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British Journal of Pharmacology

Ashutosh K Pandey, Sundararajan Venkatesh
No abstract text is available yet for this article.
December 10, 2018: British Journal of Pharmacology
Zhenyan He, Yong Gao, Linh Lieu, Sadia Afrin, Hongbo Guo, Kevin W Williams
BACKGROUND AND PURPOSE: Acute insulin administration results in a hyperpolarization and concomitant decrease of firing rate in a subpopulation of arcuate Proopiomelanocortin (POMC) and Neuropeptide Y/Agouti-related peptide (NPY/AgRP) cells. This rapid effect on cellular activity has been implicated as a cellular correlate of insulin effects on energy balance and glucose homeostasis. Recent evidence suggests that zinc in mammalian insulin formulations is required for the insulin-induced inhibition of arcuate POMC neurons, while guinea-pig insulin, which fails to bind zinc, activates POMC neurons in mice...
December 6, 2018: British Journal of Pharmacology
Xiaoying Lian, Xiaoyuan Wu, Zhongxin Li, Yingjie Zhang, Kangkang Song, Guangyan Cai, Qinggang Li, Shupeng Lin, Xiangmei Chen, Xue-Yuan Bai
BACKGROUND AND PURPOSE: The pathogenic mechanism of autosomal dominant polycystic kidney disease (ADPKD) is unclear. Similar to tumor cells, polycystic kidney cells are primarily dependent on aerobic glycolysis for ATP production. Compared with rodents, miniature pigs are more similar to humans. This study is the first time to investigate the effects of the combination of metformin and 2DG in a chronic progressive ADPKD miniature pig model. EXPERIMENTAL APPROACH: A miniature pig ADPKD model was established by inducible deletion of the PKD1 gene...
December 4, 2018: British Journal of Pharmacology
Ting Song, Peiran Wang, Xiaoyan Yu, Anhui Wang, Gaobo Chai, Yudan Fan, Zhichao Zhang
BACKGROUND AND PURPOSE: The biological significance of's multi-site phosphorylation at the loop region (T69, S70 and S87) has remained controversial for decades. This is a major obstacle for understanding apoptosis and antitumor drug development. EXPERIMENTAL APPROACH: We established a mathematical model into which a phosphorylation and de-phosphorylation process of Bcl-2 was integrated. http://www...
November 30, 2018: British Journal of Pharmacology
Rosella Abeti, Anna Zeitberger, Colm Peelo, Hiva Fassihi, Robert P E Sarkany, Alan R Lehmann, Paola Giunti
Xeroderma Pigmentosum (XP) encompasses a group of rare diseases characterised in most cases by nucleotide excision repair (NER) malfunction, resulting in an increased sensitivity to ultraviolet radiation in affected individuals. Approximately 25-30% of XP patients present with neurological symptoms, such as sensorineural deafness, mental deterioration, and ataxia. Although it is known that dysfunctional DNA repair is the primary pathogenesis in XP, growing evidence suggests that mitochondrial pathophysiology may also occur...
November 30, 2018: British Journal of Pharmacology
Julie J Loiselle, Guangdong Yang, Lingyun Wu
Hydrogen sulfide (H2 S) is the most recently recognized gasotransmitter, influencing a wide range of physiological processes. As a critical regulator of metabolism, H2 S has been suggested to be involved in the pathology of many diseases, particularly obesity, diabetes and cardiovascular disorders. Its involvement in liver health has been brought to light more recently, particularly through knockout animal models, which show severe hepatic lipid accumulation upon ablation of H2 S metabolic pathways. A complex relationship between H2 S and lipid metabolism in the liver is emerging, which has significant implications for liver disease establishment and/or progression, regardless of the disease-causing agent...
November 29, 2018: British Journal of Pharmacology
Xiaojun Zhou, Rui Zhang, Zhiwei Zou, Xue Shen, Tianyue Xie, Chunmei Xu, Jianjun Dong, Lin Liao
BACKGROUND AND PURPOSE: Sulfonylureas (SUs) were suggested to have an insulin-independent blood glucose decreasing activity due to extrapancreatic effect, however, lack of adequate in vivo evidences makes this statement controversial. Here we aimed to evaluate whether glimepiride exists extrapancreatic blood glucose-lowering activity in vivo. EXPERIMENTAL APPROACH: Sulfonylurea receptor deficient (SUR1-/- ) rat was created by TALEN technique. High-fat diet and low-dose streptozotocin were used to establish type 2 diabetic models, and which were then randomly divided into four groups: glimepiride, gliclazide, metformin and saline...
November 24, 2018: British Journal of Pharmacology
Massimo Dal Monte, Maura Calvani, Maurizio Cammalleri, Claudio Favre, Luca Filippi, Paola Bagnoli
Stress plays a role in tumorigenesis through catecholamines acting at β-adrenoceptors including β1-, β2- and β3-adrenoceptors and the use of β-adrenoceptor antagonists seems to counteract tumor growth and progression. Preclinical evidence and meta-analysis data demonstrate that melanoma shows a positive response to β-adrenoceptor blockers and in particular to propranolol acting mainly at β1- and β2-adrenoceptors. Although evidence suggesting that β3-adrenoceptors may play a role as a therapeutic target in infantile hemangiomas has been recently reviewed, a comprehensive analysis of the available data from preclinical studies supporting a possible role of β3-adrenoceptors in melanoma was not available...
November 24, 2018: British Journal of Pharmacology
M Isabel G Lopez Sanchez, Peter van Wijngaarden, Ian A Trounce
Despite clear evidence of a neuroprotective physiological role of amyloid precursor protein (APP) and its non-amyloidogenic processing products, APP has been investigated mainly in animal and cellular models of amyloid pathology in the context of Alzheimer's disease. The rare familial mutations in APP and presenilin-1/2, which sometimes drive increased amyloid beta (Aβ) production, may have unduly influenced Alzheimer's disease research. APP and its cleavage products play important roles in cellular and mitochondrial metabolism, but many studies focus solely on Aβ...
November 24, 2018: British Journal of Pharmacology
Katrin Schaper-Gerhardt, Kristine Rossbach, Eirini Nikolouli, Thomas Werfel, Ralf Gutzmer, Susanne Mommert
Atopic dermatitis (AD) and psoriasis are common skin diseases with a high negative impact on patients´ quality of life. Both diseases are mediated by a pro-inflammatory infiltrate consisting of various cell types like T cells, antigen presenting cells and granulocytes and display disturbed keratinocyte differentiation. Given the fact that histamine levels are also highly elevated in inflamed skin, it is likely that histamine plays a relevant role in disease pathology. However, antagonists blocking histamine H1 receptor (HRH1) and HRH2 are largely ineffective in reducing chronic symptoms in AD and psoriasis...
November 21, 2018: British Journal of Pharmacology
Weishuai An, Yongsheng Yu, Yuefan Zhang, Zhigang Zhang, Yunhua Yu, Xianxian Zhao
BACKGROUND AND PURPOSE: Myocardial infarction (MI) is one of the leading causes of death in China and often results in the development of heart failure. In this work, we tested the therapeutic role of Interleukin-19 (IL-19) in mice with MI and investigated the underlying molecular mechanism. EXPERIMENTAL APPROACH AND KEY RESULTS: Protein expression of IL-19 and its receptor in myocardium were upregulated 24 hrs post-MI in male mice. Male mice were injected i.p. with 10ng/g murine recombinant IL-19 immediately after surgery of MI, and it was found that IL-19 treatment decreased infarct and apoptosis in myocardium, accompanied by enhanced heme oxygenase-1 (HO-1) activities and reduced malondialdehyde (MDA) formation...
November 20, 2018: British Journal of Pharmacology
Stefan J Dekker, Floor Dohmen, Nico P E Vermeulen, Jan N M Commandeur
BACKGROUND AND PURPOSE: The aim of this study was to characterize the human cytochrome P450s (CYPs) involved in oxidative bioactivation of flucloxacillin to 5-hydroxymethylflucloxacillin, a metabolite with high cytotoxicity toward biliary epithelial cells. EXPERIMENTAL APPROACH: The CYPs involved in hydroxylation of flucloxacillin were characterized using recombinant human CYPs, pooled liver microsomes in presences of CYP-specific inhibitors, and by correlation analysis using a panel of liver microsomes from 16 donors...
November 17, 2018: British Journal of Pharmacology
Marika Heblinski, Christopher Bladen, Mark Connor
BACKGROUND AND PURPOSE: Serotonin 5-HT1B receptors are widely expressed G protein-coupled receptors and a target of triptans, the most commonly prescribed anti-migraine drugs. There is very limited information about the acute, agonist-induced regulation of 5-HT1B receptor signalling and so we sought to characterize this in a neuron-like system. EXPERIMENTAL APPROACH: Epitope-tagged human 5-HT1B receptors were expressed in mouse AtT20 cells. 5-HT1B receptor signalling was assessed using whole-cell patch-clamp recordings of endogenous G protein-gated inwardly rectified K channels (GIRK), and receptor localization measured using immunofluorescence...
November 16, 2018: British Journal of Pharmacology
Zachery Moore, Juliet M Taylor, Peter J Crack
First described clinically in 1906, Alzheimer's disease (AD) is the most common neurodegenerative disease and form of dementia worldwide. Despite its prevalence, only five therapies are currently approved for AD, all dealing with the symptoms rather than the underlying causes of the disease. A multitude of experimental evidence has suggested that the once thought inconsequential process of neuroinflammation does, in fact, contribute to the AD pathogenesis. One such central nervous system (CNS) cell type critical to this process are microglia...
November 16, 2018: British Journal of Pharmacology
K F Bruggeman, N Moriarty, E Dowd, D R Nisbet, C L Parish
With the limited capacity for self-repair in the adult central nervous system, efforts to stimulate quiescent stem cell populations within discrete brain regions, as well as harness the potential of stem cell transplants, offers significant hope for neural repair. These new cells are capable of providing trophic cues to support residual host populations and/or replace those cells lost to the primary insult. However, issues with low level adult neurogenesis, cell survival, directed differentiation, and inadequate reinnervation of host tissue have impeded the full potential of these therapeutic approaches and their clinical advancement...
November 16, 2018: British Journal of Pharmacology
Luigi Leanza, Vanessa Checchetto, Lucia Biasutto, Andrea Rossa, Roberto Costa, Magdalena Bachmann, Mario Zoratti, Ildiko Szabo
The field of mitochondrial ion channels has undergone a rapid development during the last three decades, due to the molecular identification of some of the channels residing in the outer and inner membranes. Relevant information about the function of these channels in physiological and pathological settings was gained thanks to genetic models for a few, mitochondria-specific channels. However, many ion channels have multiple localization within the cell hampering a clear-cut determination of their function by pharmacological means...
November 15, 2018: British Journal of Pharmacology
Alice Lallo, Sakshi Gulati, Maximilian W Schenk, Garima Khandelwal, Ulrika Warpman Berglund, Ioannis S Pateras, Christopher P E Chester, Therese M Pham, Christina Kalderen, Kristopher K Frese, Vassilis G Gorgoulis, Crispin Miller, Fiona Blackhall, Thomas Helleday, Caroline Dive
BACKGROUND AND PURPOSE: Small cell lung cancer (SCLC) is an aggressive disease with median survival of < 2 years. Tumour biopsies for research are scarce, especially from extensive-stage patients, with repeat sampling at disease progression rarely performed. We overcame this limitation for relevant preclinical models by developing SCLC circulating tumour cell derived explants (CDX) which mimic the donor tumour pathology and chemotherapy response. To facilitate compound screening and identification of clinically relevant biomarkers, we developed short term ex vivo cultures of CDX tumour cells...
November 14, 2018: British Journal of Pharmacology
Natasha A Karp, Neil Reavey
There has been a revolution within clinical trials to include females in the research pipeline. However, there has been limited change in the preclinical arena; yet the research here lays the ground work for the subsequent clinical trials. Sex bias has been highlighted as one of the contributing factors to the poor translation and replicability issues undermining preclinical research. There have been multiple calls for action and the funders of biomedical research are actively pushing the inclusion of sex as a biological variable...
November 12, 2018: British Journal of Pharmacology
Jingyan Li, Junying Huang, Jing Lu, Zhen Guo, Zhuoming Li, Hui Gao, Panxia Wang, Wenwei Luo, Sidong Cai, Yuehuai Hu, Kaiteng Guo, Luping Wang, Zhenzhen Li, Minghui Wang, Xiaolei Zhang, Peiqing Liu
BACKGROUND AND PURPOSE: Activation of protein kinase C-zeta (PKC-zeta) is closely linked to the pathogenesis of cardiac hypertrophy. PKC-zeta can be activated by certain lipid metabolites such as phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and ceramide. However, its endogenous negative regulators are not well defined. Here, the role of Sirtuin 1 (SIRT1)-PKC-zeta signaling axis and the underlying molecular mechanisms were investigated in cardiac hypertrophy. EXPERIMENTAL APPROACH: Cellular hypertrophy was monitored by measuring cell surface area and the mRNA levels of hypertrophic biomarkers...
November 10, 2018: British Journal of Pharmacology
Chuanhong Wu, Jianxin Chen, Ruocong Yang, Feipeng Duan, Shaojing Li, Xiuping Chen
BACKGROUND AND PURPOSE: Ischemic stroke is a leading cause of death and long-term disability. Promising neuroprotective compounds are urgently needed to overcome the clinical therapeutic limitations. Neuroprotective agents are limited to single-target agents, which further limited their clinical effectiveness. Due to the brain particular energy requirements, the energy microenvironment, centred in the mitochondria, is a new research hotspot in the complex pathology of ischemic stroke...
November 10, 2018: British Journal of Pharmacology
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