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https://www.readbyqxmd.com/read/29352745/negative-supercoiling-of-dna-by-gyrase-is-inhibited-in-salmonella-enterica-serovar-typhimurium-during-adaptation-to-acid-stress
#1
Aoife M Colgan, Heather J Quinn, Stefani C Kary, Lesley A Mitchenall, Anthony Maxwell, Andrew Ds Cameron, Charles J Dorman
DNA in intracellular Salmonella enterica serovar Typhimurium relaxes during growth in the acidified (pH 4 to 5) macrophage vacuole and DNA relaxation correlates with upregulation of Salmonella genes involved in adaptation to the macrophage environment. Bacterial ATP levels did not increase during adaptation to acid pH unless the bacterium was deficient in MgtC, a cytoplasmic-membrane-located inhibitor of proton-driven F1 F0 ATP synthase activity. Inhibiting ATP binding by DNA gyrase and topo IV with novobiocin enhanced the effect of low pH on DNA relaxation...
January 20, 2018: Molecular Microbiology
https://www.readbyqxmd.com/read/29352704/treatment-of-adult-chronic-indeterminate-chagas-disease-with-benznidazole-and-three-e1224-dosing-regimens-a-proof-of-concept-randomised-placebo-controlled-trial
#2
Faustino Torrico, Joaquim Gascon, Lourdes Ortiz, Cristina Alonso-Vega, María-Jesús Pinazo, Alejandro Schijman, Igor C Almeida, Fabiana Alves, Nathalie Strub-Wourgaft, Isabela Ribeiro
BACKGROUND: Chagas disease is a major neglected vector-borne disease. In this study, we investigated the safety and efficacy of three oral E1224 (a water-soluble ravuconazole prodrug) regimens and benznidazole versus placebo in adult chronic indeterminate Chagas disease. METHOD: In this proof-of-concept, double-blind, randomised phase 2 clinical trial, we recruited adults (18-50 years) with confirmed diagnosis of Trypanosoma cruzi infection from two outpatient units in Bolivia...
January 15, 2018: Lancet Infectious Diseases
https://www.readbyqxmd.com/read/29352503/in-vivo-effects-of-%C3%AE-opioid-receptor-agonist-%C3%AE-opioid-receptor-antagonist-peptidomimetics-following-acute-and-repeated-administration
#3
Jessica P Anand, Kelsey E Kochan, Anthony F Nastase, Deanna Montgomery, Nicholas W Griggs, John R Traynor, Henry I Mosberg, Emily M Jutkiewicz
BACKGROUND AND PURPOSE: Mu opioid receptor (μ-receptor) agonists are used for pain management, but produce adverse effects including tolerance, dependence, and euphoria. The co-administration of a μ-receptor agonist with a delta opioid receptor (δ-receptor) antagonist has been shown to produce antinociception with reduced development of some side effects. We characterized the effects of three μ-receptor agonist/δ-receptor antagonist peptidomimetics in vivo after acute and repeated administration to determine if this profile provides a viable alternative to traditional opioid analgesics...
January 19, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29352450/carrier-mediated-uptake-of-clonidine-in-cultured-human-lung-cells
#4
Marc Le Vée, Elodie Jouan, Olivier Fardel
The lung is a preferential organ site for accumulation of lipophilic basic amine drugs, so-called pneumophilic drugs and belonging to various pharmacological classes, which can result in lung toxicity. In order to investigate the mechanism involved in such pulmonary accumulation of drugs, uptake of clonidine, used here as a prototypical basic amine drug, was characterized in cultured human lung cells. Clonidine accumulation in lung alveolar A549 cells was found to be temperature- and pH-dependent; it was saturable, with a Michaelis-Menten affinity constant (Km) value of 569...
January 19, 2018: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/29352425/safety-and-efficacy-of-nanocurcumin-as-add-on-therapy-to-riluzole-in-patients-with-amyotrophic-lateral-sclerosis-a-pilot-randomized-clinical-trial
#5
Mona Ahmadi, Elmira Agah, Shahriar Nafissi, Mahmoud Reza Jaafari, Mohammad Hossein Harirchian, Payam Sarraf, Sara Faghihi-Kashani, Seyed Jalal Hosseini, Abdolreza Ghoreishi, Vajiheh Aghamollaii, Mostafa Hosseini, Abbas Tafakhori
The objective of present study was to assess the safety and efficacy of nanocurcumin as an anti-inflammatory and antioxidant agent in adults with amyotrophic lateral sclerosis (ALS). We conducted a 12-month, double-blind, randomized, placebo-controlled trial at a neurological referral center in Iran. Eligible patients with a definite or probable ALS diagnosis were randomly assigned to receive either nanocurcumin (80 mg daily) or placebo in a 1:1 ratio. A computerized random number generator was used to prepare the randomization list...
January 19, 2018: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
https://www.readbyqxmd.com/read/29352409/recent-perspectives-on-the-molecular-basis-of-biofilm-formation-by-pseudomonas-aeruginosa-and-approaches-for-treatment-and-biofilm-dispersal
#6
REVIEW
Sinosh Skariyachan, Vaishnavi Sneha Sridhar, Swathi Packirisamy, Supreetha Toplar Kumargowda, Sneha Basavaraj Challapilli
Pseudomonas aeruginosa, a Gram-negative, rod-shaped bacterium causes widespread diseases in humans. This bacterium is frequently related to nosocomial infections such as pneumonia, urinary tract infections (UTIs) and bacteriaemia especially in immunocompromised patients. The current review focuses on the recent perspectives on biofilms formation by these bacteria. Biofilms are communities of microorganisms in which cells stick to each other and often adhere to a surface. These adherent cells are usually embedded within a self-produced matrix of extracellular polymeric substance (EPS)...
January 19, 2018: Folia Microbiologica
https://www.readbyqxmd.com/read/29352318/temozolomide-induced-increase-of-tumorigenicity-can-be-diminished-by-targeting-of-mitochondria-in-in-vitro-models-of-patient-individual-glioblastoma
#7
Doreen William, Madlin Walther, Björn Schneider, Michael Linnebacher, Carl Friedrich Classen
Glioblastoma multiforme (GBM) is a highly heterogeneous and aggressive brain tumor with a dismal prognosis. Development of resistance towards cytostatic drugs like the GBM standard drug temozolomide is a severe problem in GBM treatment. One potential source of GBM relapse could be so called cancer stem like cells (CSCs). These represent an undifferentiated subpopulation of cells with high potential for tumor initiation. Furthermore, it has been shown that differentiated GBM cells can regain CSC properties when exposed to continuous temozolomide treatment in vitro...
2018: PloS One
https://www.readbyqxmd.com/read/29352276/arrhythmogenic-drugs-can-amplify-spatial-heterogeneities-in-the-electrical-restitution-in-perfused-guinea-pig-heart-an-evidence-from-assessments-of-monophasic-action-potential-durations-and-jt-intervals
#8
Oleg E Osadchii
Non-uniform shortening of the action potential duration (APD90) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD90 restitution can be amplified by drugs with clinically proved proarrhythmic potential (dofetilide, quinidine, procainamide, and flecainide) and, if so, whether these effects can translate to the appropriate changes of the ECG metrics of ventricular repolarization, such as JT intervals...
2018: PloS One
https://www.readbyqxmd.com/read/29352246/u-box-ubiquitin-ligase-ppil2-suppresses-breast-cancer-invasion-and-metastasis-by-altering-cell-morphology-and-promoting-snai1-ubiquitination-and-degradation
#9
Zhaojun Jia, Miao Wang, Shujing Li, Xiahui Li, Xiao-Yan Bai, Zhaowei Xu, Yangyang Yang, Bowen Li, Yanan Li, Huijian Wu
Metastasis is the leading cause of breast cancer fatalities. To develop new therapeutic strategies, the mechanisms underlying breast cancer invasion and metastasis need to be further investigated. Peptidylprolyl isomerase (cyclophilin)-like 2 (PPIL2) is a U-box-type E3 ubiquitin ligase belonging to the cyclophilin family. Proteins within this family are the major cytosolic binding proteins of the immunosuppressant drug cyclosporine A (CsA). Although PPIL2 has been reported to potentially be involved in cell migration, its role in breast cancer is still unclear...
January 19, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29352174/mechanical-phenotyping-of-k562-cells-by-the-micropipette-aspiration-technique-allows-identifying-mechanical-changes-induced-by-drugs
#10
Alessandro Di Cerbo, Valentina Rubino, Francesca Morelli, Giuseppina Ruggiero, Rosaria Landi, Gianandrea Guidetti, Sergio Canello, Giuseppe Terrazzano, Andrea Alessandrini
Mechanical properties of living cells can be used as reliable markers of their state, such as the presence of a pathological state or their differentiation phase. The mechanical behavior of cells depends on the organization of their cytoskeletal network and the main contribution typically comes from the actomyosin contractile system, in both suspended and adherent cells. In the present study, we investigated the effect of a pharmaceutical formulation (OTC - Ossitetraciclina liquida 20%) used as antibiotic, on the mechanical properties of K562 cells by using the Micropipette Aspiration Technique (MAT)...
January 19, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29352161/the-action-of-a-negative-allosteric-modulator-at-the-dopamine-d2-receptor-is-dependent-upon-sodium-ions
#11
Christopher J Draper-Joyce, Ravi Kumar Verma, Mayako Michino, Jeremy Shonberg, Anitha Kopinathan, Carmen Klein Herenbrink, Peter J Scammells, Ben Capuano, Ara M Abramyan, David M Thal, Jonathan A Javitch, Arthur Christopoulos, Lei Shi, J Robert Lane
Sodium ions (Na+) allosterically modulate the binding of orthosteric agonists and antagonists to many class A G protein-coupled receptors, including the dopamine D2 receptor (D2R). Experimental and computational evidences have revealed that this effect is mediated by the binding of Na+ to a conserved site located beneath the orthosteric binding site (OBS). SB269652 acts as a negative allosteric modulator (NAM) of the D2R that adopts an extended bitopic pose, in which the tetrahydroisoquinoline moiety interacts with the OBS and the indole-2-carboxamide moiety occupies a secondary binding pocket (SBP)...
January 19, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29352089/cryptic-production-of-trans-3-hydroxyproline-in-echinocandin-b-biosynthesis
#12
Johanna Mattay, Stefanie Houwaart, Wolfgang Hüttel
Echinocandins are antifungal nonribosomal hexapeptides produced by fungi. Two of the amino acids are hydroxy-l-prolines: trans-4-hydroxy-l-proline and, in most echinocandin structures, (trans-2,3)-3-hydroxy-(trans-2,4)-4-methyl-l-proline. In the case of echinocandin biosynthesis by Glarea lozoyensis, both amino acids are found in pneumocandin A0, while in pneumocandin B0 the latter residue is substituted by trans-3- hydroxy-l-proline (3-Hyp). We have recently reported that all three amino acids are generated by the 2-oxoglutarate-dependent proline hydroxylase GloF...
January 19, 2018: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/29352032/the-surprising-subtleties-of-changing-fear-memory-a-challenge-for-translational-science
#13
REVIEW
Merel Kindt
Current pharmacological and psychological treatments for disorders of emotional memory only dampen the affective response while leaving the original fear memory intact. Under adverse circumstances, these original memories regain prominence, causing relapses in many patients. The (re)discovery in neuroscience that after reactivation consolidated fear memories may return to a transient labile state, requiring a process of restabilization in order to persist, offers a window of opportunity for modifying fear memories with amnestic agents...
March 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29351623/development-of-sugar-chain-binding-single-chain-variable-fragment-antibody-to-adult-t-cell-leukemia-cells-using-glyco-nanotechnology-and-phage-display-method
#14
Kaname Muchima, Taro Todaka, Hiroyuki Shinchi, Ayaka Sato, Arisa Tazoe, Rikiya Aramaki, Yuhei Kakitsubata, Risa Yokoyama, Naomichi Arima, Masanori Baba, Masahiro Wakao, Yuji Ito, Yasuo Suda
Adult T-cell leukemia (ATL) is an intractable blood cancer caused by the infection of human T-cell leukemia virus type-1, and effective medical treatment is required. It is known that the structure and expression levels of cell surface sugar chains vary depending on cell states such as inflammation and cancer. Thus, it is expected that the antibody specific for ATL cell surface sugar chain would be an effective diagnostic tool and a strong candidate for the development of an anti-ATL drug. Here, we developed a stable sugar chain binding single chain variable fragment antibody (scFv) that can bind to ATL cells using a fiber type Sugar Chip and phage display method...
January 17, 2018: Journal of Biochemistry
https://www.readbyqxmd.com/read/29351556/testosterone-induced-benign-prostatic-hyperplasia-rat-and-dog-as-facile-models-to-assess-drugs-targeting-lower-urinary-tract-symptoms
#15
Jing Li, Yanxin Tian, Shimeng Guo, Haifeng Gu, Qianting Yuan, Xin Xie
Benign prostatic hyperplasia (BPH) is an age-related disease, affecting a majority of elderly men worldwide. Medical management of BPH is an alternative to surgical treatment of this disease. Currently, α1-adrenergic receptor (α1-AR) antagonists are among the first line drugs to treat BPH by reducing the tension of urinary track and thus the obstructive symptoms in voiding. In drug development, old male dogs with spontaneous BPH are considered the golden standard of the animal models. However, old dogs (>6 years) are expensive and not all old dogs develop BPH...
2018: PloS One
https://www.readbyqxmd.com/read/29351498/high-power-diode-laser-on-management-of-drug-induced-gingival-overgrowth-report-of-two-cases-and-long-term-follow-up
#16
Luana Campos, Marina Gallottini, Débora Pallos, Alyne Simões, Fabiana Martins
BACKGROUND: Drug-induced gingival overgrowth (DIGO) is attributed mainly to the prolonged use of calcium channel blocking agents, anticonvulsants, and anti-calcineurin inhibitors . The management of DIGO depends on the severity of the disease and includes surgical intervention and plaque control. Compared to conventional surgical treatment, the recent literature data have shown that gingivectomy using a high-power laser (HPL) is a short and easy procedure, which results in minimal postoperative discomfort and greater patient accep- tance...
January 19, 2018: Journal of Cosmetic and Laser Therapy: Official Publication of the European Society for Laser Dermatology
https://www.readbyqxmd.com/read/29351409/pharmacological-activation-of-ppar%C3%AE-inhibits-hypoxia-induced-proliferation-through-a-caveolin-1-targeted-and-dependent-mechanism-in-pasmcs
#17
Kai Yang, Mingming Zhao, Junyi Huang, Chenting Zhang, Qiu Yu Zheng, Yuqin Chen, Haiyang Jiang, Wenju Lu, Jian Wang
Previously, we and others have demonstrated that activation of peroxisome proliferator- activated receptor γ (PPARγ) by specific pharmacological agonists inhibits the pathogenesis of chronic hypoxia-induced pulmonary hypertension (CHPH) by suppressing the proliferation and migration in distal pulmonary arterial smooth muscle cells (PASMCs). Moreover, these beneficial effects of PPARγ are mediated by targeting the intracellular calcium homeostasis and store-operated calcium channel (SOCC) proteins, including the main caveolae component caveolin-1...
January 3, 2018: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29351372/a-preclinical-population-pharmacokinetic-model-for-anti-cd20-cd3-t-cell-dependent-bispecific-antibodies
#18
Gregory Z Ferl, Arthur Reyes, Liping L Sun, Melissa Cheu, Amy Oldendorp, Saroja Ramanujan, Eric G Stefanich
CD20 is a cell-surface receptor expressed by healthy and neoplastic B cells and is a well-established target for biologics used to treat B-cell malignancies. Pharmacokinetic (PK) and pharmacodynamic (PD) data for the anti-CD20/CD3 T-cell-dependent bispecific antibody BTCT4465A were collected in transgenic mouse and nonhuman primate (NHP) studies. Pronounced nonlinearity in drug elimination was observed in the murine studies, and time-varying, nonlinear PK was observed in NHPs, where three empirical drug elimination terms were identified using a mixed-effects modeling approach: i) a constant nonsaturable linear clearance term (7 mL/day/kg); ii) a rapidly decaying time-varying, linear clearance term (t½  = 1...
January 19, 2018: Clinical and Translational Science
https://www.readbyqxmd.com/read/29351081/characterization-of-phosphate-transporter-s-and-understanding-their-role-in-leishmania-donovani-parasite
#19
K J Sindhu, Amit Kumar Kureel, Sheetal Saini, Smita Kumari, Pankaj Verma, Ambak Kumar Rai
Inorganic phosphate (Pi) is shown to be involved in excretion of methylglyoxal (MG) in the promastigote form of Leishmania donovani parasite. Absence of Pi leads to its accumulation inside the parasite. Accumulation of MG is toxic to the parasite and utilizes glyoxylase as well as excretory pathways for its detoxification. In addition, Pi is also reported to regulate activities of ectoenzymes and energy metabolism (glucose to pyruvate) etc. Thus, it is known to cumulatively affect the growth of Leishmania parasite...
March 26, 2018: Acta Parasitologica
https://www.readbyqxmd.com/read/29350495/the-current-landscape-of-3d-in-vitro-tumor-models-what-cancer-hallmarks-are-accessible-for-drug-discovery
#20
REVIEW
Darren Rodenhizer, Teresa Dean, Elisa D'Arcangelo, Alison P McGuigan
Cancer prognosis remains a lottery dependent on cancer type, disease stage at diagnosis, and personal genetics. While investment in research is at an all-time high, new drugs are more likely to fail in clinical trials today than in the 1970s. In this review, a summary of current survival statistics in North America is provided, followed by an overview of the modern drug discovery process, classes of models used throughout different stages, and challenges associated with drug development efficiency are highlighted...
January 19, 2018: Advanced Healthcare Materials
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