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The effect of the APs was also present; body weight gain was increased by OLA and RIS, while OLA induced lower weight gain in the MAM rats. Further, the MAM model showed lower abdominal adiposity, while OLA increased it. Serum lipid profile revealed MAM model-induced alterations in both sexes; total, HDL and LDL cholesterol levels were increased. The MAM model did not exert significant alterations in hormonal parameters except for elevation in leptin level. The results support intrinsic metabolic dysregulation in the MAM model in both sexes, but the MAM model did not manifest higher sensitivity to metabolic effects induced by antipsychotic treatment.Blocking Fibroblast Growth Factor Receptor 1 (FGFR1) is an attractive therapeutic option for treatment of cancer subtypes with amplification and over-expression of FGFR1. Selective targeting of FGFR1 can be achieved using an antibody-based approach, as small molecule inhibitors may not discriminate between FGFR1, 2, 3 and 4 due to their highly homologous kinase domain. However, development of classical bivalent FGFR1 directed antibodies has failed due to non-tolerated body weight decreases in preclinical species. M6123 is a novel IgG-like monovalent FGFR1 specific binder with enhanced Antibody-Dependent Cellular Cytotoxicity (ADCC) effector function and inhibits tumor growth significantly in FGFR1-dependent human xenograft models without reduced body weight in tumor-bearing mice. Toxicology studies reported here characterized the safety profile of M6123 in mouse, rat, and monkey. There were significant differences among animal species under similar M6123 exposure levels. Rats showed metastatic mineralization with an imbalance in serum phosphate at low doses, while mineralization was not found in mice or monkeys, even though hyperphosphatemia was detected in mice. Subtle differences in calcium/phosphate homoeostasis feedback loops may trigger the susceptibility to mineralization among animal species; nevertheless, the exact mechanism remains unknown. Monkeys showed marked, but reversible, decreases in peripheral blood NK cells and neutrophils. The latter was associated with considerably increased neutrophilic infiltrates in the liver sinusoids and red pulp of the spleen. These effects in monkeys are likely related to the enhanced ADCC activity of M6123. Overall, M6123 showed a superior safety profile in animals compared to bivalent FGFR1 antagonists or pan-FGFR inhibitors.Development of new blood vessels in the tumor microenvironment is an essential component of tumor progression during which newly formed blood vessels nourish tumor cells and play a critical role in rapid tumor growth, invasion and metastasis. Nevertheless, how tumor cells develop new blood vessels in the tumor microenvironment (TME) have been enigmatic. Previously, we have shown specific overexpression of ANX A2 in TNBC cells regulates plasmin generation and suspected a role in neoangiogenesis. In this report, we used Matrigel plug model of in vivo angiogenesis and confirmed its role in new blood vessel development. Next, we tested if blocking of ANX A2 in aggressive human breast TME can inhibit angiogenesis and tumor growth in vivo. We showed that aggressive human breast tumor cells growing in nude mice can induce intense neoangiogenesis in the tumor mass. Blocking of ANXA2 significantly inhibited neoangiogenesis and resulted in inhibition of tumor growth. Tacrolimus nmr Interestingly, we identified that blocking of ANXA2 significantly inhibited tyrosine phosphorylation (Tyr-P) of ANXA2 implying its involvement in tyrosine signaling pathway and suggesting it may regulate angiogenesis. Taken together, our experimental evidence suggests that ANX A2 could be a novel strategy for disruption of tyrosine signaling and inhibition of neoangiogenesis in breast tumor.

This study aimed to investigate whether the protection of miR-302a-3p in myocardial ischemia-reperfusion injury (MIRI) is mediated through the suppression of mitophagy.

We constructed a mouse I/R model in vivo by the ligation of left anterior descending coronary artery for 45min followed by 2h reperfusion, and an in vitro model by treating mouse cardiomyocytes with hypoxia-reoxygenation (H/R). Knockdown experiments were then performed in vivo and in vitro to determine the effects of miR-302a-3p knockdown on the mitophagy, mitochondrial dysfunction and oxidative stress and apoptosis. The potential targets of miR-302a-3p were further studied by bioinformatics analysis, luciferase assays, quantitative real-time PCR and western blotting.

MiR-302a-3p expression was significantly upregulated in mice subjected to MIRI and in H/R-treated mouse cardiomyocytes. Functional analyses demonstrated that inhibition of miR-302a-3p protected cardiac tissues against I/R-induced apoptosis and mitophagy, mitochondrial damage and mitochondrial oxidative stress. Furthermore, FOXO3 was identified as the direct target of miR-302a-3p. Mechanistically, knockdown of FOXO3 partially reversed the cardioprotective effects of miR-302a-3p inhibitor.

Our study suggested that inhibition of miR-302a-3p promoted mitochondrial autophagy and inhibited oxidative stress by targeting FOXO3 to suppress myocardial apoptosis, representing a potential target for MIRI treatment.

Our study suggested that inhibition of miR-302a-3p promoted mitochondrial autophagy and inhibited oxidative stress by targeting FOXO3 to suppress myocardial apoptosis, representing a potential target for MIRI treatment.Social isolation (SI) is a major health risk in older people leading to cognitive decline. This study examined how SI and age influence performance in the novel object recognition (NOR) and elevated plus maze (EPM) tasks in C57BL/6 mice aged 3 or 24 months. Mice were group-housed (groups of 2-3) or isolated for 2 weeks prior to experimentation. Following NOR and EPM testing hippocampal norepinephrine (NE), 5, hydroxytryptamine (5-HT), 5, hydroxyindole acetic acid (5-HIAA), corticosterone (CORT) and interleukin-6 (IL-6) were determined and serum collected for basal CORT analysis. A separate set of mice were exposed to the forced swim test (FST), sacrificed immediately and serum CORT determined. SI impaired performance in the NOR and the FST, reduced hippocampal 5-HT, increased hippocampal IL-6 and increased serum CORT post-FST in young mice. Aged mice either failed to respond significantly to SI (NOR, FST, hippocampal 5-HT, serum CORT post FST) or SI had synergistic effects with age (hippocampal NE, 5-HIAA5-HT).