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Therapeutic target

Davide Croci, Edin Nevzati, Hiroki Danura, Salome Schöpf, Javier Fandino, Serge Marbacher, Carl Muroi
BACKGROUND: In subarachnoid hemorrhage (SAH), occurrence of cerebral vasospasm (CVS) mediated by endothelin (ET)-1 might be a result of a compartmental inflammatory response with interleukin (IL)-6 release. We aim to investigate the relationship between ET-1 and IL-6 in association of CVS. METHODS: A total of 24 New Zealand white rabbits where randomly allocated into 3 groups: SAH (n=10), IL-6 (n=10), and sham (n=4). SAH was induced by a closed cranium extracranial-intracranial shunt model...
October 19, 2016: Journal of Neurosurgical Sciences
Aditi A Sidhaye, Kanchan C Bhuran, Sneha Zambare, Munna Abubaker, Niroshini Nirmalan, Kamalinder K Singh
AIM: The intra-erythrocytic development of the malarial parasite is dependent on active uptake of nutrients, including human serum albumin (HSA), into parasitized red blood cells (pRBCs). We have designed HSA-based nanoparticles as a potential drug-delivery option for antimalarials. METHODS: Artemether-loaded nanoparticles (AANs) were designed and antimalarial activity evaluated in vitro/in vivo using Plasmodium falciparum/Plasmodium berghei species, respectively...
October 19, 2016: Nanomedicine
Rebba C Boswell-Casteel, Franklin A Hays
Equilibrative nucleoside transporters (ENTs) are polytopic integral membrane proteins that mediate the transport of nucleosides, nucleobases, and therapeutic analogs. The best-characterized ENTs are the human transporters hENT1 and hENT2. However, non-mammalian eukaryotic ENTs have also been studied (e.g., yeast, parasitic protozoa). ENTs are major pharmaceutical targets responsible for modulating the efficacy of more than 30 approved drugs. However, the molecular mechanisms and chemical determinants of ENT-mediated substrate recognition, binding, inhibition, and transport are poorly understood...
October 19, 2016: Nucleosides, Nucleotides & Nucleic Acids
Wing-Hin Lee, Ching-Yee Loo, Chean-Ring Leong, Paul M Young, Daniela Traini, Ramin Rohanizadeh
The effectiveness of conventional cancer chemotherapy is hampered by the occurrence of multidrug resistance (MDR) in tumor cells. Although many studies have reported the development of novel MDR chemotherapeutic agents, clinical success is lacking owing to the high associated toxicity. Nanoparticle-based delivery of chemotherapeutic drugs has emerged as alternative approach to treat MDR cancers via exploitation of leaky vasculature in the tumor microenvironment. Accordingly, functionalization of nanoparticles with target specific ligands can be employed to achieve significant improvements in the treatment of MDR cancer...
October 19, 2016: Expert Opinion on Drug Delivery
Ross D Blundell, Simon J Williams, Samantha D M Arras, Jessica L Chitty, Kirsten L Blake, Daniel J Ericsson, Nidhi Tibrewal, Jurgen Rohr, Y Q Andre E Koh, Ulrike Kappler, Avril A B Robertson, Mark S Butler, Matthew A Cooper, Bostjan Kobe, James A Fraser
Opportunistic fungal pathogens such as Cryptococcus neoformans are a growing cause of morbidity and mortality among immunocompromised populations worldwide. To address the current paucity of antifungal therapeutic agents, further research into fungal-specific drug targets is required. Adenylosuccinate synthetase (AdSS) is a crucial enzyme in the adeosine triphosphate (ATP) biosynthetic pathway, catalyzing the formation of adenylosuccinate from inosine monophosphate and aspartate. We have investigated the potential of this enzyme as an antifungal drug target, finding that loss of function results in adenine auxotrophy in C...
September 9, 2016: ACS Infectious Diseases
Ruijie D Teo, Jae Youn Hwang, John Termini, Zeev Gross, Harry B Gray
Corroles are exceptionally promising platforms for the development of agents for simultaneous cancer-targeting imaging and therapy. Depending on the element chelated by the corrole, these theranostic agents may be tuned primarily for diagnostic or therapeutic function. Versatile synthetic methodologies allow for the preparation of amphipolar derivatives, which form stable noncovalent conjugates with targeting biomolecules. These conjugates can be engineered for imaging and targeting as well as therapeutic function within one theranostic assembly...
October 19, 2016: Chemical Reviews
Aleksandar Antanasijevic, Nicholas J Hafeman, Smanla Tundup, Carolyn Kingsley, Rama K Mishra, Lijun Rong, Balaji Manicassamy, Duncan Wardrop, Michael Caffrey
The viral envelope protein hemagglutinin (HA) plays a critical role in influenza entry and thus is an attractive target for novel therapeutics. The small molecule tert-butylhydroquinone (TBHQ) has previously been shown to bind to HA and inhibit HA-mediated entry with low micromolar potency. However, enthusiasm for the use of TBHQ has diminished due to the compound's antioxidant properties. In this work we show that the antioxidant properties of TBHQ are not responsible for the inhibition of HA-mediated entry...
September 9, 2016: ACS Infectious Diseases
Daniel Nava Rodrigues, Gunther Boysen, Semini Sumanasuriya, George Seed, Angelo M De Marzo, Johann de Bono
Prostate cancer (PCa) is a clinically heterogeneous disease and current treatment strategies are based largely on anatomical and pathological parameters. In the recent past, several DNA sequencing studies of primary and advanced PCa have revealed recurrent patterns of genomic aberrations that expose mechanisms of resistance to available therapies and potential new drug targets. Suppression of androgen receptor (AR) signalling is the cornerstone of advanced prostate cancer treatment. Genomic aberrations of the androgen receptor or alternative splicing of its mRNA are increasingly recognized as biomarkers of resistance to AR-targeted therapy such as abiraterone or enzalutamide...
October 18, 2016: Journal of Pathology
Thavasyappan Thambi, V H Giang Phan, Doo Sung Lee
Stimuli-sensitive injectable polymeric hydrogels are one of the promising delivery vehicles for the controlled release of bioactive agents. In aqueous solutions, these polymers are able to switch sol-to-gel transitions in response to various stimuli including pH, temperature, light, enzyme and magnetic field. Therapeutic agents, including chemotherapeutic agents, protein drugs or cells, are easily mixed with the low-viscous polymer solution at room temperature. Therapeutic-agents-containing solutions are readily injected into target sites through syringe or catheter, which could form hydrogel depot and serve as bioactive molecules release carriers...
October 18, 2016: Macromolecular Rapid Communications
Bruno Borghese, Krina T Zondervan, Mauricio S Abrao, Charles Chapron, Daniel Vaiman
Endometriosis is a gynecologic disease affecting up to 10% of the women and a major cause of pain and infertility. It is characterized by the implantation of functional endometrial tissue at ectopic positions generally within the peritoneum. This complex disease has an important genetic component with a heritability estimated at around 50%. This review aims at providing recent insights into the genetic bases of endometriosis, and present a detailed overview of evidence of epigenetic alterations specific to this disease...
October 18, 2016: Clinical Genetics
Erina Takai, Yasushi Totoki, Hiromi Nakamura, Mamoru Kato, Tatsuhiro Shibata, Shinichi Yachida
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. The genomic landscape of the PDAC genome features four frequently mutated genes (KRAS, CDKN2A, TP53, and SMAD4) and dozens of candidate driver genes altered at low frequency, including potential clinical targets. Circulating cell-free DNA (cfDNA) is a promising resource to detect molecular characteristics of tumors, supporting the concept of "liquid biopsy".We determined the mutational status of KRAS in plasma cfDNA using multiplex droplet digital PCR in 259 patients with PDAC, retrospectively...
2016: Advances in Experimental Medicine and Biology
Mariana Angoa-Pérez, John H Anneken, Donald M Kuhn
The present review briefly explores the neurotoxic properties of methcathinone, mephedrone, methylone, and methylenedioxypyrovalerone (MDPV), four synthetic cathinones most commonly found in "bath salts." Cathinones are β-keto analogs of the commonly abused amphetamines and display pharmacological effects resembling cocaine and amphetamines, but despite their commonalities in chemical structures, synthetic cathinones possess distinct neuropharmacological profiles and produce unique effects. Among the similarities of synthetic cathinones with their non-keto analogs are their targeting of monoamine systems, the release of neurotransmitters, and their stimulant properties...
October 18, 2016: Current Topics in Behavioral Neurosciences
Wolfgang Löscher, Michel Gillard, Zara A Sands, Rafal M Kaminski, Henrik Klitgaard
The synaptic vesicle glycoprotein SV2A belongs to the major facilitator superfamily (MFS) of transporters and is an integral constituent of synaptic vesicle membranes. SV2A has been demonstrated to be involved in vesicle trafficking and exocytosis, processes crucial for neurotransmission. The anti-seizure drug levetiracetam was the first ligand to target SV2A and displays a broad spectrum of anti-seizure activity in various preclinical models. Several lines of preclinical and clinical evidence, including genetics and protein expression changes, support an important role of SV2A in epilepsy pathophysiology...
October 17, 2016: CNS Drugs
Ling Hou, Gang Chen, Biao Feng, Xu-Sheng Zhang, Xiu-Fen Zheng, Ying Xiang, Guang-Yuan Zhao, Wei-Ping Min
Tumor necrosis factor-alpha (TNF-α) has been found to be centrally involved in the development of ischemia-reperfusion injury (IRI)-induced inflammation and apoptosis. Knockdown of TNF-α gene using small interfering RNA (siRNA) may protect renal IRI. Renal IRI was induced in mice by clamping the left renal pedicle for 25 or 35 min. TNF-α siRNA was administered intravenously to silence the expression of TNF-α. The therapeutic effects of siRNA were evaluated in terms of renal function, histological examination, and overall survival following lethal IRI...
October 2016: Journal of Huazhong University of Science and Technology. Medical Sciences
Youngsin Jung, Erik K St Louis
REM sleep behavior disorder (RBD) is a common parasomnia disorder affecting between 1 and 7 % of community-dwelling adults, most frequently older adults. RBD is characterized by nocturnal complex motor behavior and polysomnographic REM sleep without atonia. RBD is strongly associated with synucleinopathy neurodegeneration. The approach to RBD management is currently twofold: symptomatic treatment to prevent injury and prognostic counseling and longitudinal follow-up surveillance for phenoconversion toward overt neurodegenerative disorders...
November 2016: Current Treatment Options in Neurology
Amal Akour, Violet Kasabri, Nailya Boulatova, Yasser Bustanji, Randa Naffa, Dana Hyasat, Nahla Khawaja, Haidar Bustanji, Ayman Zayed, Munther Momani
AIMS: Type 2 diabetes mellitus (T2DM) and prediabetes (pre-DM) are associated with changes in levels of metabolic markers. The main aim of this study is to compare the levels of omentin, irisin, endothelin-1, nesfatin, hepatocyte growth factor (HGF), fibroblast growth factor, and oxytocin (OXT) between normoglycemic and pre-DM/T2DM obese Jordanian patients. METHODS: One hundred and ninety-eight adult Jordanian subjects were recruited. Demographic data and clinical parameters were collected...
October 18, 2016: Acta Diabetologica
Jeganathan Manivannan, Manjunath Prashanth, Venkatesan Saravana Kumar, Manickaraj Shairam, Jayachandran Subburaj
Since there is no precise therapy for treating vascular calcification by directly targeting the vascular wall, we aim to unveil novel drug targets through mining the molecular effect of a high phosphate environment on vascular cells through computational methods. Here, we hypothesize that manipulation of the vascular pathogenic network by small molecule therapeutics predicted from prior knowledge might offer great promise. With this, we intend to understand the publicly available transcriptomic data of vascular smooth muscle cells and endothelial cells exposed to the high phosphate induced vascular calcification milieu and to re-examine the above published experiments for reasons different from those examined in the previous studies through multilevel systems biological understanding...
October 18, 2016: Molecular BioSystems
Ioanna Eleftheriadou, Ioannis Manolaras, Elaine E Irvine, Michael Dieringer, Antonio Trabalza, Nicholas D Mazarakis
OBJECTIVE: We have previously described the generation of coxsackievirus and adenovirus receptor (α CAR)-targeted vector, and shown that intramuscular delivery in mouse leg muscles resulted in specific retrograde transduction of lumbar-motor neurons (MNs). Here, we utilized the α CAR-targeted vector to investigate the in vivo neuroprotective effects of lentivirally expressed IGF-1 for inducing neuronal survival and ameliorating the neuropathology and behavioral phenotypes of the SOD1(G93A) mouse model of ALS...
October 2016: Annals of Clinical and Translational Neurology
Chan Joo Lee, Sungha Park
Despite improvements in hypertension awareness and treatment, the blood pressure (BP) control rate still remains at around 50%. One of the major determinants of low BP control results from therapeutic inertia of the physician and suboptimal compliance of the patients. Home BP self-measurement and monitoring improves patients' awareness and helps the management of hypertension. Recent technological advances are allowing for accurate measurement and telemonitoring of home BP, with a number of randomized clinical trials demonstrating the efficacy of telemonitoring for BP control...
September 2016: Pulse (Basel, Switzerland)
Steven Wang, Jie Yan, Guangde Zhou, Rebecca Heintzelman, J Steve Hou
Myeloproliferative neoplasms (MPNs) are hematopoietic malignancies characterized by unchecked proliferation of differentiated myeloid cells. The most common BCR-ABL1-negative MPNs are polycythemia vera, essential thrombocythemia, and primary myelofibrosis. The discovery of JAK2 V617F mutation has improved our understanding of the molecular basis of MPN. The high frequency of JAK2 mutation in MPN makes JAK2 mutation testing an essential diagnostic tool and potential therapeutic target for MPN. Here, we present a rare case of a 34-year-old patient who was initially diagnosed with acute myeloid leukemia (AML) with mutated NPM1...
2016: Case Reports in Hematology
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