Roadmap for alleviating the manifestations of ageing in the cardiovascular system.

Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulatory system not only supplies nutrients and oxygen to all tissues of the human body and removes by-products but also builds the largest interorgan communication network, thereby serving as a gatekeeper for healthy ageing.

Neuronal PCSK9 regulates cognitive performances via the modulation of ApoER2 synaptic localization.

PCSK9 promotes the degradation of the low-density lipoprotein receptors and its inhibition by monoclonal antibodies or gene silencing approaches results in the reduction of plasma cholesterol levels coupled to that of cardiovascular events. Notably, while the liver is the primary source of circulating PCSK9, this protein is also abundantly expressed in the brain. However, its specific functions in the brain remain poorly understood.

Metabolic reprogramming of naïve regulatory T cells by IL-7 and IL-15 promotes their persistence and performance upon adoptive transfer.

Tregs for adoptive therapy are traditionally expanded ex vivo using high doses of IL-2. However, the final Treg product has limited survival once infused in patients, potentially affecting therapeutic effectiveness. Here, we tested a novel expansion protocol in which highly purified naïve Tregs were expanded with a combination of IL-7 and IL-15, in the absence of IL-2.

ASGR1 deficiency improves atherosclerosis but alters liver metabolism in ApoE mice.

The asialoglycoprotein receptor 1 (ASGR1), a multivalent carbohydrate-binding receptor that primarily is responsible for recognizing and eliminating circulating glycoproteins with exposed galactose (Gal) or N-acetylgalactosamine (GalNAc) as terminal glycan residues, has been implicated in modulating the lipid metabolism and reducing cardiovascular disease burden. In this study, we investigated the impact of ASGR1 deficiency (ASGR1 on atherosclerosis by evaluating its effects on plaque formation, lipid metabolism, circulating immunoinflammatory response, and circulating N-glycome under the hypercholesterolemic condition in ApoE-deficient mice. After 16 weeks of a western-type diet, ApoE/ASGR1 mice presented lower plasma cholesterol and triglyceride levels compared to ApoE.

Statin-associated regulation of hepatic PNPLA3 in patients without known liver disease.

Background And Objectives: Statins are used for metabolic dysfunction-associated steatotic liver disease (MASLD) (NAFLD) treatment, but their role in this context is unclear. Genetic variants of patatin-like phospholipase domain containing 3 (PNPLA3) are associated with MASLD susceptibility and statin treatment efficacy. Access to liver biopsies before established MASLD is limited, and statins and PNPLA3 in early liver steatosis are thus difficult to study.

Lysosomes in the immunometabolic reprogramming of immune cells in atherosclerosis.

Lysosomes have a central role in the disposal of extracellular and intracellular cargo and also function as metabolic sensors and signalling platforms in the immunometabolic reprogramming of macrophages and other immune cells in atherosclerosis. Lysosomes can rapidly sense the presence of nutrients within immune cells, thereby switching from catabolism of extracellular material to the recycling of intracellular cargo. Such a fine-tuned degradative response supports the generation of metabolic building blocks through effectors such as mTORC1 or TFEB.

Identification of regulatory networks and crosstalk factors in brown adipose tissue and liver of a cold-exposed cardiometabolic mouse model.

Background: Activation of brown adipose tissue (BAT) has gained attention due to its ability to dissipate energy and counteract cardiometabolic diseases (CMDs).

Methods: This study investigated the consequences of cold exposure on the BAT and liver proteomes of an established CMD mouse model based on LDL receptor-deficient (LdlrKO) mice fed a high-fat, high-sucrose, high-cholesterol diet for 16 weeks. We analyzed energy metabolism in vivo and performed untargeted proteomics on BAT and liver of LdlrKO mice maintained at 22 °C or 5 °C for 7 days.

Dietary fats as regulators of neutrophil plasticity: an update on molecular mechanisms.

Purpose Of Review: Contemporary guidelines for the prevention of cardio-metabolic diseases focus on the control of dietary fat intake, because of their adverse metabolic effects. Moreover, fats alter innate immune defenses, by eliciting pro-inflammatory epigenetic mechanisms on the long-living hematopoietic cell progenitors which, in the bone marrow, mainly give rise to short-living neutrophils. Nevertheless, the heterogenicity of fats and the complexity of the biology of neutrophils pose challenges in the understanding on how this class of nutrients could contribute to the development of cardio-metabolic diseases via specific molecular mechanisms activating the inflammatory response.

New insights into the therapeutic options to lower lipoprotein(a).

Background: Elevated levels of lipoprotein(a) [Lp(a)] represent a risk factor for cardiovascular disease including aortic valve stenosis, myocardial infarction and stroke. While the patho-physiological mechanisms linking Lp(a) with atherosclerosis are not fully understood, from genetic studies that lower Lp(a) levels protect from CVD independently of other risk factors including lipids and lipoproteins. Hereby, Lp(a) has been considered an appealing pharmacological target.

Rewiring Endothelial Sphingolipid Metabolism to Favor S1P Over Ceramide Protects From Coronary Atherosclerosis.

Background: Growing evidence correlated changes in bioactive sphingolipids, particularly S1P (sphingosine-1-phosphate) and ceramides, with coronary artery diseases. Furthermore, specific plasma ceramide species can predict major cardiovascular events. Dysfunction of the endothelium lining lesion-prone areas plays a pivotal role in atherosclerosis.

Regional Differences in the Small Intestinal Proteome of Control Mice and of Mice Lacking Lysosomal Acid Lipase.

The metabolic contribution of the small intestine (SI) is still unclear despite recent studies investigating the involvement of single cells in regional differences. Using untargeted proteomics, we identified regional characteristics of the three intestinal tracts of C57BL/6J mice and found that proteins abundant in the mouse ileum correlated with the high ileal expression of the corresponding genes in humans. In the SI of C57BL/6J mice, we also detected an increasing abundance of lysosomal acid lipase (LAL), which is responsible for degrading triacylglycerols and cholesteryl esters within the lysosome.

Long-Term Follow-Up of Custom-Made Porous Hydroxyapatite Cranioplasties: Analysis of Infections in Adult and Pediatric Patients.

In neurosurgery, cranioplasty (CP) stands as a pivotal surgical intervention, particularly following head trauma or various neurosurgical interventions. This study scrutinizes the intricacies of CP, emphasizing its prevalence and associated complications, with a specific focus on custom-made porous hydroxyapatite (PHA) implants. The investigation spans 687 patients (with 80 patients of pediatric age, less than 14 years old) across 26 neurosurgical centers in five European countries.

The Impact of Red Yeast Rice Extract Use on the Occurrence of Muscle Symptoms and Liver Dysfunction: An Update from the Adverse Event Reporting Systems and Available Meta-Analyses.

Red yeast rice (RYR) has a cholesterol-lowering effect due to the presence of bioactive components (monacolins, mainly monacolin K) that act by inhibiting the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The European Food Safety Authority (EFSA) assessed the use of RYR and, while pointing out several uncertainties regarding the available data, raised a warning related to the safety of RYR when used as a food supplement at a dose of monacolin as low as 3 mg/day. In their decision in June 2023, EFSA approved the use of monacolins from RYR at doses less than 3 mg/day.

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.

PITX2 gain-of-function mutation associated with atrial fibrillation alters mitochondrial activity in human iPSC atrial-like cardiomyocytes.

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide; however, the underlying causes of AF initiation are still poorly understood, particularly because currently available models do not allow in distinguishing the initial causes from maladaptive remodeling that induces and perpetuates AF. Lately, the genetic background has been proven to be important in the AF onset. iPSC-derived cardiomyocytes, being patient- and mutation-specific, may help solve this diatribe by showing the initial cell-autonomous changes underlying the development of the disease.

Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice.

Background: Matrix metalloproteinase 12 (MMP12) is a macrophage-secreted protein that is massively upregulated as a pro-inflammatory factor in metabolic and vascular tissues of mice and humans suffering from cardiometabolic diseases (CMDs). However, the molecular mechanisms explaining the contributions of MMP12 to CMDs are still unclear.

Methods: We investigated the impact of MMP12 deficiency on CMDs in a mouse model that mimics human disease by simultaneously developing adipose tissue inflammation, insulin resistance, and atherosclerosis.

The inhibition of inner mitochondrial fusion in hepatocytes reduces non-alcoholic fatty liver and improves metabolic profile during obesity by modulating bile acid conjugation.

Aims: Mitochondria are plastic organelles that continuously undergo biogenesis, fusion, fission, and mitophagy to control cellular energy metabolism, calcium homeostasis, hormones, sterols, and bile acids (BAs) synthesis. Here, we evaluated how the impairment of mitochondrial fusion in hepatocytes affects diet-induced liver steatosis and obesity.

Methods And Results: Male mice selectively lacking the key protein involved in inner mitochondrial fusion, optic atrophy 1 (OPA1) (OPA1ΔHep) were fed a high fat diet (HFD) for 20 weeks.

Dendritic cell immunoreceptor 2 (DCIR2) deficiency decreases hepatic conventional dendritic cell content but not the progression of diet-induced obesity.

Aims: Inflammatory pathways and immune system dysregulation participate in the onset and progression of cardiometabolic diseases. The dendritic cell immunoreceptor 2 (DCIR2) is a C-type lectin receptor mainly expressed by conventional type 2 dendritic cells, involved in antigen recognition and in the modulation of T cell response. Here, we investigated the effect of DCIR2 deficiency during the development of obesity.