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https://www.readbyqxmd.com/read/28107387/neuronal-cell-death-and-degeneration-through-increased-nitroxidative-stress-and-tau-phosphorylation-in-hiv-1-transgenic-rats
#1
Young-Eun Cho, Myoung-Hwa Lee, Byoung-Joon Song
The underlying mechanisms for increased neurodegeneration and neurocognitive deficits in HIV-infected people are unclear. Therefore, this study was aimed to investigate the mechanisms of increased neurodegeneration in 5-month old male HIV-1 Transgenic (Tg) rats compared to the age- and gender-matched wild-type (WT) by evaluating histological changes and biochemical parameters of the key proteins involved in the cell death signaling and apoptosis. Histological and immunohistochemical analyses revealed decreased neuronal cells with elevated astrogliosis in HIV-1 Tg rats compared to WT...
2017: PloS One
https://www.readbyqxmd.com/read/28105557/the-anticancer-drug-sunitinib-promotes-autophagyand-protects-from-neurotoxicity-in-an-hiv-1-tat-model-of-neurodegeneration
#2
Jerel A Fields, Jeff Metcalf, Cassia Overk, Anthony Adame, Brian Spencer, Wolfgang Wrasidlo, Jazmin Florio, Edward Rockenstein, Johnny J He, Eliezer Masliah
Despite the success of antiretroviral therapies to control systemic HIV-1 infection, the prevalence of HIV-associated neurocognitive disorders (HANDs) has not decreased among aging patients with HIV. Autophagy pathway alterations, triggered by HIV-1 proteins including gp120, Tat, and Nef, might contribute to the neurodegenerative process in aging patients with HAND. Although no treatments are currently available to manage HAND, we have previously shown that sunitinib, an anticancer drug that blocks receptor tyrosine-kinase and cyclin kinase pathways, might be of interest...
January 19, 2017: Journal of Neurovirology
https://www.readbyqxmd.com/read/28078567/the-c-abl-inhibitor-in-parkinson-disease
#3
REVIEW
Zhi-Hua Zhou, Yun-Fan Wu, Xue-Min Wang, Yong-Zhu Han
Parkinson's disease (PD) is an insidious onset neurodegenerative disease affecting approximately 1% of the population over the age of 65. So far available therapies for PD have only aimed at improving or alleviating symptoms, but not at slowing, preventing, and reversing the course of PD. Recently, some studies have indicated that the levels and activation of Abelson non-receptor tyrosine kinase (c-Abl, Abl1) were up-regulated in the brain tissue of patients with PD and demonstrated that c-Abl inhibitors could improve motor behavior, prevent the loss of dopamine neurons, inhibit phosphorylation of Cdk5, regulate α-synuclein phosphorylation and clearance, inhibit the tyrosine phosphorylation of parkin and decrease parkin substrate, for example, PARIS (zinc finger protein 746), AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein type2), FBP1 (fuse-binding protein 1), and synphilin-1...
January 11, 2017: Neurological Sciences
https://www.readbyqxmd.com/read/28077789/biological-functions-of-cdk5-and-potential-cdk5-targeted-clinical-treatments
#4
REVIEW
Alison Shupp, Mathew C Casimiro, Richard G Pestell
Cyclin dependent kinases are proline-directed serine/threonine protein kinases that are traditionally activated upon association with a regulatory subunit. For most CDKs, activation by a cyclin occurs through association and phosphorylation of the CDK's T-loop. CDK5 is unusual because it is not typically activated upon binding with a cyclin and does not require T-loop phosphorylation for activation, even though it has high amino acid sequence homology with other CDKs. While it was previously thought that CDK5 only interacted with p35 or p39 and their cleaved counterparts, Recent evidence suggests that CDK5 can interact with certain cylins, amongst other proteins, which modulate CDK5 activity levels...
January 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28064242/cyclin-dependent-kinase-5-activity-is-required-for-allogeneic-t-cell-responses-after-hematopoietic-cell-transplantation-in-mice
#5
David Askew, Tej Pareek, Saada Eid, Sudipto Ganguly, Megan Tyler, Alex Y Huang, John J Letterio, Kenneth R Cooke
Molecular intermediates in T cell activation pathways are crucial targets for the therapy and prevention of graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (HCT). We recently identified an essential role for cyclin dependent kinase 5 (Cdk5) in T cell activation and effector function, but the contribution of Cdk5 activity to the development of GVHD has not been explored. Using an established, pre-clinical, murine, GVHD model we reveal that Cdk5 activity is increased in key target organs early after allogeneic HCT...
November 14, 2016: Blood
https://www.readbyqxmd.com/read/28052097/the-natural-flavonoid-fisetin-inhibits-cellular-proliferation-of-hepatic-colorectal-and-pancreatic-cancer-cells-through-modulation-of-multiple-signaling-pathways
#6
Mаhmoud Youns, Wael Abdel Halim Hegazy
Digestive cancers are major causes of mortality and morbidity worldwide. Fisetin, a naturally occurring flavonoid, has been previously shown anti-proliferative, anti-cancer, neuroprotective, and antioxidant activities. In our study, the anti-tumor activities in addition to regulatory effects of fisetin on some cancer cell lines were investigated. Data presented here showed that fisetin induces growth inhibition, and apoptosis in hepatic (HepG-2), colorectal (Caco-2) and pancreatic (Suit-2) cancer cell lines...
2017: PloS One
https://www.readbyqxmd.com/read/28045138/tfp5-peptide-derived-from-cdk5-activating-cofactor-p35-provides-neuroprotection-in-early-stage-of-adult-ischemic-stroke
#7
Ya-Bin Ji, Pei-Pei Zhuang, Zhong Ji, Yong-Ming Wu, Yong Gu, Xiao-Ya Gao, Su-Yue Pan, Ya-Fang Hu
Cyclin-dependent kinase 5 (CDK5) is a multifaceted protein shown to play important roles in the central nervous system. Abundant evidence indicates that CDK5 hyperactivities associated with neuronal apoptosis and death following ischemic stroke. CDK5 activity increases when its cofactor p35 cleaves into p25 during ischemia. Theoretically, inhibition of CDK5/p25 activity or reduction of p25 would be neuroprotective. TFP5, a modified 24-aa peptide (Lys254-Ala277) derived from p35, was found to effectively inhibit CDK5 hyperactivity and improve the outcomes of Alzheimer's disease and Parkinson's disease in vivo...
January 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28024901/cyclin-dependent-kinase-5-contributes-to-endoplasmic-reticulum-stress-induced-podocyte-apoptosis-via-promoting-mekk1-phosphorylation-at-ser280-in-diabetic-nephropathy
#8
Yue Zhang, Xiang Gao, Shuanggang Chen, Min Zhao, Jing Chen, Rui Liu, Shengyang Cheng, Mengyuan Qi, Shuo Wang, Wei Liu
Endoplasmic reticulum (ER) stress has been reported to be associated with podocyte apoptosis in diabetic nephropathy, but the mechanism of ER signaling in podocyte apoptosis hasn't been fully understood. Our previous studies have demonstrated that Cyclin-dependent kinase 5 (Cdk5) was associated with podocyte apoptosis in diabetic nephropathy. The present study was designed to examine whether and how Cdk5 activity plays a role in ER stress induced podocyte apoptosis in diabetic nephropathy. The results showed that along with induction of Cdk5 and apoptosis, GRP78 and its two sensors as well as CHOP and cleaved caspase-12 were induced in high glucose treated podocytes...
December 24, 2016: Cellular Signalling
https://www.readbyqxmd.com/read/28008944/amyloid-precursor-protein-modulates-nav1-6-sodium-channel-currents-through-a-go-coupled-jnk-pathway
#9
Shao Li, Xi Wang, Quan-Hong Ma, Wu-Lin Yang, Xiao-Gang Zhang, Gavin S Dawe, Zhi-Cheng Xiao
Amyloid precursor protein (APP), commonly associated with Alzheimer's disease, also marks axonal degeneration. In the recent studies, we demonstrated that APP aggregated at nodes of Ranvier (NORs) in myelinated central nervous system (CNS) axons and interacted with Nav1.6. However, the physiological function of APP remains unknown. In this study, we described reduced sodium current densities in APP knockout hippocampal neurons. Coexpression of APP or its intracellular domains containing a VTPEER motif with Nav1...
December 23, 2016: Scientific Reports
https://www.readbyqxmd.com/read/28004803/convergent-evidence-for-the-molecular-basis-of-musical-traits
#10
Jaana Oikkonen, Päivi Onkamo, Irma Järvelä, Chakravarthi Kanduri
To obtain aggregate evidence for the molecular basis of musical abilities and the effects of music, we integrated gene-level data from 105 published studies across multiple species including humans, songbirds and several other animals and used a convergent evidence method to prioritize the top candidate genes. Several of the identified top candidate genes like EGR1, FOS, ARC, BDNF and DUSP1 are known to be activity-dependent immediate early genes that respond to sensory and motor stimuli in the brain. Several other top candidate genes like MAPK10, SNCA, ARHGAP24, TET2, UBE2D3, FAM13A and NUDT9 are located on chromosome 4q21-q24, on the candidate genomic region for music abilities in humans...
December 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27998781/tfp5-is-comparable-to-mild-hypothermia-in-improving-neurological-outcomes-in-early-stage-ischemic-stroke-of-adult-rats
#11
Ya-Bin Ji, Pei-Pei Zhuang, Zhong Ji, Kai-Bin Huang, Yong Gu, Yong-Ming Wu, Su-Yue Pan, Ya-Fang Hu
AIM: We compared the efficacy of a modified truncated 24-aa peptide (TFP5), derived from the cyclin-dependent kinase 5 (CDK5)-activating cofactor p35, with mild hypothermia (MH), and determined whether the efficacy of TFP5 is affected by MH. METHODS: Ischemic stroke was induced in adult male Sprague-Dawley rats for 2h. Immediately after initiating reperfusion, TFP5, MH, or the combination of the two were administrated. 48h after reperfusion, neurological outcomes were evaluated...
December 18, 2016: Neuroscience
https://www.readbyqxmd.com/read/27991934/ras-oncogene-independent-activation-of-ralb-signaling-is-a-targetable-mechanism-of-escape-from-nras-v12-oncogene-addiction-in-acute-myeloid-leukemia
#12
E J Pomeroy, L A Lee, R D W Lee, D K Schirm, N A Temiz, J Ma, T A Gruber, E Diaz-Flores, B S Moriarity, J R Downing, K M Shannon, D A Largaespada, C E Eckfeldt
Somatic mutations that lead to constitutive activation of NRAS and KRAS proto-oncogenes are among the most common in human cancer and frequently occur in acute myeloid leukemia (AML). An inducible NRAS(V12)-driven AML mouse model has established a critical role for continued NRAS(V12) expression in leukemia maintenance. In this model genetic suppression of NRAS(V12) expression results in rapid leukemia remission, but some mice undergo spontaneous relapse with NRAS(V12)-independent (NRI) AMLs providing an opportunity to identify mechanisms that bypass the requirement for Ras oncogene activity and drive leukemia relapse...
December 19, 2016: Oncogene
https://www.readbyqxmd.com/read/27974179/browning-of-white-adipose-tissue-with-roscovitine-induces-a-distinct-population-of-ucp1-adipocytes
#13
Hong Wang, Libin Liu, Jean Z Lin, Tamar R Aprahamian, Stephen R Farmer
Brown-like adipocytes exist in several adipose depots including white (WAT) as well as brown (BAT). Activation of these UCP1(+) cells is a potential therapeutic strategy to combat obesity. Studies have shown that posttranslational modifications of PPARγ regulate select adipocyte programs. Deacetylation of K268 and K293 in the ligand-binding domain of PPARγ by Sirt1 induces browning of WAT. Phosphorylation of S273 of PPARγ by CDK5 or ERK stimulates a diabetogenic program of gene expression in WAT. Here, we report that roscovitine, a CDK inhibitor, prevents S273 phosphorylation and promotes formation of UCP1(+) (brite) adipocytes in WAT...
December 13, 2016: Cell Metabolism
https://www.readbyqxmd.com/read/27940993/cdk5-regulation-of-the-grab-mediated-rab8-rab11-cascade-in-axon-outgrowth
#14
Kotaro Furusawa, Akiko Asada, Pamela Urrutia, Christian Gonzalez-Billault, Mitsunori Fukuda, Shin-Ichi Hisanaga
: Neurons communicate with each other through their axons and dendrites. However, a full characterization of the molecular mechanisms involved in axon and dendrite formation is still incomplete. Neurite outgrowth requires the supply of membrane components for surface expansion. Two membrane sources for axon outgrowth are suggested, Golgi secretary vesicles and endocytic recycling endosomes. In non-neuronal cells, trafficking of secretary vesicles from Golgi is regulated by Rab8, a member of Rab small GTPases, and that of recycling endosomes is by Rab11, another member of Rabs...
December 9, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27926980/role-and-regulation-of-p27-in-neuronal-apoptosis
#15
Surbhi Jaiswal, Pushkar Sharma
It is necessary for the cell cycle machinery of neurons to be suppressed to promote differentiation and maintenance of their terminally differentiated state. Reactivation of the cell cycle in response to neurotoxic insults leads to neuronal cell death and some cell cycle related proteins contribute to the process. p27 kip1 (p27), an inhibitor of Cyclin Dependent Kinases (CDKs), prevents unwarranted CDK activation. In the present study, we have elucidated a novel mechanism via which p27 promotes apoptosis of neurons stimulated by neurotoxic amyloid peptide Aβ42 (Amyloid β1-42 peptide)...
December 7, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27917413/efficacy-of-s-lacosamide-in-preclinical-models-of-cephalic-pain
#16
Aubin Moutal, Nathan Eyde, Edwin Telemi, Ki Duk Park, Jennifer Y Xie, David W Dodick, Frank Porreca, Rajesh Khanna
Migraine is one of the world's most common neurological disorders. Current acute migraine treatments have sub-optimal efficacy and new therapeutic options are needed. Approaches targeting calcitonin gene related peptide (CGRP) signaling are clinically effective but small molecule antagonists have not been advanced due to toxicity. In this study, we explored the axonal growth/specification collapsin response mediator protein 2 (CRMP2) as a novel "druggable" target for inhibiting CGRP release and for potential relevance for treatment of migraine pain...
June 2016: Pain Reports (Baltimore, Md.)
https://www.readbyqxmd.com/read/27917404/the-emerging-role-of-cdk5-in-cancer
#17
Karine Pozo, James A Bibb
Cdk5 is an atypical cyclin-dependent kinase that is well characterized for its role in the central nervous system rather than in the cell cycle. However Cdk5 has been recently implicated in the development and progression of a variety of cancers including breast, lung, colon, pancreatic, melanoma, thyroid and brain tumors. This broad pro-tumorigenic role makes Cdk5 a promising drug target for the development of new cancer therapies. Here we review the contribution of Cdk5 to molecular mechanisms that confer upon tumors the ability to grow, proliferate and disseminate to secondary organs, as well as resistance to chemotherapies...
October 2016: Trends in Cancer
https://www.readbyqxmd.com/read/27909065/cdk5-directly-targets-nuclear-p21cip1-and-promotes-cancer-cell-growth
#18
Pao-Hsuan Huang, Mei-Chih Chen, Yu-Ting Peng, Wei-Hsiang Kao, Chih-Hsiang Chang, Yun-Chi Wang, Chih-Ho Lai, Jer-Tsong Hsieh, Jo-Hsin Wang, Yueh-Tsung Lee, Eugene Lin, Chia-Herng Yue, Hsin-Yi Wang, Shuen-Chi You, Ho Lin
The significance of Cdk5 in cell-cycle control and cancer biology has gained increased attention. Here we report the inverse correlation between the protein levels of Cdk5 and p21(CIP1) from cell-based and clinical analysis. Mechanistically, we identify that Cdk5 overexpression triggers the proteasome-dependent degradation of p21(CIP1) through a S130 phosphorylation in a Cdk2-independent manner. Besides, the evidence from cell-based and clinical analysis shows that Cdk5 primarily regulates nuclear p21(CIP1) protein degradation...
December 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27881952/tissue-type-plasminogen-activator-tpa-modulates-the-postsynaptic-response-of-cerebral-cortical-neurons-to-the-presynaptic-release-of-glutamate
#19
Valerie Jeanneret, Fang Wu, Paola Merino, Enrique Torre, Ariel Diaz, Lihong Cheng, Manuel Yepes
Tissue-type plasminogen activator (tPA) is a serine proteinase released by the presynaptic terminal of cerebral cortical neurons following membrane depolarization (Echeverry et al., 2010). Recent studies indicate that the release of tPA triggers the synaptic vesicle cycle and promotes the exocytosis (Wu et al., 2015) and endocytic retrieval (Yepes et al., 2016) of glutamate-containing synaptic vesicles. Here we used electron microscopy, proteomics, quantitative phosphoproteomics, biochemical analyses with extracts of the postsynaptic density (PSD), and an animal model of cerebral ischemia with mice overexpressing neuronal tPA to study whether the presynaptic release of tPA also has an effect on the postsynaptic terminal...
2016: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/27878757/targeting-ccr3-to-reduce-amyloid-%C3%AE-production-tau-hyperphosphorylation-and-synaptic-loss-in-a-mouse-model-of-alzheimer-s-disease
#20
Chunyan Zhu, Bing Xu, Xiaohong Sun, Qiwen Zhu, Yi Sui
The majority of Alzheimer's disease (AD) patients have a late onset, and chronic neuroinflammation, characterized by glial activation and secretion of pro-inflammatory cytokines and chemokines, plays a role in the pathogenesis of AD. The chemokine CCL11 has been shown to be a causative factor of cognitive decline in the process of aging, but little is known whether it is involved in the pathogenesis of AD. In the present study, we showed that CCR3, the receptor for CCL11, was expressed by hippocampal neurons and treatment of primary hippocampal neuronal cultures (14 days in vitro) with CCL11 resulted in activation of cyclin-dependent kinase 5 and glycogen synthase kinase-3β, associated with elevated tau phosphorylation at multiple sites...
November 23, 2016: Molecular Neurobiology
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