Galbraithnorton0034

Cigarette smoking is increasingly concentrated among marginalized populations with limited access to evidence-based cessation treatment. This includes racial/ethnic minorities, lower income individuals, those with lower educational attainment, and residents of rural areas. To reach Healthy People 2020 objectives, successful cessation interventions must narrow these disparities. Nicotine replacement therapy (NRT) sampling is an easily translatable and scalable intervention that could enhance treatment access and thus narrow disparities. The present study examined individual-level demographic moderators of the impact of NRT sampling on cessation-related behaviors including 1) use of a cessation medication, 2) making a 24-hour quit attempt, 3) floating abstinence, and 4) 7-day point prevalence abstinence at 6-months. Study participants included N = 1245 adult smokers enrolled in the Tobacco Intervention in Primary Care Treatment Opportunities for Providers (TIP TOP) study, a recently concluded large-scale clinical trial of NRT sampling relative to standard care within 22 primary care clinics across South Carolina. Generalized linear models examined individual-level demographic moderators of treatment effect. Results suggest that NRT sampling may be more effective among some of the most disadvantaged groups of smokers, including smokers with lower income and education, as well those who live in more rural areas. The effects of NRT sampling did not differ by race. In sum, NRT sampling is a low-cost, low-burden intervention that could be disseminated broadly to reach large numbers of smokers and potentially narrow cessation disparities. Prostate cancer (PCa) is the most common malignancy among men. Tumor metastasis and chemoresistance contribute to the major cause of the mortality. In this study, we compared the protein profiles of two prostate cancer cell lines with different metastatic potentials, and identified cofilin-1 (CFL1) was one of the most differentially expressed proteins between two cell lines. Further results suggested that cofilin-1 promoted the remodeling of F-actin cytoskeleton, and enhanced the proliferation, migration and invasion of the prostate cancer cells via activation of P38 MAPK signaling pathway. In addition, cofilin-1 elevated the expression and drug efflux activity of multidrug resistance protein 1 (MDR1) by P38 MAPK signaling pathway, resulting in decrease of the adriamycin-induced apoptosis as well as the lytic cell death, and the subsequent resistance against adriamycin. Collectively, cofilin-1 might serve as a novel target candidate for both inhibiting the metastasis and reversing the chemoresistance of PCa. V.This study has examined the in vitro and in vivo anti-diabetic properties of the peptidase-resistant analogues [D-Ser2]palmitoyl-paddlefish glucagon and [D-Ser2]palmitoyl-lamprey glucagon. The peptides stimulated insulin release from BRIN-BD11 clonal β-cells and isolated mouse pancreatic islets and also enhanced cAMP production in cells transfected with the human GLP-1 receptor and with the human glucagon receptor. The insulinotropic actions of the peptides were attenuated in INS-1 cells lacking GLP-1 and glucagon receptors. [D-Ser2]palmitoyl-paddlefish glucagon stimulated proliferation of BRIN-BD11 cells and protected against cytokine-mediated apoptosis as effectively as GLP-1. The analogue was more effective than the native peptide or the lamprey glucagon analogue in acutely lowering blood glucose and elevating plasma insulin in lean mice even when administered up to 4 h before a glucose load. Twice daily administration of [D-Ser2]palmitoyl-paddlefish glucagon to high-fat fed mice over 21 days reduced food intake, body weight, non-fasting blood glucose and plasma insulin concentrations, as well as significantly improving glucose tolerance and insulin resistance and decreasing α-cell area and pancreatic insulin content. Islet expression of the Gcgr, Glp1r, Gipr and Slc2a2 (GLUT-2) genes significantly increased. These data demonstrate that long-acting peptide [D-Ser2]palmitoyl-paddlefish glucagon exerts beneficial metabolic properties in diabetic mice via Ggcr- and Glp1r-activated pathways and so shows potential as a template for further development into an agent for treatment of patients with obesity-related Type 2 diabetes. This study investigated the effect of DAMGO-induced μ opioid receptor (MOR) internalization on morphine tolerance. Male Sprague-Dawley rats (200-250 g) aged 6-8 weeks were administered morphine via intrathecal (i.t.) injection (15 μg/10 μl twice daily for 6 days) to induce antinociceptive tolerance, which was evaluated using the tail-flick and paw-withdrawal tests. Response latency was calculated as the percentage of maximum possible effect (%MPE). A bolus of DAMGO was administered by i.t. T-705 RNA Synthesis inhibitor injection on day 6, and the tail-flick and paw-withdrawal tests were carried out 24, 48, and 72 h later. Membrane and cytosolic MOR expression was assessed by western blotting. HEK293 cells were transfected with MOR-FLAG plasmid and after 6 days of morphine treatment (10 μM), the cells were treated with 1 μM DAMGO, and MOR localization was examined by immunofluorescence analysis 30 and 60 min later. Repeated morphine treatment induced tolerance after 5 days; however, i.t. DAMGO administration restored morphine sensitivity and enhanced acute morphine-induced antinociception after 24, 48, and 72 h. In HEK293 cells, DAMGO treatment stimulated MOR internalization after 30 min and MOR recycling to the membrane after 1 h. Membrane and cytoplasmic MOR expression in vivo was unchanged 24, 48, and 72 h after i.t. DAMGO injection. Morphine does not cause significant MOR internalization or downregulation, and can readily induce tolerance. DAMGO counters this effect by enhancing receptor endocytosis, thereby reversing morphine-induced antinociceptive tolerance and restoring its analgesic efficacy. Previous reports suggest that diabetes may differentially affect the vascular beds of females and males. However, there is insufficient evidence to establish the timeline of the vascular dysfunction in diabetes, specifically in relation to sex. Here, we determined whether mesenteric arterial function is altered in UC Davis Type-2 Diabetes Mellitus (UCD-T2DM) rats and if this occurs as early as the pre-diabetic stage of the disease. Specifically, we investigated whether vascular dysfunction differs between pre-diabetic or diabetic status and if this varies by sex. We measured the responses to endothelium-dependent and -independent vasorelaxant as well as vasoconstrictor agents and explored the potential mechanisms involved in sex-specific development of arterial dysfunction in UCD-T2DM rats. In addition, indices of insulin sensitivity were assessed. We report the reduced insulin sensitivity in pre-diabetic males and diabetic females. Vascular relaxation to acetylcholine was impaired to a greater extent in mesenteric artery from males in the pre-diabetic stage than in their female counterparts. In contrast, the arteries from females with diabetes exhibited a greater impairment to acetylcholine compared with diabetic males. Additionally, the sensitivity of mesenteric artery to contractile agents in females, but not in males, after the onset of diabetes was increased. Our data suggest that the reduced insulin sensitivity through AKT may predispose vessels to injury in the pre-diabetic stage in males. On the other hand, reduced insulin sensitivity as well as enhanced responsiveness to contractile agents may predispose arteries to injury in the diabetic stage in females. Anaphylaxis during general anaesthesia is a significant clinical challenge for anaesthesiologists. Approximately 50% of perioperative anaphylaxis cases lack the presence of specific IgE antibodies. Mas-related G-protein coupled receptor X2 (MRGPRX2) in humans and its mouse orthologue Mas-related G-protein coupled receptor B2 (Mrgprb2) are crucial receptors in non-IgE-dependent histamine release. Anaesthetics such as rocuronium and atracurium cause perioperative anaphylaxis by activating histamine release via the Mrgprb2 pathway. We hypothesized that antagonistic DNA aptamers that target MRGPRX2 can prevent perioperative anaphylaxis. Selection of a DNA aptamer that specifically binds MRGPRX2 was achieved by using our modified Systematic Evolution of Ligands by Exponential enrichment (SELEX) approach. Our SELEX process used MRGPRX2-proteoliposomes synthesised by a wheat germ cell-free system as templates. The activity of the selected aptamer to inhibit histamine release from MRGPRX2-activated mast cells and in an anaphylaxis rat model transplanted with this cell line was examined. Our selection process identified aptamer-X35 with the sequence 5'-ATGACCATGACCCTCCACACTGTAGGCACCACGGGTCCCTGGCAGTTAAAAGTACGTTTGTCAGACTGTGGCAGGGAAACA-3'. In silico 2D modelling of aptamer-X35 revealed a structure with a small loop and a long stem. Aptamer-X35 inhibited histamine release from mast cells by 70%. Subcutaneous injection of 30 nmol of aptamer-X35 inhibited the anaphylactic reaction in the rat anaphylaxis model. This study demonstrated that aptamer-X35 selected by the modified SELEX approach reduced histamine release by inhibiting the MRGPRX2 pathway. Overall, our findings establish aptamer-X35 as a potential therapeutic candidate against perioperative anaphylaxis. Ischemic stroke is a leading cause of death and disability worldwide. Currently, the only pharmacological therapy for ischemic stroke is thrombolysis with tissue plasminogen activator that has a narrow therapeutic window and increases the risk of intracerebral hemorrhage. New pharmacological treatments for ischemic stroke are desperately needed, but no neuroprotective drugs have successfully made it through clinical trials. Beneficial effects of peroxisome proliferator-activated receptor alpha (PPARα) activation on vascular integrity and function have been reported, and PPARα agonists have clinically been used for many years to manage cardiovascular disease. Thus, PPARα has gained interest in recent years as a target for neurovascular disease such as ischemic stroke. Accumulating preclinical evidence suggests that PPARα activation modulates several pathophysiological hallmarks of stroke such as oxidative stress, blood-brain barrier (BBB) dysfunction, and neuroinflammation to improve functional recovery. Therefore, this review summarizes the various actions PPARα exerts in neurovascular health and disease and the potential of employing exogenous PPARα agonists for future pharmacological treatment of ischemic stroke. Neonatal hypoxic-ischemic encephalopathy remains the most important neurological problem of the newborn. Delays in diagnosing perinatal brain injuries are common, preventing access to acute therapies. Therefore, there is a critical need for therapeutic strategies that are beneficial when delivered beyond 24 h after birth. Here we show that Leukemia Inhibitory Factor (LIF) functions as an essential injury-induced neurotrophic cytokine in the CNS and that non-invasively administering LIF as late as 3 days after a hypoxic-ischemic insult improves neurological function. Using a mouse model of late preterm brain injury we show that astroglial and reactivity to hypoxia-ischemia was diminished at 3 days of recovery, but then exacerbated at 2 weeks of recovery in LIF haplodeficient mice. There also were significantly more CD68+/Iba-1+ cells in the ipsilateral striatum in LIF-Het mice compared to WT mice at 2 weeks of recovery. This desynchronized glial response was accompanied by increased neuronal cell death in the striatum and neocortex (Fluorojade C), hypomyelination (reduced MBP staining and thinner external capsule), increased extent of brain damage (Nissl) and diminished neurological function on sensorimotor tests.