Panagiotis Efentakis, Aimilia Varela, Sofia Lamprou, Eleni-Dimitra Papanagnou, Michail Chatzistefanou, Andriana Christodoulou, Constantinos H Davos, Maria Gavriatopoulou, Ioannis Trougakos, Meletios Athanasios Dimopoulos, Evangelos Terpos, Ioanna Andreadou
BACKGROUND AND PURPOSE: Cancer therapy-related cardiovascular adverse events (CAEs) in presence of comorbidities, are in the spotlight of the cardio-oncology guidelines. Carfilzomib (Cfz), indicated for relapsed/refractory multiple myeloma (MM), presents with serious CAEs. MM is often accompanied with co-existing comorbidities. However, Cfz use in MM patients with cardiometabolic syndrome (CMS) or in heart failure with reduced ejection fraction (HFrEF), is questionable. EXPERIMENTAL APPROACH: ApoE-/- and C57BL6/J male mice received 14 weeks Western Diet (WD) (CMS models)...
April 28, 2024: British Journal of Pharmacology
María Constanza Maldifassi, María José Guerra-Fernández, Daniela Ponce, Samuel Alfonso-Bueno, Jaime Maripillán, Alex H Vielma, Ximena Báez-Matus, Fernando D Marengo, Claudio Acuña-Castillo, Juan C Sáez, Agustín D Martínez, Ana M Cárdenas
BACKGROUND AND PURPOSE: ATP is highly accumulated in secretory vesicles and secreted upon exocytosis from neurons and endocrine cells. In adrenal chromaffin granules, intraluminal ATP reaches concentrations over 100 mM. However, how these large amounts of ATP contribute to exocytosis has not been investigated. EXPERIMENTAL APPROACH: Exocytotic events in bovine and mouse adrenal chromaffin cells were measured with single cell amperometry. Cytosolic Ca2+ measurements were carried out in Fluo-4 loaded cells...
April 28, 2024: British Journal of Pharmacology
Yue Ji, Yiliang Duan, Yuanyuan Li, Qingzhou Lu, Dingkang Liu, Yifan Yang, Ruilong Chang, Jing Tian, Wenbing Yao, Jun Yin, Xiangdong Gao
BACKGROUND AND PURPOSE: Because of the absence of effective therapies for metabolic dysfunction-associated steatohepatitis (MASH), there is a rising interest in fibroblast growth factor 21 (FGF21) analogues due to their potential anti-fibrotic activities in MASH treatment. PsTag-FGF21, a long-acting FGF21 analogue, has demonstrated promising therapeutic effects in several MASH mouse models. However, its efficacy and mechanism against MASH-related fibrosis remain less well defined, compared with the specific mechanisms through which FGF21 improves glucose and lipid metabolism...
April 28, 2024: British Journal of Pharmacology
Fengjiao Sun, Jiangong Wang, Lingbin Meng, Zhenyu Zhou, Yong Xu, Meizi Yang, Yixin Li, Tianrui Jiang, Bin Liu, Haijing Yan
BACKGROUND AND PURPOSE: Amyloid-β (Aβ) peptide is one of the more important pathological markers in Alzheimer's disease (AD). The development of AD impairs autophagy, which results in an imbalanced clearance of Aβ. Our previous research demonstrated that AdipoRon, an agonist of adiponectin receptors, decreased the deposition of Aβ and enhanced cognitive function in AD. However, the exact mechanisms by which AdipoRon affects Aβ clearance remain unclear. EXPERIMENTAL APPROACH: We studied how AdipoRon affects autophagy in HT22 cells and APP/PS1 transgenic mice...
April 28, 2024: British Journal of Pharmacology
Balasubramanian Haridevamuthu, Gokul Sudhakaran, Raman Pachaiappan, Muthu Kumaradoss Kathiravan, Krishnan Manikandan, Mikhlid H Almutairi, Bader O Almutairi, Selvaraj Arokiyaraj, Jesu Arockiaraj
BACKGROUND AND PURPOSE: Parkinson's disease (PD) is a prevalent neurodegenerative movement disorder characterized by motor dysfunction. Environmental factors, especially manganese (Mn), contribute significantly to PD. Existing therapies are focused on motor coordination, whereas nonmotor features such as neuropsychiatric symptoms are often neglected. Daidzein (DZ), a phytoestrogen, has piqued interest due to its antioxidant, anti-inflammatory, and anxiolytic properties. Therefore, we anticipate that DZ might be an effective drug to alleviate the nonmotor symptoms of Mn-induced Parkinsonism...
April 28, 2024: British Journal of Pharmacology
Wanbao Yang, Meenakshi Arora, Hye Won Han, Wen Jiang, Da Mi Kim, Weiqi Ai, Quan Pan, M N V Ravi Kumar, Wesley A Brashear, Yuxiang Sun, Shaodong Guo
BACKGROUND AND PURPOSE: Chronic inflammation plays a pivotal role in the development of Type 2 diabetes mellitus (T2DM). Previous studies have shown that haem oxygenase-1 (HO-1) plays a proinflammatory role during metabolic stress, suggesting that HO-1 inhibition could be an effective strategy to treat T2DM. However, the application of HO-1 inhibitors is restricted due to solubility-limited bioavailability. In this study, we encapsulated the HO-1 inhibitor, zinc protoporphyrin IX (ZnPP), within nanoparticles and investigated their role in regulating glucose homeostasis and chronic inflammation during obesity...
April 28, 2024: British Journal of Pharmacology
Javier Milara, Inés Roger, Paula Montero, Enrique Artigues, Juan Escrivá, Raquel Del Río, Julio Cortijo
BACKGROUND AND PURPOSE: IL-11 is a member of the IL-6 family of cytokine initially considered as haematopoietic and cytoprotective factor. Recent evidence indicates that IL-11 promotes lung fibrosis and pulmonary hypertension in animal models and is elevated in lung tissue of patients with pulmonary fibrosis and pulmonary hypertension. Fibrocytes are bone marrow-derived circulating cells that participate in lung fibrosis and pulmonary hypertension, but the role of IL-11 on fibrocytes is unknown...
April 28, 2024: British Journal of Pharmacology
Beatrix Bester, Kristina Koslowa, Ann-Catherine Gronau, Andrea Mietens, Cameron Nowell, Michael R Whittaker, Adrian Pilatz, Florian Wagenlehner, Betty Exintaris, Ralf Middendorff
BACKGROUND AND PURPOSE: With increasing life expectancy, benign prostatic hyperplasia (BPH) consequently affects more ageing men, illustrating the urgent need for advancements in BPH therapy. One emerging possibility may be the use of oxytocin antagonists to relax smooth muscle cells in the prostate, similar to the currently used (although often associated with side effects) α1 -adrenoceptor blockers. EXPERIMENTAL APPROACH: For the first time we used live-imaging, combined with a novel image analysis method, to investigate the multidirectional contractions of the human prostate and determine their changes in response to oxytocin and the oxytocin antagonists atosiban and cligosiban...
April 27, 2024: British Journal of Pharmacology
Divakar Budda, Berfin Gülave, J G Coen van Hasselt, Elizabeth C M de Lange
BACKGROUND AND PURPOSE: Morphine is important for treatment of acute and chronic pain. However, there is high interpatient variability and often inadequate pain relief and adverse effects. To better understand variability in the dose-effect relationships of morphine, we investigated the effects of its non-linear blood-brain barrier (BBB) transport on μ-receptor occupancy in different CNS locations, in conjunction with its main metabolites that bind to the same receptor. EXPERIMENTAL APPROACH: CNS exposure profiles for morphine, M3G and M6G for clinically relevant dosing regimens based on intravenous, oral immediate- and extended-release formulations were generated using a physiology-based pharmacokinetic model of the CNS, with non-linear BBB transport of morphine...
April 25, 2024: British Journal of Pharmacology
Sutirtha Ray, Jan-Luca Stampf, Oliver Kudlacek, Jae-Won Yang, Klaus W Schicker, Yvonne Graf, Thomas Losgott, Stefan Boehm, Isabella Salzer
BACKGROUND AND PURPOSE: The analgesic action of paracetamol involves KV 7 channels, and its metabolite N-acetyl-p-benzo quinone imine (NAPQI), a cysteine modifying reagent, was shown to increase currents through such channels in nociceptors. Modification of cysteine residues by N-ethylmaleimide, H2 O2 , or nitric oxide has been found to modulate currents through KV 7 channels. The study aims to identify whether, and if so which, cysteine residues in neuronal KV 7 channels might be responsible for the effects of NAPQI...
April 24, 2024: British Journal of Pharmacology
Peng Xu, Raymond S M Wong, Xiaoyu Yan
BACKGROUND AND PURPOSE: Our previous study reported that erythroferrone (ERFE), a newly identified hormone produced by erythroblasts, responded to recombinant human erythropoietin (rHuEPO) sensitively but its dynamics was complicated by double peaks and circadian rhythm. This study intends to elucidate the underlying mechanisms for the double peaks of ERFE dynamics and further determine whether early ERFE measurements can predict haemoglobin responses to rHuEPO. EXPERIMENTAL APPROACH: By using the purified recombinant rat ERFE protein and investigating its deposition in rats, the production of ERFE was deconvoluted...
April 23, 2024: British Journal of Pharmacology
Charlotte Buckley, Matthew D Lee, Xun Zhang, Calum Wilson, John G McCarron
BACKGROUND AND PURPOSE: The single layer of cells lining all blood vessels, the endothelium, is a sophisticated signal co-ordination centre that controls a wide range of vascular functions including the regulation of blood pressure and blood flow. To co-ordinate activities, communication among cells is required for tissue level responses to emerge. While a significant form of communication occurs by the propagation of signals between cells, the mechanism of propagation in the intact endothelium is unresolved...
April 23, 2024: British Journal of Pharmacology
Itziar Muneta-Arrate, Patricia Miranda-Azpiazu, Igor Horrillo, Rebeca Diez-Alarcia, J Javier Meana
BACKGROUND AND PURPOSE: Whereas biased agonism on the 5-HT2A receptor has been ascribed to hallucinogenic properties of psychedelics, no information about biased inverse agonism on this receptor is available. In schizophrenia, increased 5-HT2A receptor constitutive activity has been suggested, highlighting the therapeutic relevance of inverse agonism. This study characterized the modulation of G protein activity promoted by different drugs, commonly considered as 5-HT2A receptor antagonists, in post-mortem human brain cortex...
April 21, 2024: British Journal of Pharmacology
Peng Ye, Qi-Hai Wang, Wen-Ye Kong, Chun-Sheng Liu, Dan-Dan Wang, Opeyemi Joshua Olatunji, Yan Li, Jian Zuo
BACKGROUND AND PURPOSE: White adipose tissue (WAT) is involved in rheumatoid arthritis (RA). This study explored its potential as an antirheumatic target. EXPERIMENTAL APPROACH: WAT status of healthy and adjuvant-induced arthritis (AIA) rats were compared. The contribution of WAT to RA pathology was evaluated by pre-adipocyte transplant experiments and by dissecting perirenal fat pads of AIA rats. The impact of RA on WAT was investigated by culturing pre-adipocytes...
April 21, 2024: British Journal of Pharmacology
Kwang-Hyun Hur, Youyoung Lee, Audrey Lynn Donio, Seon-Kyung Kim, Bo-Ram Lee, Jee-Yeon Seo, Dooti Kundu, Kyeong-Man Kim, Stephen J Kohut, Seok-Yong Lee, Choon-Gon Jang
BACKGROUND AND PURPOSE: Methamphetamine (METH) use disorder has risen dramatically over the past decade, and there are currently no FDA-approved medications due, in part, to gaps in our understanding of the pharmacological mechanisms related to METH action in the brain. EXPERIMENTAL APPROACH: Here, we investigated whether transient receptor potential ankyrin 1 (TRPA1) mediates each of several METH abuse-related behaviours in rodents: self-administration, drug-primed reinstatement, acquisition of conditioned place preference, and hyperlocomotion...
April 21, 2024: British Journal of Pharmacology
Edgars Liepinsh, Liga Zvejniece, Laura Clemensson, Melita Ozola, Edijs Vavers, Helena Cirule, Stanislava Korzh, Sandra Skuja, Valerija Groma, Monta Briviba, Solveiga Grinberga, Wen Liu, Paweł Olszewski, Mélissa Gentreau, Robert Fredriksson, Maija Dambrova, Helgi B Schiöth
BACKGROUND AND PURPOSE: Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), and exert adverse effects on mitochondrial function, although the mechanisms underlying these effects remain unclear. We used a tamoxifen-induced Hmgcr-knockout (KO) mouse model, a multi-omics approach and mitochondrial function assessments to investigate whether decreased HMGCR activity impacts key liver energy metabolism pathways. EXPERIMENTAL APPROACH: We established a new mouse strain using the Cre/loxP system, which enabled whole-body deletion of Hmgcr expression...
April 19, 2024: British Journal of Pharmacology
Simon Guignard, Mahmoud Saifeddine, Koichiro Mihara, Majid Motahhary, Magali Savignac, Laura Guiraud, David Sagnat, Mireille Sebbag, Sokchea Khou, Corinne Rolland, Anissa Edir, Barbara Bournet, Louis Buscail, Etienne Buscail, Laurent Alric, Caroline Camare, Mouna Ambli, Nathalie Vergnolle, Morley D Hollenberg, Céline Deraison, Chrystelle Bonnart
BACKGROUND AND PURPOSE: Chymotrypsin is a pancreatic protease secreted into the lumen of the small intestine to digest food proteins. We hypothesized that chymotrypsin activity may be found close to epithelial cells and that chymotrypsin signals to them via protease-activated receptors (PARs). We deciphered molecular pharmacological mechanisms and gene expression regulation for chymotrypsin signalling in intestinal epithelial cells. EXPERIMENTAL APPROACH: The presence and activity of chymotrypsin were evaluated by Western blot and enzymatic activity tests in the luminal and mucosal compartments of murine and human gut samples...
April 18, 2024: British Journal of Pharmacology
Éva Bertalan, Matthew Joseph Rodrigues, Gebhard F X Schertler, Ana-Nicoleta Bondar
Changes in structure and dynamics elicited by agonist ligand binding at the extracellular side of G protein coupled receptors (GPCRs) must be relayed to the cytoplasmic G protein binding side of the receptors. To decipher the role of water-mediated hydrogen-bond networks in this relay mechanism, we have developed graph-based algorithms and analysis methodologies applicable to datasets of static structures of distinct GPCRs. For a reference dataset of static structures of bovine rhodopsin solved at the same resolution, we show that graph analyses capture the internal protein-water hydrogen-bond network...
April 18, 2024: British Journal of Pharmacology
Luis A Márquez, Carolina López Rubalcava, Emilio J Galván
BACKGROUND AND PURPOSE: Transient hypofunction of the NMDA receptor represents a convergence point for the onset and further development of psychiatric disorders, including schizophrenia. Although the cumulative evidence indicates dysregulation of the hippocampal formation in schizophrenia, the integrity of the synaptic transmission and plasticity conveyed by the somatosensorial inputs to the dentate gyrus, the perforant pathway synapses, have barely been explored in this pathological condition...
April 17, 2024: British Journal of Pharmacology
Nontawat Chuinsiri, Nannapat Siraboriphantakul, Luke Kendall, Polina Yarova, Christopher J Nile, Bing Song, Ilona Obara, Justin Durham, Vsevolod Telezhkin
BACKGROUND AND PURPOSE: Neuropathic pain, a debilitating condition with unmet medical needs, can be characterised as hyperexcitability of nociceptive neurons caused by dysfunction of ion channels. Voltage-gated potassium channels type 7 (Kv7), responsible for maintaining neuronal resting membrane potential and thus excitability, reside under tight control of G protein-coupled receptors (GPCRs). Calcium-sensing receptor (CaSR) is a GPCR that regulates the activity of numerous ion channels, but whether CaSR can control Kv7 channel function has been unexplored until now...
April 16, 2024: British Journal of Pharmacology
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