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Pharmacology & Therapeutics

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https://www.readbyqxmd.com/read/28723416/unravelling-the-pharmacologic-opportunities-and-future-directions-for-targeted-therapies-in-gastro-intestinal-cancers-part-2-neuroendocrine-tumours-hepatocellular-carcinoma-and-gastro-intestinal-stromal-tumours
#1
REVIEW
Cindy Neuzillet, Louis de Mestier, Benoît Rousseau, Olivier Mir, Mohamed Hebbar, Hemant M Kocher, Philippe Ruszniewski, Christophe Tournigand
Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the cancer cell molecular biology has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents, being more specific to cancer cells, were expected to be less toxic than conventional cytotoxic agents. However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms, or to an activity restricted to some tumour settings, illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies...
July 16, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28723415/pharmacology-of-human-trace-amine-associated-receptors-therapeutic-opportunities-and-challenges
#2
REVIEW
Mark D Berry, Raul R Gainetdinov, Marius C Hoener, Mohammed Shahid
The discovery in 2001 of a G protein-coupled receptor family, subsequently termed trace amine-associated receptors (TAAR), triggered a resurgence of interest in so-called trace amines. Initial optimism quickly faded, however, as the TAAR family presented a series of challenges preventing the use of standard medicinal chemistry and pharmacology technologies. Consequently the development of basic tools for probing TAAR and translating findings from model systems to humans has been problematic. Despite these challenges the last 5 years have seen considerable advances, in particular with respect to TAAR1, which appears to function as an endogenous rheostat, maintaining central neurotransmission within defined physiological limits, in part through receptor heterodimerization yielding biased signaling outputs...
July 16, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28723414/omega-3-polyunsaturated-fatty-acids-as-a-treatment-strategy-for-nonalcoholic-fatty-liver-disease
#3
REVIEW
Donald B Jump, Kelli A Lytle, Christopher M Depner, Sasmita Tripathy
Obese and type 2 diabetic (T2DM) patients have a high prevalence of nonalcoholic fatty liver disease (NAFLD). NAFLD is a continuum of chronic liver diseases ranging from benign hepatosteatosis to nonalcoholic steatohepatitis (NASH), cirrhosis and primary hepatocellular cancer (HCC). Because of its strong association with the obesity epidemic, NAFLD is rapidly becoming a major public health concern worldwide. Surprisingly, there are no FDA approved NAFLD therapies; and current therapies focus on the co-morbidities associated with NAFLD, namely, obesity, hyperglycemia, dyslipidemia, and hypertension...
July 16, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28723413/multifunctional-molecule-erp57-from-cancer-to-neurodegenerative-diseases
#4
REVIEW
Aubryanna Hettinghouse, Ronghan Liu, Chuan-Ju Liu
The protein disulfide isomerase (PDI) gene family is a protein family classically characterized by endoplasmic reticulum (ER) localization and isomerase and redox activity. ERp57, a prominent multifunctional member of the PDI family, is detected at various levels in multiple cellular localizations outside of the ER. ERp57 has been functionally linked to a host of physiological processes and numerous studies have demonstrated altered expression and aberrant functionality of ERp57 in association with diverse pathological states...
July 16, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28720427/the-challenges-and-promise-of-targeting-the-liver-x-receptors-for-treatment-of-inflammatory-disease
#5
REVIEW
Michael B Fessler
The Liver X Receptors (LXRs) are oxysterol-activated transcription factors that upregulate a suite of genes that together promote coordinated mobilization of excess cholesterol from cells and from the body. The LXRs, like other nuclear receptors, are anti-inflammatory, inhibiting signal-dependent induction of pro-inflammatory genes by nuclear factor-κB, activating protein-1, and other transcription factors. Synthetic LXR agonists have been shown to ameliorate atherosclerosis and a wide range of inflammatory disorders in preclinical animal models...
July 16, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28720431/biological-responses-to-immobilized-microscale-and-nanoscale-surface-topographies
#6
REVIEW
Shelby A Skoog, Girish Kumar, Roger J Narayan, Peter L Goering
Cellular responses are highly influenced by biochemical and biomechanical interactions with the extracellular matrix (ECM). Due to the impact of the ECM architecture on cellular responses, significant research has been dedicated towards developing biomaterials that mimic the physiological environment for design of improved medical devices. Surface topographies with microscale and nanoscale features have demonstrated an effect on numerous cellular responses including cell adhesion, migration, proliferation, gene expression, protein production, and differentiation; however, determining relationships between biological responses and surface topographies are difficult to establish due to differences in cell types and biomaterial surface properties...
July 15, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28720430/oncogenic-pathways-that-affect-antitumor-immune-response-and-immune-checkpoint-blockade-therapy
#7
REVIEW
Xianda Zhao, Subbaya Subramanian
Mechanistic insights of cancer immunology have led to the development of immune checkpoint blockade therapy (ICBT), which has elicited a remarkable clinical response in some cancer patients. Increasing evidence suggests that activation of oncogenic pathways, such as RAS/RAF/MAPK and PI3K signaling, impairs the antitumor immune response. Such oncogenic signaling, in turn, activates many inhibitory factors, including expression of immune checkpoint genes-allowing active infiltration of immunosuppressive cells into the tumor environment and inducing resistance against T-cell killing...
July 15, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28720429/stable-isotope-based-flux-studies-in-nonalcoholic-fatty-liver-disease
#8
REVIEW
Arthur McCullough, Stephen Previs, Takhar Kasumov
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with the worldwide epidemics of obesity, diabetes and cardiovascular diseases. NAFLD ranges from benign fat accumulation in the liver (steatosis) to non-alcoholic steatohepatitis (NASH), and cirrhosis which can progress to hepatocellular carcinoma and liver failure. Mass spectrometry and magnetic resonance spectroscopy-coupled stable isotope-based flux studies provide new insights into the understanding of NAFLD pathogenesis and the disease progression...
July 15, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28720428/inhibitors-of-connexin-and-pannexin-channels-as-potential-therapeutics
#9
REVIEW
Joost Willebrords, Michaël Maes, Sara Crespo Yanguas, Mathieu Vinken
While gap junctions support the exchange of a number of molecules between neighboring cells, connexin hemichannels provide communication between the cytosol and the extracellular environment of an individual cell. The latter equally holds true for channels composed of pannexin proteins, which display an architecture reminiscent of connexin hemichannels. In physiological conditions, gap junctions are usually open, while connexin hemichannels and, to a lesser extent, pannexin channels are typically closed, yet they can be activated by a number of pathological triggers...
July 15, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28716651/significance-of-a-to-i-rna-editing-of-transcripts-modulating-pharmacokinetics-and-pharmacodynamics
#10
REVIEW
Masataka Nakano, Miki Nakajima
RNA editing is a post-transcriptional process that alters the nucleotide sequence of RNA transcripts to generate transcriptome diversity. Among the various types of RNA editing, adenosine-to-inosine (A-to-I) RNA editing is the most frequent type of RNA editing in mammals. Adenosine deaminases acting on RNA (ADAR) enzymes, ADAR1 and ADAR2, convert adenosines in double-stranded RNA structures into inosines by hydrolytic deamination. Inosine forms a base pair with cytidine as if it were guanosine; therefore, the conversion may affect the amino acid sequence, splicing, microRNA targeting, and miRNA maturation...
July 15, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28716652/toxicity-profiles-of-immunotherapy
#11
REVIEW
Sophie Cousin, Antoine Italiano
Immunotherapies are changing the landscape of advanced solid tumor treatment. These therapies have different mechanisms of action and include oncolytic viruses, checkpoint inhibitors, such as CTLA-4 or PD1/PD-L1 monoclonal antibodies, and CSF-1R antibodies. Given the growing therapeutic impact of these agents in oncology, it is important to better understand their properties. Immunotherapies generate new toxicity profiles that are called immune-related adverse events and require specific management. This review focuses on the mechanisms of action of such side effects, as well as their description and their general management...
July 14, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28648830/purinergic-p2y-receptors-molecular-diversity-and-implications-for-treatment-of-cardiovascular-diseases
#12
REVIEW
Akiyuki Nishimura, Caroline Sunggip, Sayaka Oda, Takuro Numaga-Tomita, Makoto Tsuda, Motohiro Nishida
Purinergic signaling, mediated mainly by G protein-coupled P2Y receptors (P2YRs), is now attracting attention as a new therapeutic target for preventing or treating cardiovascular diseases. Observations using mice with genetically modified P2YRs and/or treated with a pharmacological P2YR inhibitor have helped us understand the physiological and pathological significance of P2YRs in the cardiovascular system. P2YR-mediated biological functions are predominantly activated by mononucleotides released from non-adrenergic, non-cholinergic nerve endings or non-secretory tissues in response to physical stress or cell injury, though recent studies have suggested the occurrence of ligand-independent P2YR function through receptor-receptor interactions (oligomerization) in several biological processes...
June 23, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28648831/glucagon-like-peptide-1-a-potential-anti-inflammatory-pathway-in-obesity-related-asthma
#13
REVIEW
Dan-Vinh Nguyen, Angela Linderholm, Angela Haczku, Nicholas Kenyon
Alterations in arginine metabolism and accelerated formation of advanced glycation end-products (AGEs), crucial mechanisms in obesity-related asthma, can be modulated by glucagon-like peptide 1 (GLP-1). l-arginine dysregulation in obesity promotes inflammation and bronchoconstriction. Prolonged hyperglycemia, dyslipidemia, and oxidative stress leads to production of AGEs, that bind to their receptor (RAGE) further potentiating inflammation. By binding to its widely distributed receptor, GLP-1 blunts the effects of RAGE activation and arginine dysregulation...
June 22, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28648829/novel-pharmacotherapies-for-cardiac-amyloidosis
#14
REVIEW
Kevin M Alexander, Avinainder Singh, Rodney H Falk
Amyloidosis refers to a range of protein misfolding disorders that can cause organ dysfunction through progressive fibril deposition. Cardiac involvement often leads to significant morbidity and mortality and increasingly has been recognized as an important cause of heart failure. The two main forms of cardiac amyloidosis, light chain (AL) and transthyretin (ATTR) amyloidosis, have distinct mechanisms of pathogenesis. Recent insights have led to the development of novel pharmacotherapies with the potential to significantly impact each disease...
June 22, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28642119/targeting-inflammation-for-the-treatment-of-alcoholic-liver-disease
#15
REVIEW
Ming-Jiang Xu, Zhou Zhou, Richard Parker, Bin Gao
Alcoholic liver disease (ALD) is a leading cause of chronic liver disease with a wide spectrum of manifestations including simple steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Liver injury in ALD is caused by chronic inflammation, which has been actively investigated as a therapeutic target for the treatment of ALD for over the last four decades. In this review, we summarize a wide variety of inflammatory mediators that have been shown to contribute to the pathogenesis of ALD, and discuss the therapeutic potential of these mediators for the treatment of ALD...
June 19, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28642118/current-state-of-the-art-for-cardiac-arrhythmia-gene-therapy
#16
REVIEW
J Kevin Donahue
Cardiac arrhythmias are a leading cause of morbidity and mortality. Currently available therapeutic options lack sufficient efficacy and safety. Gene therapy has been proposed for treatment of cardiac arrhythmias. This review will discuss the current state of development for arrhythmia gene therapy. So far, all published studies are short-term, proof-of-concept animal studies. Potential replacement of cardiac pacemakers has been shown for combination gene therapy using the HCN2 gene and either the gene for adenylate cyclase, the skeletal muscle isoform of the sodium channel, or a dominant negative mutant of the potassium channel responsible for resting membrane potential...
June 19, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28642117/soluble-epoxide-hydrolase-as-a-therapeutic-target-for-pain-inflammatory-and-neurodegenerative-diseases
#17
REVIEW
Karen M Wagner, Cindy B McReynolds, William K Schmidt, Bruce D Hammock
Eicosanoids are biologically active lipid signaling molecules derived from polyunsaturated fatty acids. Many of the actions of eicosanoid metabolites formed by cyclooxygenase and lipoxygenase enzymes have been characterized, however, the epoxy-fatty acids (EpFAs) formed by cytochrome P450 enzymes are newly described by comparison. The EpFA metabolites modulate a diverse set of physiologic functions that include inflammation and nociception among others. Regulation of EpFAs occurs primarily via release, biosynthesis and enzymatic transformation by the soluble epoxide hydrolase (sEH)...
June 19, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28642116/contrast-induced-nephropathy-basic-concepts-pathophysiological-implications-and-prevention-strategies
#18
REVIEW
Charalampos Mamoulakis, Konstantinos Tsarouhas, Irini Fragkiadoulaki, Ioannis Heretis, Martin F Wilks, Demetrios A Spandidos, Christina Tsitsimpikou, Aristides Tsatsakis
Contrast-induced nephropathy (CIN) is reversible acute renal failure observed following administration of iodinated contrast media (CM) during angiographic or other medical procedures such as urography. There are various mechanisms through which CM develop their nephrotoxic effects, including oxidative stress and apoptosis. CIN is a real-life, albeit not very rare, entity. Exact pathophysiology remains obscure and no standard diagnostic criteria apply. The Acute Kidney Injury Network criteria was recently employed but its incidence/clinical significance warrants further clarification based on recent methodological advancements, because most published studies to date were contaminated by bias...
June 19, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28642115/anti-tnf%C3%AE-therapy-in-inflammatory-lung-diseases-bn
#19
REVIEW
Rama Malaviya, Jeffrey D Laskin, Debra L Laskin
Increased levels of tumor necrosis factor (TNF) α have been linked to a number of pulmonary inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), sarcoidosis, and interstitial pulmonary fibrosis (IPF). TNFα plays multiple roles in disease pathology by inducing an accumulation of inflammatory cells, stimulating the generation of inflammatory mediators, and causing oxidative and nitrosative stress, airway hyperresponsiveness and tissue remodeling...
June 19, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28583800/analysis-of-natural-product-regulation-of-cannabinoid-receptors-in-the-treatment-of-human-disease
#20
REVIEW
S Badal, K N Smith, R Rajnarayanan
The organized tightly regulated signaling relays engaged by the cannabinoid receptors (CBs) and their ligands, G proteins and other effectors, together constitute the endocannabinoid system (ECS). This system governs many biological functions including cell proliferation, regulation of ion transport and neuronal messaging. This review will firstly examine the physiology of the ECS, briefly discussing some anomalies in the relay of the ECS signaling as these are consequently linked to maladies of global concern including neurological disorders, cardiovascular disease and cancer...
June 2, 2017: Pharmacology & Therapeutics
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