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Pharmacology & Therapeutics

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https://www.readbyqxmd.com/read/28213089/monoglyceride-lipase-as-a-drug-target-at-the-crossroads-of-arachidonic-acid-metabolism-and-endocannabinoid-signaling
#1
REVIEW
Gernot F Grabner, Robert Zimmermann, Rudolf Schicho, Ulrike Taschler
Monoglyerides (MGs) are short-lived, intermediary lipids deriving from the degradation of phospho- and neutral lipids, and monoglyceride lipase (MGL), also designated as monoacylglycerol lipase (MAGL), is the major enzyme catalyzing the hydrolysis of MGs into glycerol and fatty acids. This distinct function enables MGL to regulate a number of physiological and pathophysiological processes since both MGs and fatty acids can act as signaling lipids or precursors thereof. The most prominent MG species acting as signaling lipid is 2-arachidonoylglycerol (2-AG) which is the most abundant endogenous agonist of cannabinoid receptors in the body...
February 14, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28213088/personalized-medicine-genetic-risk-prediction-of-drug-response
#2
REVIEW
Ge Zhang, Daniel W Nebert
Pharmacogenomics (PGx), a substantial component of "personalized medicine", seeks to understand each individual's genetic composition to optimize drug therapy -- maximizing beneficial drug response, while minimizing adverse drug reactions (ADRs). Drug responses are highly variable because innumerable factors contribute to ultimate phenotypic outcomes. Recent genome-wide PGx studies have provided some insight into genetic basis of variability in drug response. These can be grouped into three categories. [a] Monogenic (Mendelian) traits include early examples mostly of inherited disorders, and some severe (idiosyncratic) ADRs typically influenced by single rare coding variants...
February 14, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28202367/exosomes-therapy-delivery-tools-and-biomarkers-of-diseases
#3
REVIEW
Lucio Barile, Giuseppe Vassalli
Virtually all cells in the organism secrete extracellular vesicles (EVs), a heterogeneous population of lipid bilayer membrane-enclosed vesicles that transport and deliver payloads of proteins and nucleic acids to recipient cells, thus playing central roles in cell-cell communications. Exosomes, nanosized EVs of endosomal origin, regulate many pathophysiological processes including immune responses and inflammation, tumour growth, and infection. Healthy subjects and patients with different diseases release exosomes with different RNA and protein contents into the circulation, which can be measured as biomarkers...
February 12, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28202366/modulation-of-the-trpv4-ion-channel-as-a-therapeutic-target-for-disease
#4
REVIEW
Megan S Grace, Sara J Bonvini, Maria G Belvisi, Peter McIntyre
Transient Receptor Potential Vanilloid 4 (TRPV4) is a broadly expressed, polymodally gated ion channel that plays an important role in many physiological and pathophysiological processes. TRPV4 knockout mice and several synthetic pharmacological compounds that selectively target TRPV4 are now available, which has allowed detailed investigation in to the therapeutic potential of this ion channel. Results from animal studies suggest that TRPV4 antagonism has therapeutic potential in oedema, pain, gastrointestinal disorders, and lung diseases such as cough, bronchoconstriction, pulmonary hypertension, and acute lung injury...
February 12, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28202365/optimising-the-use-of-medicines-to-reduce-acute-kidney-injury-in-children-and-babies
#5
REVIEW
L Oni, D B Hawcutt, M A Turner, M W Beresford, S McWilliam, C Barton, B K Park, P Murray, B Wilm, I Copple, R Floyd, M Peak, A Sharma, D J Antoine
The majority of medications in children are administered in an unlicensed or off-label manner. Paediatricians are obliged to prescribe using the limited evidence available. The 2007 EU regulation on the use of paediatric drugs means pharmaceutical companies are now obliged to (and receive incentives for) contributing to paediatric drug data and carrying out paediatric clinical trials. This is important, as the efficacy and adverse effect profiles of medicines vary across childhood. Additionally, there are significant age-related changes in the pharmacodynamic and pharmacokinetic activity of many drugs...
February 12, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28202364/fatty-acid-synthase-modern-tumor-cell-biology-insights-into-a-classical-oncology-target
#6
REVIEW
Douglas Buckley, Gregory Duke, Timothy S Heuer, Marie O'Farrell, Allan Wagman, William McCulloch, George Kemble
Decades of preclinical and natural history studies have highlighted the potential of fatty acid synthase (FASN) as a bona fide drug target for oncology. This review will highlight the foundational concepts upon which this perspective is built. Published studies have shown high levels of FASN in patient tumor tissues are present at later stages of disease and this overexpression predicts poor prognosis. Preclinical studies have shown that experimental overexpression of FASN in previously normal cells leads to changes that are critical for establishing a tumor phenotype...
February 12, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28188812/epigenetics-in-cancer-fundamentals-and-beyond
#7
REVIEW
Subhankar Biswas, C Mallikarjuna Rao
Activation of oncogenes or the deactivation of tumor suppressor genes has long been established as the fundamental mechanism leading towards carcinogenesis. Although this age old axiom is vastly accurate, thorough study over the last 15 years has given us unprecedented information on the involvement of epigenetic in cancer. Various biochemical pathways that are essential towards tumorigenesis are regulated by the epigenetic phenomenons like remodeling of nucleosome by histone modifications, DNA methylation and miRNA mediated targeting of various genes...
February 7, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28185916/dna-vaccines-for-prostate-cancer
#8
REVIEW
Christopher D Zahm, Viswa Teja Colluru, Douglas G McNeel
DNA vaccines offer many advantages over other anti-tumor vaccine approaches due to their simplicity, ease of manufacturing, and safety. Results from several clinical trials in patients with cancer have demonstrated that DNA vaccines are safe and can elicit immune responses. However, to date few DNA vaccines have progressed beyond phase I clinical trial evaluation. Studies into the mechanism of action of DNA vaccines in terms of antigen-presenting cell types able to directly present or cross-present DNA-encoded antigens, and the activation of innate immune responses due to DNA itself, have suggested opportunities to increase the immunogenicity of these vaccines...
February 6, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28185915/targeting-kinase-signaling-pathways-with-constrained-peptide-scaffolds
#9
REVIEW
Laura E Hanold, Melody D Fulton, Eileen J Kennedy
Kinases are amongst the largest families in the human proteome and serve as critical mediators of a myriad of cell signaling pathways. Since altered kinase activity is implicated in a variety of pathological diseases, kinases have become a prominent class of proteins for targeted inhibition. Although numerous small molecule and antibody-based inhibitors have already received clinical approval, several challenges may still exist with these strategies including resistance, target selection, inhibitor potency and in vivo activity profiles...
February 6, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28185914/therapeutic-strategies-and-mechanisms-of-drug-resistance-in-anaplastic-lymphoma-kinase-alk-rearranged-lung-cancer
#10
REVIEW
Ryohei Katayama
Anaplastic lymphoma kinase (ALK) gene encoding the receptor tyrosine kinase ALK is expressed as a fusion gene in a variety of carcinomas. The expression of ALK is nearly undetectable in adults, and its activation is normally regulated by its ligands, FAM150A/B. However, ALK gene rearrangements result in different ALK fusion proteins that are constitutively expressed via the active promoter of fusion partner genes. ALK fusion proteins dimerize in a ligand-independent manner and lead to the dysregulation of cell proliferation via abnormal constitutive activation of ALK tyrosine kinase...
February 6, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28185913/macrophages-and-skeletal-health
#11
REVIEW
Megan N Michalski, Laurie K McCauley
Bone is in a constant state of remodeling, a process which was once attributed solely to osteoblasts and osteoclasts. Decades of research has identified many other populations of cells in the bone that participate and mediate skeletal homeostasis. Recently, osteal macrophages emerged as vital participants in skeletal remodeling and osseous repair. The exact mechanistic roles of these tissue-resident macrophages are currently under investigation. Macrophages are highly plastic in response to their micro-environment and are typically classified as being pro- or anti-inflammatory (pro-resolving) in nature...
February 6, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28174096/retinal-biomarkers-provide-insight-into-cortical-pharmacology-and-disease
#12
REVIEW
Christine To Nguyen, Flora Hui, Jason Charng, Shajan Velaedan, Anna van Koeverden, Jeremiah Kh Lim, Zheng He, Vickie Hy Wong, Algis J Vingrys, Bang V Bui, Magnus Ivarsson
The retina is an easily accessible out-pouching of the central nervous system (CNS) and thus lends itself favourable to being a biomarker of the brain. More specifically, the presence of neuronal, vascular and blood-neural barrier parallels in the eye and brain coupled with fast and inexpensive methods to quantify retinal changes make ocular biomarkers an attractive option. This includes its utility as a biomarker for multiple cerebrovascular diseases as well as a drug pharmacology and safety biomarker for the CNS...
February 4, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28174095/anti-mitotic-agents-are-they-emerging-molecules-for-cancer-treatment
#13
REVIEW
Larissa Siqueira Penna, João Antonio Pêgas Henriques, Diego Bonatto
Mutations in cancer cells frequently result in cell cycle alterations that lead to unrestricted growth compared to normal cells. Considering this phenomenon, many drugs have been developed to inhibit different cell-cycle phases. Mitotic phase targeting disturbs mitosis in tumor cells, triggers the spindle assembly checkpoint and frequently results in cell death. The first anti-mitotics to enter clinical trials aimed to target tubulin. Although these drugs improved the treatment of certain cancers, and many anti-microtubule compounds are already approved for clinical use, severe adverse events such as neuropathies were observed...
February 4, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28174094/recent-advances-in-hepatocellular-carcinoma-therapy
#14
REVIEW
Rinku Dutta, Ram I Mahato
Hepatocellular carcinoma (HCC), also called malignant hepatoma, is one of the deadliest cancers due to its complexities, reoccurrence after surgical resection, metastasis and heterogeneity. Incidence and mortality of HCC are increasing in Western countries and are expected to rise as a consequence of the obesity epidemic. Multiple factors trigger the initiation and progression of HCC including chronic alcohol consumption, viral hepatitis B and C infection, metabolic disorders and age. Although Sorafenib is the only FDA approved drug for the treatment of HCC, numerous treatment modalities such as transcatheter arterial chemoembolization/ transarterial chemoembolization (TACE), radiotherapy, locoregional therapy and chemotherapy have been tested in the clinics...
February 4, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28174093/new-insights-into-thyroid-hormone-action
#15
REVIEW
Arturo Mendoza, Anthony N Hollenberg
Thyroid hormones (TH) are endocrine messengers essential for normal development and function of virtually every vertebrate. The hypothalamic-pituitary-thyroid axis is exquisitely modulated to maintain nearly constant TH (T4 and T3) concentrations in circulation. However peripheral tissues and the CNS control the intracellular availability of TH, suggesting that circulating concentrations of TH are not fully representative of what each cell type sees. Indeed, recent work in the field has identified that TH transporters, deiodinases and thyroid hormone receptor coregulators can strongly control tissue-specific sensitivity to a set amount of TH...
February 4, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28174092/pancreatic-cancer-models-for-translational-research
#16
REVIEW
Diana Behrens, Wolfgang Walther, Iduna Fichtner
Pancreatic cancer is a cruel, progressive disease that is highly metastatic and barely treatable, a situation that is devastating for patients, family members, oncologists, clinicians and scientists. Open questions that need to be resolved by research into pancreatic cancer relate to its aggressiveness, the underlying molecular causes, the factors that promote tumor progression, the ways cancer cells interact with their environments, and whether more effective therapeutic options can be developed. Studies over the last 15 years have provided some partial answers, but in the absence of a real cure the main agenda remains: to identify new therapeutic targets, predictive markers and novel treatment strategies that would help the disease under control...
February 4, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28174091/inhibitors-of-cyclin-dependent-kinases-as-cancer-therapeutics
#17
REVIEW
Steven R Whittaker, Aurelie Mallinger, Paul Workman, Paul A Clarke
Over the past two decades there has been a great deal of interest in the development of inhibitors of the Cyclin-dependent kinases (CDKs). This attention initially stemmed from observations that different CDK isoforms have key roles in cancer cell proliferation through loss of regulation of the cell cycle, a hallmark feature of cancer. CDKs have now been shown to regulate other processes, particularly various aspects of transcription. The early non-selective CDK inhibitors exhibited considerable toxicity and proved to be insufficiently active in most cancers...
February 4, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28174090/targeting-trk-family-proteins-in-cancer
#18
REVIEW
Yekaterina B Khotskaya, Vijaykumar R Holla, Anna F Farago, Kenna R Mills Shaw, Funda Meric-Bernstam, David S Hong
The tropomyosin receptor kinase (TRK) family includes TRKA, TRKB, and TRKC proteins, which are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. Binding of neurotrophins to TRK proteins induces receptor dimerization, phosphorylation, and activation of the downstream signaling cascades via PI3K, RAS/MAPK/ERK, and PLC-gamma. TRK pathway aberrations, including gene fusions, protein overexpression, and single nucleotide alterations, have been implicated in the pathogenesis of many cancer types, with NTRK gene fusions being the most well validated oncogenic events to date...
February 4, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28167219/the-pro-or-antiarrhythmic-actions-of-polyunsaturated-fatty-acids-and-of-cholesterol
#19
REVIEW
R Coronel
In this review, the pro- and anti-arrhythmic effects of a diet rich in fish oil fatty acids and hypercholesterolemia will be discussed in relation to two major mechanisms of arrhythmogenesis (triggered activity and re-entry). Whereas a diet rich in fish oil is pro-arrhythmic in relation to re-entry based arrhythmias (as occur in acute myocardial ischemia) and anti-arrhythmic in relation to triggered activity based arrhythmias (as occur in heart failure), the reverse is true for hypercholesterolemia. Changing the lipid composition of cardiomyocytes likely has powerful pro- or anti-arrhythmic consequences, depending on the mechanism of arrhythmias, and has corresponding therapeutic potential...
February 3, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28167218/tumor-regulation-of-the-tissue-environment-in-the-liver
#20
REVIEW
Tobias Eggert, Tim F Greten
The tumor microenvironment (TME) in the liver plays an important role in primary and metastatic liver tumor formation and tumor growth promotion. Cellular and non-cellular components of the TME significantly influence tumor development, growth, metastatic spread, anti-tumor immunity and response to tumor therapy. The cellular components of the TME in the liver not only consist of infiltrating immune cells, but also of liver-resident cells such as liver sinusoidal endothelial cells (LSEC) and hepatic stellate cells (HSC), which promote tumor growth by negatively regulating tumor-associated immune responses...
February 3, 2017: Pharmacology & Therapeutics
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