New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Cholesterol regulates mitochondrial raft-like domains during TNF/Fas-mediated hepatocellular apoptosis

Trabajo presentado a la 51st International Conference on the Bioscience of Lipids (ICBL) celebrada en Bilbao del 7 al 11 de septiembre de 2010.Lipid rafts constitute distinctive domains of biological membranes characterized by a specific lipid composition enriched in cholesterol and sphingolipids, which determine their detergent insolubility. These domains are thought to play a critical role in signal transduction and apoptosis, particularly in the plasma membrane by providing a platform for specific interactions of membrane receptors with their corresponding ligands and adaptor molecules. However, during death receptor (Fas/TNF)-mediated apoptosis of lymphocytes mitochondrial raft-like domains have been described and characterized by a multimolecular signaling complex that recruits proapoptotic Bcl-2 family proteins. Since cholesterol is a key component of raft-like domains and its trafficking to mitochondria has been shown to regulate hepatocellular susceptibility to TNF/Fas, the purpose of this study was to examine the role of cholesterol in the regulation of mitochondrial raft-like domains. [Methods]: Hepatic mitochondrial fractions were prepared from models of hepatic cholesterol loading, including cholesterol or alcohol feeding, transgenic Tg-SREBP-2 mice and NPC1 knockout mice. Mitochondrial cholesterol was determined by HPLC, while ganglioside GD3 was analyzed by immunoelectron microscopy and immunoTLC. Detergent soluble and insoluble mitochondrial fractions were processed for Western blotting for caveolin-1, human Fis 1 proteins (hFis1) and VDAC-1. [Results]: hFis1 and VDAC-1 levels in detergent-insoluble fractions were higher in mitochondria from mice fed the hypercholesterolemic diet (MitH) compared to fractions of control mice (MitC). Furthermore, cholesterol enrichment was associated with enhanced GD3 levels as examined by immunostaining and immunoelectron microscopy in MitH fractions. Interestingly, caveolin-1 was present in detergent-insoluble mitochondrial fractions only in MitH but not in MitC samples. Similar findings regarding the association of cholesterol and GD3, and the presence of hFis1, VDAC-1 and caveolin-1 in detergent-insoluble fractions were observed in mitochondria from Tg-SREBP-2 and NPC1 KO mice. In all these models, hepatocytes were highly susceptible to TNF/Fas-mediated apoptosis that was accompanied by increased GD3 levels and recruitment of Bax. [Conclusions]: These findings indicate the existence of raft-like domains in hepatic mitochondria in cholesterol loading models, which may be of significance in steatohepatitis due to the hepatocellular sensitization to TNF/Fas. The findings showing the correlation of mitochondrial caveolin-1 and cholesterol levels, suggest a potential role caveolin-1 in mitochondrial cholesterol downregulationPeer Reviewe

DDDR-32. A NEW IMMUNOMODULATORY FUNCTION OF PYRIDO-PYRIMIDINE DERIVATIVES TO IMPAIR METASTATIC GROUP 3 MEDULLOBLASTOMA IN VIVO

Medulloblastoma (MB) is an embryonal tumor of the cerebellum consti- tuting ~ 20% of pediatric brain tumors. To date, four MB molecular groups (further stratified in twelve subtypes) have been described. Among them, Groups 3 and Group 4 MB have the poorest prognosis due to their high metastatic potential. Recently, we have reported a metastatic axis driven by Prune1 overexpression in MB Group3 characterized by canonical TGF-β signaling enhancement and epithelial-mesenchymal transition. Here, we have developed a new not toxic pyrido-pyrimidine derivative with the ability to impair Prune-1-driven-axis, thus ameliorating the survival rate of a murine model of metastatic MB Group3 characterized by overexpression of human Prune1 gene in the cerebellum (under the control of MATH1 promoter). Of importance, this small molecule also is showing immunomodulatory functions thus inhibiting the conversion of tumor-infiltrating T lymphocytes (TILs) to immunosuppressive regulatory T cells (Tregs) in vivo via impairing the secretion of inflammatory cytokines from MB cells. Furthermore, this molecule can also act synergistically with the currently used modified- intensity chemotherapy (e.g. in PNET5 use of Vincristine) or potential in the combination with epigenetics drugs (e.g., LSD1/KDM1A inhibitors). Altogether these results are of importance for future targeted therapies of high-risk metastatic MB

Loss of Detection of sgN Precedes Viral Abridged Replication in COVID-19-Affected Patients—A Target for SARS-CoV-2 Propagation

The development of prophylactic agents against the SARS-CoV-2 virus is a public health priority in the search for new surrogate markers of active virus replication. Early detection markers are needed to follow disease progression and foresee patient negativization. Subgenomic RNA transcripts (with a focus on sgN) were evaluated in oro/nasopharyngeal swabs from COVID-19-affected patients with an analysis of 315 positive samples using qPCR technology. Cut-off Cq values for sgN (Cq O-methyl antisense RNA (related to the sgN sequence) can impair SARS-CoV-2 N protein synthesis, viral replication, and syncytia formation in human cells (i.e., HEK-293T cells overexpressing ACE2) upon infection with VOC Alpha (B.1.1.7)-SARS-CoV-2 variant, defining the use that this procedure might have for future therapeutic actions against SARS-CoV-2

Upregulated function of mitochondria-associated ER membranes in Alzheimer disease

Item does not contain fulltextAlzheimer disease (AD) is associated with aberrant processing of the amyloid precursor protein (APP) by gamma-secretase, via an unknown mechanism. We recently showed that presenilin-1 and -2, the catalytic components of gamma-secretase, and gamma-secretase activity itself, are highly enriched in a subcompartment of the endoplasmic reticulum (ER) that is physically and biochemically connected to mitochondria, called mitochondria-associated ER membranes (MAMs). We now show that MAM function and ER-mitochondrial communication-as measured by cholesteryl ester and phospholipid synthesis, respectively-are increased significantly in presenilin-mutant cells and in fibroblasts from patients with both the familial and sporadic forms of AD. We also show that MAM is an intracellular detergent-resistant lipid raft (LR)-like domain, consistent with the known presence of presenilins and gamma-secretase activity in rafts. These findings may help explain not only the aberrant APP processing but also a number of other biochemical features of AD, including altered lipid metabolism and calcium homeostasis. We propose that upregulated MAM function at the ER-mitochondrial interface, and increased cross-talk between these two organelles, may play a hitherto unrecognized role in the pathogenesis of AD

Short-term effectiveness of dapagliflozin versus DPP-4 inhibitors in elderly patients with type 2 diabetes: a multicentre retrospective study

Aim To compare effectiveness of dapagliflozin versus DPP-4 inhibitors on individualized HbA1c targets and extra-glycaemic endpoints among elderly patients with type 2 diabetes (T2D).Methods This was a multicentre retrospective study on patients aged 70-80 years with HbA1c above individualized target and starting dapagliflozin or DPP-4 inhibitors in 2015-2017. The primary outcome was the proportion reaching individualized HbA1c targets. Confounding by indication was addressed by inverse probability of treatment weighting (IPTW), multivariable adjustment (MVA), or propensity score matching (PSM).Results Patients initiating dapagliflozin (n = 445) differed from those initiating DPP-4i (n = 977) and balance between groups was achieved with IPTW or PSM. The median follow-up was 7.5 months and baseline HbA1c was 8.3%. A smaller proportion of patients initiating dapagliflozin attained individualized HbA1c target as compared to those initiating DPP-4 inhibitors (RR 0.73, p &lt; 0.0001). IPTW, MVA, and PSM yielded similar results. Between-group difference in the primary outcome was observed among patients with lower eGFR or longer disease duration. Dapagliflozin allowed greater reductions in body weight and blood pressure than DPP-4 inhibitors.Conclusions Elderly patients with T2D initiating dapagliflozin had a lower probability of achieving individualized HbA1c targets than those initiating DPP-4 inhibitors but displayed better improvements in extra-glycaemic endpoints