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Evogliptin, an anti-diabetic drug had positive impact on various cardiovascular events including inflammation and vascular calcification (VC), an active process driven by vascular smooth muscle cell (VSMC) phenotypic transition. Sphingolipids such as ceramide (CER) mediates inflammation and VC in the vascular tissue. We investigated whether evogliptin ameliorate phenotypic transition and pyroptosis in VSMCs as underlying cause of VC. In cultured VSMCs, isolated from the aorta of (C57/BL6) mouse, we observed more severe calcification with prior treatment of CER in Pi-treated VSMCs as detected by Alizarin Red Staining. Prior CER- stimulation led to a marked upregulation of osteogenic markers such as RUNX2, OPN, BMP2 and decreased contractile markers SM22-α and α- SMA in Pi-treated VSMCs as compared to control cells. In addition, increased expression of pyroptotic markers such as NLRP3, GSDM-D, IL-1β, IL-18, and LDH release was observed with prior treatment of CER in Pi-treated VSMCs as compared to control cells. Furthermore, MCC950 (NLRP3 inhibitor), disulfiram (GSDM-D inhibitor) and evogliptin significantly downregulated osteogenic and pyroptotic markers including LDH release in both Pi-induced only and CER + Pi-treated VSMCs. Moreover, GW4869 (SMase inhibitor) and evogliptin significantly reduced SMase activity in sphingomyelin (SM)-induced VSMCs as compared to both Pi and SM only-treated groups. Also, the cleavage efficiency of GSDM-D was high in Pi and CER + Pi groups which was reduced with prior treatment of evogliptin. Hence, our data demonstrate that evogliptin alleviates VC by blocking phenotypic transition and associated pyroptosis via modulation of NLRP3/GSDM-D mediated pathway in CER-induced VSMCs.

The ability of the antineoplastic agent epirubicin to induce aneuploidy and meiotic delay in the somatic and germinal cells of male mice was investigated by fluorescence in situ hybridization assay using labeled DNA probes and BrdU-incorporation assay. Mitomycin C and colchicine were used as positive controls for clastogen and aneugen, respectively, and these compounds produced the expected responses. The fluorescence in situ hybridization assay with a centromeric DNA probe for erythrocyte micronuclei showed that epirubicin is not only clastogenic but also aneugenic in somatic cells in vivo. By using the BrdU-incorporation assay, it could be shown that the meiotic delay caused by epirubicin in germ cells was approximately 48 h. Disomic and diploid sperm were shown in epididymal sperm hybridized with DNA probes specific for chromosomes 8, X and Y after epirubicin treatment. The observation that XX- and YY-sperm significantly prevailed over XY-sperm indicates missegregation during the second meiotic division. The results also suggest that earlier prophase stages contribute less to epirubicin-induced aneuploidy. Both the clastogenic and aneugenic potential of epirubicin can give rise to the development of secondary tumors and abnormal reproductive outcomes in cured cancer patients and medical personnel exposed to epirubicin.

BackgroundLaparoscopic sleeve gastrectomy (LSG) has become an increasingly popular bariatric procedure. LSG still conveys some risks, including early staple line complications such as bleeding and leaks. It has been proposed that staple line complications can be reduced by staple line reinforcement (SLR). This study aimed to compare the short-term efficacy and safety of the SLR during LSG by oversewing versus no SLR in an Egyptian cohort over a period of 11 years.Patients and methodsThis is a retrospective study that analyzed data from patients undergoing LSG by the same surgeon over a period of 11 years. The patients’ early postoperative complications were compared according to performing SLR.ResultsThe SLR group showed significantly longer surgery time (p = 0.021) and a lower rate of postoperative bleeding (p = 0.027). All leakage cases occurred in the non-SLR group (0.7% vs. 0.0%) without statistical significance (p = 0.212). The two mortality cases occurred in the non-SLR group. The LOS was comparable in the two groups (p = 0.289).ConclusionThis study confirms the short-term benefits of SLR by oversewing during LSG in terms of a lower incidence of 30-day morbidity, particularly bleeding, and lower rates of reoperation, with a clinically questionable longer operation time.

[This corrects the article DOI: 10.1371/journal.pone.0109942.].

Erste Ansätze des Computergestützten Lernens sind bereits in den 60er Jahren des letzten Jahrhunderts und vor allem in den USA zu finden. Eng verbunden mit der Fortentwicklung der Computertechnologie hin zum sogenannten „Personal Computer“ wurde diese Lehr- und Lernform dann Anfang der 80er Jahre in verschiedenen Ländern in größerem Maße aufgegriffen. Mit zunehmender Verbreitung der Computer auch an Schulen und Hochschulen begann die Übertragung von Lehrstoff in Form von Lehr-/Lernprogrammen auf den Rechner (vgl. Bodendorf, 1990, S 15). Das Modell des \"Programmierten Unterrichts\" aus den 50er Jahren mit seinen Grundlagen in Gestalt der behavioristischen Lerntheorien war aber weiterhin prägend für die Konzeption und Praxis des Computergestützten Lehrens/Lernens, obwohl sich im Verlauf der 70er und 80er Jahre eine Wendung von der behavioristischen zur kognitivistischen Lerntheorie vollzogen hatte (Gardner, 1989). Mangelnde Hard- und Softwareleistung sowie unzureichende pädagogische Umsetzungsmöglichkeiten degradierten die Rechner mit diesen Programmen zu Lernmaschinen (vgl. Walter, 1984, S. 9).

A total of 200 1-week-old Japanese quails were randomly allocated into five treatment groups, each consisting of 40 unsexed birds (five replicates, eight birds each). Quails were reared in traditional cages (90 × 40 × 40 cm), and feed and water were made available throughout the 5-week trial. The treatment groups were as follows: the 1st was fed basal diet, whereas the 2nd, 3rd, 4th, and 5th groups were fed with ration supplemented with nano zinc (Zn-NPs) at doses of 0.1, 0.2, 0.3, and 0.4 g/kg diet, respectively. Results showed that, a significant (p ≤ .0001) improvement in body weight, weight gain, feed intake, and feed conversion ratio was observed in birds fed diets supplemented with 0.2 g/kg of Zn-NPs. Supplementation of Zn-NPs at doses of 0.1-0.3 g/kg diet demonstrated a positive impact on the activity of ALT, AST, and LDH. The liver profile parameters were not statistically influenced (p > .05) by dietary biological nano zinc, with the exception of total cholesterol (TC), high density lipoprotein (HDL), and low density lipoprotein (LDL). Also, dietary supplementation of biological Zn-NPs at concentrations of 0.1-0.3 g/kg diet demonstrated a positive impact on superoxide dismutase (SOD), glutathione peroxidase (GPX), malondialdehyde (MDA), immunoglobulin G (IgG), and immunoglobulin M (IgM). Dietary supplementation of Zn-NPs led to an increase in beneficial microbial populations. From the obtained results, Zn-NPs supplementation at 0.2 g/kg diet had a positive effect on the performance and physiological status of growing Japanese quails. HIGHLIGHTS Zinc (Zn) is an important trace element for the general functioning of the animal body. A significant improvement in growth performance was observed in birds fed diet enriched with 0.2 g/kg of Zn-NPs. Supplementation of Zn-NPs (0.1-0.3 g/kg diet) demonstrated a positive impact on immunity and antioxidant indices

The development of nanomaterials has been speedily established in recent years, yet nanoparticles synthesized by traditional methods suffer unacceptable toxicity and the sustainability of the procedure for synthesizing such nanoparticles is inadequate. Consequently, green biosynthesis, which employs biopolymers, is gaining attraction as an environmentally sound alternative to less sustainable approaches. Chitosan-encapsulated nanoparticles exhibit exceptional antibacterial properties, offering a wide range of uses. Chitosan, obtained from shrimp shells, aided in the environmentally friendly synthesis of high-purity zinc oxide nanoparticles (ZnO NPs) with desirable features such as the extraction yield (41%), the deacetylation (88%), and the crystallinity index (74.54%). The particle size of ZnO NPs was 12 nm, while that of chitosan–ZnO NPs was 21 nm, and the bandgap energies of these nanomaterials were 3.98 and 3.48, respectively. The strong antibacterial action was demonstrated by ZnO NPs, chitosan–ZnO NPs, and chitosan–ZnO/PVP, particularly against Gram-positive bacteria, making them appropriate for therapeutic use. The photocatalytic degradation abilities were also assessed for all nanoparticles. At a concentration of 6 × 10 –5  M, chitosan removed 90.5% of the methylene blue (MB) dye, ZnO NPs removed 97.4%, chitosan-coated ZnO NPs removed 99.6%, while chitosan–ZnO/PVP removed 100%. In the case of toluidine blue (TB), at a concentration of 4 × 10 –3  M, the respective efficiencies were 96.8%, 96.8%, 99.5%, and 100%, respectively. Evaluation of radical scavenger activity revealed increased scavenging of ABTS and DPPH radicals by chitosan–ZnO/PVP compared to individual zinc oxide or chitosan–ZnO, where the IC50 results were 0.059, 0.092, 0.079 mg/mL, respectively, in the ABTS test, and 0.095, 0.083, 0.061, and 0.064 mg/mL in the DPPH test, respectively. Moreover, in silico toxicity studies were conducted to predict the organ-specific toxicity through ProTox II software. The obtained results suggest the probable safety and the absence of organ-specific toxicity with all the tested samples.

Acute liver failure (ALF) is a disease accompanied by severe liver inflammation. No effective therapy is available yet apart from liver transplantation; therefore, developing novel treatments for ALF is urgently required. Inflammatory mediators released by NF-кB activation play an essential role in ALF. Proteasome inhibitors have many medical uses, such as reducing inflammation and NF-кB inhibition, which are believed to account for most of their repurposing effects. This study was undertaken to explore the possible protective effects and the underlying mechanisms of carfilzomib, a proteasome inhibitor, in a mouse model of ALF induced by lipopolysaccharide/D-galactosamine/dimethylsulfoxide (LPS/GalN/DMSO). Carfilzomib dose-dependently protected mice from LPS/GalN/DMSO-induced liver injury, as indicated by the decrease in serum alanine aminotransferase and aspartate aminotransferase levels. LPS/GalN/DMSO increased TNF-α, NF-кB, lipid peroxidation, NO, iNOS, cyclooxygenase-II, myeloperoxidase, and caspase-3 levels. Carfilzomib administration mitigated LPS/GalN/DMSO-induced liver damage by decreasing the elevated levels of TNF-α, NF-кB, lipid peroxidation, nitric oxide, iNOS, cyclooxygenase-II, myeloperoxidase, caspase-3, and histopathological changes. A restored glutathione level was also observed in the carfilzomib-treated LPS/GalN/DMSO mice. Our results demonstrate that carfilzomib protects against LPS/GalN/DMSO-induced ALF by inhibiting NF-кB, decreasing inflammatory mediators, oxidative/nitrosative stress, neutrophil recruitment, and apoptosis, suggesting that carfilzomib may be a potential therapeutic agent for ALF.

Background Hepatocellular carcinoma (HCC) is a global life-threatening problem and therapeutic interventions are still encountered. IQGAP genes are involved in HCC oncogenesis. The modulatory effect of statins on the expression of IQGAP genes is still unclear. This study aims to study the effect of free SV and chitosan (CS) decorated simvastatin (SV) loaded solid lipid nanoparticles (C-SV-SLNs) on HCC mortality. Methods and results Plain, SV-SLN, and C-SV- SLN were prepared and characterized in terms of particle size (PS), zeta potential (ZP), and polydispersity index (PDI). The biosafety of different SLN was investigated using fresh erythrocytes, moreover, cytotoxicity was investigated using HepG2 cell lines. The effect of SLNs on IQGAPs gene expression as well as JNK, HDAC6, and HDAC8 activity was investigated using PCR and MOE-docking. The current results displayed that SV-SLNs have nanosized, negative ZP and are homogenous, CS decoration shifts the ZP of SLN into cationic ZP. Furthermore, all SLNs exhibited desirable biosafety in terms of no deleterious effect on erythrocyte integrity. SV solution and SV-SLN significantly increase the mortality of HepG2 compared to undertreated cells, however, the effect of SV-SLN is more pronounced compared to free SV. Remarkably, C-SV-SLN elicits high HepG2 cell mortality compared to free SV and SV-SLN. The treatment of HepG2 cells with SV solution, SV-SLN, or C-SV-SLN significantly upregulates the IQGAP2 gene with repression of IQGAP1 and IQGAP3 genes. MOE-docking studies revealed both SV and tenivastatin exhibit interactions with the active sites of JNK, HDAC6, and HDAC8. Moreover, tenivastatin exhibited greater interactions with magnesium and zinc compared to SV. Conclusions This research provides novel insights into the therapeutic potential of SV, SV-SLN and C-SV-SLNs in HCC treatment, modulating critical signaling cascades involving IQGAPs, JNK, and HDAC. The development of C-SV-SLNs presents a promising strategy for effective HCC therapy. Graphical abstract

Diabetes mellitus is a metabolic disease that can cause systemic problems, including testicular dysfunction. Several diabetes medications have demonstrated potential adverse effects on the male reproductive system; however, the effects of saxagliptin and dapagliflozin have not been sufficiently examined. This investigation studied the impacts of saxagliptin and dapagliflozin treatments on the gonads in a male mouse model of diabetes. Testicular disturbances were assessed by sperm DNA damage, diakinesis-metaphase I chromosome examination, and spermiogram analysis. Our results showed more sperm DNA damage, more spermatocyte chromosome aberrations, lower sperm motility/count, and more sperm morphological anomalies in diabetic mice than in the control mice. Dapagliflozin significantly restored all examined measures to the control values in diabetic mice, unlike saxagliptin, which exacerbated the reduction in sperm count and motility. Both drugs significantly restored the gonadal redox imbalances in diabetic mice by decreasing reactive oxygen species accumulation and increasing glutathione levels. In conclusion, our study presents preliminary evidence for the safety and efficacy of dapagliflozin in alleviating testicular abnormalities induced by diabetes, making it a promising candidate drug for patients with diabetes in their reproductive age. As saxagliptin may have negative effects on fertility, its prescription should be avoided in young male diabetic patients.