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Pharmacology & Therapeutics

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https://read.qxmd.com/read/30763594/cathepsins-potent-regulators-in-carcinogenesis
#1
Tejinder Pal Khaket, Taeg Kyu Kwon, Sun Chul Kang
Cathepsins (CTS) are mainly lysosomal acid hydrolases extensively involved in the prognosis of different diseases, and having a distinct role in tumor progression by regulating cell proliferation, autophagy, angiogenesis, invasion, and metastasis. As all these processes conjunctively lead to cancer progression, their site-specific regulation might be beneficial for cancer treatment. CTS regulate activation of the proteolytic cascade and protein turnover, while extracellular CTS is involved in promoting extracellular matrix degradation and angiogenesis, thereby stimulating invasion and metastasis...
February 11, 2019: Pharmacology & Therapeutics
https://read.qxmd.com/read/30759376/potential-biomarkers-for-persistent-and-neuropathic-pain-therapy
#2
Marco Sisignano, Jörn Lötsch, Michael J Parnham, Gerd Geisslinger
Persistent, in particular neuropathic pain affects millions of people worldwide. However, the response rate of patients to existing analgesic drugs is less than 50%. There are several possibilities to increase this response rate, such as optimization of the pharmacokinetic and pharmacodynamic properties of analgesics. Another promising approach is to use prognostic biomarkers in patients to determine the optimal pharmacological therapy for each individual. Here, we discuss recent efforts to identify plasma and CSF biomarkers, as well as genetic biomarkers and sensory testing, and how these readouts could be exploited for the prediction of a suitable pharmacological treatment...
February 10, 2019: Pharmacology & Therapeutics
https://read.qxmd.com/read/30759375/quenching-the-fires-pro-resolving-mediators-air-pollution-and-smoking
#3
Thomas H Thatcher, Collynn F Woeller, Claire E McCarthy, Patricia J Sime
Exposure to air pollution and other environmental inhalation hazards, such as occupational exposures to dusts and fumes, aeroallergens, and tobacco smoke, is a significant cause of chronic lung inflammation leading to respiratory disease. It is now recognized that resolution of inflammation is an active process controlled by a novel family of small lipid mediators termed "specialized pro-resolving mediators" or SPMs, derived mainly from dietary omega-3 polyunsaturated fatty acids. Chronic inflammation results from an imbalance between pro-inflammatory and pro-resolution pathways...
February 10, 2019: Pharmacology & Therapeutics
https://read.qxmd.com/read/30759374/phosphodiesterases-as-therapeutic-targets-for-respiratory-diseases
#4
Haoxiao Zuo, Isabella Cattani-Cavalieri, Nshunge Musheshe, Viacheslav O Nikolaev, Martina Schmidt
Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma, affect millions of people all over the world. Cyclic adenosine monophosphate (cAMP) which is one of the most important second messengers, plays a vital role in relaxing airway smooth muscles and suppressing inflammation. Given its vast role in regulating intracellular responses, cAMP provides an attractive pharmaceutical target in the treatment of chronic respiratory diseases. Phosphodiesterases (PDEs) are enzymes that hydrolyze cyclic nucleotides and help control cyclic nucleotide signals in a compartmentalized manner...
February 10, 2019: Pharmacology & Therapeutics
https://read.qxmd.com/read/30759373/what-doesn-t-kill-you-makes-you-stranger-dipeptidyl-peptidase-4-cd26-proteolysis-differentially-modulates-the-activity-of-many-peptide-hormones-and-cytokines-generating-novel-cryptic-bioactive-ligands
#5
Ahmed M Elmansi, Mohamed E Awad, Nada H Eisa, Dmitry Kondrikov, Khaled A Hussein, Alexandra Aguilar-Pérez, Samuel Herberg, Sudharsan Periyasamy-Thandavan, Sadanand Fulzele, Mark W Hamrick, Meghan E McGee-Lawrence, Carlos M Isales, Brian F Volkman, William D Hill
Dipeptidyl peptidase 4 (DPP4) is an exopeptidase found either on cell surfaces where it is highly regulated in terms of its expression and surface availability (CD26) or in a free/circulating soluble constitutively available and intrinsically active form. It is responsible for proteolytic cleavage of many peptide substrates. In this review we discuss the idea that DPP4-cleaved peptides are not necessarily inactivated, but rather can possess either a modified receptor selectivity, modified bioactivity, new antagonistic activity, or even a novel activity relative to the intact parent ligand...
February 10, 2019: Pharmacology & Therapeutics
https://read.qxmd.com/read/30703416/vitamin-a-signaling-and-homeostasis-in-obesity-diabetes-and-metabolic-disorders
#6
REVIEW
William S Blaner
Much evidence has accumulated in the literature over the last fifteen years that indicates vitamin A has a role in metabolic disease prevention and causation. This literature proposes that vitamin A can affect obesity development and the development of obesity-related diseases including insulin resistance, type 2 diabetes, hepatic steatosis and steatohepatitis, and cardiovascular disease. Retinoic acid, the transcriptionally active form of vitamin A, accounts for many of the reported associations. However, a number of proteins involved in vitamin A metabolism, including retinol-binding protein 4 (RBP4) and aldehyde dehydrogenase 1A1 (ALDH1A1, alternatively known as retinaldehyde dehydrogenase 1 or RALDH1), have also been identified as being associated with metabolic disease...
January 28, 2019: Pharmacology & Therapeutics
https://read.qxmd.com/read/30703415/sarcolemmal-%C3%AE-2-adrenoceptors-in-feedback-control-of-myocardial-response-to-sympathetic-challenge
#7
REVIEW
Alexey E Alekseev, Sungjo Park, Oleg Yu Pimenov, Santiago Reyes, Andre Terzic
α2-adrenoceptor (α2-AR) isoforms, abundant in sympathetic synapses and noradrenergic neurons of the central nervous system, are integral in the presynaptic feed-back loop mechanism that moderates norepinephrine surges. We recently identified that postsynaptic α2-AR, found in the myocellular sarcolemma, also contribute to a muscle-delimited feedback control capable of attenuating mobilization of intracellular Ca2+ and myocardial contractility. This previously unrecognized cardiac muscle delimited α2-AR-dependent rheostat is able to counteract competing adrenergic receptor actions...
January 28, 2019: Pharmacology & Therapeutics
https://read.qxmd.com/read/30677475/environmental-neurotoxicant-induced-dopaminergic-neurodegeneration-a-potential-link-to-impaired-neuroinflammatory-mechanisms
#8
REVIEW
Arthi Kanthasamy, Huajun Jin, Adhithiya Charli, Anantharam Vellareddy, Anumantha Kanthasamy
With the increased incidence of neurodegenerative diseases worldwide, Parkinson's disease (PD) represents the second-most common neurodegenerative disease. PD is a progressive multisystem neurodegenerative disorder characterized by a marked loss of nigrostriatal dopaminergic neurons and the formation of Lewy pathology in diverse brain regions. Although the mechanisms underlying dopaminergic neurodegeneration remain poorly characterized, data from animal models and postmortem studies have revealed that heightened inflammatory responses mediated via microglial and astroglial activation and the resultant release of proinflammatory factors may act as silent drivers of neurodegeneration...
January 22, 2019: Pharmacology & Therapeutics
https://read.qxmd.com/read/30677477/the-eye-as-a-novel-imaging-site-in-diabetes-research
#9
REVIEW
Shao-Nian Yang, Per-Olof Berggren
Diabetes develops due to deficient functional β cell mass, insulin resistance, or both. Yet, various challenges in understanding the mechanisms underlying diabetes development in vivo remain to be overcome owing to the lack of appropriate intravital imaging technologies. To meet these challenges, we have exploited the anterior chamber of the eye (ACE) as a novel imaging site to understand diabetes basics and clinics in vivo. We have developed a technology platform transplanting pancreatic islets into the ACE where they later on can be imaged non-invasively for long time...
January 21, 2019: Pharmacology & Therapeutics
https://read.qxmd.com/read/30677476/the-adenosine-a-2b-g-protein-coupled-receptor-recent-advances-and-therapeutic-implications
#10
REVIEW
Elizabeth A Vecchio, Paul J White, Lauren T May
The adenosine A2B receptor (A2B AR) is one of four adenosine receptor subtypes belonging to the Class A family of G protein-coupled receptors (GPCRs). Until recently, the A2B AR remained poorly characterised, in part due to its relatively low affinity for the endogenous agonist adenosine and therefore presumed minor physiological significance. However, the substantial increase in extracellular adenosine concentration, the sensitisation of the receptor and the upregulation of A2B AR expression under conditions of hypoxia and inflammation, suggest the A2B AR as an exciting therapeutic target in a variety of pathological disease states...
January 21, 2019: Pharmacology & Therapeutics
https://read.qxmd.com/read/30677474/are-cell-based-therapies-for-kidney-disease-safe-a-systematic-review-of-preclinical-evidence
#11
REVIEW
Milos Mihajlovic, Kimberley E Wever, Thom K van der Made, Rob B M de Vries, Luuk B Hilbrands, Rosalinde Masereeuw
The number of individuals affected by acute kidney injury (AKI) and chronic kidney disease (CKD) is constantly rising. In light of the limited availability of treatment options and their relative inefficacy, cell based therapeutic modalities have been studied. However, not many efforts are put into safety evaluation of such applications. The aim of this study was to review the existing published literature on adverse events reported in studies with genetically modified cells for treatment of kidney disease...
January 21, 2019: Pharmacology & Therapeutics
https://read.qxmd.com/read/30677473/novel-genetic-and-epigenetic-factors-of-importance-for-inter-individual-differences-in-drug-disposition-response-and-toxicity
#12
REVIEW
Volker M Lauschke, Yitian Zhou, Magnus Ingelman-Sundberg
Individuals differ substantially in their response to pharmacological treatment. Personalized medicine aspires to embrace these inter-individual differences and customize therapy by taking a wealth of patient-specific data into account. Pharmacogenomic constitutes a cornerstone of personalized medicine that provides therapeutic guidance based on the genomic profile of a given patient. Pharmacogenomics already has applications in the clinics, particularly in oncology, whereas future development in this area is needed in order to establish pharmacogenomic biomarkers as useful clinical tools...
January 21, 2019: Pharmacology & Therapeutics
https://read.qxmd.com/read/30578809/cognitive-neuropsychological-theory-reconciliation-of-psychological-and-biological-approaches-for-depression
#13
REVIEW
Beata R Godlewska
New antidepressants and individualized approaches to treatment, matching specific therapies to individual patients, are urgently needed. For this, a better understanding of processes underpinning the development of depressive symptoms and response to medications are required. The cognitive neuropsychological model offers a novel approach uniquely combining biological and psychological approaches to explain how antidepressants exert their effect, why there is a delay in the onset of their clinical effect, and how changes in emotional processing are an essential step for a clinical antidepressant effect to take place...
December 19, 2018: Pharmacology & Therapeutics
https://read.qxmd.com/read/30557632/effective-effectors-how-t-cells-access-and-infiltrate-the-central-nervous-system
#14
REVIEW
Kendra L Congdon, Luis A Sanchez-Perez, John H Sampson
Several Phase II and III clinical trials have demonstrated that immunotherapy can induce objective responses in otherwise refractory malignancies in tumors outside the central nervous system. In large part, effector T cells mediate much of the antitumor efficacy in these trials, and potent antitumor T cells can be generated through vaccination, immune checkpoint blockade, adoptive transfer, and genetic manipulation. However, activated T cells must still traffic to, infiltrate, and persist within tumor in order to mediate tumor lysis...
December 14, 2018: Pharmacology & Therapeutics
https://read.qxmd.com/read/30557631/organic-anion-transporting-polypeptide-2b1-more-than-a-glass-full-of-drug-interactions
#15
REVIEW
Savannah J McFeely, Lanxiang Wu, Tasha K Ritchie, Jashvant Unadkat
The importance of uptake transporters in determining drug disposition is increasingly appreciated. While the focus of regulatory agencies worldwide has been on the hepatic organic anion transporting polypeptides (OATPs)-1B1 and-1B3, there is another isoform of the OATP sub-family, OATP2B1, which should be considered equally relevant. Unlike the other members of the OATP sub-family, OATP2B1 is expressed in multiple organs in humans, including in the intestine and the liver. Similar to other OATPs, OATP2B1 mediates the hepatic and intestinal uptake of many drugs and endogenous compounds...
December 14, 2018: Pharmacology & Therapeutics
https://read.qxmd.com/read/30557630/kit-as-a-therapeutic-target-for-non-oncological-diseases
#16
REVIEW
Asuncion Martinez-Anton, Delphine Gras, Arnaud Bourdin, Patrice Dubreuil, Pascal Chanez
KIT is a receptor tyrosine kinase that after binding to its ligand stem cell factor activates signaling cascades linked to biological processes such as proliferation, differentiation, migration and cell survival. Based on studies performed on SCF and/or KIT mutant animals that presented anemia, sterility, and/or pigmentation disorders, KIT signaling was mainly considered to be involved in the regulation of hematopoiesis, gametogenesis, and melanogenesis. More recently, novel animal models and ameliorated cellular and molecular techniques have led to the discovery of a widen repertoire of tissue compartments and functions that are being modulated by KIT...
December 14, 2018: Pharmacology & Therapeutics
https://read.qxmd.com/read/30557629/mechanisms-of-cardiac-ethanol-toxicity-and-novel-treatment-options
#17
REVIEW
Julian Mustroph, Simon Lebek, Lars S Maier, Stefan Neef
Ethanol can acutely and chronically alter cardiomyocyte and whole-organ function in the heart. Importantly, ethanol acutely and chronically predisposes to arrhythmias, while chronic abuse can induce heart failure. However, the molecular mechanisms of ethanol toxicity in the heart are incompletely understood. In this review, we summarize the current mechanistic knowledge on cardiac ethanol toxicity, with a focus on druggable pathways. Ethanol effects on excitation-contraction coupling, oxidative stress, apoptosis, and cardiac metabolism, as well as effects of ethanol metabolites will be discussed...
December 14, 2018: Pharmacology & Therapeutics
https://read.qxmd.com/read/30529041/immune-mechanisms-mediating-abscopal-effects-in-radioimmunotherapy
#18
REVIEW
María E Rodriguez-Ruiz, I Rodriguez, Olwen Leaman, Fernando López Campos, Angel Montero, Antonio J Conde, J J Aristu, Pedro Lara, Manuel Calvo Felipe, Ignacio Melero
Radiotherapy of cancer has been traditionally considered as a local therapy without noticeable effects outside the irradiated fields. However, ionizing radiation exerts multiple biological effects on both malignant and stromal cells that account for a complex spectrum of mechanisms beyond simple termination of cancer cells. In the era of immunotherapy, interest in radiation-induced inflammation and cell death has considerably risen, since these mechanisms lead to profound changes in the systemic immune response against cancer antigens...
December 5, 2018: Pharmacology & Therapeutics
https://read.qxmd.com/read/30529040/hmgb1-and-repair-focus-on-the-heart
#19
REVIEW
Laura Pellegrini, Eleonora Foglio, Elena Pontemezzo, Antonia Germani, Matteo Antonio Russo, Federica Limana
High-mobility group box 1 (HMGB1) is one of the most abundant proteins in eukaryotes and the best characterized damage-associated molecular pattern (DAMP). The biological activities of HMGB1 depend on its subcellular location, context and post-translational modifications. Inside the nucleus, HMGB1 is engaged in many DNA events such as DNA repair, transcription regulation and genome stability; in the cytoplasm, its main function is to regulate the autophagic flux while in the extracellular environment, it possesses more complicated functions and it is involved in a large variety of different processes such as inflammation, migration, invasion, proliferation, differentiation and tissue regeneration...
December 5, 2018: Pharmacology & Therapeutics
https://read.qxmd.com/read/30521885/rna-therapy-are-we-using-the-right-molecules
#20
REVIEW
Ai-Ming Yu, Chao Jian, Allan H Yu, Mei-Juan Tu
Small-molecule and protein/antibody drugs mainly act on genome-derived proteins to exert pharmacological effects. RNA based therapies hold the promise to expand the range of druggable targets from proteins to RNAs and the genome, as evidenced by several RNA drugs approved for clinical practice and many others under active trials. While chemo-engineered RNA mimics have found their success in marketed drugs and continue dominating basic research and drug development, these molecules are usually conjugated with extensive and various modifications...
December 4, 2018: Pharmacology & Therapeutics
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