Towards precision medicine: defining and characterizing adipose tissue dysfunction to identify early immunometabolic risk in symptom-free adults from the GEMM family study

Interactions between macrophages and adipocytes are early molecular factors influencing adipose tissue (AT) dysfunction, resulting in high leptin, low adiponectin circulating levels and low-grade metaflammation, leading to insulin resistance (IR) with increased cardiovascular risk. We report the characterization of AT dysfunction through measurements of the adiponectin/leptin ratio (ALR), the adipo-insulin resistance index (Adipo-IRi), fasting/postprandial (F/P) immunometabolic phenotyping and direct F/P differential gene expression in AT biopsies obtained from symptom-free adults from the GEMM family study. AT dysfunction was evaluated through associations of the ALR with F/P insulin-glucose axis, lipid-lipoprotein metabolism, and inflammatory markers. A relevant pattern of negative associations between decreased ALR and markers of systemic low-grade metaflammation, HOMA, and postprandial cardiovascular risk hyperinsulinemic, triglyceride and GLP-1 curves was found. We also analysed their plasma non-coding microRNAs and shotgun lipidomics profiles finding trends that may reflect a pattern of adipose tissue dysfunction in the fed and fasted state. Direct gene differential expression data showed initial patterns of AT molecular signatures of key immunometabolic genes involved in AT expansion, angiogenic remodelling and immune cell migration. These data reinforce the central, early role of AT dysfunction at the molecular and systemic level in the pathogenesis of IR and immunometabolic disorders

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Microglial Cytokines Induce Invasiveness and Proliferation of Human Glioblastoma through Pyk2 and FAK Activation

Glioblastoma is the most aggressive brain tumor in adults. Multiple lines of evidence suggest that microglia create a microenvironment favoring glioma invasion and proliferation. Our previous studies and literature reports indicated the involvement of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) in glioma cell proliferation and invasion, stimulated by tumor-infiltrating microglia. However, the specific microglia-released factors that modulate Pyk2 and FAK signaling in glioma cells are unknown. In this study, 20 human glioblastoma specimens were evaluated with the use of RT-PCR and western blotting. A Pierson correlation test demonstrated a correlation (0.6–1.0) between the gene expression levels for platelet-derived growth factor β(PDGFβ), stromal-derived factor 1α (SDF-1α), IL-6, IL-8, and epidermal growth factor (EGF) in tumor-purified microglia and levels of p-Pyk2 (Y579/Y580) and p-FAK(Y925) in glioma cells. siRNA knockdown against Pyk2 or FAK in three primary glioblastoma cell lines, developed from the investigated specimens, in combination with the cytokine receptor inhibitors gefitinib (1 μM), DMPQ (200 nM), and burixafor (1 μM) identified EGF, PDGFβ, and SDF-1α as key extracellular factors in the Pyk2- and FAK-dependent activation of invadopodia formation and the migration of glioma cells. EGF and IL-6 were identified as regulators of the Pyk2- and FAK-dependent activation of cell viability and mitosis

Angiotensin II: Cardioprotection in Young and Aged Rats

Angiotensin II preconditioning (APC) has been shown to reproduce the cardioprotective effects of ischemic preconditioning (IPC). However, the molecular mechanisms mediating the effects of APC remain unknown. In this study, Langendorff-perfused rat hearts were subjected to IPC, APC, or their combination (IPC/APC) followed by ischemia/reperfusion (IR). The following variables were determined: left-ventricular developed pressure (LVDP), the first derivative of developed pressure (dP/dt), the rate pressure product (RPP), and lactate dehydrogenase (LDH). Infarct size (IS) was determined in a subset of hearts at the end of the perfusion protocols. IPC, and less potently APC, significantly increased the percent recoveries of LVDP, the dP/dt, and RPP compared with control. Furthermore, the post-ischemic recovery of the heart was significantly higher for IPC/APC compared with IPC or APC. The improvements in cardiac function by IPC, APC, and IPC/APC were associated with similar reductions in LDH release and IS. These results indicate that APC and IPC interact through mechanisms that protect the heart and improve cardiac function after IR. To determine whether the actions of APC and IPC on cardiac function depend on PKC-dependent mechanisms, the translocation of PKCϵ, PKCδ, Akt, ERK1/2, JNK, p38 MAPK and GSK-3β to mitochondria was determined. Significant increases in mitochondrial PKCϵ/PKCδ ratio, Akt, ERK1/2, JNK, and inhibition of permeability transition pore (mPTP) opening were observed. Chelerythrine, a pan-PKC inhibitor, abolished the enhancements of PKCδ but increased PKCδ expression, and inhibited Akt, ERK1/2, and JNK protein levels. The drug did not affect on the APC- and IPC/APC-induced cardioprotection but enhanced the post-ischemic LVDP in controls. Losartan, an angiotensin II type 1 receptor (AT1-R) blocker, abolished the APC-stimulated increase of LVDP and reduced PKCϵ, Akt, ERK1/2, JNK, and p38. Both drugs reduced ischemic contracture and LDH release and abolished the inhibition of mPTP by the preconditioning. Chelerythrine also prevented the reduction of IS by APC and IPC/APC. These results suggest that the cardioprotection induced by APC and IPC/APC involves an AT1-R-dependent translocation of PKCϵ and survival kinases to the mitochondria leading to mPTP inhibition. In chelerythrine-treated hearts, however, alternate mechanisms appear to maintain cardiac function. To evaluate the role that mitochondrial AT1-Rs and angiotensin II type 2 receptors (AT2-Rs) play in APC, losartan (L, AT1-R blocker), PD 123,319 (PD, AT2-R blocker) or their combination (L+PD), were infused before the preconditioning protocols. The following variables were evaluated: mitochondrial AT1-R, AT2-R, PKCϵ, PKCδ, Akt, PKG-1, MAPKs (ERK1/2, JNK, p38), mitochondrial respiration, cardiac function, and IS. The results indicate that expression of mitochondrial AT1-Rs and AT2-Rs were enhanced by APC 1.91-fold and 2.32-fold, respectively. Expression of AT2-R was abolished by PD but not by L, whereas the AT1-R levels were abrogated by both blockers. The AT1-R response profile to L and PD was also shared by PKCϵ, Akt, MAPKs, and PKG-1, but not by PKCδ. A marked increase in state 3 (1.84-fold) and respiratory control index (1.86-fold) of mitochondria was observed with PD regardless of L treatment. PD also enhanced the post-ischemic recovery of RPP by 74% (p < 0.05) compared with APC alone. Losartan, however, inhibited the rate pressure product (RPP) by 44% (p < 0.05) before IR and reduced the APC-induced increase of post-ischemic cardiac recovery by 73% (p < 0.05). Finally, L enhanced the reduction of IS by APC through a PD-sensitive mechanism. These findings suggest that APC upregulates angiotensin II receptors in mitochondria and that AT2-Rs are cardioprotective through their permissive action on AT1-R signaling and the suppression of cardiac function. To examine whether mitochondria-generated reactive oxygen species (ROS) play a crucial role in the loss of cardioprotection in aging, the effects of XJB-5-131 (XJB), a mitochondria-targeted ROS and electron scavenger, on cardiac resistance to ischemia-reperfusion (IR)-induced oxidative stress in aged rats was determined. In this study male adult (5-month old) and aged (29-month old) Fischer Brown Norway (F344/BN) rats were randomly assigned to the following groups: adult (A), adult+XJB (AX), aged (O), and aged+XJB (OX). XJB was administered 3 times per week (3mg/kg body weight, IP) for four weeks. At the end of the treatment period, LVDP and RPP were determined prior, during and after IR. Ca2+-induced swelling, an indicator of permeability transition pore (mPTP) opening, was determined in isolated mitochondria at the end of the reperfusion period. XJB improved post-ischemic recovery of aged hearts, as evidenced by greater LVDP and RPP than the untreated, aged-matched group. The state 3 respiration rates at complexes I, II and IV of mitochondria isolated from XJB-treated aged hearts were 57% (P < 0.05), 25% (P < 0.05) and 28% (P < 0.05), respectively, higher than controls. (Abstract shortened by ProQuest.

Microglial Cytokines Induce Invasiveness and Proliferation of Human Glioblastoma through Pyk2 and FAK Activation

Glioblastoma is the most aggressive brain tumor in adults. Multiple lines of evidence suggest that microglia create a microenvironment favoring glioma invasion and proliferation. Our previous studies and literature reports indicated the involvement of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) in glioma cell proliferation and invasion, stimulated by tumor-infiltrating microglia. However, the specific microglia-released factors that modulate Pyk2 and FAK signaling in glioma cells are unknown. In this study, 20 human glioblastoma specimens were evaluated with the use of RT-PCR and western blotting. A Pierson correlation test demonstrated a correlation (0.6–1.0) between the gene expression levels for platelet-derived growth factor β(PDGFβ), stromal-derived factor 1α (SDF-1α), IL-6, IL-8, and epidermal growth factor (EGF) in tumor-purified microglia and levels of p-Pyk2 (Y579/Y580) and p-FAK(Y925) in glioma cells. siRNA knockdown against Pyk2 or FAK in three primary glioblastoma cell lines, developed from the investigated specimens, in combination with the cytokine receptor inhibitors gefitinib (1 μM), DMPQ (200 nM), and burixafor (1 μM) identified EGF, PDGFβ, and SDF-1α as key extracellular factors in the Pyk2- and FAK-dependent activation of invadopodia formation and the migration of glioma cells. EGF and IL-6 were identified as regulators of the Pyk2- and FAK-dependent activation of cell viability and mitosis

Prostate cancer mortality according to marginalization status in Mexican states from 1980 to 2013

Objective.To assess prostate cancer (PC) mortality in Mexico from 1980 to 2013, according to the state marginalization level. Materials and methods. Using age-adjusted rates in men ≥ 40 years old, we estimated trends and agecohort-period effects of PC mortality from 1980-2013 according to state marginalization status by using a joinpoint regression model and a Poisson regression model proposed by Holford. Results. The PC mortality risk has increased nationwide at a constant rate (2% annually) during the past 13 years. The highest annual increase was observed among states with very high (4.4%) and high (7.7%) marginalization rates. In contrast, states with very low levels of marginaliza- tion showed a significant reduction of 1.5% per year. The main changes were observed in the 1945-1950 birth year cohorts. Conclusions. Differences in PC mortality across regions of Mexico may reflect differences in the timing of the diagnosis and treatment of PC. DOI: http://dx.doi.org/10.21149/spm.v58i2.778