Evaluation of the anti-depressant potential of metformin in conditioned defeat model in golden Syrian hamsters

Background: Depression is a prevalent mood condition that has an impact on daily functioning. Globally, depression affects 264 million people. The current pharmacotherapy of depression has a lot of shortcomings. Therefore, there is a need to explore newer therapy that alleviate the symptoms of depression. Metformin was found to possess antioxidant potential and hypothesized to decrease the levels of branched-chain amino-acids essential for tryptophan uptake (precursor for serotonin synthesis). The study was designed to validate the efficacy of metformin as an anti-depressant in conditioned defeat model in male golden Syrian hamsters using open field test (OFT), forced swim test (FST) and Serum serotonin levels. Methods: After obtaining IAEC approval, the study was carried out using 8 golden Syrian hamsters each that were randomly assigned to four groups. The disease control group received 1mL normal saline, positive control was given fluoxetine 12 mg/kg, two groups of metformin 240 mg/kg given pre-insult and post-insult. The variables assessed on every third day included OFT and FST. Following the behavioral tests, serotonin-ELISA was done. To analyse the outcomes, appropriate statistical tests were applied. Results: On standardization, the model was established to a 16-day model. Further, results highlighted a significant difference in OFT, FST and serotonin levels with the metformin group and fluoxetine compared to disease control (p<0.001). However, no significant difference was observed between the fluoxetine and metformin groups (p>0.05), signifying the comparable results. Conclusions: Metformin (240 mg/kg) alleviated the depressive symptoms by modulating both behavioral and serotonin levels

AKT/Protein Kinase B Regulation of BCL Family Members during Oxysterol-induced Apoptosis

Cells of the vasculature, including macrophages, smooth muscle cells, and endothelial cells, exhibit apoptosis in culture upon treatment with oxidized low density lipoprotein, as do vascular cells of atherosclerotic plaque. Several lines of evidence support the hypothesis that the apoptotic component of oxidized low density lipoprotein is one or more oxysterols, which have been shown to induce apoptosis through the mitochondrial pathway. Activation of the mitochondrial pathway of apoptosis is regulated by members of the BCL family of proteins. In this study, we demonstrate that, in the murine macrophage-like cell line P388D1, oxysterols (25-hydroxycholesterol and 7-ketocholesterol) induced the degradation of the prosurvival protein kinase AKT (protein kinase B). This led, in turn, to the activation of the BCL-2 homology-3 domain-only proteins BIM and BAD and down-regulation of the anti-apoptotic multi-BCL homology domain protein BCL-xL. These responses would be expected to activate the pro-apoptotic multi-BCL homology domain proteins BAX and BAK, leading to the previously reported release of cytochrome c observed during oxysterol-induced apoptosis. Somewhat surprisingly, small interfering RNA knockdown of BAX resulted in a complete block of the induction of apoptosis by 25-hydroxycholesterol

Isolation of a Somatic Cell Mutant Resistant to the Induction of Apoptosis by Oxidized Low Density Lipoprotein

Oxidized low density lipoprotein (oxLDL) induces apoptosis in macrophages, smooth muscle cells, and endothelial cells. To elucidate the molecular mechanism of oxLDL-induced cytotoxicity and determine its tissue specificity, we have used Chinese hamster ovary (CHO)-K1 cells expressing human CD36 (CHO/CD36). Expression of CD36 rendered these cells susceptible to killing by oxLDL. This cytotoxicity was due to the induction of apoptosis. Therefore, CD36 expression is the only requirement for oxLDL-induced apoptosis. Oxysterols apparently mediate the cytotoxicity of oxLDL in macrophage foam cells and endothelial cells. 25-Hydroxycholesterol, at concentrations higher than 1 μg/ml, killed CHO-K1 cells, by apoptosis, in medium supplemented with serum as a source of cholesterol. These effects were not seen in a 25-hydroxycholesterol-resistant CHO/CD36 mutant (OX(R)), which was otherwise capable of undergoing apoptosis in response to staurosporine. This mutant was also resistant to killing by oxLDL, suggesting that oxysterols are at least partially responsible for the toxic effects of oxLDL. Oxysterol-induced apoptosis did not involve regulation of sterol regulatory element-binding protein proteolysis or the cholesterol biosynthetic pathway. 25-Hydroxycholesterol stimulated calcium uptake by CHO-K1 cells within 2 min after addition. Treatment of CHO or THP-1 (macrophage) cells with the calcium channel blocker nifedipine prevented 25-hydroxycholesterol induction of apoptosis. OX(R) showed no enhanced calcium uptake in response to 25- hydroxycholesterol

Arachidonate Metabolism and the Signaling Pathway of Induction of Apoptosis by Oxidized LDL/Oxysterol

Owing at least in part to oxysterol components that can induce apoptosis, oxidized LDL (oxLDL) is cytotoxic to mammalian cells with receptors that can internalize it. Vascular cells possess such receptors, and it appears that the apoptotic response of vascular cells to the oxysterols borne by oxLDL is an important part of the atherogenic effects of oxLDL. Thus, an analysis of the signaling pathway of apoptotic induction by oxysterols is of value in understanding the development of atherosclerotic plaque. In a prior study, we demonstrated an induction of calcium ion flux into cells treated with 25-hydroxycholesterol (25-OHC) and showed that this response is essential for 25-OHC-induced apoptosis. One possible signal transduction pathway initiated by calcium ion fluxes is the activation of cytosolic phospholipase A2 (cPLA2). In the current study, we demonstrate that activation of cPLA2 does occur in both macrophages and fibroblasts treated with 25-OHC or oxLDL. Activation is evidenced by 25-OHC-induced relocalization of cPLA2 to the nuclear envelope and arachidonic acid release. Loss of cPLA2 activity, either through genetic knockout in mice, or by treatment with a cPLA2 inhibitor, results in an attenuation of arachidonic acid release as well as of the apoptotic response to oxLDL in peritoneal macrophages or to 25-OHC in cultured fibroblast and macrophage cell lines

Object Sub-Categorization and Common Framework Method using Iterative AdaBoost for Rapid Detection of Multiple Objects

Object detection and tracking in real time has numerous applications and benefits in various fields like survey, crime detection etc. The idea of gaining useful information from real time scenes on the roads is called as Traffic Scene Perception (TSP). TSP actually consists of three subtasks namely, detecting things of interest, recognizing the discovered objects and tracking of the moving objects. Normally the results obtained could be of value in object recognition and tracking, however the detection of a particular object of interest is of higher value in any real time scenario. The prevalent systems focus on developing unique detectors for each of the above-mentioned subtasks and they work upon utilizing different features. This obviously is time consuming and involves multiple redundant operations. Hence in this paper a common framework using the enhanced AdaBoost algorithm is proposed which will examine all dense characteristics only once thereby increasing the detection speed substantially. An object sub-categorization strategy is proposed to capture the intra-class variance of objects in order to boost generalisation performance even more. We use three detection applications to demonstrate the efficiency of the proposed framework: traffic sign detection, car detection, and bike detection. On numerous benchmark data sets, the proposed framework delivers competitive performance using state-of-the-art techniques

Impact of the SARS-CoV-2 Pandemic on Hospitalizations in an Acute Psychiatric Ward

Rosaria Di Lorenzo,1 Matteo Reami,2 Diego Dragone,1 Martina Morgante,1 Giulia Panini,1 Paola Ferri,3 Sergio Rovesti3 1Mental Health Department and Drug Abuse, AUSL-Modena, Modena, 41124, Italy; 2School of Medicine & Surgery, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy; 3Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, 41125, ItalyCorrespondence: Rosaria Di Lorenzo, Tel +39-335-5410018, Email [email protected]; [email protected]: The Sars-CoV-2 pandemic imposed unprecedented and drastic changes in health care organizations all over the world.Purpose: To evaluate the impact of the pandemic on hospitalizations in an acute psychiatric ward.Patients and Methods: We retrospectively identified and compared acute psychiatric hospitalizations in the Service for Psychiatric Diagnosis and Care (SPDC) of AUSL-Modena during the pre-pandemic (n = 1858) and pandemic period (n = 1095), from 01/01/2017 to 31/12/2022. Data were statistically analyzed using STATA12.Results: We collected 1858 hospitalizations in the pre-pandemic and 1095 in the pandemic. During the pandemic, we observed a progressively sharp reduction in voluntary hospitalizations, whereas involuntary ones remained stable with an increase in 2022 (p < 0.001), longer hospital stays (12.32 mean days vs 10.03; p < 0.001), longer periods of involuntary hospitalizations (8.45 mean days vs 5.72; p < 0.001), more frequent aggressive behaviour (16.10% vs 9.12%; p < 0.001) and referral to psychiatric communities at discharge (11.04% vs 6.13%; p < 0.001); non-Italians (p = 0.001), people with disability pension (p < 0.001) and Support Administrator (p < 0.001) were more frequently hospitalized.Conclusion: During the pandemic, voluntary psychiatric hospitalizations decreased, but not involuntary ones, and the most vulnerable people in serious clinical conditions were hospitalized.Keywords: psychiatric hospitalizations, COVID-19 pandemic, community mental health, psychiatric involuntary treatmen

How underground systems can contribute to meet the challenges of energy transition

The paper provides an overview of the several scientific and technical issues and challenges to be addressed for underground storage of carbon dioxide, hydrogen and mixtures of hydrogen and natural gas. The experience gained on underground energy systems and materials is complemented by new competences to adequately respond to the new needs raised by transition from fossil fuels to renewables. The experimental characterization and modeling of geological formations (including geochemical and microbiological issues), fluids and fluid-flow behavior and mutual interactions of all the systems components at the thermodynamic conditions typical of underground systems as well as the assessment and monitoring of safety conditions of surface facilities and infrastructures require a deeply integrated teamwork and fit-for-purpose laboratories to support theoretical research. The group dealing with large-scale underground energy storage systems of Politecnico di Torino has joined forces with the researchers of the Center for Sustainable Future Technologies of the Italian Institute of Technology, also based in Torino, to meet these new challenges of the energy transition era, and evidence of the ongoing investigations is provided in this paper

Costameric integrin and sarcoglycan protein levels are altered in a Drosophila model for Limb-girdle muscular dystrophy type 2H

Mutations in two different domains of the ubiquitously expressed TRIM32 protein give rise to two clinically separate diseases, one of which is Limb-girdle muscular dystrophy type 2H (LGMD2H). Uncovering the muscle-specific role of TRIM32 in LGMD2H pathogenesis has proven difficult, as neurogenic phenotypes, independent of LGMD2H pathology, are present in TRIM32 KO mice. We previously established a platform to study LGMD2H pathogenesis using Drosophila melanogaster as a model. Here we show that LGMD2H disease-causing mutations in the NHL domain are molecularly and structurally conserved between fly and human TRIM32. Furthermore, transgenic expression of a subset of myopathic alleles (R394H, D487N, and 520fs) induce myofibril abnormalities, altered nuclear morphology, and reduced TRIM32 protein levels, mimicking phenotypes in patients afflicted with LGMD2H. Intriguingly, we also report for the first time that the protein levels of βPS integrin and sarcoglycan δ, both core components of costameres, are elevated in TRIM32 disease-causing alleles. Similarly, murine myoblasts overexpressing a catalytically inactive TRIM32 mutant aberrantly accumulate α- and β-dystroglycan and α-sarcoglycan. We speculate that the stoichiometric loss of costamere components disrupts costamere complexes to promote muscle degeneration

Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms

Background: Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN. Methods: Malignant CD14+ monocytes and CD34+ haematopoietic progenitor cells were isolated from peripheral blood/bone marrow mononuclear cells. The inhibition of CFU-GM colonies and the apoptotic effect on CD14+ and CD34+ induced by trabectedin were evaluated. Trabectedin's effects were also investigated in vitro on THP-1, and in vitro and in vivo on MV-4-11 cell lines. Results: On CMML/JMML cells, obtained from 20 patients with CMML and 13 patients with JMML, trabectedin - at concentration pharmacologically reasonable, 1-5 nM - strongly induced apoptosis and inhibition of growth of haematopoietic progenitors (CFU-GM). In these leukaemic cells, trabectedin downregulated the expression of genes belonging to the Rho GTPases pathway (RAS superfamily) having a critical role in cell growth and cytoskeletal dynamics. Its selective activity on myelomonocytic malignant cells was confirmed also on in vitro THP-1 cell line and on in vitro and in vivo MV-4-11 cell line models. Conclusions: Trabectedin could be good candidate for clinical studies in JMML/CMML patients