Pd(II) complexes with N-heteroaromatic hydrazone ligands: Anticancer activity, in silico and experimental target identification.

Anticancer activity of Pd complexes 1-5 with bidentate N-heteroaromatic hydrazone ligands was investigated on human acute monocytic leukemia (THP-1; cells in a suspension) and human mammary adenocarcinoma (MCF-7; two-dimensional layer and three-dimensional spheroid tumor model) cell lines. For the Pd(II) complexes with condensation products of ethyl hydrazainoacetate and quinoline-8-carboxaldehyde (complex 1) and 2-formylpyridine (complex 3), for which apoptosis was determined as a mechanism of anticancer activity, further investigation revealed that they arrest the cell cycle in G0/G1 phase, induce generation of reactive oxygen species and inhibit Topoisomerase I in vitro. In silico studies corroborate experimental findings that these complexes show topoisomerase inhibition activity in the micromolar range and indicate binding to a DNA's minor groove as another potential target.

Clozapine increased c-Fos protein expression in several brain subregions of socially isolated rats.

Chronic social stress and/or pharmacological treatments differentially modulate the expression of c-Fos, a marker of neuronal activity, in subregions of the rat brain. Here, we examined the effect of the atypical antipsychotic Clozapine (Clz) (20 mg/kg/day for 3 weeks) on the neuronal activation pattern of c-Fos protein expression in stress-relevant brain subregions of adult male Wistar rats exposed to chronic social isolation (CSIS: 3 weeks), an animal model of depression and schizophrenia, and controls. The protein expression of c-Fos was also used to map neuronal populations in brain subregions activated by CSIS alone.

Generalized Poincaré plots analysis of heart period dynamics in different physiological conditions: Trained vs. untrained men.

Background: Recently we proposed a new method called generalized Poincaré plot (gPp) analysis which gave a new insight into the pattern of neurocaridac control. In this study we examined potential of gPp method to reveal changes in cardiac neural control in young athletes during three conditions: supine rest, running and relaxation, with respect to untrained subjects.

Methods: This method is based on the quantification of Pearson's correlation coefficients r(j, k), between symmetrical (j = k) and asymmetrical summed j previous and k following RR intervals up to the 100th order (j,k≤100).

Glutathione "Redox Homeostasis" and Its Relation to Cardiovascular Disease.

More people die from cardiovascular diseases (CVD) than from any other cause. Cardiovascular complications are thought to arise from enhanced levels of free radicals causing impaired "redox homeostasis," which represents the interplay between oxidative stress (OS) and reductive stress (RS). In this review, we compile several experimental research findings that show sustained shifts towards OS will alter the homeostatic redox mechanism to cause cardiovascular complications, as well as findings that show a prolonged antioxidant state or RS can similarly lead to such cardiovascular complications.

Leukocyte- and platelet-rich fibrin as graft material improves microRNA-21 expression and decreases oxidative stress in the calvarial defects of diabetic rabbits.

Objective: Leukocyte- and platelet-rich fibrin (L-PRF) represents a natural, low-cost product which may promote tissue healing by mechanisms not fully elucidated. Diabetes mellitus (DM) disrupts bone healing by inducing inflammation and oxidative stress (OS), mechanisms regulated by microRNAs (miRs). The aim of the present study was to investigate the microRNA-21 (miR-21) involvement in diabetic bone regeneration using L-PRF alone or in combination with a standard grafting material.

MEASUREMENT OF URANIUM IN URINE, HAIR AND NAILS IN SUBJECTS OF NISKA BANJA TOWN, A HIGH NATURAL BACKGROUND RADIATION AREA OF SERBIA.

Urine, hair and nail samples were collected from a population of both sex aged from 40 to 87 years in Niška Banja (227 km south of Belgrade, Serbia) with a high level of natural radioactivity (HLNRA). To assess and monitor the public exposure, urine samples for each subject (24 h period) were collected and concentration of uranium (U) was analysed using alpha-particle spectrometry. Human hair and nails considered as bio-indicators of the public exposure to radionuclides over a long period of months or even years and concentration of U was determined using inductively coupled plasma-mass spectrometry.

Synthesis, In Silico, and In Vitro Evaluation of Anti-Leishmanial Activity of Oxadiazoles and Indolizine Containing Compounds Flagged against Anti-Targets.

Due to the lack of approved vaccines against human leishmaniasis and the limitations of the current chemotherapy inducing side effects and drug resistance, development of new, effective chemotherapeutic agents is essential. This study describes the synthesis of a series of novel oxadiazoles and indolizine-containing compounds. The compounds were screened in silico using an EIIP/AQVN filter followed by ligand-based virtual screening and molecular docking to parasite arginase.

Virtual Screen for Repurposing of Drugs for Candidate Influenza a M2 Ion-Channel Inhibitors.

Influenza A virus (IAV) matrix protein 2 (M2), an ion channel, is crucial for virus infection, and therefore, an important anti-influenza drug target. Adamantanes, also known as M2 channel blockers, are one of the two classes of Food and Drug Administration-approved anti-influenza drugs, although their use was discontinued due to prevalent drug resistance. Fast emergence of resistance to current anti-influenza drugs have raised an urgent need for developing new anti-influenza drugs against resistant forms of circulating viruses.

Modulation of Hippocampal Antioxidant Defense System in Chronically Stressed Rats by Lithium.

This study examined the effects of lithium on gene expression and activity of the antioxidant enzymes copper zinc superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) in the hippocampus of chronically stressed rats. In addition, we examined the effects of lithium on anxiety behaviors, hippocampal concentrations of dopamine (DA) and malondialdehyde (MDA), protein levels of brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), dopamine transporter (DAT), and catechol-O-methyltransferase (COMT), as well as activity of monoamine oxidase (MAO) in chronically stressed rats. The investigated parameters were quantified by real-time RT-PCR, Western blot analyses, and assays of enzyme activities.

A Model for Potential B-cell Precursors of Broadly Neutralizing HIV-1 Antibodies Selection and Antibody Affinity Maturation.

The goal of this report was to propose a model, wherein synergy between the B-cell antigen receptor (BCR) and toll-like receptor (TLR) signaling is involved in the selection of the B-cell precursors of HIV-1 broadly neutralizing antibodies (bnAbs) with long heavy chain complementarity determining regions 3, from immature/transitional B cells. The model predicts the involvement of Ab/HIV-1 complexes in a way that Ab from the complex binds both BCRs and HIV-1, while on internalization of HIV-1 TLR ligands such as CpG motifs interacts with TLR9. The result of BCR and TLR9 orchestrated signaling is a formation of somatically mutated memory B cells potential precursors of bnAbs.

Drug Delivery Systems for Diabetes Treatment.

Background: Insulin is essential for the treatment of Type 1 diabetes mellitus (T1DM) and is necessary in numerous cases of Type 2 diabetes mellitus (T2DM). Prolonged administration of anti-diabetic therapy is necessary for the maintenance of the normal glucose levels and thereby preventing vascular complications. A better understanding of the disease per se and the technological progress contribute to the development of new approaches with the aim to achieve better glycemic control.

Conserved HA-peptide NG34 formulated in pCMV-CTLA4-Ig reduces viral shedding in pigs after a heterosubtypic influenza virus SwH3N2 challenge.

Swine influenza viruses (SIVs), the causal agents of swine influenza, are not only important to control due to the economic losses in the swine industry, but also can be pandemic pathogens. Vaccination is one of the most relevant strategies to control and prevent influenza infection. Current human vaccines against influenza induce strain-specific immunity and annual update is required due to the virus antigenic shift phenomena.

Importance of Copy Number Alterations of and Genes in Triple Negative Breast Cancer.

Background: Triple negative breast cancer (TNBC) is characterized by aggressive clinical course and is unresponsive to anti-HER2 and endocrine therapy. TNBC is difficult to treat and is often lethal. Given the need to find new targets for therapy we explored clinicopathological significance of copy number gain of and .

Melatonin treatment affects changes in adrenal gene expression of catecholamine biosynthesizing enzymes and norepinephrine transporter in the rat model of chronic-stress-induced depression.

This study investigated the effects of melatonin treatment on adrenal catecholamine content, synthesis, uptake, and vesicular transport induced by the chronic unpredictable mild stress (CUMS) model of depression in rats. This entailed quantifying the norepinephrine, epinephrine, mRNA, and protein levels of tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DBH), phenylethanolamine -methyltransferase (PNMT), norepinephrine transporter (NET), and vesicular monoamine transporter 2 (VMAT2) in the adrenal medulla. CUMS caused a significant depletion of norepinephrine stores and protein levels of TH, DBH, and NET, whereas the gene expression of PNMT was increased.

Early Effects of Hyperbaric Oxygen on Inducible Nitric Oxide Synthase Activity/Expression in Lymphocytes of Type 1 Diabetes Patients: A Prospective Pilot Study.

This study aimed at examining the early effects of hyperbaric oxygen therapy (HBOT) on inducible nitric oxide synthase (iNOS) activity/expression in lymphocytes of type 1 diabetes mellitus (T1DM) patients. A group of 19 patients (mean age: 63 ± 2.1) with T1DM and with the peripheral arterial disease were included in this study.

Functional characterization of β-adrenergic and insulin receptor heteromers.

This study aimed to functionally characterize β-adrenergic (βAR) and insulin receptor (IR) heteromers in regard to β-arrestin 2 (βarr2) recruitment and cAMP signaling and to examine the involvement of the cytoplasmic portion of the IR β chain in heteromerization with βAR. Evidence for βAR:IR:βarr2 complex formation and the specificity of the IR:βarr2 interaction was first provided by bioinfomatics analysis. Receptor-heteromer investigation technology (HIT) then provided functional evidence of βAR:IR heterodimerization by showing isoproterenol-induced but not insulin-induced GFP-βarr2 recruitment to the βAR:IR complex; the IR:βarr2 interaction was found to only be constitutive.

Hypothesis related to the regulation of inducible nitric oxide synthase during carotid endarterectomy.

Sudden occlusion of an artery caused by a thrombus or emboli is the most frequent cause of acute brain ischemia (ABI). Carotid endarterectomy (CEA) represents the gold standard for preventing strokes of carotid origin. However, neuronal damage caused by ischemia and/or reperfusion may contribute to a poor clinical outcome after CEA.

Subregion-specific Protective Effects of Fluoxetine and Clozapine on Parvalbumin Expression in Medial Prefrontal Cortex of Chronically Isolated Rats.

Dysregulation of GABAergic system is becoming increasingly associated with depression, psychiatric disorder that imposes severe clinical, social and economic burden. Special attention is paid to the fast-spiking parvalbumin-positive (PV+) interneurons, GABAergic neurons which are highly susceptible to redox dysregulation and oxidative stress and implicated in a variety of psychiatric diseases. Here we analyzed the number of PV+ and cleaved caspase-3-positive (CC3+) cells in the rat medial prefrontal cortical (mPFC) subregions following chronic social isolation (CSIS), an animal model of depression and schizophrenia.

Comparative pyrolysis kinetics of various biomasses based on model-free and DAEM approaches improved with numerical optimization procedure.

The pyrolysis process of various types of biomass (agricultural and wood by-products) in non-isothermal conditions using simultaneous thermal analyses (STA) was investigated. Devolatilization kinetics was implemented through combined application of model-free methods and DAEM (distributed activation energy model) using Gaussian distribution functions of activation energies. Results obtained were used in the curve prediction of the rate of mass loss against temperature at various heating rates by numerical optimization.

Nonlinear calcium ion waves along actin filaments control active hair-bundle motility.

Calcium ions (Ca) tune and control numerous diverse aspects of cochlear and vestibular physiological processes. This paper is focused on the Ca control of mechanotransduction in sensory hair cells in the context of polyelectrolyte properties of actin filaments within the hair-bundles of inner ear. These actin filaments appear to serve as efficient pathways for the flow of Ca ions inside stereocilia.

Antioxidant Activity of Selected Polyphenolics in Yeast Cells: The Case Study of Montenegrin Merlot Wine.

Screens of antioxidant activity (AA) of various natural products have been a focus of the research community worldwide. This work aimed to differentiate selected samples of Merlot wines originated from Montenegro, with regard to phenolic profile and antioxidant capacity studied by survival rate, total sulfhydryl groups and activities of glutathione peroxidase (GPx), glutathione reductase and catalase in H₂O₂⁻stressed cells. In this study, DPPH assay was also performed.

Cooperation of intrathymic T15 idiotype-bearing B and complementary T cells in ontogeny of natural Treg cells involved in establishment of T15 clonal dominance.

The mechanisms for dominant T15 idiotype selection are not well understood, yet the significance of idiotypic regulation has been suggested. We proposed that to become dominant V regions of a given subset of B-1a cell must establish a functional idiotypic network with complementary T cells. Features required for the cells involved in immune network and steps preceding the establishment of clonal dominance are suggested.

Oxytocin modulates the expression of norepinephrine transporter, β-adrenoceptors and muscarinic M receptors in the hearts of socially isolated rats.

Social stress produces behavioral alterations, and autonomic and cardiac dysfunction in animals. In addition to the well-known roles of oxytocin on birth and maternal bonding, recent evidence shows that this neuropeptide possesses cardio-protective properties. However less is known about its role in the regulation of the autonomic nervous system.

Discriminant analysis of cardiovascular and respiratory variables for classification of road cyclists by specialty.

Background: Different variables determine the performance of cyclists, which brings up the question how these parameters may help in their classification by specialty. The aim of the study was to determine differences in cardiorespiratory parameters of male cyclists according to their specialty: flat riders (N.=21), hill riders (N.