Equivalence assessment of creams with quali-quantitative differences in light of the EMA and FDA regulatory framework.

EMA and FDA are upgrading guidelines on assessing the quality and the equivalence of topically applied drug products for developing copies of originator products and supporting post-marketing variations. For topical products having remarkably similar composition, both EMA and FDA accept the equivalence on the bases of the comparison of rheological properties and in vitro drug release constant (k) and skin permeation flux (J) values, instead of clinical studies. This work aims to evaluate the feasibility to expand this approach to variations of the composition of complex semi-solid preparations.

ASGR1 deficiency diverts lipids toward adipose tissue but results in liver damage during obesity.

Background: Asialoglycoprotein receptor 1 (ASGR1), primarily expressed on hepatocytes, promotes the clearance and the degradation of glycoproteins, including lipoproteins, from the circulation. In humans, loss-of-function variants of ASGR1 are associated with a favorable metabolic profile and reduced incidence of cardiovascular diseases. The molecular mechanisms by which ASGR1 could affect the onset of metabolic syndrome and obesity are unclear.

A Drosophila model targets Eiger/TNFα to alleviate obesity-related insulin resistance and macrophage infiltration.

Obesity is associated with various metabolic disorders, such as insulin resistance and adipose tissue inflammation (ATM), characterized by macrophage infiltration into adipose cells. This study presents a new Drosophila model to investigate the mechanisms underlying these obesity-related pathologies. We employed genetic manipulation to reduce ecdysone levels to prolong the larval stage.

Proteomics Studies Suggest That Nitric Oxide Donor Furoxans Inhibit In Vitro Vascular Smooth Muscle Cell Proliferation by Nitric Oxide-Independent Mechanisms.

Physiologically, smooth muscle cells (SMC) and nitric oxide (NO) produced by endothelial cells strictly cooperate to maintain vasal homeostasis. In atherosclerosis, where this equilibrium is altered, molecules providing exogenous NO and able to inhibit SMC proliferation may represent valuable antiatherosclerotic agents. Searching for dual antiproliferative and NO-donor molecules, we found that furoxans significantly decreased SMC proliferation in vitro, albeit with different potencies.

A Novel Drosophila Model to Investigate Adipose Tissue Macrophage Infiltration (ATM) and Obesity highlights the Therapeutic Potential of Attenuating Eiger/TNFα Signaling to Ameliorate Insulin Resistance and ATM.

Obesity is a global health concern associated with various metabolic disorders including insulin resistance and adipose tissue inflammation characterized by adipose tissue macrophage (ATM) infiltration. In this study, we present a novel model to investigate the mechanisms underlying ATM infiltration and its association with obesity-related pathologies. Furthermore, we demonstrate the therapeutic potential of attenuating Eiger/TNFα signaling to ameliorate insulin resistance and ATM.

Garbage in, toxic data out: a proposal for ethical artificial intelligence sustainability impact statements.

Data and autonomous systems are taking over our lives, from healthcare to smart homes very few aspects of our day to day are not permeated by them. The technological advances enabled by these technologies are limitless. However, with advantages so too come challenges.

Targeting of the Lipid Metabolism Impairs Resistance to BRAF Kinase Inhibitor in Melanoma.

Drug resistance limits the achievement of persistent cures for the treatment of melanoma, in spite of the efficacy of the available drugs. The aim of the present study was to explore the involvement of lipid metabolism in melanoma resistance and assess the effects of its targeting in cellular models of melanoma with acquired resistance to the BRAF-inhibitor PLX4032/Vemurafenib. Since transcriptional profiles pointed to decreased cholesterol and fatty acids synthesis in resistant cells as compared to their parental counterparts, we examined lipid composition profiles of resistant cells, studied cell growth dependence on extracellular lipids, assessed the modulation of enzymes controlling the main nodes in lipid biosynthesis, and evaluated the effects of targeting Acetyl-CoA Acetyltransferase 2 (ACAT2), the first enzyme in the cholesterol synthesis pathway, and Acyl-CoA Cholesterol Acyl Transferase (ACAT/SOAT), which catalyzes the intracellular esterification of cholesterol and the formation of cholesteryl esters.

Artichoke and bergamot extracts: a new opportunity for the management of dyslipidemia and related risk factors.

The relationship between low LDL-C (cholesterol associated with low-density lipoprotein) and a lower relative risk of developing cardiovascular disease (CVD) has been widely demonstrated. Although from a pharmacological point of view, statins, ezetimibe and PCSK inhibitors, alone or in combination are the front and center of the therapeutic approaches for reducing LDL-C and its CV consequences, in recent years nutraceuticals and functional foods have increasingly been considered as a valid support in the reduction of LDL-C, especially in patients with mild/moderate hyperlipidemia - therefore not requiring pharmacological treatment - or in patients intolerant to statins or other drugs. An approach also shared by the European Atherosclerosis Society (EAS).

Oxidized LDL-dependent pathway as new pathogenic trigger in arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is hallmarked by ventricular fibro-adipogenic alterations, contributing to cardiac dysfunctions and arrhythmias. Although genetically determined (e.g.

Treatment of dyslipidemia in kidney transplantation.

: Lipid disorders are frequent after kidney transplantation (KT) and KT recipients are considered at high- or very-high cardiovascular risk. Among many concurring factors, a major role is played by immunosuppressants.: General measures to manage lipid disorders first include physical activity and diet counseling.

LIPA gene mutations affect the composition of lipoproteins: Enrichment in ACAT-derived cholesteryl esters.

Background And Aims: Cholesteryl ester storage disease (CESD) due to LIPA gene mutations is characterized by hepatic steatosis, hypercholesterolemia and hypoalphalipoproteinemia, exposing affected patients to an increased cardiovascular risk. Further insights into the impact of LIPA gene mutations on lipid/lipoprotein metabolism are limited. Aim of the study was to investigate the effect of carrying one or two mutant LIPA alleles on lipoprotein composition and function.

Recombinant LCAT (Lecithin:Cholesterol Acyltransferase) Rescues Defective HDL (High-Density Lipoprotein)-Mediated Endothelial Protection in Acute Coronary Syndrome.

Objective- Aim of this study was to evaluate changes in LCAT (lecithin:cholesterol acyltransferase) concentration and activity in patients with an acute coronary syndrome, to investigate if these changes are related to the compromised capacity of HDL (high-density lipoprotein) to promote endothelial nitric oxide (NO) production, and to assess if rhLCAT (recombinant human LCAT) can rescue the defective vasoprotective HDL function. Approach and Results- Thirty ST-segment-elevation myocardial infarction (STEMI) patients were enrolled, and plasma was collected at hospital admission, 48 and 72 hours thereafter, at hospital discharge, and at 30-day follow-up. Plasma LCAT concentration and activity were measured and related to the capacity of HDL to promote NO production in cultured endothelial cells.

PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor.

Aims: PCSK9 loss of function genetic variants are associated with lower low-density lipoprotein cholesterol but also with higher plasma glucose levels and increased risk of Type 2 diabetes mellitus. Here, we investigated the molecular mechanisms underlying this association.

Methods And Results: Pcsk9 KO, WT, Pcsk9/Ldlr double KO (DKO), Ldlr KO, albumin AlbCre+/Pcsk9LoxP/LoxP (liver-selective Pcsk9 knock-out mice), and AlbCre-/Pcsk9LoxP/LoxP mice were used.

The dataset describes: Phenotypic changes induced by cholesterol loading in smooth muscle cells isolated from the aortae of C57BL/6 mice.

The data presented in this article is related to the research article entitled " (Castiglioni et al., 2017) [1]. This data describes the characterization of the phenotypic changes induced by cholesterol loading in smooth muscle cells (SMCs) isolated from the aortae of C57BL/6 mice.

ABCA1 and HDL are required to modulate smooth muscle cells phenotypic switch after cholesterol loading.

Background And Aims: Cholesterol-loaded smooth muscle cells (SMCs) modify their phenotypic behavior becoming foam cells. To characterize the role of ABCA1 and HDL in this process, we evaluated HDL effects on cholesterol-induced phenotypic changes in SMCs expressing or not ABCA1.

Methods: SMCs, isolated from the aortae of wild-type (WT) and Abca1 knock-out (KO) mice, were cholesterol-loaded using a "water-soluble cholesterol''.

Could changes in adiponectin drive the effect of statins on the risk of new-onset diabetes? The case of pitavastatin.

Statins represent the elective lipid-lowering strategy in hyperlipidemic and high cardiovascular-risk patients. Despite excellent safety and tolerability, reversible muscle-related and dose-dependent adverse events may decrease a patient's compliance. Large meta-analyses, post-hoc and genetic studies showed that statins might increase the risk of new-onset diabetes (NOD), particularly in insulin-resistant, obese, old patients.

Cyclosporine A impairs the macrophage reverse cholesterol transport in mice by reducing sterol fecal excretion.

Despite the efficacy in reducing acute rejection events in organ transplanted subjects, long term therapy with cyclosporine A is associated with increased atherosclerotic cardiovascular morbidity. We studied whether this drug affects the antiatherogenic process of the reverse cholesterol transport from macrophages in vivo. Cyclosporine A 50 mg/kg/d was administered to C57BL/6 mice by subcutaneous injection for 14 days.

Nitric oxide-donating atorvastatin attenuates neutrophil recruitment during vascular inflammation independent of changes in plasma cholesterol.

Purpose: Polymorphonuclear neutrophils, the first leukocytes to infiltrate the inflamed tissue, can make important contributions to vascular inflammatory processes driving the development of atherosclerosis. We herein investigated the effects of atorvastatin and NCX 6560 (a nitric oxide (NO)-donating atorvastatin derivative that has completed a successful phase 1b study) on neutrophilic inflammation in carotid arteries of normocholesterolemic rabbits subjected to perivascular collar placement.

Methods: Atorvastatin or NCX 6560 were administered orally (5 mg/kg/day or equimolar dose) to New Zealand White rabbits for 6 days, followed by collar implantation 1 h after the last dose.

Combined effects of ascorbic acid and phosphate on rat VSMC osteoblastic differentiation.

Background: Ascorbic acid (AA) supplementation has been suggested to afford erythropoietin hyporesponsiveness and high levels of ferritin in haemodialysis (HD) patients. However, little is known about the possible side effects of this policy on vascular calcification (VC). VC, induced by a high-phosphate and uraemic milieu, is characterized by a passive deposition of calcium-phosphate (Ca-P) and an active transformation of vascular smooth muscle cells (VSMCs) in osteoblastic-like cells.

Free cholesterol alters macrophage morphology and mobility by an ABCA1 dependent mechanism.

Objective: To investigate whether the morphological and functional changes typical of cell immobilization induced by free cholesterol (FC) accumulation in macrophages is related to the activity of the ATP-binding cassette transporter (ABCA1).

Methods And Results: FC loading induced actin rearrangement with ruffling and cell spreading in macrophages that normally express ABCA1, but to a significant lesser extent in ABCA1-KO mouse peritoneal macrophages (MPMs) and in normal cells upon pharmacological inhibition of ABCA1 with probucol. In ABCA1-KO MPMs and in probucol-treated J774 cell migration was inhibited to a lower extent by FC as compared to control cells.

Adding a statin to a combination of ACE inhibitor and ARB normalizes proteinuria in experimental diabetes, which translates into full renoprotection.

The capacity of renin-angiotensin system (RAS) inhibitors to delay progression of diabetic nephropathy depends on the time at which therapy is started. A multimodal intervention is required to afford renoprotection in overt diabetic nephropathy. Here we assessed the effects of maximal RAS inhibition by angiotensin-converting enzyme (ACE) inhibitor plus angiotensin II type 1 receptor blocker (ARB) in combination with statin in rats with overt diabetic nephropathy.

Do structural differences in statins correlate with clinical efficacy?

Purpose Of Review: Statins, by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase, decrease the synthesis not only of cholesterol but also of nonsteroidal mevalonate derivatives. While the first effect translates into plasma cholesterol reductions, the second is related to nonlipid-lowering (pleiotropic) properties. Purpose of this review is to assess the correlation between differences in statin structures and clinical effects.

Increased atherosclerosis and vascular inflammation in APP transgenic mice with apolipoprotein E deficiency.

Objective: Atherosclerosis is associated with Alzheimer's disease (AD) in humans, but the nature of this link is still elusive. Aim of this study was to investigate aortic atherosclerosis development in a mouse model with central nervous system (CNS) restricted beta-amyloid precursor protein (APP) overexpression.

Methods And Results: APP23 mice, overexpressing the Swedish mutated human APP selectively in the brain, were crossed with mice lacking apolipoprotein E (ApoE KO).