Search results for "PHARMACOLOGY"

Pharmacological Profile of AZD8871 (LAS191351), a Novel Inhaled Dual M3 Receptor Antagonist/β2-Adrenoceptor Agonist Molecule with Long-Lasting Effect…

2019

AZD8871 is a novel muscarinic antagonist and β2-adrenoceptor agonist in development for chronic obstructive pulmonary disease. This study describes the pharmacological profile of AZD8871 in in vitro and in vivo assays. AZD8871 is potent at the human M3 receptor (pIC50 in binding assays: 9.5) and shows kinetic selectivity for the M3 (half-life: 4.97 hours) over the M2 receptor (half-life: 0.46 hour). It is selective for the β2-adrenoceptor over the β1 and β3 subtypes (3- and 6-fold, respectively) and shows dual antimuscarinic and β2-adrenoceptor functional activity in isolated guinea pig tissue (pIC50 in electrically stimulated trachea: 8.6; pEC50 in spontaneous tone isolated trachea: 8.8, r…

Agonist‐induced desensitisation of β 3 ‐adrenoceptors: Where, when, and how?

2019

β3 -Adrenoceptor agonists have proven useful in the treatment of overactive bladder syndrome, but it is not known whether their efficacy during chronic administration may be limited by receptor-induced desensitisation. Whereas the β2 -adrenoceptor has phosphorylation sites that are important for desensitisation, the β3 -adrenoceptor lacks these; therefore, it had been assumed that β3 -adrenoceptors are largely resistant to agonist-induced desensitisation. While all direct comparative studies demonstrate that β3 -adrenoceptors are less susceptible to desensitisation than β2 -adrenoceptors, desensitisation of β3 -adrenoceptors has been observed in many models and treatment settings. Chimeric …

The β3 -adrenoceptor agonist mirabegron increases human atrial force through β1 -adrenoceptors: an indirect mechanism?

2017

Background and Purpose Mirabegron has been classified as a β3-adrenoceptor agonist approved for overactive bladder syndrome. We investigated possible cardiac effects of mirabegron in the absence or presence of β-adrenoceptor subtype antagonists. In view of its phenylethanolamine structure, we investigated whether mirabegron has indirect sympathomimetic activity by using neuronal uptake blockers. Experimental Approach Right atrial trabeculae, from non-failing hearts, were paced and contractile force measured at 37°C. Single concentrations of mirabegron were added in the absence or presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), β3 (L-748,337), β1 (CGP 20712A),…

Amyloid in Alzheimer’s Disease: Guilty Beyond Reasonable Doubt?

2017

Recently failed antiamyloidogenic trials call for an objective reassessment of the dominating amyloid cascade hypothesis of Alzheimer's disease (AD). Ongoing efforts focusing on amyloid β protein (Aβ), its deposition, and its removal need to be complemented by more intensive research in new directions. Those may either integrate amyloid pathology or will propose pathogenetic routes independent of Aβ in the search for the causes of AD.

Antiinflammatory and antioxidant activities of a polyphenol‐rich extract from Zizyphus lotus L fruit pulp play a protective role against obesity

2018

Zizyphus lotus (Zl) is used widely as a source of food and for the treatment of various ailments. Therefore, we investigated the biological activities of Zl against obesity and related disorders. Hence, male Wistar rats received either control diet, high fat diet (HFAD), or HFAD supplemented with the Zl pulp (HFADP) for 14 weeks. RAW 264.7 cells were used for the determination of antiinflammatory activities in vitro. It was observed that HFDP resulted in significantly reduced weight, blood sugar, and oxidative stress than HFAD. In addition, Zl extract co‐treatment with LPS reduced the mRNA expression of MCP‐1, pro‐inflammatory cytokines (IL‐6, TNF‐α), and increased the level of IL‐10, an an…

Bacterial Biofilm Inhibition in the Development of Effective Anti-Virulence Strategy

2018

There is an urgent need for new therapeutic strategies to counteract the global threat of antibiotic resistance, which has become, in recent years, one of the major public health concern. An important contribution to the microbial survival in hostile environments has been given by the capability of pathogens to form sessile communities able to adhere to biotic or abiotic surfaces, known as biofilms.

Comparative protein profiling of B16 mouse melanoma cells susceptible and non-susceptible to alphavirus infection: Effect of the tumor microenvironme…

2016

Alphavirus vectors are promising tools for cancer treatment. However, relevant entry mechanisms and interactions with host cells are still not clearly understood. The first step toward a more effective therapy is the identification of novel intracellular alterations that could be associated with cancer aggressiveness and could affect the therapeutic potential of these vectors. In this study, we observed that alphaviruses efficiently infected B16 mouse melanoma tumors/tumor cells in vivo, whereas their transduction efficiency in B16 cells under in vitro conditions was blocked. Therefore, we further aimed to understand the mechanisms pertaining to the differential transduction efficacy of alp…

2021

BackgroundMultiple synergistic combination approaches with cancer drugs are developed to overcome primary resistance to immunotherapy; however, the mechanistic rationale to combine chemoradiotherapy (CRT) with immune checkpoint inhibitors remains elusive.MethodsThis study described the immunological landscape of tumor microenvironment (TME) exposed to CRT. Tumor samples from patients with rectal cancer (n=43) treated with neoadjuvant CRT or radiotherapy were analyzed by nanostring and immunohistochemistry. Studies in mice were performed using three syngeneic tumors (TC1, CT26 and MC38). Tumor-bearing mice were treated either with platinum-based CRT, radiotherapy or chemotherapy. Anti-CTLA-4…

Differential glutamatergic and GABAergic contributions to the tetrad effects of Δ9-tetrahydrocannabinol revealed by cell-type-specific reconstitution…

2020

Δ9-tetrahydrocannabinol (THC), the major psychoactive ingredient of Cannabis sativa, exerts its actions through the endocannabinoid system by stimulation of the cannabinoid type 1 (CB1) receptor. The widespread distribution of this receptor in different neuronal cell types and the plethora of functions that is modulated by the endocannabinoid system explain the versatility of the effects of THC. However, the cell types involved in the different THC effects are still not fully known. Conditional CB1 receptor knock-out mice were previously used to identify CB1 receptor subpopulations that are "necessary" for the tetrad effects of a high dose of THC: hypothermia, hypolocomotion, catalepsy and …

Cardiac β3‐adrenoceptors—A role in human pathophysiology?

2019

As β3 -adrenoceptors were first demonstrated to be expressed in adipose tissue they have received much attention for their metabolic effects in obesity and diabetes. After the existence of this subtype had been suggested to be present in the heart, studies focused on its role in cardiac function. While the presence and functional role of β3 -adrenoceptors in the heart has not uniformly been detected, there is a broad consensus that they become up-regulated in pathological conditions associated with increased sympathetic activity such as heart failure and diabetes. When detected, the β3 -adrenceptor has been demonstrated to mediate negative inotropic effects in an inhibitory G protein-depend…