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Pharmacology and physiology

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https://www.readbyqxmd.com/read/28646272/rhesus-cochlear-and-vestibular-functions-are-preserved-after-inner-ear-injection-of-saline-volume-sufficient-for-gene-therapy-delivery
#1
Chenkai Dai, Mohamed Lehar, Daniel Q Sun, Lani Swarthout Rvt, John P Carey, Tim MacLachlan, Doug Brough, Hinrich Staecker, Alexandra M Della Santina, Timothy E Hullar, Charles C Della Santina
Sensorineural losses of hearing and vestibular sensation due to hair cell dysfunction are among the most common disabilities. Recent preclinical research demonstrates that treatment of the inner ear with a variety of compounds, including gene therapy agents, may elicit regeneration and/or repair of hair cells in animals exposed to ototoxic medications or other insults to the inner ear. Delivery of gene therapy may also offer a means for treatment of hereditary hearing loss. However, injection of a fluid volume sufficient to deliver an adequate dose of a pharmacologic agent could, in theory, cause inner ear trauma that compromises functional outcome...
June 23, 2017: Journal of the Association for Research in Otolaryngology: JARO
https://www.readbyqxmd.com/read/28645025/decreased-functional-connectivity-and-disrupted-neural-network-in-the-prefrontal-cortex-of-affective-disorders-a-resting-state-fnirs-study
#2
Huilin Zhu, Jie Xu, Jiangxue Li, Hongjun Peng, Tingting Cai, Xinge Li, Shijing Wu, Wei Cao, Sailing He
BACKGROUND: Affective disorders (AD) have been conceptualized as neural network-level diseases. In this study, we utilized functional near infrared spectroscopy (fNIRS) to investigate the spontaneous hemodynamic activities in the prefrontal cortex (PFC) of the AD patients with or without medications. METHODS: 42 optical channels were applied to cover the superior frontal gyrus (SFG), middle frontal gyrus (MFG), and inferior frontal gyrus (IFG), which constitute one of the most important affective networks of the brain...
June 17, 2017: Journal of Affective Disorders
https://www.readbyqxmd.com/read/28644898/spatio-temporal-orientation-of-microtubules-controls-conical-cell-shape-in-arabidopsis-thaliana-petals
#3
Huibo Ren, Xie Dang, Xianzhi Cai, Peihang Yu, Yajun Li, Shanshan Zhang, Menghong Liu, Binqing Chen, Deshu Lin
The physiological functions of epidermal cells are largely determined by their diverse morphologies. Most flowering plants have special conical-shaped petal epidermal cells that are thought to influence light capture and reflectance, and provide pollinator grips, but the molecular mechanisms controlling conical cell shape remain largely unknown. Here, we developed a live-confocal imaging approach to quantify geometric parameters of conical cells in Arabidopsis thaliana (A.thaliana). Through genetic screens, we identified katanin (KTN1) mutants showing a phenotype of decreased tip sharpening of conical cells...
June 23, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28644070/particulate-matter-disrupts-human-lung-endothelial-cell-barrier-integrity-via-rho-dependent-pathways
#4
Ting Wang, Yuka Shimizu, Xiaomin Wu, Gabriel T Kelly, Xiaoyan Xu, Lichun Wang, Zhongqing Qian, Yin Chen, Joe G N Garcia
Increased exposure to ambient particulate matter (PM) is associated with elevated morbidity and mortality in patients with cardiopulmonary diseases and cancer. We and others have shown that PM induces lung microvascular barrier dysfunction which potentially enhances the systemic toxicity of PM. However, the mechanisms by which PM disrupts vascular endothelial integrity remain incompletely explored. We hypothesize that PM induces endothelial cell (EC) cytoskeleton rearrangement via Rho GTPase-dependent pathways to facilitate vascular hyperpermeability...
June 23, 2017: Pulmonary Circulation
https://www.readbyqxmd.com/read/28644055/regulation-of-transient-receptor-potential-melastatin-4-channel-by-sarcoplasmic-reticulum-inositol-triphosphate-receptors-role-in-human-detrusor-smooth-muscle-function
#5
Aaron Provence, Eric S Rovner, Georgi V Petkov
We recently reported key physiological roles for Ca(2+)-activated transient receptor potential melastatin 4 (TRPM4) channels in detrusor smooth muscle (DSM). However, the Ca(2+)-signaling mechanisms governing TRPM4 channel activity in human DSM cells are unexplored. As the TRPM4 channels are activated by Ca(2+), inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca(2+) release from the sarcoplasmic reticulum represents a potential Ca(2+) source for TRPM4 channel activation. We used clinically-characterized human DSM tissues to investigate the molecular and functional interactions of the IP3Rs and TRPM4 channels...
June 23, 2017: Channels
https://www.readbyqxmd.com/read/28643273/chronic-constipation-in-rome-iv-era-the-indian-perspective
#6
REVIEW
Uday C Ghoshal
Chronic constipation (CC) is a common problem in the community and in gastroenterology practice all over the world including India. After release of Rome IV guidelines in April 2016, there is increasing interest among gastroenterologists and physicians in India to look into special issues on CC in the Indian perspective. There are important differences in the bowel habit, definition, epidemiology, and pathophysiology including dietary factors and management of CC in India as compared to the West. As severity and frequency of abdominal pain, a symptom essential to diagnose constipation-predominant irritable bowel syndrome (IBS-C) rather than functional constipation (FC), is less common among Indian patients, FC is commoner than IBS-C in India...
June 23, 2017: Indian Journal of Gastroenterology: Official Journal of the Indian Society of Gastroenterology
https://www.readbyqxmd.com/read/28643088/potential-therapeutic-applications-of-human-anti-m%C3%A3-llerian-hormone-amh-analogues-in-reproductive-medicine
#7
REVIEW
Vitaly A Kushnir, David B Seifer, David H Barad, Aritro Sen, Norbert Gleicher
Members of the transforming growth factor-beta (TGF-beta) superfamily are key regulators of various physiological processes. Anti-Müllerian hormone (AMH) which is also commonly known as Müllerian-inhibiting substance (MIS) is a member of the TGF-beta superfamily and an important regulator of reproductive organ differentiation and ovarian follicular development. While AMH has been used for diagnostic purposes as a biomarker for over 15 years, new potential therapeutic applications of recombinant human AMH analogues are now emerging as pharmacologic agents in reproductive medicine...
June 22, 2017: Journal of Assisted Reproduction and Genetics
https://www.readbyqxmd.com/read/28642541/can-uk-undergraduate-dental-programmes-provide-training-in-non-surgical-facial-aesthetics
#8
T W M Walker, F Gately, S Stagnell, A Kerai, C Mills, S Thomas
Aim Recently, more and more dentists have found themselves engaging in the delivery of non-surgical facial aesthetics (NSFA) as part of their regular practice routine. NSFA is a growing field in aesthetic medicine that is practised by a range of clinicians including doctors, dentists and registered prescriber nurses and is an industry estimated to be worth over £3 billion in the UK alone. In the past few years, several public scandals in aesthetic medicine have prompted reactions by several bodies including the Government and Royal Colleges...
June 23, 2017: British Dental Journal
https://www.readbyqxmd.com/read/28642370/in-vitro-cytochrome-p450-46a1-cyp46a1-activation-by-neuroactive-compounds
#9
Natalia Mast, Kyle W Anderson, Kevin M Johnson, Thanh T N Phan, F Peter Guengerich, Irina A Pikuleva
Cytochrome P450 46A1 (CYP46A1, cholesterol 24-hydroxylase) is the enzyme responsible for the majority of cholesterol elimination from the brain. Previously, we found that the anti-HIV drug efavirenz (EFV) can pharmacologically activate CYP46A1 in mice. Herein, we investigated whether CYP46A1 could also be activated by endogenous compounds, including major neurotransmitters. In vitro experiments with purified recombinant CYP46A1 indicated that CYP46A1 is activated by L-glutamate (L-Glu), L-aspartate, γ-aminobutyric acid, and acetylcholine, with L-Glu eliciting the highest increase (3-fold) in CYP46A1-mediated cholesterol 24-hydroxylation...
June 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28640982/mechanisms-of-sphingosine-1-phosphate-mediated-vasoconstriction-of-rat-afferent-arterioles
#10
Zhengrong Guan, Fuchenchu Wang, Xiangqin Cui, Edward W Inscho
AIM: Sphingosine-1-phosphate (S1P) influences resistance vessel function and is implicated in renal pathological processes. Previous studies revealed that S1P evoked potent vasoconstriction of the preglomerular microvasculature, but the underlying mechanisms remain incompletely defined. We postulated that S1P-mediated preglomerular microvascular vasoconstriction involves activation of voltage-dependent L-type calcium channels (L-VDCC) and the rho/rho kinase pathway. METHODS: Afferent arteriolar reactivity was assessed in vitro using the blood-perfused rat juxtamedullary nephron preparation and diameter was measured during exposure to physiological and pharmacological agents...
June 22, 2017: Acta Physiologica
https://www.readbyqxmd.com/read/28640972/understanding-adaptogenic-activity-specificity-of-the-pharmacological-action-of-adaptogens-and-other-phytochemicals
#11
REVIEW
Alexander Panossian
Adaptogens are stress-response modifiers that increase an organism's nonspecific resistance to stress by increasing its ability to adapt and survive. The classical reductionist model is insufficiently complex to explain the mechanistic aspects of the physiological notion of "adaptability" and the adaptogenic activity of adaptogens. Here, I demonstrate that (1) the mechanisms of action of adaptogens are impossible to rationally describe using the reductionist concept of pharmacology, whereas the network pharmacology approach is the most suitable method; and (2) the principles of systems biology and pharmacological networks appear to be more suitable for conceptualizing adaptogen function and are applicable to any phytochemical...
June 22, 2017: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/28640632/gut-microbiota-nitric-oxide-and-microglia-as-pre-requisites-for-neurodegenerative-disorders
#12
Joyce Ka Yu Tse
Regulating fluctuating endogenous nitric oxide (NO) levels is necessary for proper physiological functions. Aberrant NO pathways are implicated in a number of neurological disorders, including Alzheimer's Disease (AD) and Parkinson's Disease. The mechanism of NO in oxidative and nitrosative stress with pathological consequences involves reactions with reactive oxygen species (e.g. superoxide) to form the highly reactive peroxynitrite, hydrogen peroxide, hypochloride ions and hydroxyl radical. NO levels are typically regulated by endogenous nitric oxide synthases (NOS), and inflammatory iNOS is implicated in the pathogenesis of neurodegenerative diseases, in which elevated NO mediates axonal degeneration and activates cyclooxygenases to provoke neuroinflammation...
June 22, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28640312/speciation-in-human-blood-of-metvan-a-vanadium-based-potential-anti-tumor-drug
#13
Daniele Sanna, Valeria Ugone, Giovanni Micera, Péter Buglyó, Linda Bíró, Eugenio Garribba
The first report on the anti-cancer activity of the compound Metvan, [V(IV)O(Me2phen)2(SO4)], where Me2phen is 4,7-dimethyl-1,10-phenanthroline, dates back to 2001. Although it was immediately identified as one of the most promising multitargeted anti-cancer V compounds, no development on the medical experimentation was carried out. One of the possible reasons is the lack of information on its speciation in aqueous solution and its thermodynamic stability, factors which influence the transport in the blood and the final form which reaches the target organs...
June 22, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28639248/p2x-receptor-activation
#14
Toshimitsu Kawate
Extracellular ATP-gated P2X receptors are trimeric non-selective cation channels important for many physiological events including immune response and neural transmission. These receptors belong to a unique class of ligand-gated ion channels composed of only six transmembrane helices and a relatively small extracellular domain that harbors three ATP-binding pockets. The crystal structures of P2X receptors, including the recent P2X3 structures representing three different stages of the gating cycle, have provided a compelling structural foundation for understanding how this class of ligand-gated ion channels function...
June 22, 2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28636998/physiologically-based-pharmacokinetic-modeling-for-predicting-irinotecan-exposure-in-human-body
#15
Yingfang Fan, Najia Mansoor, Tasneem Ahmad, Rafeeq Alam Khan, Martin Czejka, Syed Sharib, Dong-Hua Yang, Mansoor Ahmed
Colorectal cancer is the third leading cause of cancer-related deaths in the United States. Treatment of colorectal cancer remains a challenge to clinicians as well as drug developers. Irinotecan, a Camptothecin derivative, is successfully used for the treatment of this rapidly progressing malignancy and finds its place in the first line of therapeutic agents. Irinotecan is also effective in treating SCLC, malignant glioma and pancreatic adenocarcinoma. However, its adverse effects limit its clinical application...
June 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28633455/fetal-metabolic-stress-disrupts-immune-homeostasis-and-induces-pro-inflammatory-responses-in-hiv-1-and-cart-exposed-infants
#16
Johannes C Schoeman, Gontse P Moutloatse, Amy C Harms, Rob J Vreeken, Henriette J Scherpbier, Liesbeth Van Leeuwen, Taco W Kuijpers, Carools J Reinecke, Ruud Berger, Thomas Hankemeier, Madeleine J Bunders
Increased morbidity and fetal growth restriction are reported in uninfected children born to HIV-1-infected women treated with antiretroviral (ARV) therapy. Viruses and/or pharmacological interventions such as ARVs can induce metabolic stress skewing the cell's immune response and restricting (cell) growth. Novel metabolomic techniques provided the opportunity to investigate the impact of fetal HIV-1 and combination ARV therapy (cART)-exposure on the infants' immune-metabolome. Peroxidized lipids, generated by reactive oxygen species, were increased in cART/HIV-1-exposed infants, indicating altered mitochondrial functioning...
June 17, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28633424/three-dimensional-3d-heparg-spheroid-model-with-physiologically-relevant-xenobiotic-metabolism-competence-and-hepatocyte-functionality-for-liver-toxicity-screening
#17
Sreenivasa C Ramaiahgari, Suramya Waidyanatha, Darlene Dixon, Michael J DeVito, Richard S Paules, Stephen S Ferguson
Effective prediction of human responses to chemical and drug exposure is of critical importance in environmental toxicology research and drug development. While significant progress has been made to address this challenge using in vitro liver models, these approaches often fail due to inadequate tissue model functionality. Herein, we describe the development, optimization, and characterization of a novel three-dimensional (3D) spheroid model using differentiated HepaRG cells that achieve and maintain physiologically-relevant levels of xenobiotic metabolism (CYP1A2, CYP2B6, and CYP3A4/5)...
June 15, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28632451/prolyl-oligopeptidase-and-its-role-in-the-organism-attention-to-the-most-promising-and-clinically-relevant-inhibitors
#18
Katerina Babkova, Jan Korabecny, Ondrej Soukup, Eugenie Nepovimova, Daniel Jun, Kamil Kuca
Prolyl oligopeptidase (POP), also called prolyl endopeptidase, is a cytosolic enzyme investigated by several research groups. It has been proposed to play an important role in physiological processes such as modulation of the levels of several neuronal peptides and hormones containing a proline residue. Due to its proteolytic activity and physiological role in cell signaling pathways, inhibition of POP offers an emerging approach for the treatment of Alzheimer's and Parkinson's diseases as well as other diseases related to cognitive impairment...
June 20, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28630339/ucp1-deficiency-causes-brown-fat-respiratory-chain-depletion-and-sensitizes-mitochondria-to-calcium-overload-induced-dysfunction
#19
Lawrence Kazak, Edward T Chouchani, Irina G Stavrovskaya, Gina Z Lu, Mark P Jedrychowski, Daniel F Egan, Manju Kumari, Xingxing Kong, Brian K Erickson, John Szpyt, Evan D Rosen, Michael P Murphy, Bruce S Kristal, Steven P Gygi, Bruce M Spiegelman
Brown adipose tissue (BAT) mitochondria exhibit high oxidative capacity and abundant expression of both electron transport chain components and uncoupling protein 1 (UCP1). UCP1 dissipates the mitochondrial proton motive force (Δp) generated by the respiratory chain and increases thermogenesis. Here we find that in mice genetically lacking UCP1, cold-induced activation of metabolism triggers innate immune signaling and markers of cell death in BAT. Moreover, global proteomic analysis reveals that this cascade induced by UCP1 deletion is associated with a dramatic reduction in electron transport chain abundance...
June 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28629966/pharmacological-characterisation-and-functional-roles-for-egg-laying-of-a-%C3%AE-adrenergic-like-octopamine-receptor-in-the-brown-planthopper-nilaparvata-lugens
#20
Shun-Fan Wu, Xiao-Min Jv, Jian Li, Guang-Jian Xu, Xiao-Yi Cai, Cong-Fen Gao
Octopamine, the invertebrate counterpart of adrenaline and noradrenaline, controls and modulates many physiological and behavioral processes in protostomes. It mediates its effects by binding to specific receptors belonging to the superfamily of G-protein coupled receptors. We report the cloning of a cDNA from the brown planthopper (Nloa2b2) sharing high similarity with members of the OA2B2 receptor class. Activation of NlOA2B2 by octopamine increased the production of cAMP in a dose-dependent manner (EC50 = 114 nM)...
June 16, 2017: Insect Biochemistry and Molecular Biology
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