Effects of Wi-Fi Radiofrequency Radiation on Carbapenem-Resistant Klebsiella pneumoniae.

The hazardous consequences of electromagnetic field (EMF) exposure represent a public health concern. Common sources of EMF include smartphones and wireless fidelity (Wi-Fi). The aim of our study is to assess whether exposure to Wi-Fi radiofrequency radiation influences the pathogenic traits of carbapenem-resistant Klebsiella pneumoniae. The susceptibility to antibiotics was evaluated by the determination of minimum inhibitory concentrations (MIC). In this study, K. pneumoniae showed a non-linear response to treatments with Colistin and Gentamycin following different Wi-Fi exposure periods. Transmission electron microscopy revealed morphological changes in the bacterial cell membrane within 24 h of Wi-Fi exposure. Crystal violet quantification and quantitative real-time polymerase chain reaction showed that the ability to form biofilms was greater in Wi-Fi exposed K. pnemoniae when compared to control. Moreover, higher levels of bcsA, mrkA, and luxS messenger RNAs were observed. Our data suggest that Wi-Fi exposure can influence bacteria in a stressful way, leading to an alteration in their antibiotic susceptibility, morphological changes, and cumulative biofilm formation. © 2021 Bioelectromagnetics Society.

Serum Cadmium Levels and Risk of Metabolic Syndrome: A Cross-Sectional Study.

The increase in the prevalence of metabolic disorders globally is becoming a public health concern. Previous studies have reported an association between environmental exposures to hazardous substances, including various heavy metals, and the risk for metabolic syndrome. However, reports on the contributions of cadmium (Cd) to the risk for obesity and diabetes remain inconsistent. This study aims to investigate an association between serum Cd levels (SCL) and diabesity and dyslipidemia risk scores. A total of 140 subjects were identified from a public academic institution in Lebanon. Socio-demographic information, diabesity, and obesity risk scores were determined using an interview-based adapted FINDRISC questionnaire and analysis of an acquired blood sample. SCL was quantified using inductively coupled plasma mass spectrometry (ICP-MS). The statistical analysis relied on a chi-squared test and multivariate logistic regression models, along with checks for confounders and effect modifiers. Our results showed a Cd geometric mean of 4.04 µg/L (± 2.5). High SCL was significantly associated with higher dyslipidemia risk (OR: 3.05 [95% CI: 1.19-7.86], P = 0.02), even after adjusting for confounders. However, SCL did not show a statistically significant association with diabetes and obesity outcomes. Elevated SCL increases the risk of dyslipidemia and alters the blood lipid profile. In addition, our findings do not support a role for Cd in diabesity.

Diagnostic accuracy of the Finnish Diabetes Risk Score for the prediction of undiagnosed type 2 diabetes, prediabetes, and metabolic syndrome in the Lebanese University.

BACKGROUND: Risk scores were mainly proved to predict undiagnosed type 2 diabetes mellitus (UT2DM) in a non-invasive manner and to guide earlier clinical treatment. The objective of the present study was to assess the performance of the Finnish Diabetes Risk Score (FINDRISC) for detecting three outcomes: UT2DM, prediabetes, and the metabolic syndrome (MS). METHODS: This was a prospective, cross-sectional study during which employees aged between 30 and 64, with no known diabetes and working within the faculties of the Lebanese University (LU) were conveniently recruited. Participants completed the FINDRISC questionnaire and their glucose levels were examined using both fasting blood glucose (FBG) and oral glucose tolerance tests (OGTT). Furthermore, they underwent lipid profile tests with anthropometry. RESULTS: Of 713 subjects, 397 subjects (55.2% female; 44.8% male) completed the blood tests and thus were considered as the sample population. 7.6% had UT2DM, 22.9% prediabetes and 35.8% had MS, where men had higher prevalence than women for these 3 outcomes (P = 0.001, P = 0.003 and P = 0.001) respectively. The AUROC value with 95% Confidence Interval (CI) for detecting UT2DM was 0.795 (0.822 in men and 0.725 in women), 0.621(0.648 in men and 0.59 in women) for prediabetes and 0.710 (0.734 in men and 0.705 in women) for MS. The correspondent optimal cut-off point for UT2DM was 11.5 (sensitivity = 83.3% and specificity = 61.3%), 9.5 for prediabetes (sensitivity = 73.6% and specificity = 43.1%) and 10.5 (sensitivity = 69.7%; specificity = 56.5%) for MS. CONCLUSION: The FINDRISC can be considered a simple, quick, inexpensive, and non-invasive instrument to use in a Lebanese community of working people who are unaware of their health status and who usually report being extremely busy because of their daily hectic work for the screening of UT2DM and MS. However, it poorly screens for prediabetes in this context.

Thyroxine (T4) Transfer from Blood to Cerebrospinal Fluid in Sheep Isolated Perfused Choroid Plexus: Role of Multidrug Resistance-Associated Proteins and Organic Anion Transporting Polypeptides.

Thyroxine (T4) enters the brain either directly across the blood-brain barrier (BBB) or indirectly via the choroid plexus (CP), which forms the blood-cerebrospinal fluid barrier (B-CSF-B). In this study, using isolated perfused CP of the sheep by single-circulation paired tracer and steady-state techniques, T4 transport mechanisms from blood into lateral ventricle CP has been characterized as the first step in the transfer across the B-CSF-B. After removal of sheep brain, the CPs were perfused with 125I-T4 and 14C-mannitol. Unlabeled T4 was applied during single tracer technique to assess the mode of maximum uptake (Umax) and the net uptake (Unet) on the blood side of the CP. On the other hand, in order to characterize T4 protein transporters, steady-state extraction of 125I-T4 was measured in presence of different inhibitors such as probenecid, verapamil, BCH, or indomethacin. Increasing the concentration of unlabeled-T4 resulted in a significant reduction in Umax%, which was reflected by a complete inhibition of T4 uptake into CP. In fact, the obtained Unet% decreased as the concentration of unlabeled-T4 increased. The addition of probenecid caused a significant inhibition of T4 transport, in comparison to control, reflecting the presence of a carrier mediated process at the basolateral side of the CP and the involvement of multidrug resistance-associated proteins (MRPs: MRP1 and MRP4) and organic anion transporting polypeptides (Oatp1, Oatp2, and Oatp14). Moreover, verapamil, the P-glycoprotein (P-gp) substrate, resulted in ~34% decrease in the net extraction of T4, indicating that MDR1 contributes to T4 entry into CSF. Finally, inhibition in the net extraction of T4 caused by BCH or indomethacin suggests, respectively, a role for amino acid "L" system and MRP1/Oatp1 in mediating T4 transfer. The presence of a carrier-mediated transport mechanism for cellular uptake on the basolateral membrane of the CP, mainly P-gp and Oatp2, would account for the efficient T4 transport from blood to CSF. The current study highlights a carrier-mediated transport mechanism for T4 movement from blood to brain at the basolateral side of B-CSF-B/CP, as an alternative route to BBB.

Mast cells and ionizing radiation induce a synergistic expression of inflammatory genes in endothelial cells by a mechanism involving p38α MAP kinase and (p65) NF-κB activation.

Vascular endothelium is a key compartment involved in the development of normal tissue toxicity associated with cancer radiation therapy, i.e., acute inflammation and late fibrosis. Radiation-induced endothelial cell activation has been extensively studied, and activated endothelial cells are characterized by increased expression of inflammatory mediators and adhesion molecules, and activation of the coagulation and thrombosis pathways. However, little is known about the role of vascular endothelium interaction with resident immune cells, such as mast cells on its response to irradiation. Here, we report that endothelial exposure to mast cell conditioned medium and irradiation induces a synergistic expression of many inflammatory genes including interleukin-6 and interleukin-8, CXCL2 and E-selectin. This synergy is blocked by the histamine H1 receptor antagonist mepyramine and partially mimicked by exogenous histamine addition before irradiation. Using pharmacological and molecular inhibition approaches, we show the p38α MAP kinase and p65 (NF-κB) dependence of the synergy. Moreover, our data show a link between both pathways, with p65 (NF-κB) being downstream of p38. These data highlight the possible exacerbation of the radiation-induced endothelial inflammatory response by its interactions with immune cells. It also suggest that p38α MAP kinase and p65 (NF-κB) inhibition in vascular endothelium may limit excessive tissue inflammation induced by radiation therapy, and thereby limit the associated acute and late tissue damage.

The TG-interacting factor TGIF1 regulates stress-induced proinflammatory phenotype of endothelial cells.

The endothelium contributes to the control of the tissue inflammatory response following stress and in particular after exposure to ionizing radiation. We previously showed that the TG-interacting factor 1 (TGIF1) plays a role in radiation-induced normal tissue injury. In this study we hypothesized that this protein could play a role in inflammation. The role of TGIF1 in the stress-induced proinflammatory phenotype was investigated in human endothelial cells. In HUVECs ionizing radiation induces TGIF1 expression as well as a proinflammatory phenotype associated with up-regulation of IL-6, IL-8, CXCL1, MIP-2, and MCP-1. TGIF1 overexpression enhances the radiation-induced proinflammatory phenotype whereas TGIF1 silencing limits both the TNF-α- and radiation-induced overexpression of proinflammatory cytokines. Interestingly, in vivo, in radiation-induced intestinal inflammation in mice, TGIF1 genetic deficiency is associated with a reduced radiation-induced overexpression of proinflammatory molecules. In HUVECs, TNF-α- and radiation-induced NF-κB pathway activation is not influenced by TGIF1 expression, whereas TGIF1 knockdown inhibits both TNF-α- and radiation-induced p38 MAPK pathway activation. This study demonstrates that TGIF1 plays a role in TNF-α- and radiation-induced inflammation and suggests that it could be a target in limiting this event in the vascular compartment.

PAI-1-dependent endothelial cell death determines severity of radiation-induced intestinal injury.

Normal tissue toxicity still remains a dose-limiting factor in clinical radiation therapy. Recently, plasminogen activator inhibitor type 1 (SERPINE1/PAI-1) was reported as an essential mediator of late radiation-induced intestinal injury. However, it is not clear whether PAI-1 plays a role in acute radiation-induced intestinal damage and we hypothesized that PAI-1 may play a role in the endothelium radiosensitivity. In vivo, in a model of radiation enteropathy in PAI-1 -/- mice, apoptosis of radiosensitive compartments, epithelial and microvascular endothelium was quantified. In vitro, the role of PAI-1 in the radiation-induced endothelial cells (ECs) death was investigated. The level of apoptotic ECs is lower in PAI-1 -/- compared with Wt mice after irradiation. This is associated with a conserved microvascular density and consequently with a better mucosal integrity in PAI-1 -/- mice. In vitro, irradiation rapidly stimulates PAI-1 expression in ECs and radiation sensitivity is increased in ECs that stably overexpress PAI-1, whereas PAI-1 knockdown increases EC survival after irradiation. Moreover, ECs prepared from PAI-1 -/- mice are more resistant to radiation-induced cell death than Wt ECs and this is associated with activation of the Akt pathway. This study demonstrates that PAI-1 plays a key role in radiation-induced EC death in the intestine and suggests that this contributes strongly to the progression of radiation-induced intestinal injury.

The TGF-ß/Smad repressor TG-interacting factor 1 (TGIF1) plays a role in radiation-induced intestinal injury independently of a Smad signaling pathway.

Despite advances in radiation delivery protocols, exposure of normal tissues during the course of radiation therapy remains a limiting factor of cancer treatment. If the canonical TGF-ß/Smad pathway has been extensively studied and implicated in the development of radiation damage in various organs, the precise modalities of its activation following radiation exposure remain elusive. In the present study, we hypothesized that TGF-ß1 signaling and target genes expression may depend on radiation-induced modifications in Smad transcriptional co-repressors/inhibitors expressions (TGIF1, SnoN, Ski and Smad7). In endothelial cells (HUVECs) and in a model of experimental radiation enteropathy in mice, radiation exposure increases expression of TGF-ß/Smad pathway and of its target gene PAI-1, together with the overexpression of Smad co-repressor TGIF1. In mice, TGIF1 deficiency is not associated with changes in the expression of radiation-induced TGF-ß pathway-related transcripts following localized small intestinal irradiation. In HUVECs, TGIF1 overexpression or silencing has no influence either on the radiation-induced Smad activation or the Smad3-dependent PAI-1 overexpression. However, TGIF1 genetic deficiency sensitizes mice to radiation-induced intestinal damage after total body or localized small intestinal radiation exposure, demonstrating that TGIF1 plays a role in radiation-induced intestinal injury. In conclusion, the TGF-ß/Smad co-repressor TGIF1 plays a role in radiation-induced normal tissue damage by a Smad-independent mechanism.

Conditional inactivation of TGF-ß type II receptor in smooth muscle cells and epicardium causes lethal aortic and cardiac defects.

To understand the role of TGF-ß signaling in cardiovascular development, we generated mice with conditional deletion of the TGF-ß type II receptor (TßRII) gene (Tgfbr2) in cells expressing the smooth muscle cell-specific protein SM22α. The SM22α promoter was active in tissues involved in cardiovascular development: vascular smooth muscle cells (VSMCs), epicardium and myocardium. All SM22-Cre(+/-)/Tgfbr2 (flox/flox) embryos died during the last third of gestation. About half the mutant embryos exhibited heart defects (ventricular myocardium hypoplasia and septal defects). All mutant embryos displayed profound vascular abnormalities in the descending thoracic aorta (irregular outline and thickness, occasional aneurysms and elastic fiber disarray). Restriction of these defects to the descending thoracic aorta occurred despite similar levels of Tgfbr2 invalidation in the other portions of the aorta, the ductus arteriosus and the pulmonary trunk. Immunocytochemistry identified impairment of VSMC differentiation in the coronary vessels and the descending thoracic aorta as crucial for the defects. Ventricular myocardial hypoplasia, when present, was associated to impaired α-SMA differentiation of the epicardium-derived coronary VSMCs. Tgfbr2 deletion in the VSMCs of the descending thoracic aorta diminished the number of α-SMA-positive VSMC progenitors in the media at E11.5 and drastically decreased tropoelastin (from E11.5) and fibulin-5 (from E.12.5) synthesis and/or deposition. Defective elastogenesis observed in all mutant embryos and the resulting dilatation and probable rupture of the descending thoracic aorta might explain the late embryonic lethality. To conclude, during mouse development, TGF-ß plays an irreplaceable role on the differentiation of the VSMCs in the coronary vessels and the descending thoracic aorta.

Density-dependent shift of transforming growth factor-beta-1 from inhibition to stimulation of vascular smooth muscle cell growth is based on unconventional regulation of proliferation, apoptosis and contact inhibition.

BACKGROUND: TGF-beta shifts from inhibition to stimulation of vascular smooth muscle cell (vSMC) growth when cell density increases. How proliferation and apoptosis contribute to this shift is still unknown. METHODS: In sparse and confluent V8 vSMC treated or not with TGF-beta(1) (1 ng/ml) for 3 days, cell number, mitotic activity, cell-cycle-regulatory protein levels, caspase-3 and phosphoinositide 3-kinase (PI3-K) activities were studied. RESULTS: In TGF-beta(1)-treated cells, (i) the growth curve rose constantly compared to controls, reaching post-confluent densities; (ii) mitotic activity, which was constant at all cell densities, was lower than in sparse but higher than in contact-inhibited control cells, and (iii) apoptosis occurred at sparse densities only. The mechanism of proliferation control by TGF-beta(1) was very unconventional in V8 vSMCs: (i) p15(INK4b) and cyclin D levels were similar in cells treated or not with TGF-beta(1), and (ii) p27(Kip1) levels remained very low even at high densities while cyclin E levels were not markedly decreased. TGF-beta(1)-induced apoptosis in sparse cultures and its reversal in dense cultures were inversely correlated to PI3-K activation. CONCLUSIONS: TGF-beta(1) slowed sparse V8 vSMC growth by inhibiting proliferation and inducing apoptosis. TGF-beta(1)-treated confluent vSMCs escaped contact inhibition and kept growing through unconventional regulation of p27(Kip1), cyclin E and suppression of apoptosis.