles was also performed. Results Patients with both, a reduced cholesterol efflux capacity and an elevated level of IL-1b, exhibited the highest risk of recurrent MACE at one year compared to patients with both high cholesterol efflux capacity and low IL-1b (adjusted HR: 3.28; 95% CI: 1.83 to 5.89, p&amp;lt;0.0001) (Figure). In this high-risk subgroup, patients exhibited HDL particles defective for ABCA1-dependent efflux capacity with enhanced pro-inflammatory activity as a potential explanation for our clinical findings. Conclusion Defective cholesterol efflux capacity and elevated IL-1β increase synergistically the residual cardiovascular risk in MI patients.

Abstract 12520: Advancements in the Treatment of Atherosclerosis

Background: Endotheliotoxic hyperlipidemia provide impaired eNOS derived NO production, excessive free-radicals, adhesive molecule generation, vascular lipid accumulation, atherosclerosis development &amp; progression. NO replacement by NO donors can restore NO deficit. HDLs have anti-atherogenic properties and are carriers of excessive cellular cholesterol via reverse cholesterol transport (RCT) pathway. Lipoprotein enrichment by anionic phosphatidylinositol (PI) increases the negative surface potential of lipoproteins and stimulate RCT. PI stimulates rapid flux and clearance of plasma choles-l by increased hepatic uptake. Objective: Regression of atherosclerosis stimulating RCT with experimental combination of NO donor in PI nanocapsules (AlphaX1). Methods: 30 rabbits fed with 2%cholesterol diet for 6 months After 6 m subdivided in 3 groups. G1-10 without treatment. G2-treated with AlphaX1 for 10 days, G3-treated for 20 days. 5 rabbits-control. Animals sacrificed after 10 and 20 days of treatment. Abdominal aorta, part snap frozen in cryostat-OilRedO staining, part exposed for morphology and electron microscopy. Results: Morphology (x100-x27000): G1-numerous vacuoles with neutral lipids and foam cells under endothelium, proliferation of solitary smooth muscle cells containing lipid vacuoles; G2-moderate deposition of lipid vacuoles &amp; foam cells in sub-endothelium, restoration of endothelium. G3-express reduction of lipid vacuoles &amp; foam cells, restoration of elastic fibers, regeneration of endothelium.OilRedO, C 1.4±0.2% G1 38.2±3.6%. G2 7.3±0.8%, G3 2.3±0.6%. Conclusion: Data shows evidence that AlphaX1 provide regeneration of endothelial cells, restoration of elastic fibers (probably due to regulation of fibulin5 by PI3K/Akt), anti-inflammatory effect, clearance of foam cells from neutral lipids and regression of atherosclerosis. AlphaX1 provide antiatherogenic properties of NO and PI, probably by reduction in cytokines production, decrease in adhesion molecules expression, monocyte-endothelium adhesion inhibition, increased cholesterol efflux and plasma clearance via hepatic uptake. AlphaX1 could be a potential new therapeutic agent for prophylaxis &amp; treatment of hyperlipidemia and atherosclerosis.

Atheroprotective Effect of Fucoidan in THP-1 Macrophages by Potential Upregulation of ABCA1.

Targeting foam cells reduces the risk and pathophysiology of atherosclerosis, of which they are one of its early hallmarks. The precise mechanism of action of fucoidan, a potential anti-atherogenic drug, is still unknown. Our objective was to assess the ability of fucoidan to regulate expression of ATP-binding cassette transporter A1 (ABCA1) in ox-LDL-induced THP-1 macrophages. Molecular docking was used to predict how fucoidan interacts with anti-foam cell markers, and further in vitro experiments were performed to evaluate the protective effect of fucoidan on modulating uptake and efflux of lipids. THP-1 macrophages were protected by 50 µg/mL of fucoidan and were then induced to form foam cells with 25 µg/mL of ox-LDL. Expression levels were assessed using RT-qPCR, and an Oil Red O stain was used to observe lipid accumulation in THP-1 macrophages. In addition, ABCA1 protein was examined by Western blot, and cellular cholesterol efflux was determined using fluorescently labeled cholesterol. Under a light microscope, decreased lipid accumulation in ox-LDL-induced-THP-1 macrophages pre-treated with fucoidan showed a significant effect, although it did not affect the expression of scavenger receptors (SR-AI and CD36). It is interesting to note that fucoidan dramatically increased the gene and protein expression of ABCA1, perhaps via the liver X receptor-α (LXR-α). Moreover, fucoidan's ability to increase and control the efflux of cholesterol from ox-LDL-induced THP-1 macrophages revealed how it may alter ABCA1's conformation and have a major effect on how it interacts with apolipoprotein A (ApoA1). In vitro results support a rationale for predicting fucoidan and its interaction with its receptor targets' predicted data, hence validating its anti-atherogenic properties and suggesting that fucoidan could be promising as an atheroprotective.

Metabolic-Dysfunction-Associated Steatotic Liver Disease-Its Pathophysiology, Association with Atherosclerosis and Cardiovascular Disease, and Treatments.

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease that affects more than a quarter of the global population and whose prevalence is increasing worldwide due to the pandemic of obesity. Obesity, impaired glucose metabolism, high blood pressure and atherogenic dyslipidemia are risk factors for MASLD. Therefore, insulin resistance may be closely associated with the development and progression of MASLD. Hepatic entry of increased fatty acids released from adipose tissue, increase in fatty acid synthesis and reduced fatty acid oxidation in the liver and hepatic overproduction of triglyceride-rich lipoproteins may induce the development of MASLD. Since insulin resistance also induces atherosclerosis, the leading cause for death in MASLD patients is cardiovascular disease. Considering that the development of cardiovascular diseases determines the prognosis of MASLD patients, the therapeutic interventions for MASLD should reduce body weight and improve coronary risk factors, in addition to an improving in liver function. Lifestyle modifications, such as improved diet and increased exercise, and surgical interventions, such as bariatric surgery and intragastric balloons, have shown to improve MASLD by reducing body weight. Sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to improve coronary risk factors and to suppress the occurrence of cardiovascular diseases. Both SGLT2i and GLP-1 have been reported to improve liver enzymes, hepatic steatosis and fibrosis. We recently reported that the selective peroxisome proliferator-activated receptor-alpha (PPARα) modulator pemafibrate improved liver function. PPARα agonists have multiple anti-atherogenic properties. Here, we consider the pathophysiology of MASLD and the mechanisms of action of such drugs and whether such drugs and the combination therapy of such drugs could be the treatments for MASLD.