👤 Maria Pino

To date, despite the new lipid-lowering drugs, some subjects do not reach LDL-cholesterol and/or lipoprotein(a) [Lp(a)] goals and lipoprotein apheresis (LA) plays a role in atherosclerosis prevention. The aim of this study is to paint a portrait of the current LA activity in Italy, collecting data via an electronic survey. Forty-seven centers were contacted, data from 142 patients (male 67%) were obtained from 15 sites. Two sites had discontinued LA treatment. In the active sites, a median of 17 [14-26] LA treatment/patient per year was performed; 7/13 sites used more than one LA system, with venous vascular access used in 87% of cases. High Lp(a) plasma concentrations (> 60 mg/dL or ≥ 145 nmol/L) were recorded in 73/142 patients; 14/36 homozygous familial hypercholesterolemia patients were on lomitapide or evinacumab therapy. The PORTRAIT survey would like to promote a network to better manage the patients on chronic LA. Show less

White adipose tissue (WAT) expansion occurs through generation of new adipocytes from adipose progenitor cells (APC). The objective of this study was to characterize and validate a new transcriptional profile of APC. Single-cell (sc)/nuclei (sn) RNA-Seq was performed on nuclei from whole WAT (n = 20), cells from WAT stromal vascular fraction (n = 5), and cultured APC in vitro (n = 8) using ICELL8 smart-Seq technology. Additional snRNA-Seq was performed on WAT using 10x genomic platform. Pseudotime analyses and differentiation of hiPSCs was used to track the temporal patterns of novel gene signatures. Immunohistochemistry was performed to validate a new marker. A pre-adipocyte population was found across the four independent datasets that expressed known pre-adipocyte markers (ZNF423 and DLK1) in addition to genes typically associated with neurogenes (DPP10, PTRPT, CTNNA2, NRXN3, CTNNA2, PTPRD, CNTNAP2 and RBFOX1). The expression of these genes were temporally regulated with adipocyte differentiation. Immunohistochemistry analyses confirmed these pre-adipocytes are located in the neurovascular niche of WAT but are not neurons or endothelial cells. This work has defined a new transcriptional signature of pre-adipocytes in human subcutaneuous WAT that are distinct from mesencyhmal stem cell populations and represent novel targets for WAT expansion. Show less

Declines in skeletal muscle and cognitive function in older adults have been linked to abnormalities in abdominal subcutaneous adipose tissue (ASAT), yet the underlying molecular mediators remain poorly understood. Here, leveraging ASAT transcriptomics and explant-conditioned media proteomics from participants in the Study of Muscle, Mobility and Aging (SOMMA; age ≥70 years, n = 229), we identified ASAT gene clusters and secreted proteins strongly associated with comprehensive assessments of physical and cognitive function in older adults. ASAT inflammation and secreted immunoglobulins were identified as key signatures of aging-associated physical and cognitive performance limitations. Systems genetics analysis confirmed secreted-SERPINF1 as a negative regulator of skeletal muscle contraction and highlighted its potential role in inducing inflammation in the heart in silico. Additionally, novel ASAT-secreted proteins such as NID2 and APOA4 were implicated in mediating ASAT crosstalk with skeletal muscle and brain in silico. Our framework provides insights into ASAT-driven tissue crosstalk underlying physical and cognitive performance in older adults and offers a valuable resource for understanding the role of ASAT in human aging. Show less

Declines in skeletal muscle and cognitive function in older adults have been linked to abnormalities in abdominal subcutaneous adipose tissue (ASAT), yet the underlying molecular mediators remain poorly understood. Here, leveraging ASAT transcriptomics and explant-conditioned media proteomics from participants in the Study of Muscle, Mobility and Aging (SOMMA; age ≥70 years, n = 229), we identified ASAT gene clusters and secreted proteins strongly associated with comprehensive assessments of physical and cognitive function in older adults. ASAT inflammation and secreted immunoglobulins were identified as key signatures of aging-associated physical and cognitive performance limitations. Systems genetics analysis confirmed secreted-SERPINF1 as a negative regulator of skeletal muscle contraction and highlighted its potential role in inducing inflammation in the heart Show less

Familial hypercholesterolemia (FH) is characterized by elevated LDL-C and an increased risk of premature cardiovascular events. Inclisiran is a small interfering RNA that inhibits hepatic PCSK9 synthesis and promotes LDL-C clearance by enhancing LDLR expression on hepatocytes. This study aimed to evaluate the efficacy of six-months add-on inclisiran on lipid profile and PWV in FH; furthermore, we investigated the association between LDL-C reduction and PWV variation. This prospective observational study involved 78 genetically confirmed FH subjects with an LDL-C off-target despite high-intensity statins plus ezetimibe. All subjects obtained biochemical analysis and PWV evaluation at baseline and after six months add-on inclisiran. After six months add-on inclisiran, 41 % of subjects achieved LDL-C targets. Significant reductions of LDL-C (-41.5 %, p < 0.001), ApoB (-33.7 %, p < 0.01), Non-HDL-C (-35.9 %, p < 0.001), and Lp(a) (-18 %, p < 0.01) were observed, while PWV improved by 14.4 % (p < 0.001). In a secondary analysis, the Primary prevention group showed a higher prevalence of subjects on LDL-C target than the Secondary prevention group (59 % vs 23.1 %, p < 0.001). Both groups exhibited significant improvements of lipid profile and PWV (Δ - 14.1 %, p < 0.01 and Δ - 14.6 %, p < 0.001, respectively). Linear regression showed a significant association between ΔPWV and ΔLDL-C in the whole study population as well as in the Primary and Secondary prevention groups (p for all <0.001). Inclisiran significantly improved lipid profile and PWV in FH subjects. ΔPWV was significantly associated with ΔLDL-C. Show less

Familial hypercholesterolemia (FH) is less rare than one might think and, despite highly effective lipid-lowering therapies (LLT), more than half of the patients treated do not reach the lipid target indicated by the guidelines. In these patients, lipoprotein apheresis (LA) is the most effective tool to lowering apo-B containing atherogenic lipoproteins. In own center, since 1994, thanks to routinely cascade testing performed in patients who start LA, we have identified a pediatric population (30 subjects) that we analyzed retrospectively. Cascade screening, performed in subject with premature cardiovascular events or inherited dyslipidemias, is an effective approach to identified pediatric FH, a condition that pediatricians should also be aware. A dedicate network is required to investigate the involved genetic mutations and to set up a management program, including lipoprotein (a) measurement and subclinical atherosclerosis evaluation. Moreover, it is important that medical staff use a therapeutic pathway to help patients overcome discomfort associated with disease and chronic LLT, as well as improve adherence to lipid-lowering drugs. Show less

Familial hypercholesterolemia (FH) is characterized by lifelong elevated LDL-C levels and increased cardiovascular risk. PCSK9 inhibitors (PCSK9i) reduce LDL-C and Lp(a), however, the effect of dual lipid reduction on mechanical vascular function remains unclear. The aim of this study was to evaluate the efficacy of PCSK9i in reducing LDL-C and Lp(a) and to assess the relationship between the dual lipid reduction and the mechanical vascular profile improvement in FH subjects. This prospective observational study included 301 genetically confirmed FH subjects treated with PCSK9i added to high-intensity statins and ezetimibe. Biochemical and PWV measurements were performed at baseline and after six months. Subjects were stratified into four groups based on median values of ΔLDL-C and ΔLp(a). After six months of add-on PCSK9i, 44.9% of FH subjects achieved their LDL-C targets. Reductions were observed in LDL-C (− 49.8%, Dual lipid reduction with PCSK9i was associated with a pronounced mechanical vascular profile improvement in FH subjects; however, an intensive Lp(a) reduction may be needed to achieve a greater mechanical vascular benefit. Show less

Imidacloprid (IMI), the most widely used worldwide neonicotinoid biocide, produces cognitive disorders after repeated and single treatment. However, little was studied about the possible mechanisms that produce this effect. Cholinergic neurotransmission regulates cognitive function. Most cholinergic neuronal bodies are present in the basal forebrain (BF), regulating memory and learning process, and their dysfunction or loss produces cognition decline. BF SN56 cholinergic wild-type or acetylcholinesterase (AChE), β-amyloid-precursor-protein (βAPP), Tau, glycogen-synthase-kinase-3-beta (GSK3β), beta-site-amyloid-precursor-protein-cleaving enzyme 1 (BACE1), and/or nuclear-factor-erythroid-2-related-factor-2 (NRF2) silenced cells were treated for 1 and 14 days with IMI (1 μM-800 μM) with or without recombinant heat-shock-protein-70 (rHSP70), recombinant proteasome 20S (rP20S) and with or without N-acetyl-cysteine (NAC) to determine the possible mechanisms that mediate this effect. IMI treatment for 1 and 14 days altered cholinergic transmission through AChE inhibition, and triggered cell death partially through oxidative stress generation, AChE-S overexpression, HSP70 downregulation, P20S inhibition, and Aβ and Tau peptides accumulation. IMI produced oxidative stress through reactive oxygen species production and antioxidant NRF2 pathway downregulation, and induced Aβ and Tau accumulation through BACE1, GSK3β, HSP70, and P20S dysfunction. These results may assist in determining the mechanisms that produce cognitive dysfunction observed following IMI exposure and provide new therapeutic tools. Show less

Cadmium (Cd) produces cognition decline following single and repeated treatment, although the complete mechanisms are still unrevealed. Basal forebrain (BF) cholinergic neurons innervate the cortex and hippocampus, regulating cognition. Cd single and repeated exposure induced BF cholinergic neuronal loss, partly through thyroid hormones (THs) disruption, which may cause the cognition decline observed following Cd exposure. However, the mechanisms through which THs disruption mediate this effect remain unknown. To research the possible mechanisms through which Cd-induced THs deficiency may mediate BF neurodegeneration, Wistar male rats were treated with Cd for 1- (1 mg/kg) or 28-days (0.1 mg/kg) with or without triiodothyronine (T3, 40 μg/kg/day). Cd exposure promoted neurodegeneration, spongiosis, gliosis and several mechanisms related to these alterations (increased H Show less

Acute and long-term paraquat (PQ) exposure produces hippocampal neurodegeneration and cognition decline. Although some mechanisms involved in these effects were found, the rest are unknown. PQ treatment, for 1 and 14 days, upregulated interferon-gamma signaling, which reduced insulin levels and downregulated the insulin pathway through phosphorylated-c-Jun N-terminal-kinase upregulation, increasing glucose levels and the production of Aβ Show less