APX3330 Promotes Neurorestorative Effects after Stroke in Type One Diabetic Rats

APX3330 is a selective inhibitor of APE1/Ref-1 redox activity. In this study, we investigate the therapeutic effects and underlying mechanisms of APX3330 treatment in type one diabetes mellitus (T1DM) stroke rats. Adult male Wistar rats were induced with T1DM and subjected to transient middle cerebral artery occlusion (MCAo) and treated with either PBS or APX3330 (10mg/kg, oral gavage) starting at 24h after MCAo, and daily for 14 days. Rats were sacrificed at 14 days after MCAo and, blood brain barrier (BBB) permeability, ischemic lesion volume, immunohistochemistry, cell death assay, Western blot, real time PCR, and angiogenic ELISA array were performed. Compared to PBS treatment, APX3330 treatment of stroke in T1DM rats significantly improves neurological functional outcome, decreases lesion volume, and improves BBB integrity as well as decreases total vessel density and VEGF expression, while significantly increases arterial density in the ischemic border zone (IBZ). APX3330 significantly increases myelin density, oligodendrocyte number, oligodendrocyte progenitor cell number, synaptic protein expression, and induces M2 macrophage polarization in the IBZ of T1DM stroke rats. Compared to PBS treatment, APX3330 treatment significantly decreases plasminogen activator inhibitor type-1 (PAI-1), monocyte chemotactic protein-1 and matrix metalloproteinase 9 (MMP9) and receptor for advanced glycation endproducts expression in the ischemic brain of T1DM stroke rats. APX3330 treatment significantly decreases cell death and MMP9 and PAI-1 gene expression in cultured primary cortical neurons subjected to high glucose and oxygen glucose deprivation, compared to untreated control cells. APX3330 treatment increases M2 macrophage polarization and decreases inflammatory factor expression in the ischemic brain as well as promotes neuroprotective and neurorestorative effects after stroke in T1DM rats

A case for the standardized letter of recommendation in otolaryngology residency selection

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102208/1/lary24431.pd

Epidermal growth factor receptor, p16, cyclin D1, and p53 staining patterns for inverted papilloma

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/101829/1/alr21215.pd

Hereditary Hemorrhagic Telangiectasia (HHT) Research Outcomes Registry

HHT has an estimated prevalence of 1 in 5000, affecting children and adults, in multiple organs. The disease is characterized by the presence of vascular malformations (VMs), including arteriovenous malformations (AVMs) of the lung, liver, brain, spinal cord and smaller mucosal lesions (telangiectasia)of the nose, mouth and GI tract. The purpose of this study is to prospectively and longitudinally characterize major outcomes of Hereditary Hemorrhagic Telangiectasia (HHT), including frequent symptoms (epistaxis, migraines, etc.) as well as severe complications (death, stroke, heart failure, anemia, etc.), and identify their determinants. Furthermore, to identify predictors of epidemic/pandemic infections amongst HHT patients and the effects on; epistaxis (severity, topical nasal medication, nasal intervention, etc); disease severity (hospital admission, requiring ventilation, venous thromboembolism, death); HHT outcome and care (health care utilization, access to care, screening, preventative treatment). Baseline clinical and demographic data will be collected from participating HHT patients along with annual outcomes data, and entered into the Our HHT registry. For subjects who agree to give a saliva sample, the goal is to create a DNA repository of HHT subjects as a resource for future genetic, pharmacogenetics and targeted therapy studies and replicate and further characterize genetic associations with HHT phenotypes Related PAFs: 18-PAF08760, Multidisciplinary HHT Care through HemophiliaTreatment Centers: A Pilot Project Direct Sponsor: CureHHT Related Awards: AWD016993 (9/30/2019 -9/29/2021), AWD012515 (9/30/2015 -9/29/2020) Related UFAs: 22-UFA01123 (OUR HHT Registry, Active, Data Use Agreement, 11/1/2021-1/1/2030), 22-UFA01143 (OUR HHT Registry, UFA Hold, Material Transfer Agreement)http://deepblue.lib.umich.edu/bitstream/2027.42/175355/2/Our HHT Registry HUM00198400.pdfDescription of Our HHT Registry HUM00198400.pdf : Accepted versio

Enhancement of Inducible Nitric Oxide Synthase Activity by Low Molecular Weight Peptides Derived from Protamine: A Potential Therapy for Chronic Rhinosinusitis

Nitric oxide (NO) is a key immune defense agent that is produced from l-arginine in the airways by leukocytes and airway epithelial cells, primarily via inducible nitric oxide synthase (iNOS). Deficiencies in nasal NO levels have been associated with diseases such as primary ciliary dyskinesia and chronic rhinosinusitis. Herein, we demonstrate a proof-of-concept regarding a potential new therapeutic approach for such disorders. We show that arginine-rich low molecular weight peptides (LMWPs) derived from the FDA-approved protamine (obtained from salmon sperm) are effective at significantly raising NO production in both RAW 264.7 mouse macrophage and LA4 mouse epithelial cell lines. LMWP is produced using a stable, easily produced immobilized thermolysin gel column followed by size-exclusion purification. Monomeric l-arginine induces concentration-dependent increases in NO production in stimulated RAW 264.7 and LA4 cells, as measured by stable nitrite in the cell media. In stimulated RAW 264.7 cells, LMWP significantly increases iNOS expression and total NO production 12–24 h post-treatment compared to cells given equivalent levels of monomeric l-arginine. For stimulated LA4 cells, LMWPs are effective in significantly increasing NO production compared to equivalent l-arginine monomer concentrations over 24 h but do not substantially enhance iNOS expression. The use of the arginase inhibitor S-boronoethyl-l-cysteine in combination with LMWPs results in even higher NO production by stimulated RAW 264.7 cells and LA4 cells. Increases in NO due to LMWPs, compared to l-arginine, occur only after 4 h, which may be due to iNOS elevation rather than increased substrate availability