Soft nanoparticles as antimicrobial agents and carriers of microbiocides for enhanced inhibition activity.

Antibiotic resistance continues to pose significant health challenges. Considering severe limitations in the discovery and supply of new antibiotics, there is an unmet need to design alternative and more effective strategies for addressing this global issue. Use of polymeric nanoparticles with cationic shell surfaces offers a highly promising approach to coupling their inherent bactericidal action with sustained delivery of small lipophilic microbicides.

Significance of the Wnt signaling pathway in coronary artery atherosclerosis.

Introduction: The progression of coronary atherosclerosis is an active and regulated process. The Wnt signaling pathway is thought to play an active role in the pathogenesis of several cardiovascular diseases; however, a better understanding of this system in atherosclerosis is yet to be unraveled.

Methods: In this study, real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting were used to quantify the expression of Wnt3a, Wnt5a, and Wnt5b in the human coronary plaque, and immunohistochemistry was used to identify sites of local expression.

Single Functional Group Platform for Multistimuli Responsivities: Tertiary Amine for CO/pH/ROS-Triggered Cargo Release in Nanocarriers.

The design of multistimuli-responsive soft nanoparticles (NPs) often presents synthetic complexities and limited breadth in exploiting changes surrounding physiological environments. Nanocarriers that could collectively take advantage of several endogenous stimuli can offer a powerful tool in nanomedicine. Herein, we have capitalized on the chemical versatility of a single tertiary amine to construct miktoarm polymer-based nanocarriers that respond to dissolved CO, varied pH, reactive oxygen species (ROS), and ROS + CO.

Adcy9 Gene Inactivation Improves Cardiac Function After Myocardial Infarction in Mice.

Background: Polymorphisms in the adenylate cyclase 9 (ADCY9) gene influence the benefits of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on cardiovascular events after acute coronary syndrome. We hypothesized that Adcy9 inactivation could improve cardiac function and remodelling following myocardial infarction (MI) in absence of CETP activity.

Methods: Wild-type (WT) and Adcy9-inactivated (Adcy9) male mice, transgenic or not for human CETP (tgCETP), were subjected to MI by permanent left anterior descending coronary artery ligation and studied for 4 weeks.

Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humans.

The large HDL particles generated by administration of cholesteryl ester transfer protein inhibitors (CETPi) remain poorly characterized, despite their potential importance in the routing of cholesterol to the liver for excretion, which is the last step of the reverse cholesterol transport. Thus, the effects of the CETPi dalcetrapib and anacetrapib on HDL particle composition were studied in rabbits and humans. The association of rabbit HDL to the LDL receptor (LDLr) in vitro was also evaluated.

High-density lipoprotein cholesterol efflux capacity in patients with obstructive sleep apnea and its relation with disease severity.

Background: Obstructive sleep apnea (OSA) is linked to an accelerated risk of cardiovascular disease (CVD). Some key CVD risk factors are present in patients suffering from OSA such as hypertension, inflammation, oxidative stress, and dyslipidemia. High-density lipoprotein (HDL) cholesterol efflux capacity (CEC) is proposed as a reliable biomarker of HDL function and the present study aimed to quantify this biomarker in patients with OSA.

Adenylate cyclase type 9 antagonizes cAMP accumulation and regulates endothelial signalling involved in atheroprotection.

Aims: The adenylate cyclase type 9 (ADCY9) gene appears to determine atherosclerotic outcomes in patients treated with dalcetrapib. In mice, we recently demonstrated that Adcy9 inactivation potentiates endothelial function and inhibits atherogenesis. The objective of this study was to characterize the contribution of ADCY9 to the regulation of endothelial signalling pathways involved in atherosclerosis.

A sex-specific evolutionary interaction between and .

Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 () gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction is still unknown. Here, we characterized selective signals at the locus associated with the pharmacogenomic response in human populations and we show that rs1967309 region exhibits signatures of positive selection in several human populations. Furthermore, we identified a variant in , rs158477, which is in long-range linkage disequilibrium with rs1967309 in the Peruvian population.

Colchicine reduces atherosclerotic plaque vulnerability in rabbits.

Background And Aims: The anti-inflammatory agent colchicine is gaining interest as a treatment for coronary artery disease. However, the effects of colchicine in atherosclerotic animal models are mostly unknown. This study aimed to evaluate colchicine in a rabbit model of atherosclerosis.

Inhibition of the 3CL Protease and SARS-CoV-2 Replication by Dalcetrapib.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 3CL protease is a promising target for inhibition of viral replication by interaction with a cysteine residue (Cys145) at its catalytic site. Dalcetrapib exerts its lipid-modulating effect by binding covalently to cysteine 13 of a cholesteryl ester transfer protein. Because 12 free cysteine residues are present in the 3CL protease, we investigated the potential of dalcetrapib to inhibit 3CL protease activity and SARS-CoV-2 replication.

ApoA-I mimetic does not improve left ventricular diastolic dysfunction in rabbits without aortic valve stenosis.

Background: We previously demonstrated that high-density lipoprotein (HDL) infusions may improve left ventricular diastolic dysfunction (LVDD) in an aortic valve stenosis (AVS) model. Whether the benefit was direct or mediated by the observed reduction in AVS severity is not clear. Here, we aimed to test the direct effect of an ApoA-I mimetic on LVDD in the absence of AVS.

Colchicine reduces lung injury in experimental acute respiratory distress syndrome.

The acute respiratory distress syndrome (ARDS) is characterized by intense dysregulated inflammation leading to acute lung injury (ALI) and respiratory failure. There are no effective pharmacologic therapies for ARDS. Colchicine is a low-cost, widely available drug, effective in the treatment of inflammatory conditions.

Cardiac inflammation and diastolic dysfunction in hypercholesterolemic rabbits.

Background: Left ventricular diastolic dysfunction (LVDD) is present in more than 50% of patients suffering from heart failure. LVDD animal models are limited and its underlying mechanisms remain largely unknown. Aortic valve stenosis (AVS) may cause LVDD, and we recently reported LVDD in an AVS rabbit model.

In Vivo Near-Infrared Fluorescence Imaging of Atherosclerosis Using Local Delivery of Novel Targeted Molecular Probes.

This study aimed to evaluate the feasibility and accuracy of a technique for atherosclerosis imaging using local delivery of relatively small quantities (0.04-0.4 mg/kg) of labeled-specific imaging tracers targeting ICAM-1 and unpolymerized type I collagen or negative controls in 13 rabbits with atheroma induced by balloon injury in the abdominal aorta and a 12-week high-cholesterol diet.

Synthetic Methodologies to Gold Nanoshells: An Overview.

Gold nanostructures that can be synthetically articulated to adapt diverse morphologies, offer a versatile platform and tunable properties for applications in a variety of areas, including biomedicine and diagnostics. Among several conformational architectures, gold nanoshells provide a highly advantageous combination of properties that can be fine-tuned in designing single or multi-purpose nanomaterials, especially for applications in biology. One of the important parameters for evaluating the efficacy of gold nano-architectures is their reproducible synthesis and surface functionalization with desired moieties.

Variants at the APOE /C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High-Density Lipoprotein Cholesterol.

Background Macrophage cholesterol efflux to high-density lipoproteins ( HDLs ) is the first step of reverse cholesterol transport. The cholesterol efflux capacity ( CEC ) of HDL particles is a protective risk factor for coronary artery disease independent of HDL cholesterol levels. Using a genome-wide association study approach, we aimed to identify pathways that regulate CEC in humans.

Examining the Role of and Treatment Directed at IL-1β in Atherosclerosis.

Purpose: The purpose of this review was to examine the role of IL-1β in the inflammatory process central to the development of atherosclerosis and to discuss current clinical evidence for treatments targeting IL-1β in coronary artery disease.

Recent Findings: IL-1β has been shown to modulate atherosclerotic plaque progression by upregulating the synthesis of adhesion molecules on endothelial cells, as well increasing activation and proliferation of vascular smooth muscle cells. Animal studies have further suggested that alterations in the balance between agonists and antagonists of IL-1β are important in promoting atherosclerosis.

Elevated level of lecithin:cholesterol acyltransferase (LCAT) is associated with reduced coronary atheroma burden.

Background And Aims: Lecithin:cholesterol acyltransferase (LCAT), a key enzyme in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT), has been associated with atheroprotection. However, its relation to plaque characteristics has not been confirmed to date. We aimed to determine the relationship between plasma LCAT mass concentration and plaque burden in a multi-center imaging study.

ADCY9 (Adenylate Cyclase Type 9) Inactivation Protects From Atherosclerosis Only in the Absence of CETP (Cholesteryl Ester Transfer Protein).

Background: Pharmacogenomic studies have shown that ADCY9 genotype determines the effects of the CETP (cholesteryl ester transfer protein) inhibitor dalcetrapib on cardiovascular events and atherosclerosis imaging. The underlying mechanisms responsible for the interactions between ADCY9 and CETP activity have not yet been determined.

Methods: Adcy9-inactivated ( Adcy9) and wild-type (WT) mice, that were or not transgenic for the CETP gene (CETPtg Adcy9 and CETPtg Adcy9), were submitted to an atherogenic protocol (injection of an AAV8 [adeno-associated virus serotype 8] expressing a PCSK9 [proprotein convertase subtilisin/kexin type 9] gain-of-function variant and 0.

Expression of the Frizzled receptors and their co-receptors in calcified human aortic valves.

The cellular mechanisms that induce calcific aortic stenosis are yet to be unraveled. Wnt signaling is increasingly being considered as a major player in the disease process. However, the presence of Wnt Frizzled (Fzd) receptors and co-receptors LRP5 and 6 in normal and diseased human aortic valves remains to be elucidated.

Dalcetrapib and anacetrapib differently impact HDL structure and function in rabbits and monkeys.

Inhibition of cholesteryl ester transfer protein (CETP) increases HDL cholesterol (HDL-C) levels. However, the circulating CETP level varies and the impact of its inhibition in species with high CETP levels on HDL structure and function remains poorly characterized. This study investigated the effects of dalcetrapib and anacetrapib, the two CETP inhibitors (CETPis) currently being tested in large clinical outcome trials, on HDL particle subclass distribution and cholesterol efflux capacity of serum in rabbits and monkeys.

Development of a new bioactivatable fluorescent probe for quantification of apolipoprotein A-I proteolytic degradation in vitro and in vivo.

Background And Aims: The potential benefits of high-density lipoproteins (HDL) against atherosclerosis are attributed to its major protein component, apolipoprotein A-I (apoA-I). Most of the apoA-I in the vascular wall appears to be in its lipid-poor form. The latter, however, is subjected to degradation by proteases localized in atherosclerotic plaques, which, in turn, has been shown to negatively impact its atheroprotective functions.

CETP: Pharmacogenomics-Based Response to the CETP Inhibitor Dalcetrapib.

High-density lipoproteins are involved in reverse cholesterol transport and possess anti-inflammatory and antioxidative properties. Paradoxically, CETP (cholesteryl ester transfer protein) inhibitors have been shown to increase inflammation as revealed by a raised plasma level of high-sensitivity C-reactive protein. CETP inhibitors did not improve clinical outcomes in large-scale clinical trials of unselected patients with coronary disease.

Beneficial Effects of Reconstituted High-Density Lipoprotein (rHDL) on Circulating CD34+ Cells in Patients after an Acute Coronary Syndrome.

Background: High-density lipoproteins (HDL) favorably affect endothelial progenitor cells (EPC). Circulating progenitor cell level and function are impaired in patients with acute coronary syndrome (ACS). This study investigates the short-term effects of reconstituted HDL (rHDL) on circulating progenitor cells in patients with ACS.