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Pharmacology & Therapeutics

G André Ng
Antiarrhythmic drug therapy has seen significant challenges over the past 3 decades with unexpected results from clinical trials such as CAST, SWORD and more recently PALLAS showing harm in patients whom antiarrhythmic drugs were given based on their intended antiarrhythmic actions and previously demonstrated efficacy. These results question whether the precise mechanism of action of the drugs was understood and highlight the complexity of the situation where there is the combination of multiple actions of the antiarrhythmic drugs on various molecular systems, some of which may be unknown with associated adverse outcome, and their interaction with pre-existing abnormality in disease states in patients treated...
October 12, 2016: Pharmacology & Therapeutics
Ursula Ravens, Katja E Odening
Despite the epidemiological scale of atrial fibrillation, current treatment strategies are of limited efficacy and safety. Ideally, novel drugs should specifically correct the pathophysiological mechanisms responsible for atrial fibrillation with no other cardiac or extracardiac actions. Atrial-selective drugs are directed toward cellular targets with sufficiently different characteristics in atria and ventricles to modify only atrial function. Several potassium (K(+)) channels with either predominant expression in atria or distinct electrophysiological properties in atria and ventricles can serve as atrial-selective drug targets...
October 12, 2016: Pharmacology & Therapeutics
Yong Chen, Ruping Pan, Alexander Pfeifer
MicroRNAs (miRNAs) are small non-coding RNA molecules consisting of approximately 20 to 22 nucleotides. They play a very important role in the regulation of gene expression. miRNAs can be found in different species and a variety of organs and tissues including adipose tissue. There are two types of adipose tissue in mammals: White adipose tissue (WAT) is the largest energy storage, whereas brown adipose tissue (BAT) dissipates energy to maintain body temperature. BAT was first identified in hibernating animals and newborns as a defense against cold...
October 11, 2016: Pharmacology & Therapeutics
A Caporali, A Martello, V Miscianinov, D Maselli, R Vono, G Spinetti
During physiological development and after a stressor event, vascular cells communicate with each other to evoke new vessel formation - a process known as angiogenesis. This communication occurs via direct contact and via paracrine release of proteins and nucleic acids, both in a free form or encapsulated into micro-vesicles. In diseases with an altered angiogenic response, such as cancer and diabetic vascular complications, it becomes of paramount importance to tune the cell communication process. Endothelial cell growth and migration are essential processes for new vessel formation, and pericytes, together with some classes of circulating monocytes, are important endothelial regulators...
October 11, 2016: Pharmacology & Therapeutics
Chiara Cencioni, Sandra Atlante, Matteo Savoia, Fabio Martelli, Antonella Farsetti, Maurizio C Capogrossi, Andreas M Zeiher, Carlo Gaetano, Francesco Spallotta
Organ-specific mesenchymal cells naturally reside in the stroma, where they are exposed to some environmental variables affecting their biology and functions. Risk factors such as diabetes or aging influence their adaptive response. In these cases, permanent epigenetic modifications may be introduced in the cells with important consequences on their local homeostatic activity and therapeutic potential. Numerous results suggest that mesenchymal cells, virtually present in every organ, may contribute to tissue regeneration mostly by paracrine mechanisms...
October 11, 2016: Pharmacology & Therapeutics
Julian Mustroph, Stefan Neef, Lars S Maier
Calcium/calmodulin-dependent protein kinase II (CaMKII) has emerged as key enzyme in many cardiac pathologies, especially heart failure (HF), myocardial infarction and cardiomyopathies, thus leading to contractile dysfunction and malignant arrhythmias. While many pathways leading to CaMKII activation have been elucidated in recent years, hardly any clinically viable compounds affecting CaMKII activity have progressed from basic in vitro science to in vivo studies. This review focuses on recent advances in anti-arrhythmic strategies involving CaMKII...
October 11, 2016: Pharmacology & Therapeutics
Deborah L Clarke, Lynne A Murray, Bruno Crestani, Matthew A Sleeman
Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneumonia of unknown cause, characterised by progressive worsening in lung function and dyspnoea with an associated prognosis similar to or worse than many cancers. As a better understanding emerges around the pathogenesis and mechanisms driving disease pathology, a host of novel agents are being tested both pre-clinically and clinically. However even with this deeper understanding and positive pre-clinical supportive data, negative trial outcomes are frequently reported, highlighting the problems faced in treating such a heterogeneous disease with a varied clinical course...
September 13, 2016: Pharmacology & Therapeutics
David L Ebenezer, Panfeng Fu, Viswanathan Natarajan
Sphingosine-1-phosphate (S1P), a simple, bioactive sphingolipid metabolite, plays a key role, both intracellularly and extracellularly, in various cellular processes such as proliferation, survival, migration, inflammation, angiogenesis, and endothelial barrier integrity. The cellular S1P level is low and is tightly regulated by its synthesis and degradation. Sphingosine Kinases (SphKs) 1 and 2, catalyze the ATP-dependent phosphorylation of sphingosine to S1P, while the degradation is mediated by the reversible dephosphorylation catalyzed by the S1P phosphatases and lipid phosphate phosphatases and the irreversible degradation to hexadecenal and ethanolamine phosphate by sphingosine-1-phosphate lyase (S1PL)...
September 10, 2016: Pharmacology & Therapeutics
K-S N Atretkhany, M S Drutskaya, S A Nedospasov, S I Grivennikov, D V Kuprash
Relationship between inflammation and cancer is now well-established and represents a paradigm that our immune response does not necessarily serves solely to protect us from infections and cancer. Many specific mechanisms that link chronic inflammation to cancer promotion and metastasis have been uncovered in the recent years. Here we are focusing on the effects that tumors may exert on inflammatory cascades, tuning the immune system ability to cause tumor promotion or regression. In particular, we discuss the contributions of chemokines, cytokines and exosomes to the processes such as induction of inflammation and tumorigenesis...
September 6, 2016: Pharmacology & Therapeutics
Eleonora Grandi, Mary M Maleckar
Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with increased risk of cerebrovascular stroke, and with several other pathologies, including heart failure. Current therapies for AF are targeted at reducing risk of stroke (anticoagulation) and tachycardia-induced cardiomyopathy (rate or rhythm control). Rate control, typically achieved by atrioventricular nodal blocking drugs, is often insufficient to alleviate symptoms. Rhythm control approaches include antiarrhythmic drugs, electrical cardioversion, and ablation strategies...
September 6, 2016: Pharmacology & Therapeutics
Tarek Magdy, Brian T Burmeister, Paul W Burridge
The cardiotoxicity of certain chemotherapeutic agents is now well-established, and has led to the development the field cardio-oncology, increased cardiac screening of cancer patients, and limitation of patients' maximum cumulative chemotherapeutic dose. The effect of chemotherapeutic regimes on the heart largely involves cardiomyocyte death, leading to cardiomyopathy and heart failure, or the induction of arrhythmias. Of these cardiotoxic drugs, those resulting in clinical cardiotoxicity can range from 8 to 26% for doxorubicin, 7-28% for trastuzumab, or 5-30% for paclitaxel...
September 5, 2016: Pharmacology & Therapeutics
Junko Kurokawa, Masami Kodama, Colleen E Clancy, Tetsushi Furukawa
Female sex is an independent risk factor for development of torsade de pointes (TdP) arrhythmias not only in congenital long QT syndromes but also in acquired long QT syndromes. Clinical and experimental evidences suggest that the gender differences may be due to, at least in part, gender differences in regulation of rate-corrected QT (QTC) interval between men and women. In adult women, both QTC interval and arrhythmic risks in TdP alter cyclically during menstrual cycle, suggesting a critical role of female sex hormones in cardiac repolarization process...
September 4, 2016: Pharmacology & Therapeutics
Ilia Goltsman, Emad Khoury, Joseph Winaver, Zaid Abassi
The ever-growing global burden of congestive heart failure (CHF) and type 2 diabetes mellitus (T2DM) as well as their co-existence necessitate that anti-diabetic pharmacotherapy will modulate the cardiovascular risk inherent to T2DM while complying with the accompanying restrictions imposed by CHF. The thiazolidinedione (TZD) family of peroxisome proliferator-activated receptor γ (PPARγ) agonists initially provided a promising therapeutic option in T2DM owing to anti-diabetic efficacy combined with pleiotropic beneficial cardiovascular effects...
September 3, 2016: Pharmacology & Therapeutics
Karen M Mann, Haoqiang Ying, Joseph Juan, Nancy A Jenkins, Neal G Copeland
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with a high mortality rate. Genetic and biochemical studies have shown that RAS signaling mediated by KRAS plays a pivotal role in disease initiation, progression and drug resistance. RAS signaling affects several cellular processes in PDAC, including cellular proliferation, migration, cellular metabolism and autophagy. 90% of pancreatic cancer patients harbor somatic oncogenic point mutations in KRAS, which lead to constitutive activation of the molecule...
September 3, 2016: Pharmacology & Therapeutics
Danielle L Michell, Kasey C Vickers
microRNAs (miRNA) are small non-coding RNAs (sRNA) that post-transcriptionally regulate gene (mRNA) expression and are implicated in many biological processes and diseases. Many miRNAs have been reported to be altered in cardiovascular disease (CVD); both cellular and extracellular miRNA levels are affected by hypercholesterolemia and atherosclerosis. We and other groups have reported that lipoproteins transport miRNAs in circulation and these lipoprotein signatures are significantly altered in hypercholesterolemia and coronary artery disease (CAD)...
September 2, 2016: Pharmacology & Therapeutics
Iain R Murray, James E Baily, William C W Chen, Ayelet Dar, Zaniah N Gonzalez, Andrew R Jensen, Frank A Petrigliano, Arjun Deb, Neil C Henderson
Pericytes are periendothelial mesenchymal cells residing within the microvasculature. Skeletal muscle and cardiac pericytes are now recognized to fulfill an increasing number of functions in normal tissue homeostasis, including contributing to microvascular function by maintaining vessel stability and regulating capillary flow. In the setting of muscle injury, pericytes contribute to a regenerative microenvironment through release of trophic factors and by modulating local immune responses. In skeletal muscle, pericytes also directly enhance tissue healing by differentiating into myofibers...
September 2, 2016: Pharmacology & Therapeutics
Amber J Giles, Christopher D Chien, Caitlin M Reid, Terry J Fry, Deric M Park, Rosandra N Kaplan, Mark R Gilbert
Hematopoietic cells are increasingly recognized as playing key roles in tumor growth and metastatic progression. Although many studies have focused on the functional interaction of hematopoietic cells with tumor cells, few have examined the regulation of hematopoiesis by the hematopoietic stem cell (HSC) niche in the setting of cancer. Hematopoiesis occurs primarily in the bone marrow, and processes including expansion, mobilization, and differentiation of hematopoietic progenitors are tightly regulated by the specialized stem cell niche...
September 2, 2016: Pharmacology & Therapeutics
Ravi Thakur, Durga Prasad Mishra
Matricellular proteins (MCPs) are the non-structural extracellular matrix (ECM) proteins with various regulatory functions. MCPs are critical regulators of ECM homeostasis and are often found dysregulated in various malignancies. They interact with various ECM structural proteins like integrins, growth factor receptors and growth factors to modulate their availability and activity. Cancer supporting MCPs are known to induce proliferation, migration and invasion of cancer cells. MCPs also support cancer stem (like) cell growth and induce a drug resistant state...
September 2, 2016: Pharmacology & Therapeutics
Sebastian A Lewandowski, Linda Fredriksson, Daniel A Lawrence, Ulf Eriksson
: Neurological disorders account for a majority of non-malignant disability in humans and are often associated with dysfunction of the blood-brain barrier (BBB). Recent evidence shows that despite apparent variation in the origin of neural damage, the central nervous system has a common injury response mechanism involving platelet-derived growth factor (PDGF)-CC activation in the neurovascular unit and subsequent dysfunction of BBB integrity. Inhibition of PDGF-CC signaling with imatinib in mice has been shown to prevent BBB dysfunction and have neuroprotective effects in acute damage conditions, including traumatic brain injury, seizures or stroke, as well as in neurodegenerative diseases that develop over time, including multiple sclerosis and amyotrophic lateral sclerosis...
August 12, 2016: Pharmacology & Therapeutics
Joby Cole, Paul Morris, Mark J Dickman, David H Dockrell
Epigenetic modifications are increasingly recognized as playing an important role in the pathogenesis of infectious diseases. They represent a critical mechanism regulating transcriptional profiles in the immune system that contributes to the cell-type and stimulus specificity of the transcriptional response. Recent data highlight how epigenetic changes impact macrophage functional responses and polarization, influencing the innate immune system through macrophage tolerance and training. In this review we will explore how post-translational modifications of histone tails influence immune function to specific infectious diseases...
August 9, 2016: Pharmacology & Therapeutics
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