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Experimental therapeutics

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https://www.readbyqxmd.com/read/28734777/inhibitor-mechanisms-in-the-s1-binding-site-of-the-dopamine-transporter-defined-by-multi-site-molecular-tethering-of-photoactive-cocaine-analogs
#1
Danielle Krout, Akula Bala Pramod, Rejwi Acharya Dahal, Michael J Tomlinson, Babita Sharma, James D Foster, Mu-Fa Zou, Comfort Boatang, Amy Hauck Newman, John R Lever, Roxanne A Vaughan, L Keith Henry
Dopamine transporter (DAT) blockers like cocaine and many other abused and therapeutic drugs bind and stabilize an inactive form of the transporter inhibiting reuptake of extracellular dopamine (DA). The resulting increases in DA lead to the ability of these drugs to induce psychomotor alterations and addiction, but paradoxical findings in animal models indicate that not all DAT antagonists induce cocaine-like behavioral outcomes. How this occurs is not known, but one possibility is that uptake inhibitors may bind at multiple locations or in different poses to stabilize distinct conformational transporter states associated with differential neurochemical endpoints...
July 19, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28734678/improvement-of-adipose-tissue-derived-cells-by-low-energy-extracorporeal-shock-wave-therapy
#2
Eleni Priglinger, Christina M A P Schuh, Carolin Steffenhagen, Christoph Wurzer, Julia Maier, Sylvia Nuernberger, Wolfgang Holnthoner, Christiane Fuchs, Susanne Suessner, Dominik Rünzler, Heinz Redl, Susanne Wolbank
BACKGROUND: Cell-based therapies with autologous adipose tissue-derived cells have shown great potential in several clinical studies in the last decades. The majority of these studies have been using the stromal vascular fraction (SVF), a heterogeneous mixture of fibroblasts, lymphocytes, monocytes/macrophages, endothelial cells, endothelial progenitor cells, pericytes and adipose-derived stromal/stem cells (ASC) among others. Although possible clinical applications of autologous adipose tissue-derived cells are manifold, they are limited by insufficient uniformity in cell identity and regenerative potency...
July 19, 2017: Cytotherapy
https://www.readbyqxmd.com/read/28733584/therapeutic-effects-of-sphingosine-kinase-inhibitor-n-n-dimethylsphingosine-dms-in-experimental-chronic-chagas-disease-cardiomyopathy
#3
Juliana Fraga Vasconcelos, Cássio Santana Meira, Daniela Nascimento Silva, Carolina Kymie Vasques Nonaka, Pâmela Santana Daltro, Simone Garcia Macambira, Pablo Daniel Domizi, Valéria Matos Borges, Ricardo Ribeiro-Dos-Santos, Bruno Solano de Freitas Souza, Milena Botelho Pereira Soares
Chagas disease cardiomyopathy is a parasite-driven inflammatory disease to which there are no effective treatments. Here we evaluated the therapeutic potential of N,N-dimethylsphingosine(DMS), which blocks the production of sphingosine-1-phosphate(S1P), a mediator of cellular events during inflammatory responses, in a model of chronic Chagas disease cardiomyopathy. DMS-treated, Trypanosoma cruzi-infected mice had a marked reduction of cardiac inflammation, fibrosis and galectin-3 expression when compared to controls...
July 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28733245/engineered-nanoparticles-for-the-detection-treatment-and-prevention-of-atherosclerosis-how-close-are-we
#4
REVIEW
Luong T H Nguyen, Aristo Muktabar, Jinkai Tang, Vinayak P Dravid, C Shad Thaxton, Subbu Venkatraman, Kee Woei Ng
Atherosclerosis is one of the leading causes of morbidity and mortality worldwide. Nanotechnology has provided the possibility of designing nanoparticles that can translocate through tissues and home in to atherosclerotic plaques to achieve desired diagnostic, therapeutic, theranostic or 'theralivery' outcomes. Although nanomedicine approaches have demonstrated exciting possibilities, clinical reality is still distant and challenges are aplenty, such as specificity of targeting and nanotoxicity. Nevertheless, developments in formulations, delivery strategies and experimental models over the coming years will generate new knowledge to define the true potential of this field...
July 18, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28733187/a-confidence-building-exercise-in-data-and-identifiability-modeling-cancer-chemotherapy-as-a-case-study
#5
Marisa C Eisenberg, Harsh V Jain
Mathematical modeling has a long history in the field of cancer therapeutics, and there is increasing recognition that it can help uncover the mechanisms that underlie tumor response to treatment. However, making quantitative predictions with such models often requires parameter estimation from data, raising questions of parameter identifiability and estimability. Even in the case of structural (theoretical) identifiability, imperfect data and the resulting practical unidentifiability of model parameters can make it difficult to infer the desired information, and in some cases, to yield biologically correct inferences and predictions...
July 18, 2017: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/28733045/induction-of-live-cell-phagocytosis-by-a-specific-combination-of-inflammatory-stimuli
#6
Takamasa Ishidome, Takeshi Yoshida, Rikinari Hanayama
Conditions of severe hyper-inflammation can lead to uncontrolled activation of macrophages, and the ensuing phagocytosis of live cells. However, relationships between inflammatory stimuli and uncontrolled phagocytosis of live cells by macrophages are poorly understood. To identify mediators of this process, we established phagocytosis assays of live cells by stimulating macrophages with CpG DNA, interferon-γ, and anti-interleukin-10 receptor antibody. In this model, various cell surface receptors were upregulated on macrophages, and phagocytosis of live cells was induced in a Rac1-dependent manner...
July 13, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28732082/osteosarcoma-enters-a-post-genomic-era-with-in-silico-opportunities-generation-of-the-high-dimensional-database-for-facilitating-sarcoma-biology-research-a-report-from-the-children-s-oncology-group-and-the-quadw-foundation
#7
Jason Glover, Tsz-Kwong Man, Donald A Barkauskas, David Hall, Tanya Tello, Mary Beth Sullivan, Richard Gorlick, Katherine Janeway, Holcombe Grier, Ching Lau, Jeffrey A Toretsky, Scott C Borinstein, Chand Khanna, Timothy M Fan
The prospective banking of osteosarcoma tissue samples to promote research endeavors has been realized through the establishment of a nationally centralized biospecimen repository, the Children's Oncology Group (COG) biospecimen bank located at the Biopathology Center (BPC)/Nationwide Children's Hospital in Columbus, Ohio. Although the physical inventory of osteosarcoma biospecimens is substantive (>15,000 sample specimens), the nature of these resources remains exhaustible. Despite judicious allocation of these high-value biospecimens for conducting sarcoma-related research, a deeper understanding of osteosarcoma biology, in particular metastases, remains unrealized...
2017: PloS One
https://www.readbyqxmd.com/read/28732052/protein-asparagine-deamidation-prediction-based-on-structures-with-machine-learning-methods
#8
Lei Jia, Yaxiong Sun
Chemical stability is a major concern in the development of protein therapeutics due to its impact on both efficacy and safety. Protein "hotspots" are amino acid residues that are subject to various chemical modifications, including deamidation, isomerization, glycosylation, oxidation etc. A more accurate prediction method for potential hotspot residues would allow their elimination or reduction as early as possible in the drug discovery process. In this work, we focus on prediction models for asparagine (Asn) deamidation...
2017: PloS One
https://www.readbyqxmd.com/read/28732007/a-data-driven-modeling-approach-to-identify-disease-specific-multi-organ-networks-driving-physiological-dysregulation
#9
Warren D Anderson, Danielle DeCicco, James S Schwaber, Rajanikanth Vadigepalli
Multiple physiological systems interact throughout the development of a complex disease. Knowledge of the dynamics and connectivity of interactions across physiological systems could facilitate the prevention or mitigation of organ damage underlying complex diseases, many of which are currently refractory to available therapeutics (e.g., hypertension). We studied the regulatory interactions operating within and across organs throughout disease development by integrating in vivo analysis of gene expression dynamics with a reverse engineering approach to infer data-driven dynamic network models of multi-organ gene regulatory influences...
July 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28731692/quinolinyl-nitrone-rp19-induces-neuroprotection-after-transient-brain-ischemia
#10
Maria Irene Ayuso, Emma Martinez-Alonso, Mourad Chioua, Alejandro Escobar-Peso, Rafael Gonzalo-Gobernado, Joan Montaner, José Marco-Contelles, Alberto Alcazar
There is a need to develop additional effective therapies for ischemic stroke. Nitrones, which were first developed as reactive oxygen species (ROS)-trapping compounds, have been proposed as neuroprotective agents for ischemic stroke, a ROS-related disorder. The previous reported ROS-trapping compound, quinolyl nitrone RP19, is here being assayed to induce neuroprotection to ischemia-reperfusion injury in three experimental ischemia models: (i), oxygen-glucose deprivation (OGD) on primary neuronal cultures; (ii), transient global cerebral ischemia in four-vessel occlusion model; and (iii), transient focal cerebral ischemia in middle cerebral artery occlusion (tMCAO) model...
July 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28730444/oxime-ether-lipids-as-transfection-agents-assembly-and-complexation-with-sirna
#11
Anu Puri, Serena Zampino, Mathias Viard, Bruce A Shapiro
RNAi-based therapeutic approaches to combat cancer and other diseases are currently an area of great interest. However, practical applications of this approach rely on optimal tools to carry and deliver siRNA to the desired site. Oxime ether lipids (OELs) are a class of molecules among other various carriers being examined for siRNA delivery. OELs, relatively new candidates, belong to a class of non-glycerol based lipids and have begun to claim their place as an siRNA delivery carrier in the field of RNAi therapy...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28730433/computational-prediction-of-the-immunomodulatory-potential-of-rna-sequences
#12
Gandharva Nagpal, Kumardeep Chaudhary, Sandeep Kumar Dhanda, Gajendra Pal Singh Raghava
Advances in the knowledge of various roles played by non-coding RNAs have stimulated the application of RNA molecules as therapeutics. Among these molecules, miRNA, siRNA, and CRISPR-Cas9 associated gRNA have been identified as the most potent RNA molecule classes with diverse therapeutic applications. One of the major limitations of RNA-based therapeutics is immunotoxicity of RNA molecules as it may induce the innate immune system. In contrast, RNA molecules that are potent immunostimulators are strong candidates for use in vaccine adjuvants...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28730427/-basic-research-in-ophthalmology-in-germany-and-its-international-context
#13
REVIEW
U Schlötzer-Schrehardt, C Cursiefen
BACKGROUND: Experimental basic research provides the foundations for the elucidation of pathophysiological mechanisms of diseases and the development of novel diagnostic and therapeutic strategies for ophthalmological diseases. The objective of this contribution is to provide an overview of the international interconnection of basic research in ophthalmology in Germany. METHODS: The international context of ophthalmological research conducted in Germany is presented by means of personal experiences and data published by the German Ophthalmological Society (DOG), the German Research Foundation (DFG) and the European Union (EU)...
July 20, 2017: Der Ophthalmologe: Zeitschrift der Deutschen Ophthalmologischen Gesellschaft
https://www.readbyqxmd.com/read/28730419/the-intriguing-connections-of-leptin-to-hyperparathyroidism
#14
REVIEW
Stergios A Polyzos, Leonidas Duntas, Jens Bollerslev
PURPOSE: Leptin has been implicated in bone metabolism, but the association with parathyroid gland function has not been fully clarified. This review aimed to summarize evidence of the association between leptin and hyperparathyroidism, both primary and secondary, elucidating the potential pathophysiologic and therapeutic consequences between leptin and parathyroid hormone, hopefully prompting the design of new studies. RESULTS: Experimental studies indicate a positive loop between leptin and parathyroid hormone in primary hyperparathyroidism...
July 20, 2017: Endocrine
https://www.readbyqxmd.com/read/28730284/a-novel-interplay-between-hotair-and-dna-methylation-in-osteosarcoma-cells-indicates-a-new-therapeutic-strategy
#15
Xingang Li, Hongming Lu, Guilian Fan, Miao He, Yu Sun, Kai Xu, Fengjun Shi
PURPOSE: Osteosarcoma (OS) is one of the most prevalent primary malignant bone tumors in adolescent. HOTAIR is highly expressed and associated with the epigenetic modifications, especially DNA methylation, in cancer. However, the regulation mechanism between HOTAIR and DNA methylation and the biological effects of them in the pathogenesis of osteosarcoma remains elusive. METHOD: Through RNA-sequencing and computational analysis, followed by a variety of experimental validations, we report a novel interplay between HOTAIR, miR-126, and DNA methylation in OS...
July 20, 2017: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/28730237/therapeutic-potential-of-certain-drug-combinations-on-paclitaxel-induced-peripheral-neuropathy-in-rats
#16
Cristina Elena Zbârcea, IonuŢ Cosmin Ciotu, Veronica Bild, Cornel ChiriŢă, Alexandra Mihaela Tănase, Oana Cristina Şeremet, Emil Ştefănescu, Andreea LetiŢia Arsene, Alexandra Eugenia Bastian, Floriana Elvira Ionică, Simona Negreş
BACKGROUND AND AIMS: Experimental research and clinical data support the potential combination therapy for the treatment of neuropathic pain. We aimed to investigate the analgesic effect of the following associations: gabapentin + etifoxine; tramadol + etifoxine; gabapentin + tramadol, in an experimental model of peripheral neuropathy induced by paclitaxel. MATERIALS AND METHODS: Neuropathy was induced in male Wistar rats by the daily administration of 2 mg÷kg body weight (bw) paclitaxel intraperitoneally, four days in a row...
2017: Romanian Journal of Morphology and Embryology, Revue Roumaine de Morphologie et Embryologie
https://www.readbyqxmd.com/read/28730231/chondroprotective-effects-of-pulsed-shortwave-therapy-in-rabbits-with-experimental-osteoarthritis
#17
Rodica Ana Ungur, Adrian Florea, Alexandru Flaviu Tăbăran, Iuliu Călin Scurtu, Ioan Onac, Ileana Monica Borda, László Irsay, Viorela Mihaela Ciortea, Eleonora Dronca, Mihnea Tudor Zdrenghea, ŞoimiŢa Mihaela Suciu
INTRODUCTION: Osteoarthritis (OA) represents a public health challenge since the pathogenic treatment, able to induce cartilage regeneration, still remains unknown. Ageing of the population and increasing OA prevalence have led to a lot of research, aiming to identify treatments acting on chondrocytes that play a determinant role in cartilage degeneration÷regeneration balance. Pulsed shortwave therapy (with the classical application form - Diapulse) is a physiotherapy method with anabolic effects demonstrated on nervous, conjunctive and vascular tissues, but its effects on OA cartilage are not known...
2017: Romanian Journal of Morphology and Embryology, Revue Roumaine de Morphologie et Embryologie
https://www.readbyqxmd.com/read/28729640/radiation-induced-liver-disease-current-understanding-and-future-perspectives
#18
REVIEW
Jieun Kim, Youngmi Jung
Although radiotherapy (RT) is used for the treatment of cancers, including liver cancer, radiation-induced liver disease (RILD) has emerged as a major limitation of RT. Radiation-induced toxicities in nontumorous liver tissues are associated with the development of numerous symptoms that may limit the course of therapy or have serious chronic side effects, including late fibrosis. Although the clinical characteristics of RILD patients have been relatively well described, the understanding of RILD pathogenesis has been hampered by a lack of reliable animal models for RILD...
July 21, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28728997/sepsis-reconsidered-identifying-novel-metrics-for-behavioral-landscape-characterization-with-a-high-performance-computing-implementation-of-an-agent-based-model
#19
Chase Cockrell, Gary An
OBJECTIVES: Sepsis affects nearly 1 million people in the United States per year, has a mortality rate of 28-50% and requires more than $20 billion a year in hospital costs. Over a quarter century of research has not yielded a single reliable diagnostic test or a directed therapeutic agent for sepsis. Central to this insufficiency is the fact that sepsis remains a clinical/physiological diagnosis representing a multitude of molecularly heterogeneous pathological trajectories. Advances in computational capabilities offered by High Performance Computing (HPC) platforms call for an evolution in the investigation of sepsis to attempt to define the boundaries of traditional research (bench, clinical and computational) through the use of computational proxy models...
July 17, 2017: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/28728928/gtf-231-a-mixture-of-gymnemic-acid-trigonelline-and-ferulic-acid-significantly-ameliorates-oxidative-stress-in-experimental-type-2-diabetes-in-rats
#20
Roshana Devi Vellai, Sharmila Chandiran, Subramanian Sorimuthu Pillai
OBJECTIVES: According to a report by the United States National Health and Nutrition Examination Survey, nearly 60% of patients with diabetes have more than one complication caused by chronic diabetes. Type 2 diabetes is a multifactorial metabolic disorder that accounts for more than 95% of people with diabetes and usually requires multitargeted therapeutic interventions. It arises due to insufficient insulin secretion or its action or both. Recently, we reported that the oral administration of gymnemic acid, trigonelline and ferulic acid in the ratio of 2:3:1 (GTF-231), a mixture of 3 phytoingredients at a concentration of 300 mg/kg body weight significantly improved the glucose homeostasis in rats with low-dose streptozotocin-induced type 2 diabetes that were fed with high-fat diet...
July 17, 2017: Canadian Journal of Diabetes
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