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drug target disease

Adam S Darwich, Howard J Burt, Amin Rostami-Hodjegan
Physiologically-based pharmacokinetic (PBPK) models provide a framework for in vitro-in vivo extrapolation of metabolic drug clearance. Many of the concepts in PBPK can have consequential impact on more mechanistic systems pharmacology models. In the gut wall, turnover of enzymes and enterocytes are typically lumped into one rate constant that describes the time dependent enzyme activity. This assumption may influence predictability of any sustained and dynamic effects such as mechanism-based inhibition (MBI), particularly when considering translation from healthy to gut disease...
February 15, 2019: European Journal of Pharmaceutical Sciences
Gincy George, V P Snijesh, Sowmya Bekshe Lokappa, Jobin Varkey
BACKGROUND: Parkinson's disease (PD) is a complex neurodegenerative movement disorder that primarily results due to the loss of dopaminergic neurons in the substantia nigra region. Studying gene expression in the substantia nigra region would potentially unravel disease-relevant protein-protein interactions. METHODS: In this study we have used network science approach to prioritize candidate genes by focussing on differentially expressed genes (DEGs) that interact with established PD associated-genes (PDAG)...
February 15, 2019: Gene
Nuria Codina, David Hilton, Cheng Zhang, Nesrine Chakroun, Shahina S Ahmad, Stephen J Perkins, Paul A Dalby
Protein aggregation is the underlying cause of many diseases, and also limits the usefulness of many natural and engineered proteins in biotechnology. Better mechanistic understanding and characterization of aggregation-prone states, is needed to guide protein engineering, formulation, and drug-targeting strategies that prevent aggregation. While several final aggregated states - notably amyloids - have been characterized structurally, very little is known about the native structural conformers that initiate aggregation...
February 15, 2019: Journal of Molecular Biology
Gustavo Roberto Villas Boas, Roseli Boerngen de Lacerda, Marina Meirelles Paes, Priscila Gubert, Wagner Luis da Cruz Almeida, Vanessa Cristina Rescia, Pablinny Moreira Galdino de Carvalho, Adryano Augustto Valladao de Carvalho, Silvia Aparecida Oesterreich
Major depressive disorder (MDD), also known as unipolar depression, is one of the leading causes of disability and disease worldwide. The signs and symptoms are low self‑esteem, anhedonia, feeling of worthlessness, sense of rejection and guilt, suicidal thoughts, among others. This review focuses on studies with molecular-based approaches involving MDD to obtain an integrated, more detailed and comprehensive view of the brain changes produced by this disorder and its treatment and how the Central Nervous System (CNS) produces neuroplasticity to orchestrate adaptive defensive behaviors...
February 15, 2019: European Journal of Pharmacology
Afsaneh Lavasanifar, Cierra N Sharp, Erik A Korte, Tyler Yin, Keivan Hosseinnijad, Saeed A Jortani
Long Interspersed Nuclear Element-1 (LINE-1) are DNAs that compromise 17% of our genome. LINE-1 expression is triggered by environmental stressors and accomplished through its demethylation leading to genomic instability. Expression of LINE-1 is regulated in adult somatic tissues through several endogenous defensive mechanisms but is found to be associated with tumorigenesis in several cancers. This finding, has inspired the use of different indicators of LINE-1 activation, as biomarkers in cancer diagnostics and even therapeutic targets in recent years...
February 15, 2019: Clinica Chimica Acta; International Journal of Clinical Chemistry
Masaki Arioka, Fumi Takahashi-Yanaga
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that causes swelling, bone erosion, and joint disorder. Patients with RA therefore suffer from pain and physiological disability, and have a decreased quality of life. During the progression of RA, many different types of cells and inflammatory factors influence each other with an important role. A better understanding of the pathology of RA should therefore lead to the development of effective anti-rheumatoid drugs, such as the anti-TNFα antibody...
February 15, 2019: Biochemical Pharmacology
Xingyi Li, Wenkai Li, Min Zeng, Ruiqing Zheng, Min Li
Genes that are thought to be critical for the survival of organisms or cells are called essential genes. The prediction of essential genes and their products (essential proteins) is of great value in exploring the mechanism of complex diseases, the study of the minimal required genome for living cells and the development of new drug targets. As laboratory methods are often complicated, costly and time-consuming, a great many of computational methods have been proposed to identify essential genes/proteins from the perspective of the network level with the in-depth understanding of network biology and the rapid development of biotechnologies...
February 18, 2019: Briefings in Bioinformatics
Elizabeth M Anderson, Jin Zhang, Greg Russell, Isai G Bowline, Braghadheeswar Thyagarajan, DengFeng Li, Lijun Ma, Erica R Anderson, Mariana Murea
Introduction: Mitochondrial dysfunction plays an important role in the pathophysiology of kidney disease. Inhibitors of mitochondrial metabolism are being developed for the treatment of solid organ and hematologic malignancies. We describe the incidence and clinical features of acute kidney injury (AKI) in patients treated with the antimitochondrial drug CPI-613. Methods: We identified 33 patients with relapsed or refractory malignancy, previously enrolled in 3 open-label phase II studies, who received single-agent CPI-613 chemotherapy...
February 2019: KI Reports
Paul Perco, Michelle Pena, Hiddo J L Heerspink, Gert Mayer
Diabetic kidney disease (DKD) is a complex and multifactorial disorder associated with deregulations in a large number of different biological pathways on the molecular level. Using the 2 established biomarkers, estimated glomerular filtration rate (eGFR) and albuminuria will not allow allocating patients to tailored therapy. Molecular multimarker panels as sensors for the deregulation of the various disease mechanisms combined with a better understanding of how investigational as well as approved drugs interfere with these disease processes forms the basis for platform trials in DKD...
February 2019: KI Reports
Cameron M Armstrong, Allen C Gao
Current therapies for advanced prostate cancer, such as enzalutamide and abiraterone, focus on inhibiting androgen receptor (AR) activity and reducing downstream signaling pathways to inhibit tumor growth. Unfortunately, cancer cells are very adaptable and, over time, these cells develop mechanisms by which they can circumvent therapeutics. One of the many mechanisms that have been discovered is the generation of AR variants. These variants are generated through alternative splicing of the full length AR and often lack the ligand binding domain...
January 2019: Asian Journal of Urology
Igor S Lukashevich, Slobodan Paessler, Juan Carlos de la Torre
Lassa virus (LASV) is a highly prevalent mammarenavirus in West Africa and is maintained in nature in a persistently infected rodent host, Mastomys natalensis , which is widely spread in sub-Saharan Africa. LASV infection of humans can cause Lassa fever (LF), a disease associated with high morbidity and significant mortality. Recent evidence indicates an LASV expansion outside its traditional endemic areas. In 2017, the World Health Organization (WHO) included LASV in top-priority pathogens and released a Target Product Profile (TPP) for vaccine development...
2019: F1000Research
Manish Bodas, Neeraj Vij
Cystic fibrosis (CF), a fatal genetic disorder predominant in the Caucasian population, is caused by mutations in the cystic fibrosis transmembrane conductance regulator ( Cftr ) gene. The most common mutation is the deletion of phenylalanine from the position-508 (F508del-CFTR), resulting in a misfolded-CFTR protein, which is unable to fold, traffic and retain its plasma membrane (PM) localization. The resulting CFTR dysfunction, dysregulates variety of key cellular mechanisms such as chloride ion transport, airway surface liquid (ASL) homeostasis, mucociliary-clearance, inflammatory-oxidative signaling, and proteostasis that includes ubiquitin-proteasome system (UPS) and autophagy...
2019: Frontiers in Pharmacology
Ya'nan Yang, Song Li, Yiting Sun, Di Zhang, Zeyi Zhao, Lian Liu
Purpose: Peritoneal metastasis is the most common pathway for the spread of ovarian cancer. Ovarian cancer cells in ascites prefer to aggregate into the more chemoresistant multicellular spheroids (MCSs), leading to treatment failure and disease recurrence. We previously established a suspension MCS model of ovarian cancer cells in vitro and found that the MCS cells acquired drug resistance to cisplatin. In the present study, we aimed to uncover the underlying mechanism of the platinum resistance of MCS and the potential targets to reverse the drug resistance...
2019: OncoTargets and Therapy
Emanuela Cova, Laura Pandolfi, Miriam Colombo, Vanessa Frangipane, Simona Inghilleri, Monica Morosini, Simona Mrakic-Sposta, Sarah Moretti, Manuela Monti, Ymera Pignochino, Silvia Benvenuti, Davide Prosperi, Giulia Stella, Patrizia Morbini, Federica Meloni
Purpose: Malignant pleural mesothelioma (MPM) is an aggressive tumor characterized by poor prognosis. Its incidence is steadily increasing due to widespread asbestos exposure. There is still no effective therapy for MPM. Pemetrexed (Pe) is one of the few chemotherapeutic agents approved for advanced-stage disease, although the objective response to the drug is limited. The use of gold nanoparticles (GNPs) as a drug delivery system promises several advantages, including specific targeting of malignant cells, with increased intracellular drug accumulation and reduced systemic toxicity, and, in the case of MPM, direct treatment administration into the pleural space...
2019: International Journal of Nanomedicine
Anu Rani, Amit Anand, Kewal Kumar, Vipan Kumar
Chalcones are attractive to synthetic chemists because they are easy to prepare, have a large number of replaceable hydrogens, thereby having significant biological potential. Chalcones and their derivatives (carbocyclic as well as heterocyclic) exhibit a range of biological properties including anticancer, antimalarial, antioxidant, anti-inflammatory and anti-tubercular activities. Their promising biological profile, along with their ease of synthetic manipulations, have triggered the design and development of new chalcone derivatives as well as their conjugates with active pharmacophores affording therapeutic templates targeting various diseases...
March 2019: Expert Opinion on Drug Discovery
Ki Young Choi, Hwa Seung Han, Eun Sook Lee, Jung Min Shin, Benjamin D Almquist, Doo Sung Lee, Jae Hyung Park
There is a rapidly increasing interest in developing stimuli-responsive nanomaterials for treating a variety of diseases. By enabling the activation of function locally at the sites of interest, it is possible to increase therapeutic efficacy significantly while simultaneously reducing adverse side effects. While there are many sophisticated nanomaterials available, they are often highly complex and not easily transferrable to industrial scales and clinical settings. However, nanomaterials based on hyaluronic acid offer a compelling strategy for reducing their complexity while retaining several desirable benefits such as active targeting and stimuli-responsive degradation...
February 18, 2019: Advanced Materials
Dharmaraja Allimuthu, Zita Hubler, Fadi J Najm, Hong Tang, Ilya Bederman, William Seibel, Paul J Tesar, Drew J Adams
Small molecules that promote oligodendrocyte formation have been identified in "drug repurposing" screens to nominate candidate therapeutics for diseases in which myelin is lost, including multiple sclerosis. We recently reported that many such molecules enhance oligodendrocyte formation not by their canonical targets but by inhibiting a narrow range of enzymes in cholesterol biosynthesis. Here we identify enhancers of oligodendrocyte formation obtained by screening a structurally diverse library of 10,000 small molecules...
January 31, 2019: Cell Chemical Biology
Chen-Shan Chen Woodcock, Stephen Y Chan
Pulmonary hypertension (PH) and its severe subtype pulmonary arterial hypertension (PAH) encompass a set of multifactorial diseases defined by sustained elevation of pulmonary arterial pressure and pulmonary vascular resistance leading to right ventricular failure and subsequent death. Pulmonary hypertension is characterized by vascular remodeling in association with smooth muscle cell proliferation of the arterioles, medial thickening, and plexiform lesion formation. Despite our recent advances in understanding its pathogenesis and related therapeutic discoveries, PH still remains a progressive disease without a cure...
February 17, 2019: Journal of Cardiovascular Pharmacology and Therapeutics
Anthony B DeNicola, Yi Tang
Mutated RNA splicing machinery drives many human diseases and is a promising therapeutic target for engineering and small molecule therapy. In the case of mutations in individual genes that cause them to be incorrectly spliced, engineered splicing factors can be introduced to correct splicing of these aberrant transcripts and reduce the effects of the disease phenotype. Mutations that occur in certain splicing factor genes themselves have been implicated in many cancers, particularly myelodysplastic syndromes...
February 14, 2019: Current Opinion in Biotechnology
Andrew D J Pearson, Nicole Scobie, Koenraad Norga, Franca Ligas, Davy Chiodin, Amos Burke, Veronique Minard-Colin, Peter Adamson, Lynley V Marshall, Arun Balakumaran, Bouchra Benettaib, Pankaj Bhargava, Catherine M Bollard, Ellen Bolotin, Simon Bomken, Jochen Buechner, Birgit Burkhardt, Hubert Caron, Christopher Copland, Pierre Demolis, Anton Egorov, Mahdi Farhan, Gerhard Zugmaier, Thomas Gross, Danielle Horton-Taylor, Wolfram Klapper, Giovanni Lesa, Robert Marcus, Rodney R Miles, Kerri Nottage, Lida Pacaud, Rosanna Ricafort, Martin Schrappe, Jaroslav Sterba, Remus Vezan, Susan Weiner, Su Young Kim, Gregory Reaman, Gilles Vassal
Paediatric Strategy Forums have been created by the multistakeholder organisation, ACCELERATE, and the European Medicines Agency to facilitate dialogue between all relevant stakeholders and suggest strategies in critical areas of paediatric oncology drug development. As there are many medicines being developed for B-cell malignancies in adults but comparatively few in children with these malignancies, a Paediatric Strategy Forum was held to discuss the best approach to develop these products for children. It was concluded that as current frontline therapy is highly successful, despite associated acute toxicity, de-escalation of this or substitution of presently used drugs with new medicines can only be undertaken when there is an effective salvage regimen, which is currently not available...
February 14, 2019: European Journal of Cancer
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