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https://www.readbyqxmd.com/read/28434076/%C3%AE-synuclein-nonhuman-primate-models-of-parkinson-s-disease
#1
REVIEW
David J Marmion, Jeffrey H Kordower
Proper understanding of the mechanism(s) by which α-synuclein misfolds and propagates may hold the key to unraveling the complex pathophysiology of Parkinson's disease. A more complete understanding of the disease itself, as well as establishing animal models that fully recapitulate pathological and functional disease progression, are needed to develop treatments that will delay, halt or reverse the disease course. Traditional neurotoxin-based animal models fail to mimic crucial aspects of Parkinson's and thus are not relevant for the study of neuroprotection and disease-modifying therapies...
April 22, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/28433679/part-i-design-synthesis-and-biological-evaluation-of-novel-pyrazole-benzimidazole-conjugates-as-checkpoint-kinase-2-chk2-inhibitors-with-studying-their-activities-alone-and-in-combination-with-genotoxic-drugs
#2
Shadia A Galal, Ahmed S Abdelsamie, Samia A Shouman, Yasmin M Attia, Hamed I Ali, Ashraf Tabll, Reem El-Shenawy, Yasmine S El Abd, Mamdouh M Ali, Abeer E Mahmoud, Abeer H Abdel-Halim, Amal A Fyiad, Adel S Girgis, Hoda I El-Diwani
Activated checkpoint kinase 2 (Chk2) is a tumor suppressor as one of the main enzymes that affect the cell cycle. 2-Biarylbenzimidazoles are potent selective class of Chk2 inhibitors; the structure-based design was applied to synthesize a new series of this class with replacing the lateral aryl group by substituted pyrazoles. Ten pyrazole-benzimidazole conjugates from the best fifty candidates according to docking programs have been subjected to chemical synthesis in this study. The activities of the conjugates 5-14 as checkpoint kinase inhibitors and as antitumor alone and in combination with genotoxic drugs were evaluated...
April 14, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28433662/iron-and-thiol-redox-signaling-in-cancer-an-exquisite-balance-to-escape-ferroptosis
#3
REVIEW
Shinya Toyokuni, Fumiya Ito, Kyoko Yamashita, Yasumasa Okazaki, Shinya Akatsuka
Epidemiological data indicate a constant worldwide increase in cancer mortality, although the age of onset is increasing. Recent accumulation of genomic data on human cancer via next-generation sequencing confirmed that cancer is a disease of genome alteration. In many cancers, the Nrf2 transcription system is activated via mutations either in Nrf2 or Keap1 ubiquitin ligase, leading to persistent activation of the genes with antioxidative functions. Furthermore, deep sequencing of passenger mutations is clarifying responsible cancer causative agent(s) in each case, including aging, APOBEC activation, smoking and UV...
April 19, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28433417/mechanistic-insights-into-epigenetic-modulation-of-ethanol-consumption
#4
Igor Ponomarev, Claire E Stelly, Hitoshi Morikawa, Yuri A Blednov, R Dayne Mayfield, R Adron Harris
There is growing evidence that small-molecule inhibitors of epigenetic modulators, such as histone deacetylases (HDAC) and DNA methyltransferases (DNMT), can reduce voluntary ethanol consumption in animal models, but molecular and cellular processes underlying this behavioral effect are poorly understood. We used C57BL/6J male mice to investigate the effects of two FDA-approved drugs, decitabine (a DNMT inhibitor) and SAHA (an HDAC inhibitor), on ethanol consumption using two tests: binge-like drinking in the dark (DID) and chronic intermittent every other day (EOD) drinking...
March 12, 2017: Alcohol
https://www.readbyqxmd.com/read/28433110/animal-models-of-wilson-disease
#5
Valentina Medici, Dominik Huster
Wilson disease (WD) is caused by ATPase copper-transporting beta (ATP7B) mutations and results in copper toxicity in liver and brain. Although the defective gene was identified in 1993, the specific mechanisms underlying copper toxicity and the remarkable phenotypic diversity of the disease are still poorly understood. Animal models harboring defects in the ATP7B homolog have helped to reveal new insights into pathomechanisms of WD. Four rodent models with ATP7B gene defects have been described - the Long-Evans Cinnamon (LEC) rat, inbred mouse models (toxic milk (tx), the Jackson Laboratory toxic milk (tx-j)), and the genetically engineered ATP7B(-/-) (knockout) mouse - all of which develop liver disease to different extents...
2017: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/28433106/novel-perspectives-on-wilson-disease-treatment
#6
Christian Rupp, Wolfgang Stremmel, Karl-Heinz Weiss
Wilson disease is an autosomal-recessive copper overload disorder causing hepatic and neurologic symptoms. Commonly used medical therapy shows satisfactory results with regard to hepatic disease but only limited effects in neurologically affected patients. In recent years several new therapy options have been developed, showing promising results that might improve the management of Wilson disease in the near future. Optimization of treatment regimens depending on biochemical response pattern seems worthwhile, especially in the decoppering phase of therapy...
2017: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/28433052/metabolomics-strategies-to-define-the-role-of-metabolism-in-virus-infection-and-pathogenesis
#7
Marianne Manchester, Anisha Anand
Metabolomics is an analytical profiling technique for measuring and comparing large numbers of metabolites present in biological samples. Combining high-throughput analytical chemistry and multivariate data analysis, metabolomics offers a window on metabolic mechanisms. Because they intimately utilize and often rewire host metabolism, viruses are an excellent choice to study by metabolomics techniques. Studies of the effects of viruses on metabolism during replication in vitro and infection in animal models or human subjects have provided novel insights into these networks and provided new targets for therapy and biomarker development...
2017: Advances in Virus Research
https://www.readbyqxmd.com/read/28432779/nmdar-independent-hippocampal-long-term-depression-impairment-after-status-epilepticus-in-a-lithium-pilocarpine-model-of-temporal-lobe-epilepsy
#8
Andrey D Ivanov, Aleksey V Zaitsev
Temporal lobe epilepsy is usually associated with cognitive decline and memory deficits. Despite numerous existing studies on various animal models, the mechanisms of these deficits remain largely unclear. A specific form of long-term synaptic efficacy changes - long-term depression (LTD) - is thought to play an important role in memory formation and learning. However, extremely little is known about the possible alteration of LTD induction and dynamics after a status epilepticus (SE). In the present work we investigated the acute and delayed effects of lithium-pilocarpine-induced SE on NMDAR-dependent and NMDAR-independent hippocampal LTD in vitro...
April 22, 2017: Synapse
https://www.readbyqxmd.com/read/28432752/incretin-based-glucose-lowering-medications-and-the-risk-for-acute-pancreatitis-and-or-pancreatic-cancer-risk-reassuring-data-from-cardio-vascular-outcome-trials
#9
Michael A Nauck, Juris J Meier, Wolfgang E Schmidt
Incretin-based medications (glucagon-like peptide-1 [GLP-1] receptor agonists and inhibitors of dipeptidyl peptidase-4 [DPP-4] are glucose-lowering drugs approved and introduced after 2006 (1). Although both classes of drugs appeared to be relatively safe based on results from clinical trials and standard animal toxicology studies, epidemiological data (2, 3) and histological findings (4) in genetically modified rodents exposed to such agents have raised concern that pancreatitis and pancreatic cancer may be long-term risks associated with this therapy...
April 22, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28432400/-the-intestinal-microbiome-and-metabolic-diseases-from-obesity-to-diabetes-and-nonalcoholic-steatohepatitis
#10
S C Bischoff
BACKGROUND: The intestinal microbiome consists of about 10 million genes, many of which encode digestive enzymes. This explains why animal and human experiments revealed that the intestinal microbiome adapts to food intake and optimizes energy harvest from food. This function is considered beneficial in states of lack of food, but following overnutrition, it might support the development of obesity. OBJECTIVES: The relevance of the intestinal microbiome for the pathogenesis of obesity and associated metabolic diseases such as fatty liver disease and type 2 diabetes mellitus and for the clinical management of such diseases shall be discussed...
April 21, 2017: Der Internist
https://www.readbyqxmd.com/read/28432262/quantitative-imaging-of-cerebral-thromboemboli-in-vivo-the-effects-of-tissue-type-plasminogen-activator
#11
Dong-Eog Kim, Jeong-Yeon Kim, Dawid Schellingerhout, Ju Hee Ryu, Su-Kyoung Lee, Sangmin Jeon, Ji Sung Lee, Jiwon Kim, Hee Jeong Jang, Jung E Park, Eo Jin Kim, Ick Chan Kwon, Cheol-Hee Ahn, Matthias Nahrendorf, Kwangmeyung Kim
BACKGROUND AND PURPOSE: Quantitative imaging for the noninvasive assessment of thrombolysis is needed to advance basic and clinical thrombosis-related research and tailor tissue-type plasminogen activator (tPA) treatment for stroke patients. We quantified the evolution of cerebral thromboemboli using fibrin-targeted glycol chitosan-coated gold nanoparticles and microcomputed tomography, with/without tPA therapy. METHODS: We injected thrombi into the distal internal carotid artery in mice (n=50)...
April 21, 2017: Stroke; a Journal of Cerebral Circulation
https://www.readbyqxmd.com/read/28432072/translocase-of-inner-membrane-50-functions-as-a-novel-protective-regulator-of-pathological-cardiac-hypertrophy
#12
Kai Tang, Yifan Zhao, Hailing Li, Mengyun Zhu, Weiming Li, Weijing Liu, Guofu Zhu, Dachun Xu, Wenhui Peng, Ya-Wei Xu
BACKGROUND: Translocase of inner membrane 50 (TIM50) is a member of the translocase of inner membrane (TIM) complex in the mitochondria. Previous research has demonstrated the role of TIM50 in the regulation of oxidative stress and cardiac morphology. However, the role of TIM50 in pathological cardiac hypertrophy remains unknown. METHODS AND RESULTS: In the present study we found that the expression of TIM50 was downregulated in hypertrophic hearts. Using genetic loss-of-function animal models, we demonstrated that TIM50 deficiency increased heart and cardiomyocyte size with more severe cardiac fibrosis compared with wild-type littermates...
April 21, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28431621/two-decades-of-glatiramer-acetate-from-initial-discovery-to-the-current-development-of-generics
#13
REVIEW
Bianca Weinstock-Guttman, Kavita V Nair, Joseph L Glajch, Tanmoy C Ganguly, Daniel Kantor
Multiple sclerosis (MS) is a chronic, incurable, inflammatory disease of the central nervous system (CNS). In the United States, several US Food and Drug Administration (FDA)-approved disease-modifying treatments (DMTs) are available, including glatiramer acetate (GA; Copaxone®), one of the most longstanding treatments. GA was discovered serendipitously in the late 1960s/early 1970s while attempting to produce a synthetic antigen capable of inducing experimental autoimmune encephalomyelitis (EAE), an animal model of autoimmune inflammatory CNS disorders, including MS...
May 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28431414/intratracheal-instillation-of-neutrophils-rescues-bacterial-overgrowth-initiated-by-trauma-damage-associated-molecular-patterns
#14
Kiyoshi Itagaki, Ingred Riça, Jing Zhang, Dave Gallo, Melissa DePrato, Leo E Otterbein, Carl J Hauser
BACKGROUND: Nosocomial pneumonias are common in trauma patients and so interventions to prevent and treat nosocomial pneumonia may improve outcomes. Our prior work strongly suggests that tissue injury predisposes to infections like nosocomial pneumonia because mitochondrial debris originating from injured cells contains damage-associated molecular patterns that can reduce neutrophil (PMN) migration into the airway and diminish PMN function in response to bacterial inoculation of the airway...
May 2017: Journal of Trauma and Acute Care Surgery
https://www.readbyqxmd.com/read/28430812/nacl-cotransporter-abundance-in-urinary-vesicles-is-increased-by-calcineurin-inhibitors-and-predicts-thiazide-sensitivity
#15
Omar A Z Tutakhel, Arthur D Moes, Marco A Valdez-Flores, Marleen L A Kortenoeven, Mathijs V D Vrie, Sabina Jeleń, Robert A Fenton, Robert Zietse, Joost G J Hoenderop, Ewout J Hoorn, Luuk Hilbrands, René J M Bindels
Animal studies have shown that the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus can activate the thiazide-sensitive NaCl cotransporter (NCC). A common side effect of CNIs is hypertension. Renal salt transporters such as NCC are excreted in urinary extracellular vesicles (uEVs) after internalization into multivesicular bodies. Human studies indicate that CNIs also increase NCC abundance in uEVs, but results are conflicting and no relationship with NCC function has been shown. Therefore, we investigated the effects of CsA and Tac on the abundance of both total NCC (tNCC) and phosphorylated NCC at Thr60 phosphorylation site (pNCC) in uEVs, and assessed whether NCC abundance in uEVs predicts the blood pressure response to thiazide diuretics...
2017: PloS One
https://www.readbyqxmd.com/read/28430642/immunocompetent-mouse-allograft-models-for-development-of-therapies-to-target-breast-cancer-metastasis
#16
Yuan Yang, Howard H Yang, Ying Hu, Peter H Watson, Huaitian Liu, Thomas R Geiger, Miriam R Anver, Diana C Haines, Philip Martin, Jeffrey E Green, Maxwell P Lee, Kent W Hunter, Lalage M Wakefield
Effective drug development to combat metastatic disease in breast cancer would be aided by the availability of well-characterized preclinical animal models that (a) metastasize with high efficiency, (b) metastasize in a reasonable time-frame, (c) have an intact immune system, and (d) capture some of the heterogeneity of the human disease. To address these issues, we have assembled a panel of twelve mouse mammary cancer cell lines that can metastasize efficiently on implantation into syngeneic immunocompetent hosts...
February 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28429751/preclinical-study-of-raav2-strail-pharmaceutical-efficacy-biodistribution-and-safety-in-animals
#17
Q Ru, W Li, X Wang, S Zhang, L Chen, Y Zhang, Y Ge, Y Zu, Y Liu, D Zheng
The recombinant sTRAIL has been in clinical trial for various human malignancies. However, the half-life time of sTRAIL is very short, which might be an important factor influencing its clinical efficacy for cancer therapy. We previously reported the recombinant adeno-associated virus (AAV)-encoding sTRAIL95-281-mediated sTRAIL expression in vivo up to 8 months and suppressed tumor growth markedly in mouse xenografts. In the present study, we further evaluated the clinical potency for cancer gene therapy and the safety in mouse and non-human primates...
April 21, 2017: Cancer Gene Therapy
https://www.readbyqxmd.com/read/28429669/what-can-pharmacological-models-of-retinal-degeneration-tell-us
#18
M H Reisenhofer, J Balmer, V Enzmann
Animal models with pharmacologically induced retinal degeneration including sodium iodate (NaIO3) and N-methyl-N-nitrosourea (MNU) have been extensively used in ophthalmic research to investigate retinal degeneration. NaIO3 induces degeneration of the retinal pigment epithelium (RPE) followed by photoreceptor (PRC) cell death, mimicking features of age-related macular degeneration. In contrast, MNU leads to rapid destruction of the PRCs only, enabling the use of the MNU model to investigate degeneration induced in retinitis pigmentosa...
March 31, 2017: Current Molecular Medicine
https://www.readbyqxmd.com/read/28429491/bringing-the-human-pancreas-into-focus-new-paradigms-for-the-understanding-of-type-1-diabetes
#19
REVIEW
N G Morgan
Type 1 diabetes affects increasingly large numbers of people globally (including at least half a million children under the age of 14 years) and it remains an illness with life-long and often devastating consequences. It is surprising, therefore, that the underlying aetiology of Type 1 diabetes remains poorly understood. This is largely because the cellular and molecular processes leading to the loss of β cells in the pancreas have rarely been studied at, or soon after, the onset of disease. Where such studies have been undertaken, a number of surprises have emerged which serve to challenge conventional wisdom...
April 20, 2017: Diabetic Medicine: a Journal of the British Diabetic Association
https://www.readbyqxmd.com/read/28429194/photobiomodulation-therapy-associated-with-treadmill-training-in-the-oxidative-stress-in-a-collagen-induced-arthritis-model
#20
Solange Almeida Dos Santos, Marcia Ataize Dos Santos Vieira, Maira Cécilia Brandão Simões, Andrey Jorge Serra, Ernesto Cesar Leal-Junior, Paulo de Tarso Camillo de Carvalho
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by chronic and systemic inflammation, which leads to the destruction of the cartilage and bone and affects tissues in multiple joints. Oxidative stress has been implicated with regards to involvement in various disease conditions, such as diabetes mellitus and neurodegenerative, respiratory, cardiovascular, and RA diseases. In vivo experimental studies using photobiomodulation therapy (PBMT) have shown positive effects in reducing lipid peroxidation and in increasing antioxidant activity...
April 21, 2017: Lasers in Medical Science
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