Polycystic ovary syndrome (PCOS) is a complex disorder characterized by endocrine and metabolic abnormalities such as obesity and insulin resistance. PCOS is also associated with psychiatric ...disorders and cognitive impairment. The animal model of PCOS was induced by treating rats with 5α-dihydrotestosterone (5α-DHT) and additionally modified to induce adiposity by litter size reduction (LSR). Spatial learning and memory were assessed using the Barnes Maze test, and striatal markers of synaptic plasticity were analyzed. Striatal insulin signaling was estimated by the levels of insulin receptor substrate 1 (IRS1), its inhibitory phosphorylation at Ser307, and glycogen synthase kinase-3α/β (GSK3α/β) activity. Both LSR and DHT treatment significantly decreased striatal protein levels of IRS1, followed by increased GSK3α/β activity in small litters. Results of the behavioral study showed that LSR had a negative effect on learning rate and memory retention, whereas DHT treatment did not induce impairment in memory formation. While protein levels of synaptophysin, GAP43, and postsynaptic density protein 95 (PSD-95) were not altered by the treatments, DHT treatment induced an increase in phosphorylation of PSD-95 at Ser295 in both normal and small litters. This study revealed that LSR and DHT treatment suppressed insulin signaling by downregulating IRS1 in the striatum. However, DHT treatment did not have an adverse effect on learning and memory, probably due to compensatory elevation in pPSD-95-Ser295, which had a positive effect on synaptic strength. This implies that hyperandrogenemia in this setting does not represent a threat to spatial learning and memory, opposite to the effect of overnutrition-related adiposity.
•Small litter rearing and DHT treatment induce insulin resistance in the striatum.•Small litter rearing induces learning and memory impairment.•DHT treatment potentiates synaptic transmission through phosphorylation of PSD-95.•Hyperandrogenism does not affect spatial learning/memory in this PCOS animal model.
This study aimed to estimate the serological status and dynamic changes in the prevalence of Parvovirus B19 (PVB19) antibodies within the general population residing in the northern part of the ...Republic of Serbia (Province of Vojvodina) during a 16-year period. Serum samples were analyzed for Human PVB19-specific IgM and IgG antibodies using enzyme-linked immunosorbent assay (ELISA). Throughout the study period, the overall seroprevalence was 49.51%. Approximately 10% of patients exhibited a serologic profile positive for PVB19 IgM antibodies. Notably, seroprevalence varied significantly, ranging from 9.12% in the pediatric cohort (ages 1-4 years) to 65.50% in the adult demographic (40-59 years old). Seroprevalence was higher (51.88%) among women compared to men (42.50%). Immunologically naive pregnant women in the age groups 26-36 and 36-45 years had 45% (OR = 0.55, 95% CI: 0.31-1.00) and 52% (OR = 0.48; 95% CI: 0.24-0.94) lower odds of having negative IgM and IgG compared to those in age group 16-25 years old. Improved knowledge of the epidemiology of PVB19 may assist clinicians in the differential diagnosis of PVB19 clinical manifestations. The PVB19 detection is particularly important for monitoring individuals in risk groups such as women of reproductive age, medical staff, patients with hematological disorders, and those with immunodeficiency.
In seismically active areas, knowledge of the actual behavior of bridges under seismic load is extremely important, as they are crucial elements of the transport infrastructure. To assess their ...seismic resistance, it is necessary to know the key indicators of their seismic response. Bridges built before the adoption of standards for seismic detailing may still contain structural reserves due to the properties of the used materials and construction approach. For example, smooth reinforcement which is found in older bridges due to the material properties, detailing principles, and lower bond strength compared to ribbed reinforcement, allows for greater deformations. In bridges, columns are vital elements employed in the dissipation of seismic energy. Their cross-sections often deviate from the regular square, rectangular, or round cross-sections, which are typically found in building. Based on the behavior of the columns in the vicinity of potential plastic joints, we can determine their deformability. This paper presents an experimental study of seismic resistance indicators around a potential plastic joint for a column with an atypical cross-section, without seismic details and with smooth reinforcement. The experimental results are compared with the numerical and analytical, but also with the experimental results on samples with ribbed reinforcement. Conclusions are made about the behavior of such column elements and their seismic resistance indicators, allowing for the application of an analytical or numerical method with realistic material and element properties and derivation of correction factors due to the effect of the smooth-reinforcement slippage from the anchorage area.
Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults, characterized by a highly invasive nature and therapy resistance. Combination of menadione and ascorbic acid (AA+MD) ...exerts strong ROS-mediated anti-GBM activity in vitro. The objective of this study was to improve AA+MD anti-GBM potential by modulating the activity of Akt and c-Jun N-terminal kinase (JNK), molecules with an important role in GBM development. The effects of Akt and JNK modulation on AA+MD toxicity in U251 human glioblastoma cells were assessed by cell viability assays, flow cytometry, RNA interference and plasmid overexpression, and immunoblot analysis. The AA+MD induced severe oxidative stress, an early increase in Akt phosphorylation followed by its strong inhibition, persistent JNK activation, and U251 cell death. Small molecule Akt kinase inhibitor 10-DEBC enhanced, while pharmacological and genetic Akt activation decreased, AA+MD-induced toxicity. The U251 cell death potentiation by 10-DEBC correlated with an increase in the combination-induced autophagic flux and was abolished by genetic autophagy silencing. Additionally, pharmacological JNK inhibitor SP600125 augmented combination toxicity toward U251 cells, an effect linked with increased ROS accumulation. These results indicate that small Akt and JNK kinase inhibitors significantly enhance AA+MD anti-GBM effects by autophagy potentiation and amplifying deleterious ROS levels.
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Simple and scalable synthetic approach was used for the preparation of thirteen novel tacrine derivatives consisting of tacrine and N-aryl-piperidine-4-carboxamide moiety connected by ...a five-methylene group linker. An anti-Alzheimer disease (AD) potential of newly designed tacrine derivatives was evaluated against two important AD targets, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). In vitro pharmacological evaluation showed strong ChE inhibitory activity of all compounds, with IC50 values ranging from 117.5 to 455 nM for AChE and 34 to 324 nM for BuChE. As a representative of the series with the best cytotoxicity / ChE inhibitory activity ratio, expressed as the selectivity index (SI), 2-chlorobenzoyl derivative demonstrated mixed-type inhibition on AChE and BuChE, suggesting binding to both CAS and PAS of the enzymes. It also exhibited antioxidant capacity and neuroprotective potential against amyloid-β (Aβ) toxicity in the culture of neuron-like cells. In-depth computational analysis corroborated well with in vitro ChE inhibition, illuminating that all compounds exhibit significant potential in targeting both enzymes. Molecular dynamics (MD) simulations revealed that 2-chlorobenzoyl derivative, created complexes with AChE and BuChE that demonstrated sufficient stability throughout the observed MD simulation. Computationally predicted ADME properties indicated that these compounds should have good blood–brain barrier (BBB) permeability, an important factor for CNS-targeting drugs. Overall, all tested compounds showed promising pharmacological behavior, highlighting the multi-target potential of 2-chlorobenzoyl derivative which should be further investigated as a new lead in the drug development process.
Introduction/Objective. Acute disseminated encephalomyelitis (ADEM) is the most common demyelinating disease of the central nervous system in pediatric patients. We aimed to evaluate the clinical ...profile of children with ADEM and to discern prognostic factors for disease outcome. Methods. A 20-year retrospective?prospective study was conducted in a cohort with the diagnosis of ADEM. Results. The study included 36 patients, with range of follow-up period of 6?120 months (median of 26 months). Prior infection was reported in 72.2% of the patients. In the clinical presentation of the disease, motor deficit was most common (81.1%), followed by ataxia (77.8%). More than a third of patients had back and limb pain or abdominal visceral pain, which highly correlated with MRI findings of myelitis. Abnormal brain CT findings were evident in 22.2% of the patients, and this was associated with higher Expanded Disability Status Scale (EDSS) and quicker progression of the disease. Median EDSS was 0 at the most recent follow-up visit, in all the patients. EDSS 0?2.5 was verified in 29 (80.6%) of the patients, while three (8.3%) patients scored 7?9.5 at the last visit. Two patients had a lethal outcome. Conclusions. ADEM is a serious disease in pediatric patients, but with a good prognosis, which is illustrated by the fact that 80.6% of our patients had a complete or almost complete recovery.
We investigated the ability of graphene quantum dot (GQD) nanoparticles to protect SH-SY5Y human neuroblastoma cells from oxidative/nitrosative stress induced by iron-nitrosyl complex sodium ...nitroprusside (SNP). GQD reduced SNP cytotoxicity by preventing mitochondrial depolarization, caspase-2 activation, and subsequent apoptotic death. Although GQD diminished the levels of nitric oxide (NO) in SNP-exposed cells, NO scavengers displayed only a slight protective effect, suggesting that NO quenching was not the main protective mechanism of GQD. GQD also reduced SNP-triggered increase in the intracellular levels of hydroxyl radical (•OH), superoxide anion (O2•−), and lipid peroxidation. Nonselective antioxidants, •OH scavenging, and iron chelators, but not superoxide dismutase, mimicked GQD cytoprotective activity, indicating that GQD protect cells by neutralizing •OH generated in the presence of SNP-released iron. Cellular internalization of GQD was required for optimal protection, since a removal of extracellular GQD by extensive washing only partly diminished their protective effect. Moreover, GQD cooperated with SNP to induce autophagy, as confirmed by the inhibition of autophagy-limiting Akt/PRAS40/mTOR signaling and increase in autophagy gene transcription, protein levels of proautophagic beclin-1 and LC3-II, formation of autophagic vesicles, and degradation of autophagic target p62. The antioxidant activity of GQD was not involved in autophagy induction, as antioxidants N-acetylcysteine and dimethyl sulfoxide failed to stimulate autophagy in SNP-exposed cells. Pharmacological inhibitors of early (wortmannin, 3-methyladenine) or late stages of autophagy (NH4Cl) efficiently reduced the protective effect of GQD. Therefore, the ability of GQD to prevent the in vitro neurotoxicity of SNP depends on both •OH/NO scavenging and induction of cytoprotective autophagy.
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•Graphene quantum dots (GQD) protect SH-SY5Y cells from sodium nitroprusside (SNP).•GQD inhibit SNP-induced apoptotic death of SH-SY5Y neuronal cells.•Quenching of NO and .•OH contributes to GQD-mediated protection from SNP toxicity•GQD induce autophagy associated with reduced Akt/mTOR signaling.•GQD-induced autophagy is cytoprotective independently of their antioxidant activity.
We investigated the ability of the ascorbic acid (AA) and menadione (MD) combination, the well-known reactive oxidative species- (ROS-) generating system, to induce autophagy in human U251 ...glioblastoma cells. A combination of AA and MD (AA+MD), in contrast to single treatments, induced necrosis-like cell death mediated by mitochondrial membrane depolarization and extremely high oxidative stress. AA+MD, and to a lesser extent MD alone, prompted the appearance of autophagy markers such as autophagic vacuoles, autophagosome-associated LC3-II protein, degradation of p62, and increased expression of beclin-1. While both MD and AA+MD increased phosphorylation of AMP-activated protein kinase (AMPK), the well-known autophagy promotor, only the combined treatment affected its downstream targets, mechanistic target of rapamycin complex 1 (mTORC1), Unc 51-like kinase 1 (ULK1), and increased the expression of several autophagy-related genes. Antioxidant N-acetyl cysteine reduced both MD- and AA+MD-induced autophagy, as well as changes in AMPK/mTORC1/ULK1 activity and cell death triggered by the drug combination. Pharmacological and genetic autophagy silencing abolished the toxicity of AA+MD, while autophagy upregulation enhanced the toxicity of both AA+MD and MD. Therefore, by upregulating oxidative stress, inhibiting mTORC1, and activating ULK1, AA converts MD-induced AMPK-dependent autophagy from nontoxic to cytotoxic. These results suggest that AA+MD or MD treatment in combination with autophagy inducers could be further investigated as a novel approach for glioblastoma therapy.
Schinzel-Giedion syndrome (SGS) is a rare genetic syndrome characterized by severe developmental delay, facial dysmorphism, seizures, and multiple congenital malformations. Affected children have ...increased risk of developing neuroepithelial brain tumors.
We are reporting a case of a 20 months-old boy with profound psychomotor delay, distinctive facial features, congenital cardiac defect and renal malformation, associated with drug-resistant seizures and progressive brain atrophy. Detailed metabolic and genetic investigation was performed. Finally, whole exome sequencing identified a pathogenic variant in SETBP1 gene, which further confirmed the diagnosis of Schinzel-Giedion syndrome.
In conclusion, determining the etiology of disorders characterized by craniofacial dysmorphia, epilepsy, and severe psychomotor retardation is complex and often requires an exhaustive clinical, neuroradiological, metabolic and genetic examination. In the cases with developmental epileptic encephalopathy associated with craniofacial dysmorphic features, renal, cardiac and other congenital malformations, the diagnosis of Schinzel-Giedion syndrome has to be excluded. Given the association of SGS with an increased risk of tumors, accurate diagnosis enables regular monitoring, facilitating early detection and treatment of potential complications or associated disorders.
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•Novel PU network nanocomposites containing embedded MSNs are successfully prepared.•The addition of MSNs improves surface, thermal and mechanical properties of PUs.•Materials exhibit ...promising traits for application as coatings for medical devices.
Novel polyurethane nanocomposite (PUN) materials containing different surface-functionalized mesoporous silica nanoparticles (MSNs) were prepared by in situ polymerization methodology. Polyurethane network was formed from poly(dimethylsiloxane)-based macrodiol (PDMS), 4,4′-methylenediphenyldiisocyanate (MDI), and hyperbranched polyester of the second pseudo-generation (BH-20; used as crosslinking agent). PU and PU/MSN nanocomposites contained equal ratios of soft PDMS and hard MDI-BH-20 segments. Non-functionalized and surface-functionalized (with 3-(trihydroxysilyl)propyl methylphosphonate (FOMSN) and 2-methoxy(polyethyleneoxy)6−9propyltrimethoxysilane (PEGMSN)) MSNs were used as the nanofillers at a concentration of 1 wt%. Prepared materials were characterized by Fourier transform infrared (FTIR) spectroscopy, atomic force microscopy (AFM), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic mechanical thermal analyses (DMTA), nanoindentation, equilibrium swelling and water absorption measurements. Characteristics of the prepared PUNs when in contact with a biological environment were assessed through testing their biocompatibility, protein adsorption and adhesion of endothelial cells. The favourable influence of MSNs on the physico-chemical and biological characteristics of these novel PUN materials was identified, which evidences their vast applicability potential as coatings for medical devices and implants.
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