Beta-adrenergic Receptor Agonist Research Articles

Role of Tocolytics in Preterm

Tocolytics are the drugs that are used to prolong the time of child birth, for a short period - up to 2 days. If the labour starts too early during pregnancy also termed as preterm birth, which is supposed to be one of the major cause of neonatal mortality and morbidity, all over the world. Administration of tocolytic agents can help in preterm labour to delay the preterm labour by 48 hours. Tocolytics temporarily slow the contractions and hence it is possible to transport the patient to a hospital, where specialized care can be provided to premature baby and also corticosteroids can be administered, which help mature the baby’s lungs. Different class of drugs are studied as tocolytics. Beta-Adrenergic receptor agonists like Terbutaline, Ritodrine, Fenoterol, Metaproterenol, Hexoprenaline, Albuterol, Orciprenaline, Nylidrin. Calcium channel blockers like Nicardipine and Nifedipine. Magnesium Sulfate. Nonsteroidal anti-inflammatories or prostaglandin inhibitors like Indomethacin, and Oxytocin inhibitors like Atosiban were found effective in different studies with some side effects, are discussed here briefly. Some Nitrates, alcohol, Progesterone have also been tried with not much significant effect. Calcium channel blocker specially Nifedipine is most studied and found to be safer and effective for tocolysis. Individual uterine relaxant therapy should take into account individual differences in metabolism and response to drugs.. Short term use of tocolytics has been proven more effective and safer than longer use of it for pre-term labour.

Isoproterenol injected into the basolateral amygdala rescues amyloid β1-42-induced conditioned fear memory deficit via reducing intracellular Zn2+ toxicity

On the basis of amyloid β (Aβ) peptides as triggers in atrophy of structures in the limbic system, here we postulated that Aβ1-42-induced intracellular Zn2+ toxicity in the basolateral amygdala contributes to conditioned fear memory. Aβ1-42 increased intracellular Zn2+ level in the amygdala after local injection of Aβ1-42 into the basolateral amygdala, resulting in conditioned fear memory deficit via attenuated LTP at perforant pathway-basolateral amygdala synapses. Co-injection of isoproterenol, a beta-adrenergic receptor agonist, reduced Aβ1-42-mediated increase in intracellular Zn2+, resulting in rescue of the memory deficit and attenuated LTP. The present study suggests that beta-adrenergic activity induced by isoproterenol in the basolateral amygdala rescues the impairment of conditioned fear memory by Aβ1-42. The rescuing effect may be linked with reducing Aβ1-42-induced intracellular Zn2+ toxicity. Furthermore, Aβ1-42 injection into the basolateral amygdala also attenuated LTP at perforant pathway-dentate granule cell synapses, while co-injection of isoproterenol rescued it, suggesting that Aβ1-42 toxicity in the basolateral amygdala also affects hippocampus-dependent memory. It is likely that beta-adrenergic receptor activation in the basolateral amygdala rescues the limbic system exposed to Aβ1-42 toxicity.

Cell therapy rescues aging-induced beta-1 adrenergic receptor and GRK2 dysfunction in the coronary microcirculation.

Our past study showed that coronary arterioles isolated from adipose-derived stromal vascular fraction (SVF)-treated rats showed amelioration of the age-related decrease in vasodilation to beta-adrenergic receptor (β-AR) agonist and improved β-AR-dependent coronary flow and microvascular function in a model of advanced age. We hypothesized that intravenously (i.v.) injected SVF improves coronary microvascular function in aged rats by re-establishing the equilibrium of the negative regulators of the internal adrenergic signaling cascade, G-protein receptor kinase 2 (GRK2) and G-alpha inhibitory (Gαi) proteins, back to youthful levels. Female Fischer-344 rats aged young (3 months, n = 24), old (24 months, n = 26), and old animals that received 1 × 107 green fluorescent protein (GFP+) SVF cells (O + SVF, n = 11) 4 weeks prior to sacrifice were utilized. Overnight urine was collected prior to sacrifice for catecholamine measurements. Cardiac samples were used for western blotting while coronary arterioles were isolated for pressure myography studies, immunofluorescence staining, and RNA sequencing. Coronary microvascular levels of the β1 adrenergic receptor are decreased with advancing age, but this decreased expression was rescued by SVF treatment. Aging led to a decrease in phosphorylated GRK2 in cardiomyocytes vs. young control with restoration of phosphorylation status by SVF. In vessels, there was no change in genetic transcription (RNAseq) or protein expression (immunofluorescence); however, inhibition of GRK2 (paroxetine) led to improved vasodilation to norepinephrine in the old control (OC) and O + SVF, indicating greater GRK2 functional inhibition of β1-AR in aging. SVF works to improve adrenergic-mediated vasodilation by restoring the β1-AR population and mitigating signal cascade inhibitors to improve vasodilation.

EH Domain-Containing 2 Deficiency Restricts Adipose Tissue Expansion and Impairs Lipolysis in Primary Inguinal Adipocytes

Lipid uptake can be facilitated via caveolae, specific plasma membrane invaginations abundantly expressed in adipocytes. The dynamin-related protein EH domain-containing 2 (EHD2) stabilizes caveolae at the cell surface. Here, we have examined the importance of EHD2 for lipid handling using primary adipocytes isolated from EHD2 knockout (Ehd2−/−) C57BL6/N mice. Following high-fat diet (HFD) feeding, we found a clear impairment of epididymal, but not inguinal, adipose tissue expansion in Ehd2−/− compared with Ehd2+/+ (WT) mice. Cell size distribution analysis revealed that Ehd2−/− mice had a lower proportion of small adipocytes, and an accumulation of medium-sized adipocytes in both epididymal and inguinal adipose tissue. Further, PPARγ activity, FABP4 and caveolin-1 expression were decreased in adipocytes isolated from Ehd2−/− mice. Inguinal adipocytes isolated from Ehd2−/− mice displayed reduced lipolysis in response to beta adrenergic receptor agonist, which was associated with reduced phosphorylation of perilipin-1 and hormone sensitive lipase (HSL). This impairment could not be rescued using a cAMP analog, indicating that impaired lipolysis in Ehd2−/− primary adipocytes likely occurs at the level of, or downstream of, protein kinase A (PKA). Altogether, these findings pinpoint the importance of EHD2 for maintained intracellular lipid metabolism, and emphasize differences in mechanisms regulating lipid handling in various adipose-tissue depots.

Segmental analysis by speckle-tracking echocardiography of the left ventricle response to isoproterenol in male and female mice

We studied by conventional and speckle-tracking echocardiography, the response of the left ventricle (LV) to a three-week continuous infusion of isoproterenol (Iso), a non-specific beta-adrenergic receptor agonist in male and female C57Bl6/J mice. Before and after Iso (30 mg/kg/day), we characterized LV morphology and function as well as global and segmental strain. We observed that Iso reduced LV ejection in both male (−8.7%) and female (−14.7%) mice. Several diastolic function parameters were negatively regulated in males and females such as E/A, E/E′, isovolumetric relaxation time. Global longitudinal (GLS) and circumferential (GCS) strains were reduced by Iso in both sexes, GLS by 31% and GCS by about 20%. For the segmental LV analysis, we measured strain, strain rate, reverse strain rate, peak speckle displacement and peak speckle velocity in the parasternal long axis. We observed that radial strain of the LV posterior segments were more severely modulated by Iso than those of the anterior wall in males. In females, on the other hand, both posterior and anterior wall segments were negatively impacted by Iso. Longitudinal strain showed similar results to the radial strain for both sexes. Strain rate, on the other hand, was only moderately changed by Iso. Reverse strain rate measurements (an index of diastolic function) showed that posterior LV segments were negatively regulated by Iso. We then studied the animals 5 and 17 weeks after Iso treatment. Compared to control mice, LV dilation was still present in males. Ejection fraction was decreased in mice of both sex compared to control animals. Diastolic function parameters, on the other hand, were back to normal. Taken together, our study indicates that segmental strain analysis can identify LV regions that are more negatively affected by a cardiotoxic agent such as Iso. In addition, cessation of Iso was not accompanied with a complete restoration of cardiac function after four months.

Cardiac Myosin Activation for the Treatment of Systolic Heart Failure.

Left ventricular systolic dysfunction is the hallmark pathology in heart failure with reduced ejection fraction. Increasing left ventricular contractility with beta-adrenergic receptor agonists, phosphodiesterase-3 inhibitors, or levosimendan has failed to improve clinical outcomes and, in some situations, increased the risk of sudden cardiac death. Beta-adrenergic receptor agonists and phosphodiesterase-3 inhibitors retain an important role in advanced heart failure. Thus, there remains an unmet need for safe and effective therapies to improve left ventricular systolic function. Two novel cardiac myotropes, omecamtiv mecarbil and danicamtiv, target cardiac myosin to increase left ventricular systolic performance. Neither omecamtiv mecarbil nor danicamtiv affects cardiomyocyte calcium handling, the proposed mechanism underlying the life-threatening arrhythmias associated with cardiac calcitropes and calcium sensitizers. Phase 2 clinical trials have demonstrated that these cardiac myosin activators prolong left ventricular systolic ejection time and promote left ventricular and atrial reverse remodeling. At higher plasma concentrations, these agents may be associated with myocardial ischemia and impaired diastolic function. An ongoing phase 3 clinical trial will estimate the clinical efficacy and safety of omecamtiv mecarbil. An additional study of these agents, which have minimal hemodynamic and renal effects, is warranted in patients with advanced heart failure refractory to guideline-directed neurohormonal blockers.

INTERVENÇÕES FARMACÊUTICAS SOBRE O USO DE DISPOSITIVOS INALATÓRIOS: O CUIDADO FARMACÊUTICO NO CONTROLE DA ASMA

A asma é uma doença crônica heterogênea, cujo tratamento é dividido entre a farmacoterapia de manutenção e a sintomática. O controle eficiente e prolongado das manifestações clínicas e funcionais da asma pode ser obtido pelo uso de corticosteroides, agonistas de beta-receptores de curta e longa duração, frequentemente incorporados a dispositivos inalatórios. Estudos destacam que o cuidado farmacêutico centrado no estabelecimento da autogestão do tratamento da asma se mostra promissor. O objetivo foi buscar evidências sobre intervenções farmacêuticas e seus desfechos relacionados à administração de dispositivos inalatórios para pacientes asmáticos. Trata-se de uma revisão integrativa e síntese narrativa. Foram localizados e incluídos nesta pesquisa oito artigos originais que apontam evidências de que as intervenções farmacêuticas são capazes de reduzir problemas relacionados ao uso de dispositivos inalatórios, proporcionando a autogestão do tratamento da asma. Conclui-se que as intervenções conduzidas por farmacêuticos melhoram o uso de inaladores, refletindo positivamente no controle da doença e reduzindo problemas relacionados a medicamentos.

A narrative review of research advances in mesenchymal stem cell therapy for asthma.

Asthma is a chronic inflammatory disease of the airways that involves multiple cells, including inflammatory cells, structural cells, and cellular components. Glucocorticoids and beta-receptor agonists are still the first choices for asthma treatment. However, the asthma symptoms may still be poorly controlled in some patients after an optimal treatment. Mesenchymal stem cells (MSCs) are characterized by the potential for multi-directional differentiation and can exert immunomodulatory and anti-inflammatory effects. Its role in treating asthma has increasingly been recognized in recent years. In this review article, we sought to summarize the recent advances in the therapeutic effects of MSCs on several types of asthma and explain the relevant mechanisms. Articles on asthma treatment with MSCs as of January 2020 were searched in PubMed, Google Scholar, and Web of Science databases. It was found that MSCs have therapeutic effects on allergic asthma, non-allergic asthma and occupational asthma; gene-modified or pretreated MSCs improves the therapeutic effects of MSCs in asthma; MSC-derived conditioned medium or extracellular vesicles possess the considerable curative effect as MSC on asthma; and MSCs exert their therapeutic effects on asthma by restoring Th1/Th2 balance, reversing Th17/Tregs imbalance, inhibiting DC maturation, and promoting the switch of M1 to M2 and repairing epithelial injury. Thus, MSCs may be a promising treatment for asthma.

Effectiveness of drugs acting on adrenergic receptors in the treatment for tobacco or alcohol use disorders: systematic review and meta-analysis.

To assess the efficacy of drugs directly acting on alpha- and beta-adrenergic receptors in the treatment of patients suffering from tobacco or alcohol use disorder. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, studies were identified through PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials and clinicaltrial.gov. We selected only randomized controlled trials with adult patients with tobacco or alcohol use disorders according to DSM-5 criteria. Interventions included any molecule having a direct pharmacological action on alpha- or beta-adrenergic receptors (agonist or antagonist). Comparators were placebo or other validated pharmacotherapies. The duration of the intervention was a minimum of 1month, with 3months of follow-up. Measurements included smoking cessation for tobacco; for alcohol, we selected abstinence, alcohol consumption (drinks per day or week) and heavy drinking days (HDD). Ten studies with tobacco and six with alcohol use disorder were included in the qualitative synthesis and fifteen studies in the quantitative analysis. We found that clonidine, an alpha-2 agonist, significantly increased smoking abstinence [relative risk=1.39 with a 95% confidence interval (CI)=1.04, 1.84]. Beta-blockers had no significant effect on smoking abstinence. The alpha-1 antagonists prazosin and doxazosin decreased alcohol consumption [SMD=-0.32 (-0.56, -0.07)] but had no effect on abstinence or HDD. The noradrenaline system may represent a promising mechanism to target in tobacco and alcohol use disorders.

Electrical Neurostimulation Promotes Brown Adipose Tissue Thermogenesis.

BackgroundBrown adipose tissue (BAT) is present in humans and rodents, and contributes to energy expenditure by converting energy stored in lipids and glucose into heat. Beta adrenergic receptor (β-AR) agonists have been proposed as pharmacological tools to activate BAT, but they lack selectivity for this tissue. This study aimed to investigate the possibility to apply electrical neurostimulation as a novel approach to activate BAT by promoting the sympathetic outflow towards BAT.MethodsMale C57BL/6J mice were treated with either unilateral electrical neurostimulation of interscapular BAT or with the β3-AR agonist CL316,243. Thermogenesis, nutrient uptake by BAT and downstream signaling of adrenergic receptors in BAT were examined.ResultsElectrical neurostimulation and β3-AR agonism acutely increased heat production by BAT, as evidenced by an increase in local temperature in BAT, without influencing the core body temperature. Both treatments acutely increased tyrosine hydroxylase content in the nerve terminals thereby confirming enhanced sympathetic activity. In addition, we identified increased phosphorylation of hormone-sensitive lipase coinciding with reduced intracellular lipids in BAT, without affecting acute nutrient uptake from plasma. The increased BAT temperature as induced by electrical neurostimulation was reversed by β3-AR antagonism.ConclusionElectrical neurostimulation acutely promotes thermogenesis in BAT as dependent on β3-AR signaling. We anticipate that electrical neurostimulation may be further developed as a novel strategy to activate BAT and thereby combat (cardio)metabolic diseases.

Re: Identification and Local Delivery of Vasodilators for the Reduction of Ureteral Contractions.

No AccessJournal of UrologyUrological Survey1 Dec 2020Re: Identification and Local Delivery of Vasodilators for the Reduction of Ureteral Contractions Anthony AtalaMD Anthony AtalaAnthony Atala More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001285.02AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Re: Identification and Local Delivery of Vasodilators for the Reduction of Ureteral Contractions." The Journal of Urology, 204(6), p. 1385 Suggested Reading : Systemic and topical drug administration in the pig ureter: effect of phosphodiesterase inhibitors alpha1, beta and beta2-adrenergic receptor agonists and antagonists on the frequency and amplitude of ureteral contractions. J Urol 2001; 166: 714. Link, Google Scholar © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 204Issue 6December 2020Page: 1385-1385 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Anthony Atala More articles by this author Expand All Advertisement PDF DownloadLoading ...

Beta adrenergic receptor activation inhibits oral cancer migration and invasiveness

ObjectiveThe aim of this study was to verify β2-AR expression in oral squamous cell carcinoma cell lines (SCC-9 and SCC-25), and to investigate the role of this receptor in migration and invasion of these neoplastic cells. DesignSCC-9 and SCC-25 cells were investigated for gene and protein expression of β2-AR. Cell migration and invasion were analyzed by wound healing assay and transwell invasion camera system. Different concentrations (0.1, 1 and 10 μM) of norepinephrine were used to stimulate, and 1 μM propranolol was used to block the beta-adrenergic receptors on cancer cells. Differences in median values of SCC-9 and SCC-25 and β2-AR protein expression were analyzed by Friedman test and in case of significant differences; pairwise comparisons were performed using Bonferroni correction. ResultsThe results showed that the β2-AR gene and protein expression were observed in both oral cancer cell lines. The concentration of 10 μM of norepinephrine significantly inhibited (p ≤ 0.05) migration of SCC-9 and SCC-25 cell lines. Furthermore, there was a significant reduction (p ≤ 0.05) in the effect of norepinephrine on cell migration when the β2-AR was inhibited by propranolol. The blockade by propranolol showed a tendency to reverse the effect of norepinephrine on the invasiveness of SCC-9 and SCC-25. ConclusionsThe use of beta-adrenergic receptor agonists could become an adjuvant therapeutic target in the treatment of this malignancy.

Abstract IA11: Overcoming immune evasion in pediatric brain tumors

Abstract Many immunotherapies act by enhancing T-cell killing of tumor cells. Cytotoxic T cells recognize antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. Our studies suggest that medulloblastomas and high-grade gliomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. Treatment with tumor necrosis factor or lymphotoxin beta receptor agonist rescues expression of Erap1, Tap1, and MHC-I on p53 mutant tumor cells. In vivo, TNF treatment prolongs survival and markedly augments the efficacy of the immune checkpoint inhibitor anti-PD-1. These studies identify p53 as a key regulator of immune evasion in vivo and suggest that TNF could be used to enhance sensitivity of p53-mutant tumors to immunotherapy. Citation Format: Alexandra Garancher, Hiromichi Suzuki, Svasti Haricharan, Meher B. Masihi, Jessica M. Rusert, Paula S. Norris, Florent Carrette, Megan M. Romero, Sorana A. Morrissy, Patryk Skowron, Florence M.G. Cavalli, Hamza Farooq, Vijay Ramaswamy, Alaide Morcavallo, Jacob J. Henderson, James M. Olson, Yoon-Jae Cho, Xiao-Nan Li, Louis Chesler, Marco A. Marra, Oren J. Becher, Linda M. Bradley, Carl F. Ware, Michael D. Taylor, Robert J. Wechsler-Reya. Overcoming immune evasion in pediatric brain tumors [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA11.

Formoterol Stimulation In Vitro Influences Myogenic Regulatory Factors During Myogenesis In Human Skeletal Muscle Cells

The process of myogenesis within skeletal muscle (SKM) is essential for growth and repair and is coordinated via the expression of myogenic regulatory genes. Previous animal studies have reported that formoterol, a beta-adrenergic receptor agonist, has stimulating effects on genes related to SKM mitochondrial function and biogenesis, similar to effects found for exercise. Lesser known is the potential “exercise mimetic” influence that formoterol stimulation may have during the stages of myogenesis, especially in human SKM cells. PURPOSE: To investigate the effects of formoterol stimulation on expression of myogenic regulatory genes during myogenesis in human SKM cells. METHODS: Human SKM myoblasts (n = 6 per group) were cultured and differentiated until mature myotube formation (Day 6). Groups included control cells (CON) and cells stimulated by 30nM formoterol for 3h prior to RNA extraction points (FORM). Total RNA was extracted during mid-myogenesis (Day 4) and at terminal differentiation (Day 6) (a cell culture model of investigating myogenesis). Gene expression for Myogenic factor 5 (Myf5), Myogenic differentiation 1(MyoD), and Myogenin (MyoG) was determined by qPCR. Data were analyzed using repeated measures ANOVA. RESULTS: Significant differences between conditions and time points are detailed in Table 1. CONCLUSIONS: For the FORM group, Myf5 expression was elevated at D6 compared to CON while MyoG and MyoD expression was lower than CON for D4 and D6. The interpretation is that FORM stimulation increased stimulus of D4 myoblast proliferation and, thus, delayed initiation of differentiation. These results, coupled with other preliminary data from our lab showing increased mitochondrial biogenesis with this model of investigation, suggests that this exercise mimetic stimulation may cause shift in the cell towards bioenergetic preference rather than fusion of myotubes.Table 1

Gut dysmotility in functional gastrointestinal disorders. Potential for therapeutic adjustment in terms of clinical case management

Gastrointestinal motility disorders can be a leading pathogenetic factor contributing to the development of many common gastroenterological diseases. Motor disorders can be a pathogenetic mechanism of development of both organic pathology (developmental abnormalities, acquired diseases, etc.), and functional gastrointestinal diseases associated with impaired nervous, humoral, metabolic and local regulation. (the latter are quite common in clinical practice). Correction of digestive motility disorders is determined by an understanding of the mechanisms of its complex regulation, which allows you to find the necessary points of application of drugs and select the necessary therapy. The motility of the gastrointestinal tract is primarily affected by prokinetics. Opioids used for many years are considered to be one of the most promising groups of prokinetics with proven effectiveness, they can both enhance and weaken the motor. A mu-, kappa-, and beta-receptor agonist, trimebutin, which acts on all receptors at the same time, coordinates the work of the intestines, and normalizes motility by reducing visceral sensitivity. Trimebutin favorably affects both hyperkinetic and hypokinetic forms of disorders of the motor activity of the gastrointestinal tract. This mechanism of action of trimebutin allows its effective use in patients with functional diseases of the digestive system, including those with the syndrome of their intersection. Trimebutin may be the drug of choice for such a combined pathology as irritable bowel syndrome and functional dyspepsia, the use of which is presented in the article on a clinical example of these two diseases.

VGLUT2-expressing neurons in the vestibular nuclear complex mediate gravitational stress-induced hypothermia in mice

The vestibular system, which is essential for maintaining balance, contributes to the sympathetic response. Although this response is involved in hypergravity load-induced hypothermia in mice, the underlying mechanism remains unknown. This study showed that hypergravity (2g) decreased plasma catecholamines, which resulted in hypoactivity of the interscapular brown adipose tissue (iBAT). Hypothermia induced by 2g load was significantly suppressed by administration of beta-adrenergic receptor agonists, suggesting the involvement of decrease in iBAT activity through sympathoinhibition. Bilateral chemogenetic activation of vesicular glutamate transporter 2 (VGLUT2)-expressing neurons in the vestibular nuclear complex (VNC) induced hypothermia. The VGLUT2-expressing neurons contributed to 2g load-induced hypothermia, since their deletion suppressed hypothermia. Although activation of vesicular gamma-aminobutyric acid transporter-expressing neurons in the VNC induced slight hypothermia instead of hyperthermia, their deletion did not affect 2g load-induced hypothermia. Thus, we concluded that 2g load-induced hypothermia resulted from sympathoinhibition via the activation of VGLUT2-expressing neurons in the VNC.

Modulation of long-term and short-term plasticity in the dentate gyrus granule cells by activating the β-adrenergic receptors of the basolateral amygdala

The beta-adrenergic receptors of the basolateral amygdala (BLA) are involved in modulating emotional memory formation in the hippocampus. The molecular mechanisms of this involvement are still unclear. In this study, we investigate the effects of the beta-adrenergic receptors of the BLA involvements during the major cellular mechanisms that underlie memory formation in hippocampal sub-regions. Wistar rats were injected with the selective beta receptor agonist, clenbuterol (15 ng/0.5 μl) bilaterally into the BLA. Then, the long-term potentiation (LTP) and the paired-pulse responses were recorded. Control rats were injected by saline at the same volume. Our data indicated that the injection of clenbuterol into the BLA area enhanced the amplitude of the population spike (PS) but not the slope of the excitatory postsynaptic potential (EPSP). In addition, short-term plasticity in the dentate gyrus (DG) region was significantly changed at 500 ms inter-pulse interval. These results suggest that the activation of the beta-adrenergic receptors of the BLA can improve LTP induction, which depends on the short-term plasticity with a mechanism related to the GABAergic transmission. Thus, it can be concluded that the adrenergic system of the BLA engages with long-term and short-term plasticity.

Effects of three beta adrenergic receptor agonists on growth performance, blood biochemical parameters, fatty acids composition and carnitine palmitoyltransferase I gene expression of rainbow trout, Oncorhynchus mykiss

Different beta 1 and 2 adrenergic receptor agonists may be various biological and physiological effects on fish species. An experiment was designed to study the effects of feeding ractopamine, terbutaline and metaproterenol; as beta1, beta2 and less selective beta 2 adrenergic receptor agonists, respectively; on body weight gain, feed conversion ratio, concentration of biochemical parameters in the serum, gene expression of carnitine palmitoyltransferase I in liver and meat and also, fatty acids profile of filet meat of the rainbow trout. One hundred ninety two of juvenile rainbow trout were randomly assigned to 16 fiber glass tanks and fed one of four dietary treatments containing control (0), ractopamine, terbutaline and metaproterenol at levels of 10 ppm in diet for 8-week feeding trials. It was found that metaproterenol and ractopamine improved final body weight, body weight gain and feed conversion ratio of fish. The serum concentrations of phosphorus and albumin were also significantly increased by all beta adrenergic agonists and ractopamine reduced triglyceride level (p<0.05). The fatty acids level of fish filet was significantly increased by the dietary supplement of various beta adrenergic agonists (p<0.05) but ractopamine had a greater effect. The gene expression of carnitine palmitoyltransferase I in liver was significantly (P<0.05) increased by all beta adrenergic agonists. The present study showed that various beta1 and beta 2 adrenergic receptor agonists had same physiological effects on rainbow trout but it seems ractopamine, as a beta 1 adrenergic receptor, had more potential on fatty acid metabolism and growth response of rainbow trout.

Effect of adeno-associated virus (AAV)-mediated overexpression of PEPCK-M (Pck2) on Clenbuterol-induced muscle growth.

We previously identified PEPCK-M (encoded by the Pck2 gene) to be highly up-regulated in skeletal muscle of pigs treated with Ractopamine, an anabolic beta-adrenergic receptor agonist. To determine whether PEPCK-M had a causative role in modulating the skeletal muscle growth response to Ractopamine, we used adeno-associated virus 1 (AAV1) to over-express Pck2 (AAV-Pck2) in murine skeletal muscle. A contralateral limb design was employed, such that each mouse served as its own control (injected with a GFP-only expressing AAV1, labelled AAV-GFP). Daily injections of Clenbuterol (1 mg/kg for 21 days) or vehicle control were also carried out to assess the effects of AAV-Pck2 overexpression on the anabolic response to a beta-adrenergic agonist. AAV-Pck2 overexpression in leg muscles of male C57BL6/J mice for 4 weeks (6–10 weeks of age) increased Pck2 mRNA (~100-fold), protein (not quantifiable) and enzyme activity (~3-fold). There was a trend (p = 0.0798) for AAV-Pck2 overexpression to reduce TA muscle weights, but there was no significant effect on muscle fibre diameters or myosin heavy chain isoform (MyHC) mRNA expression. When skeletal muscle growth was induced by daily administration of Clenbuterol (for 21 days), overexpression of AAV-Pck2 had no effect on the growth response, nor did it alter the expression of Phosphoserine Aminotransferase-1 (Psat1) or Asparagine Synthetase (Asns) mRNA or the Clenbuterol-induced decreases in MyHC IIa and IIx mRNA expression (p = 0.0065 and p = 0.0267 respectively). However AAV-Pck2 overexpression reduced TA muscle weights (p = 0.0434), particularly in the Control (vehicle treated) mice (p = 0.059 for AAV x Clenbuterol interaction) and increased the expression of Seryl-tRNA Synthetase (Sars) mRNA (p = 0.0477). Hence, contrary to the original hypothesis, AAV-Pck2 overexpression reduced TA muscle weights and did not mimic or alter the muscle hypertrophic effects of the beta-adrenergic agonist, Clenbuterol.

TNF superfamily cytokines overcome immune evasion in medulloblastoma

Abstract Many immunotherapies act by enhancing T cell killing of tumor cells. CD8+ cytotoxic T cells recognize antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. Here we show that medulloblastomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. Treatment with tumor necrosis factor (TNF) or lymphotoxin beta receptor agonist (LTβRag) rescues expression of Erap1, Tap1 and MHC-I on p53-mutant tumor cells. In vivo, TNF treatment prolongs survival and markedly augments the efficacy of the immune checkpoint inhibitor anti-PD-1. These studies identify p53 as a key regulator of immune evasion in vivo, and suggest that TNF could be used to enhance sensitivity of p53-mutant tumors to immunotherapy.