Iterleukin 1 alpha is a marker of endothelial cellular senescent

BACKGROUND: The functional changes associated with endothelial senescence may be involved in human aging and age-related vascular disorders. Since the inflammatory cytokine interleukin (IL-)1 inhibits endothelial growth, we evaluated the expression of IL-1α, IL-1β and their antagonist, the IL-1 receptor antagonist (IL-1ra), in endothelial in vitro senescence and quiescence. We also examined the expression of IL-1α in human senescent and progeric fibroblasts. RESULTS: We found that the overexpression of IL-1α specifically characterizes endothelial senescence. No modulation of this cytokine was observed in endothelial quiescence and in senescent or progeric human fibroblasts. The expression of IL-1β and IL-1ra was also assessed and found not to be affected by senescence. CONCLUSION: Our results indicate that a dysfunction of the cytokine network associates with aging and point to a specific role of IL-1α in endothelial senescence

Association of candidate pharmacogenetic markers with platinum-induced ototoxicity:PanCareLIFE dataset

Genetic association studies suggest a genetic predisposi- tion for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase ( TPMT ) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross- sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnos- tic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes ( ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, and ACYP2 ) were genotyped. The genotype and phenotype data represent a resource for conducting meta- analyses to derive a more precise pooled estimate of the ef- fects of genes on the risk of hearing loss due to platinum treatment

Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset

Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 x 10(-13)) and African ancestries (rs2066702; P = 2.2 x 10(-9)). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.Peer reviewe

From East to West and Return: A Western Interpretation of Acupuncture

Acupuncture, a complementary therapy originated in China over 3000 years ago, is widely practiced in western countries. There is an urgent need to define the mechanisms underlying some clinical effects obtained by acupuncture. A placebo effect is sustained by neuroimaging evidence indicating the activation of areas in the brain that are involved in expectation after real and sham acupuncture. However, only real acupuncture modulates the activity of specific regions in the brain some of which involved in the perception of pain. Basic research applied to the field of acupuncture is beginning to offer a scientific interpretation to these events. Indeed, the stimulation of acupoints alters the architecture of the connective tissue and this local mechanical stress is delivered to the keratinocytes, mast cells and fibroblasts, which react in several manners, including the release of various molecules that act on peripheral nerve endings. Consequently, locally generated signals can be transmitted to the neural centers. In the light of these achievements and urging more research in the field, it can be concluded that there are common denominators between acupuncture and western medicine

Magnesium homeostasis in colon carcinoma LoVo cells sensitive or resistant to doxorubicin

Neoplastic cells accumulate magnesium, an event which provides selective advantages and is frequently associated with TRPM7overexpression. Little is known about magnesium homeostasis in drug-resistant cancer cells. Therefore, we used the colon cancer LoVo cell model and compared doxorubicin-resistant to sensitive cells. In resistant cells the concentration of total magnesium is higher while its influx capacity is lower than in sensitive cells. Accordingly, resistant cells express lower amounts of the TRPM6 and 7, both involved in magnesium transport. While decreased TRPM6 levels are due to transcriptional regulation, post-transcriptional events are involved in reducing the amounts of TRPM7. Indeed, the calpain inhibitor calpeptin markedly increases the levels of TRPM7 in resistant cells. In doxorubicin-sensitive cells, silencing TRPM7 shifts the phenotype to one more similar to resistant cells, since in these cells silencing TRPM7 significantly decreases the influx of magnesium, increases its intracellular concentration and increases resistance to doxorubicin. On the other hand, calpain inhibition upregulates TRPM7, decreases intracellular magnesium and enhances the sensitivity to doxorubicin of resistant LoVo cells. We conclude that in LoVo cells drug resistance is associated with alteration of magnesium homeostasis through modulation of TRPM7. Our data suggest that TRPM7 expression may be an additional undisclosed player in chemoresistance

Modulation of gene expression in endothelial cells by hyperlipaemic postprandial serum from healthy volunteers

A single high-fat challenge induces plasmatic pro-inflammatory and pro-oxidative responses in the postprandial state, even in healthy men. This period is also associated with vascular endothelial dysfunction, which is an early event in the development of cardiovascular diseases. However, knowledge about the mechanisms involved in postprandial hyperlipaemia-induced endothelial dysfunction is sparse. An objective of our study was to characterize the behaviour and gene expression of vascular endothelial cells exposed to postprandial hyperlipaemic sera. Human umbilical vein endothelial cells (HUVECs) were cultured in media containing 10% serum from healthy men withdrawn either before or 4 h after a high-fat challenge. Endothelial cell proliferation, adhesion and migration were then assessed. The transcriptomic profiles of endothelial cells exposed to pre and postprandial sera were also compared. Exposure to postprandial hyperlipaemic sera significantly decreased HUVEC proliferation when compared to preprandial serum (P < 0.0001), while no changes in migration or endothelial/monocyte interactions were observed. The transcriptomic analysis revealed changes in the expression of 675 genes, of which 431 have a known function. Among them, a set of differentially expressed genes was linked to cell cycle regulation and apoptosis and are regulated in favour of cell cycle arrest or death. This result was confirmed by measuring the induction of apoptosis after postprandial sera exposure (P = 0.011). Taken together, the transcriptomic results and pathway analysis showed that postprandial serum promotes apoptosis in HUVECs, potentially through the activation of the p53 network. We conclude that upon postprandial serum exposure, vascular endothelial cells transcriptionally regulate genes involved in the control of cell cycle and death to favour growth arrest and apoptosis. These findings support the hypothesis that postprandial hyperlipaemia is associated with vascular dysfunction and offer new insights into the mechanisms involved