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Noscapine Inhibits Rotenone-Induced Neurotoxicity: Involvement associated with Oxidative Anxiety, Neuroinflammation and also Autophagy Pathways.
Paraoxonase-2 regulates reactive oxygen species production in mitochondria. Stimulating its expression has therapeutic potential for diseases where oxidative stress plays a significant role in the pathology. Evidence suggests that the anti-diabetic drug pioglitazone may provide neuroprotection in Parkinson's disease, Alzheimer's disease, brain trauma and ischemia, but the biochemical pathway(s) responsible has not been fully elucidated. Here we report that pioglitazone (10 mg/kg/day) for 5 days significantly increased paraoxonase-2 expression in mouse striatum. Thus, this result highlights paraoxonase-2 as a target for neuroprotective strategies and identifies pioglitazone as a tool to study the role of paraoxonase-2 in brain. Chondroitin sulphate proteoglycans (CSPGs) are inhibitors to axon regeneration and plasticity. A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS4) is a human enzyme that catalyses the proteolysis of CSPG protein cores. Infusion of ADAMTS4 into the damaged spinal cord was previously shown to improve functional recovery SCI, however, this therapy is limited in its enzyme form. Adeno-associated viral (AAV) vector gene therapy has emerged as the vector of choice for safe, robust and long-term transgene expression in the central nervous system. Here, an AAV expression cassette containing ADAMTS4 under the control of the astrocytic GfaABC1D promoter was packaged into an AAV5 vector. Sustained expression of ADAMTS4 was achieved in vitro and in vivo leading to degradation of CSPGs. Compared to a contusion only group, AAV-ADAMTS4 resulted in significantly decreased lesion size, increased sprouting of hindlimb corticospinal tract axons, increased serotonergic fiber density caudal to a contusive spinal cord injury. Hindlimb-specific exercise rehabilitation was used to drive neuroplasticity towards improving functional connections. The combination of hindlimb rehabilitation with AAV-ADAMTS4 led to functional recovery after SCI compared to a contusion only group. Thus, long-term degradation of CSPGs through AAV-ADAMTS4 gene therapy in a combinational approach with rehabilitation represents a candidate for further preclinical development. Interleukin-33 (IL-33) is known to activate the regulatory T lymphocytes (Tregs), which are negatively correlated with brain damage after ischemic stroke. In this study, we aimed to investigate the role of Tregs in IL-33-mediated neuroprotection and elucidate the underlying mechanisms. In vivo, male C57BL/6 N mice were subjected to 60 min of transient middle cerebral artery occlusion (tMCAO), followed by daily administration of vehicle or IL-33 immediately after injury. Tregs were depleted by intraperitoneal administration of anti-CD25 antibody (anti-CD25Ab). Behavioral changes, brain edema, neuronal injury, Treg percentages, and cytokine expression levels were investigated in each group. In vitro experiments, primary mouse neuronal cells were subjected to oxygen-glucose deprivation (OGD) for 3 h. Vehicle- or drug-conditioned Tregs were applied to the neurons at the time of induction of hypoxia. Neuronal apoptosis and cytokine expression were measured in each group. The results indicate that intraperitoneal administration of anti-CD25Ab reduced CD4 + CD25 + Foxp3+ Tregs, increased infarct volume, enhanced stroke-induced cell death, and decreased sensorimotor functions. Notably, IL-33 increased CD4 + CD25 + Foxp3+ Tregs in the spleen and brain. However, blockading ST2 attenuated these effects of IL-33. The supernatant of the IL-33-treated Treg culture reduced neuronal apoptosis and elevated the production of the Treg cytokines IL-10, IL-35, and transforming growth factor-β (TGF-β). Anti-CD25Ab abrogated the neuroprotective effect of IL-33. Mechanistically, the neuroprotective effects of IL-33 were associated with reduction in apoptosis-related proteins and production of Tregs related cytokines. Overall, these findings showed that IL-33 afforded neuroprotection against ischemic brain injury by enhancing ST2-dependent regulatory T-cell expansion and activation via a mechanism involving anti-apoptosis proteins and cytokines, representing a promising immune modulatory target for the treatment of stroke. Thaumatin-like proteins (TLPs), which belong to pathogenesis-related (PR) protein family 5 (PR5), are involved in plant host defense and various developmental processes. The functions of the TLP family have been extensively discussed in multiple organisms, whereas the detailed information of this family in melon has not been reported yet. In this study, we identified 28 TLP genes in the melon genome and a N-terminal signal peptide was found highly conserved within each member of this family. Phylogeny analysis indicated that TLPs from melon and other plant species were clustered into ten groups. Twelve segmental and seven tandem duplication gene pairs that underwent purifying selection were identified. Pemigatinib TLP genes expressed differentially in different tissues/organs, and were significantly induced after Podosphaera xanthii infection. TLPs in breeding line MR-1 tend to express early after pathogen infection compared with cultivar Top Mark. Our study provides a comprehensive understanding of the melon TLP family and demonstrates their potential roles in disease resistance, therefore provides more reference for further research. OBJECTIVE Concerns over resident ability to practice effectively after graduation have led to the competency-based medical education movement. Entrustable professional activities (EPAs) may facilitate competency-based medical education in surgery, but implementation is challenging. This manuscript describes 1 strategy used to implement EPAs into an academic general surgery residency. DESIGN, SETTING, PARTICIPANTS A mobile application was developed incorporating 5 EPAs developed by the American Board of Surgery; residents and faculty from the Departments of Surgery, Emergency Medicine, and Hospital Medicine at a single tertiary care center were trained in its use. Entrustment levels and free text feedback were collected. Self-assessment was paired with supervisor assessment, and faculty assessments were used to inform clinical competency committee entrustment decisions. Feedback was regularly solicited from app users and results distributed on a monthly basis. RESULTS One thousand seven hundred and twenty microassessments were collected over the first 16 months of implementation; 898 (47.
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