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Po-Chang Chiang, Karthik Nagapudi, Peter W Fan, Jia Liu
With the rising cost of drug research, "do more with less" has become a new emphasis in the pharmaceutical industry. Consequently, the early analysis of PK/PD, efficacy, and safety parameters for a new drug target is critical for ensuring informed decision-making as soon as possible during the drug discovery process. When ADME properties of compounds are suboptimalwhich is especially true during the early stages of drug discovery, obtaining the desired exposure can be challenging via the most common routes (oral, IV)...
June 14, 2018: Journal of Pharmaceutical Sciences
Lei Chen, Dengwei Zhang, Yilan Zhou, Cheng Liu, Shuangliang Che
A wide dynamic range, high precision, non-contact and large bandwidth angular displacement measurement (ADM) is greatly necessary for the applications such as industrial control and military equipment. This paper proposes a simple and effective ADM method based on Doppler Effect, heterodyne detection and diffuse reflection, which can fulfill these requirements simultaneously. Two beams of parallel light generated by a pair of laser Doppler vibrometers are incident upon the surface of rotational target, then data processing unit acquires the velocity of dual laser incident points on the moving target, and resolves the rotational angular displacement and translation displacement of target through the relationship between dual laser beams dynamically...
June 14, 2018: Scientific Reports
Mohamed El-Naggar, Wagdy M Eldehna, Hadia Almahli, Amr Elgez, Mohamed Fares, Mahmoud M Elaasser, Hatem A Abdel-Aziz
In connection with our research program on the development of new isatin-based anticancer candidates, herein we report the synthesis of two novel series of thiazolidinone-isatin conjugates ( 4a ⁻ n ) and thiazolo[3,2- a ]benzimidazolone-isatin conjugates ( 7a ⁻ d ), and in vitro evaluation of their antiproliferative activity towards two breast cancer cell lines; triple negative MDA-MB-231, and MCF-7. Compounds 4m and 7b emerged as the most active congeners against MDA-MB-231 cells (IC50 = 7.6 ± 0.5 and 13...
June 12, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Obdulia Rabal, Juan A Sánchez-Arias, Edurne San José-Eneriz, Xabier Agirre, Irene De Miguel, Leire Garate, Estibaliz Miranda, Elena Sáez, Sergio Roa, Jose Angel Martinez-Climent, Yingying Liu, Wei Wu, Musheng Xu, Felipe Prosper, Julen Oyarzabal
Epigenetic regulators that exhibit aberrant enzymatic activities or expression profiles are potential therapeutic targets for cancers. Specifically, enzymes responsible for methylation at histone-3 lysine-9 (like G9a) and aberrant DNA hypermethylation (DNMTs) have been implicated in a number of cancers. Recently, molecules bearing a 4-aminoquinoline scaffold were reported as dual inhibitors of these targets and showed a significant in-vivo efficacy in animal models of hematological malignancies. Here, we report a detailed exploration around three growing vectors born by this chemotype...
June 11, 2018: Journal of Medicinal Chemistry
Lijuan Song, Wenjun You, Peng Wang, Feng Li, Huakun Liu
BACKGROUND: Diabetes mellitus (DM) is a major risk factor for coronary artery disease (CAD), and the complications of CAD are the leading cause of deaths among people with DM. Herein, this study aims to identify the common genes and pathways between diabetes and myocardial infarction (MI) to provide more clues for the related mechanism studies. METHODS: Differentially expressed genes (DEGs) were identified using the cutoff (|log2(fold change)|>0.45 and P value<0...
June 11, 2018: Experimental and Clinical Endocrinology & Diabetes
Yiwen Wang, Bernard Moussian, Elke Schaeffeler, Matthias Schwab, Anne T Nies
Solute carrier membrane transporters (SLCs) control cell exposure to small-molecule drugs, thereby contributing to drug efficacy and failure and/or adverse effects. Moreover, SLCs are genetically linked to various diseases. Hence, in-depth knowledge of SLC function is fundamental for a better understanding of disease pathophysiology and the drug development process. Given that the model organism Drosophila melanogaster (fruit fly) expresses SLCs, such as for the excretion of endogenous and toxic compounds by the hindgut and Malpighian tubules, equivalent to human intestine and kidney, this system appears to be a promising preclinical model to use to study human SLCs...
June 8, 2018: Drug Discovery Today
Vincent J Santora, Theresa A Almos, Richard Barido, Jillian Basinger, Chris L Bellows, Brett Carder Bookser, J Guy Breitenbucher, Nicola J Broadbent, Clifford Cabebe, Chih-Kun Chai, Mi Chen, Stephine Chow, De Michael Chung, Lindsay Crickard, Anne M Danks, Graeme Freestone, Dany Gitnick, Varsha Gupta, Christine Hoffmaster, Andrew R Hudson, Alan P Kaplan, Michael R Kennedy, Dong Lee, James Limberis, Kiev Ly, Chi Ching Mak, Brittany Masatsugu, Andrew C Morse, Jim Na, David Neul, John Nikpur, Marco Peters, Robert E Petroski, Joel Renick, Kristen Sebring, Samantha Sevidal, Ali Tabatabaei, Jenny Wen, Yingzhuo Yan, Zachary W Yoder, Douglas Zook
We report here the identification and optimization of a novel series of potent GlyT1 inhibitors. A ligand design campaign that utilized known GlyT1 inhibitors as starting points led to the identification of a novel series of pyrrolo[3,4-c]pyrazoles amides (21-50) with good in vitro potency. Subsequent optimization of physicochemical and in vitro ADME properties produced several compounds with promising pharmacokinetic profiles. In vivo inhibition of GlyT1 was demonstrated for select compounds within this series by measuring the elevation of glycine in the cerebrospinal fluid (CSF) of rats after a single oral dosing of 10 mg/kg...
June 11, 2018: Journal of Medicinal Chemistry
Yu-Feng Li, Jiating Zhao, Yuxi Gao, Chunying Chen, Zhifang Chai
Metallomics, focusing on the global and systematic understanding of the metal uptake, trafficking, role, and excretion in biological systems, has attracted more and more attention. Metal-related nanomaterials, including metallic and metal-containing nanomaterials, have unique properties compared to their macroscale counterparts and therefore require special attention. The absorption, distribution, metabolism, excretion (ADME) behavior of metal-related nanomaterials in the biological systems is influenced by their physicochemical properties, the exposure route, and the microenvironment of the deposition site...
2018: Advances in Experimental Medicine and Biology
Bart I Roman, Rita C Guedes, Christian V Stevens, Alfonso T García-Sosa
In multitarget drug design, it is critical to identify active and inactive compounds against a variety of targets and antitargets. Multitarget strategies thus test the limits of available technology, be that in screening large databases of compounds vs. a large number of targets, or in using in silico methods for understanding and reliably predicting these pharmacological outcomes. In this paper, we have evaluated the potential of several in silico approaches to predict the target, antitarget and physicochemical profile of ( S )-blebbistatin, the best-known myosin II ATPase inhibitor, and a series of analogs thereof...
2018: Frontiers in Chemistry
Paul Lancett, Beth Williamson, Patrick Barton, Rob J Riley
Progression of new chemical entities is a multi-parametric process involving a balance of potency, ADME and safety properties. To accurately predict human pharmacokinetics and estimate human efficacious dose, the use of in vitro measures of clearance is often essential. Low metabolic clearance is often targeted to facilitate in vivo exposure and achieve appropriate half-life. Suspension primary human hepatocytes (PHH) have been successfully utilised in predictions of clearance. However, incubation times are limited, hindering the limit of quantification...
June 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Geok- Hoon Lim, Andrew Baildam
BACKGROUND: Risk-reducing mastectomy (RRM) with tissue expander then implant-based breast reconstruction conventionally involved immediate submuscular placement of tissue expanders during mastectomy, then after expansion, replacement of expanders for permanent implants in a second stage operation. Use of acellular dermal matrix (ADM) can achieve a single staged operation but ADMs are costly and may have potential complications. We aim to assess the feasibility of placement of implants as a first stage before RRM as a novel technique of reconstruction which avoids the need for serial outpatient expansion and ADM...
June 2, 2018: Plastic and Reconstructive Surgery
Kian Banks, Lee Squiteri, Athanasios Bramos, Maxwell B Johnson, Daniel J Gardner, Austin Pourmoussa, Eunson Jung, Gene Lee, David Perrault, Alexander Fedenko, Gene H Kim, Bo Han, Young-Kwon Hong, David A Kulber, Alex K Wong
BACKGROUND: Carpometacarpal (CMC) osteoarthritis affects 8-12% of the general population. Surgical management provides symptomatic relief for 78% of patients who fail conservative therapy, but little consensus exists regarding which surgical procedure provides superior patient outcomes. Recent human trials substituted exogenous acellular dermal matrices (ADMs) in the bone space, but there is no quantitative histological data on the outcome of ADMs in this environment. We aimed to quantify the revascularization and recellularization of ADMs in the joint space using a rabbit model...
June 5, 2018: Plastic and Reconstructive Surgery
Philip W Brownjohn, Rebekah L Blakemore, Jonathan A Fox, Jonathan Shemmell
Paired muscle stimulation is used clinically to facilitate the performance of motor tasks for individuals with motor dysfunction. However, the optimal temporal relationship between stimuli for enhancing movement remains unknown. We hypothesized that synchronous, muscle stimulation would increase the extent to which stimulated muscles are concurrently prepared for movement. We validated a measure of muscle-specific changes in corticomotor excitability prior to movement. We used this measure to examine the preparation of the first dorsal interosseous (FDI), abductor digiti minimi (ADM), abductor pollicis brevis (APB) muscles prior to voluntary muscle contractions before and after paired muscle stimulation at four interstimulus intervals (0, 5, 10, and 75 ms)...
June 7, 2018: Journal of Motor Behavior
Lisa Gfrerer, Eric C Liao
Direct-to-implant reconstruction after mastectomy is routinely performed with excellent oncologic and aesthetic outcomes. Several different techniques for placement of the prosthesis including total and partial subpectoral coverage have been described. Prepectoral implant placement is increasingly reported as a safe method, while patient selection and techniques are areas of further work. Most prepectoral prosthesis placement techniques describe complete acellular dermal matrix (ADM) coverage of the implant, often requiring multiple or larger ADM sheets than a comparable subpectoral implant procedure, resulting in high cost per reconstructed breast...
April 2018: Plastic and Reconstructive Surgery. Global Open
Keyianoosh Z Paydar, Garrett A Wirth, Donald S Mowlds
Fenestrated acellular dermal matrix (ADM) has improved patient outcomes in both direct-to-implant and 2-stage tissue expander/implant breast reconstruction. This technical alteration utilizes optimal fenestration overlap to enhance the breast reconstruction experience. We present a novel, surgeon-designed shaped fenestrated ADM, placed in the recently repopularized prepectoral pocket for anterior coverage of implants in direct-to-implant and 2-stage breast reconstruction. A retrospective review of 10 patients (18 breasts) who underwent direct-to-implant or 2-stage breast reconstruction utilizing fenestrated shaped ADM in the prepectoral plane at a major academic institution in 2016 was conducted...
April 2018: Plastic and Reconstructive Surgery. Global Open
Kankan Chen, Yue Chen, Zhi Chen, Yuye Shi, Zhengmei He, Banghe Ding, Chunling Wang, Liang Yu
The relapse and resistance to cytarabine (Ara-C) therapy is still a dominating obstacle to the successful clinical treatment of acute myeloid leukemia (AML). Recent studies have shown that dysregulation of miRNAs might modulate the resistance of cancer cells to anticancer drugs; yet, the mechanism is not fully understood. In this study, we showed a significant downregulation of miR-134 in human multidrug-resistant leukemia cells and relapsed/refractory AML patient samples. Overexpression of miR-134 sensitized K562/A02 and HL-60/ADM cells to Ara-C, inhibited cell colony formation, and enhanced the ability of Ara-C to induce apoptosis...
2018: OncoTargets and Therapy
Brooke C Matson, Kelsey E Quinn, Bruce A Lessey, Steven L Young, Kathleen M Caron
OBJECTIVE: To test adrenomedullin (Adm, ADM) as a downstream target of signal transducer and activator of transcription 3 (STAT3) in endometrial cells and to test midregional proadrenomedullin (MR-proADM) as a biomarker of endometriosis. DESIGN: Cross-sectional analysis of Adm expression in eutopic endometrium and of MR-proADM in plasma from women with and without endometriosis; and prospective study of MR-proADM levels in women with endometriosis undergoing surgical resection of ectopic lesions...
June 2, 2018: Fertility and Sterility
Javier I Ottaviani, Reedmond Y Fong, Gina Borges, Hagen Schroeter, Alan Crozier
Plant-derived, dietary (poly)phenols have potential effects on disease-risk reduction and primary disease prevention. The characterization of (poly)phenol absorption, distribution, metabolism and excretion (ADME) is recognized as crucial step to further advance nutritional and biomedical research of these compounds; and given that (poly)phenols are extensively metabolized after ingestion, accurate assessments of their in vivo metabolites is required. It has become common practice to use unmetabolized parent compounds as reference standards when quantifying (poly)phenol metabolites by LC-MS, although little is known about the accuracy of this approach...
June 2, 2018: Free Radical Biology & Medicine
Cristina Tintori, Giulia Iovenitti, Elisa Rita Ceresola, Roberto Ferrarese, Claudio Zamperini, Annalaura Brai, Giulio Poli, Elena Dreassi, Valeria Cagno, David Lembo, Filippo Canducci, Maurizio Botta
Although highly active antiretroviral therapies (HAART) remarkably increased life expectancy of HIV positive people, the rate of novel HIV-1 infections worldwide still represent a major concern. In this context, pre-exposure prophylaxis (PrEP) approaches such as vaginal microbicide gels topically releasing antiretroviral drugs, showed to have a striking impact in limiting HIV-1 spread. Nevertheless, the co-presence of other genital infections, particularly those due to HSV-1 or 2, constitute a serious drawback that strongly limits the efficacy of PrEP approaches...
2018: PloS One
Tianqiao Yong, Shaodan Chen, Yizhen Xie, Ou Shuai, Xiangmin Li, Diling Chen, Jiyan Su, Chunwei Jiao, Yalei Liang
Agrocybe aegerita has long been utilized for promoting diuresis in traditional Chinese medicine (TCM) with a close correlation to hypouricemia. Ethanol (AAE) and water (AAW) extracts of the compound led to a remarkable decrease in serum uric acid levels (SUA) in hyperuricemia mice, approaching that of the normal control. Both AAE and AAW exhibited suppression effects on hepatic xanthine oxidase (XOD) activities and elevation effects on renal OAT1 (organic anion transporter 1). However, only little negative impact was observed on the inner organ functions...
2018: Frontiers in Pharmacology
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