Impact of Polychlorinated Biphenyls Contamination on Estrogenic Activity in Human Male Serum

Polychlorinated biphenyls (PCBs) are thought to cause numerous adverse health effects, but their impact on estrogen signaling is still not fully understood. In the present study, we used the ER-CALUX bioassay to determine estrogenic/antiestrogenic activities of the prevalent PCB congeners and PCB mixtures isolated from human male serum. The samples were collected from residents of an area with an extensive environmental contamination from a former PCB production site as well as from a neighboring background region in eastern Slovakia. We found that the lower-chlorinated PCBs were estrogenic, whereas the prevalent higher-chlorinated PCB congeners 138, 153, 170, 180, 187, 194, 199, and 203, as well as major PCB metabolites, behaved as anti-estrogens. Coplanar PCBs had no direct effect on estrogen receptor (ER) activation in this in vitro model. In human male serum samples, high levels of PCBs were associated with a decreased ER-mediated activity and an increased dioxin-like activity, as determined by the DR-CALUX assay. 17β-Estradiol (E(2)) was responsible for a major part of estrogenic activity identified in total serum extracts. Significant negative correlations were found between dioxin-like activity, as well as mRNA levels of cytochromes P450 1A1 and 1B1 in lymphocytes, and total estrogenic activity. For sample fractions containing only persistent organic pollutants (POPs), the increased frequency of anti-estrogenic samples was associated with a higher sum of PCBs. This suggests that the prevalent non-dioxin-like PCBs were responsible for the weak antiestrogenic activity of some POPs fractions. Our data also suggest that it might be important to pay attention to direct effects of PCBs on steroid hormone levels in heavily exposed subjects

Circadian Integration of Glutamatergic Signals by Little SAAS in Novel Suprachiasmatic Circuits

Neuropeptides are critical integrative elements within the central circadian clock in the suprachiasmatic nucleus (SCN), where they mediate both cell-to-cell synchronization and phase adjustments that cause light entrainment. Forward peptidomics identified little SAAS, derived from the proSAAS prohormone, among novel SCN peptides, but its role in the SCN is poorly understood.Little SAAS localization and co-expression with established SCN neuropeptides were evaluated by immunohistochemistry using highly specific antisera and stereological analysis. Functional context was assessed relative to c-FOS induction in light-stimulated animals and on neuronal circadian rhythms in glutamate-stimulated brain slices. We found that little SAAS-expressing neurons comprise the third most abundant neuropeptidergic class (16.4%) with unusual functional circuit contexts. Little SAAS is localized within the densely retinorecipient central SCN of both rat and mouse, but not the retinohypothalamic tract (RHT). Some little SAAS colocalizes with vasoactive intestinal polypeptide (VIP) or gastrin-releasing peptide (GRP), known mediators of light signals, but not arginine vasopressin (AVP). Nearly 50% of little SAAS neurons express c-FOS in response to light exposure in early night. Blockade of signals that relay light information, via NMDA receptors or VIP- and GRP-cognate receptors, has no effect on phase delays of circadian rhythms induced by little SAAS.Little SAAS relays signals downstream of light/glutamatergic signaling from eye to SCN, and independent of VIP and GRP action. These findings suggest that little SAAS forms a third SCN neuropeptidergic system, processing light information and activating phase-shifts within novel circuits of the central circadian clock

Electrophysiologic Studies and Radiofrequency Catheter Ablation of Ectopic Atrial Tachycardia in Children

Ectopic atrial tachycardia (EAT) often resists medical therapy, making radiofrequency catheter ablation (RFCA) the preferred treatment. This study reviewed the records of 35 patients who underwent electrophysiologic studies (EPS) and 39 RFCA procedures for EAT during a 10-year period. Of the 35 patients, 10 (28%) presented with decreased ventricular function and tachycardia-induced cardiomyopathy (TIC). The EAT originated on the right atrial side in 19 patients (54%) and on the left atrial side in the remaining 16 patients (46%). The right atrial sites included the right atrial appendage (RAA) (n = 9, 25%), the tricuspid annulus (n = 7, 20%), and the crista terminalis (n = 3). The left atrial sites included the left atrial appendage (LAA) (n = 6, 17%), the pulmonary veins (n = 5, 14%), the mitral annulus (n = 3), and the posterior wall of the left atrium (n = 2). The mechanism of all EAT probably is automaticity. All EATs could be abolished using RFCA. Follow-up data were available for all patients 2 to 8 years after RFCA. All 35 patients remained recurrence free, and ventricular function improved for all 10 patients with TIC. The origin of EAT in children differed from its origin in adults. The authors conclude that RFCA is a safe and effective treatment option for children with refractory EAT and should be considered early in the course of their illness

Canonical NF-κB promotes lung epithelial cell tumour growth by downregulating the metastasis suppressor CD82 and enhancing epithelial-to-mesenchymal cell transition

Copyright: © 2021 by the authors. Background: The development of non-small cell lung cancer (NSCLC) involves the progressive accumulation of genetic and epigenetic changes. These include somatic oncogenic KRAS and EGFR mutations and inactivating TP53 tumour suppressor mutations, leading to activation of canonical NF-κB. However, the mechanism(s) by which canonical NF-κB contributes to NSCLC is still under investigation. Methods: Human NSCLC cells were used to knock-down RelA/p65 (RelA/p65KD) and investigate its impact on cell growth, and its mechanism of action by employing RNA-seq analysis, qPCR, immunoblotting, immunohistochemistry, immunofluorescence and functional assays. Results: RelA/p65KD reduced the proliferation and tumour growth of human NSCLC cells grown in vivo as xenografts in immune-compromised mice. RNA-seq analysis identified canonical NF-κB targets mediating its tumour promoting function. RelA/p65KD resulted in the upregulation of the metastasis suppressor CD82/KAI1/TSPAN27 and downregulation of the proto-oncogene ROS1, and LGR6 involved in Wnt/β-catenin signalling. Immunohistochemical and bioinformatics analysis of human NSCLC samples showed that CD82 loss correlated with malignancy. RelA/p65KD suppressed cell migration and epithelial-to-mesenchymal cell transition (EMT), mediated, in part, by CD82/KAI1, through integrin-mediated signalling involving the mitogenic ERK, Akt1 and Rac1 proteins. Conclusions: Canonical NF-κB signalling promotes NSCLC, in part, by downregulating the metastasis suppressor CD82/KAI1 which inhibits cell migration, EMT and tumour growth.Institutional Program Grant for the Development of Research Institutes “Advanced research activities in biomedical and agro-alimentary technologies, ARABAT (BITAD)” (MIS5002469) of the operational program “Competitiveness, Entrepreneurship and Innovation” (NSRF2014-20, EU-ERDF); research grant in Biomedical Sciences from FONDATION SANTÉ; STAVROS NIARCHOS Foundation-FORTH Fellowship for PhD candidates of the program ARCHERS: Advancing young researchers’ human capital in cutting edge technologies in the preservation of cultural heritage and the tackling of societal challenges; Biomedical Research Division, IMBB-FORTH; University of Ioannina Research Committee

Up-regulation of multiple proteins and biological processes during maxillary expansion in rats

<p>Abstract</p> <p>Background</p> <p>Maxillary expansion (ME) is a common practice in orthodontics that aims to increase the constricted maxillary arch width. Relapse often occurs, however, and better treatment strategies are needed. In order to develop a more effective method, this study was designed to further examine the process of tissue remodeling during ME, to identify the changes in expression of several proteins of interest, and to clarify the molecular mechanism responsible for tissue remodeling.</p> <p>Methods</p> <p>Male Wistar rats were randomly divided into control and ME groups. The rats were euthanized at various intervals over 11 days, and the dissected palates were prepared for histological examination. The structure of the midpalatal sutures changed little during the first three days. Proteins from samples in the ground midpalatal tissues obtained on the third day were subjected to two-dimensional polyacrylamide gel electrophoresis (2-DE) and matrix assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis. Validation of protein expression was performed by Western blot analyses.</p> <p>Results</p> <p>From day 5, chondrocytes in the inner layer of suture cartilage and osteoblasts at the end of the suture cartilage began to proliferate, and the skeletal matrix increased later adjacent to the cartilage in the ME group. Comparative proteomic analysis showed increases in 22 protein spots present in the ME group. The changes in three proteins closely related to osteogenesis (parathyroid hormone, osteoprotegerin and vimentin) were confirmed by Western blotting.</p> <p>Conclusion</p> <p>Many proteins are over-expressed during ME, and they may play an important role in the remodeling process.</p

Annexin II represents metastatic potential in clear-cell renal cell carcinoma

BACKGROUND: Annexin II (ANX2) is a multi-functional protein involved in cell proliferation and membrane physiology and is related to cancer progression. The purpose of this study was to assess ANX2 expression in clear-cell (cc) renal cell carcinoma (RCC)

Creatine Monohydrate and Conjugated Linoleic Acid Improve Strength and Body Composition Following Resistance Exercise in Older Adults

Aging is associated with lower muscle mass and an increase in body fat. We examined whether creatine monohydrate (CrM) and conjugated linoleic acid (CLA) could enhance strength gains and improve body composition (i.e., increase fat-free mass (FFM); decrease body fat) following resistance exercise training in older adults (>65 y). Men (N = 19) and women (N = 20) completed six months of resistance exercise training with CrM (5g/d)+CLA (6g/d) or placebo with randomized, double blind, allocation. Outcomes included: strength and muscular endurance, functional tasks, body composition (DEXA scan), blood tests (lipids, liver function, CK, glucose, systemic inflammation markers (IL-6, C-reactive protein)), urinary markers of compliance (creatine/creatinine), oxidative stress (8-OH-2dG, 8-isoP) and bone resorption (Ν-telopeptides). Exercise training improved all measurements of functional capacity (P<0.05) and strength (P<0.001), with greater improvement for the CrM+CLA group in most measurements of muscular endurance, isokinetic knee extension strength, FFM, and lower fat mass (P<0.05). Plasma creatinine (P<0.05), but not creatinine clearance, increased for CrM+CLA, with no changes in serum CK activity or liver function tests. Together, this data confirms that supervised resistance exercise training is safe and effective for increasing strength in older adults and that a combination of CrM and CLA can enhance some of the beneficial effects of training over a six-month period. Trial Registration. ClinicalTrials.gov NCT0047390