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ACS Chemical Neuroscience

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https://read.qxmd.com/read/30785719/tdp-43-a-key-therapeutic-target-beyond-amyotrophic-lateral-sclerosis
#1
Valle Palomo, Carlota Tosat-Bitrian, Vanesa Nozal, Siranjeevi Nagaraj, Angeles Martin-Requero, Ana Martínez
Accumulation of TDP-43 in the cytoplasm of diseased neurons is the pathological hallmark of Frontotemporal Dementia-TDP (FTLD-TDP) and Amyotrophic Lateral Sclerosis (ALS), two diseases that lack of efficacious medicine to prevent or to stop disease progression. The discovery that mutations in the TARDBP gene (coding for the nuclear protein known as TDP-43) in both FTLD and ALS patients provided evidence for a link between TDP-43 alterations and neurodegeneration. The knowledge of TDP-43 function has advanced profoundly in the last years, however its complete role and the molecular mechanisms that lead to disease have yet to be fully understood...
February 20, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30785261/abnormal-microtubule-dynamics-impair-the-nuclear-cytoplasmic-transport-in-dementia
#2
Timir Tripathi, Jupitara Kalita
Disrupted nuclear-cytoplasmic transport (NCT) is a common pathophysiological event in several neurodegenerative disorders. However, the correlation between the mutations in the pathogenic microtubule-associated protein tau and NCT and neuronal dysfunction is not yet clearly understood. A recent study revealed that tau is mislocalized to the neuronal cell body and, thus, deforms the nuclear membrane in the frontotemporal dementia (FTD). This causes a defect in NCT, leading to neurodegeneration. The microtubule depolymerization could rescue the NCT defects as well as neurodegeneration...
February 20, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30785257/cryo-electron-microscopy-uncovers-key-residues-within-the-core-of-alpha-synuclein-fibrils
#3
Ritobrita Chakraborty, Krishnananda Chattopadhyay
Recent expeditious advances in the determination of the 3-D structure of fibrils of alpha-synuclein, the intrinsically disordered protein associated with the neurodegenerative Parkinson's disease (PD), have identified amino acid contacts that form the fibril's inter-protofilament interface. The residues that constitute this "steric zipper" interface determine the morphology of the fibrils as well as toxicity of the oligomeric building units or "kernels" which lead to the formation of the protofilaments...
February 20, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30785256/the-contributions-of-mtor-activation-mediated-upregulation-of-synapsin-ii-and-neurite-outgrowth-to-hyperalgesia-in-stz-induced-diabetic-rats
#4
Wan-You He, Bin Zhang, Wei-Cheng Zhao, Jian He, Lei Zhang, Qing-Ming Xiong, Jing Wang, Han-Bing Wang
Painful diabetic neuropathy (PDN) is among the common complications in diabetes mellitus (DM), with its underlying mechanisms largely unknown. Synapsin II is primarily expressed in the spinal dorsal horn, and its upregulation mediates a superfluous release of glutamate and a deficiency of GABAergic interneuron synaptic transmission, which is directly implicated in the facilitation of pain signals in the hyperalgesic nociceptive response. Recently, synapsin II has been revealed to be associated with the modulation of neurite outgrowth, whereas the process of this neuronal structural neuroplasticity following neuronal hyperexcitability still remains unclear...
February 20, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30784262/how-chirality-determines-the-selective-inhibition-of-histone-deacetylase-6-a-lesson-from-trichostatin-a-enantiomers-based-on-molecular-dynamics
#5
Yang Zhang, Junbiao Ying, Jiajun Hong, Fengcheng Li, Tingting Fu, Fengyuan Yang, Guoxun Zheng, Xiaojun Yao, Yan Lou, Yun Qing Qiu, Weiwei Xue, Feng Zhu
Histone deacetylase 6 (HDAC6) plays a key role in a variety of neurological disorders, which makes it attractive drug target for the treatment of Alzheimer's disease, Parkinson disease and memory/learning impairment. The selectivity of HDAC6 inhibitors (sHDAC6Is) are widely considered to be susceptible to their sizes of Cap group and their physicochemical properties of linker or zinc-binding group, which makes the discovery of new sHDAC6Is extremely difficult. With the discovery of the distinct selectivity between Trichostatin A (TSA) enantiomers, the chirality residing in the connective units between TSA's Cap and linker shows a great impact on its selectivity...
February 20, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30767510/locked-azobenzene-testing-the-scope-of-a-unique-photoswitchable-scaffold-for-cell-physiology
#6
Ek Raj Thapaliya, Jun Zhao, Graham C R Ellis-Davies
Azobenzenes are the most widely studied photoswitches, and have become popular optical probes for biological systems. The cis configuration is normally metastable, meaning the trans configuration is always thermodynamically favored. The unique exception to this rule is an azobenzene having a two-carbon bridge between ortho positions, substitutions that lock the photoswitch in its cis configuration. Only thoroughly chemically characterized relatively recently, we describe the first applications of this locked-azobenzene (or "LAB") scaffold with two derivatives designed to control ion flow in pyramidal neurons in acutely isolated brain slices...
February 15, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30763071/nanovector-mediated-drug-delivery-in-spinal-cord-injury-a-multitarget-approach
#7
Simonetta Papa, Filippo Rossi, Irma Vismara, Gianluigi Forloni, Pietro Veglianese
Many pre-clinical studies seek cures for spinal cord injury (SCI) but when the results are translated to clinical trials they give scant efficacy. One possible reason is that most strategies use treatments directed toward a single pathological mechanism, while a multitherapeutic approach needs to be tested to significantly improve outcomes after SCI. Most of the pre-clinical reports gave better outcomes when a combination of different compounds was used instead of a single drug. This promising approach, however, must still be improved because it raises some criticism: i) the Blood-Spinal Cord barrier limits drug distribution, ii) it is hard to understand the interactions among the pharmacological components after systemic administration, iii) the timing of treatments is crucial: the spread of the lesion is a process finely regulated over time, so therapies must be scheduled at precise times during the post-injury course...
February 14, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30763068/the-anticancer-drug-tamoxifen-affects-catecholamine-transmitter-release-and-storage-from-single-cells
#8
Zahra Taleat, Anna Larsson, Andrew G Ewing
Electrochemical measurements of exocytosis combined with intracellular vesicle impact electrochemical cytometry have been used to evaluate the effect of an anticancer drug, tamoxifen, on catecholamine release at the single cell level. Tamoxifen has been used for over 40 years to treat estrogen receptor positive breast cancers during both early stages of the disease and in the adjuvant setting. Tamoxifen causes memory and cognitive dysfunction, but the reasons for the cognitive impairment and memory problems induced by this anti-cancer drug are not well known...
February 14, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30763065/photoconversion-of-fm1-43-reveals-differences-in-synaptic-vesicle-recycling-and-sensitivity-to-pharmacological-disruption-of-actin-dynamics-in-individual-synapses
#9
Alberto Rampérez, David Bartolome-Martin, Angeles García-Pascual, Jose Sanchez-Prieto, Magdalena Torres
The cycling of synaptic vesicles ensures that neurons can communicate adequately through their synapses on repeated occasions when activity is sustained, and several steps in this cycle are modulated by actin. The effects of pharmacological stabilization of actin with jasplakinolide or its depolymerization with latrunculin A was assessed on the synaptic vesicle cycle at individual boutons of cerebellar granule cells, using FM1-43 imaging to track vesicle recycling and its photoconversion to specifically label recycled organelles...
February 14, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30763064/ordered-and-disordered-segments-of-amyloid-%C3%AE-drive-sequential-steps-of-the-toxic-pathway
#10
Barun Kumar Maity, Anand Kant Das, Simli Dey, Ullhas Kaarthi Moorthi, Amandeep Kaur, Arpan Dey, Dayana Surendran, Rucha Pandit, Mamata Kallianpur, Bappaditya Chandra, Muralidharan Chandrakesan, Senthil Arumugam, Sudipta Maiti
While the roles of intrinsically disordered protein domains in driving many interactions are increasingly well-appreciated, the mechanism of toxicity of disease-causing disordered proteins remains poorly understood. A prime example is Alzheimer's disease (AD) associated amyloid beta (Aβ). Aβ oligomers are highly toxic partially structured peptide assemblies with a distinct ordered region (residues ~10-40) and a shorter disordered region (residues ~1-9). Here, we investigate the role of this disordered domain and its relation to the ordered domain in the manifestation of toxicity through a set of Aβ fragments and stereo-isomers designed for this purpose...
February 14, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30763060/identifying-new-amp-activated-protein-kinase-inhibitors-that-protect-against-ischemic-brain-injury
#11
Jae-Won Eom, Tae-Youn Kim, Bo-Ra Seo, Hwangseo Park, Jae-Young Koh, Yang-Hee Kim
We recently reported that AMP-activated protein kinase (AMPK) contributes to zinc-induced neuronal death by inducing Bim, a pro-apoptotic Bcl-2 homology domain 3-only protein, in a liver kinase B1 (LKB1)-dependent manner. Current data suggest AMPK plays key roles in excitotoxicity and ischemic brain injury, with zinc neurotoxicity representing at least one mechanism of ischemic neuronal death. Inhibition of AMPK could be a viable therapeutic strategy to prevent ischemic brain injury following stroke. This prompted our search for novel inhibitors of AMPK activity and zinc-induced neuronal death using cultured mouse cortex and a rat model of brain injury after middle cerebral artery occlusion (MCAO)...
February 14, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30758946/characterization-of-17-cyclopropylmethyl-3-14%C3%AE-dihydroxy-4-5%C3%AE-epoxy-6%C3%AE-indole-7-carboxamido-morphinan-nan-as-a-novel-opioid-receptor-modulator-for-opioid-use-disorder-treatment
#12
Samuel Obeng, Abdulmajeed Jali, Yi Zheng, Huiqun Wang, Kathryn Schwienteck, Chongguang Chen, David L Stevens, Hamid Akbarali, William L Dewey, Matthew L Banks, Lee-Yuan Liu-Chen, Dana E Selley, Yan Zhang
The opioid crisis is a significant public health issue with more than 115 people dying from opioid overdose per day in the US. The aim of the present study was to characterize the in vitro and in vivo pharmacological effects of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(indole-7-carboxamido)morphinan (NAN), a  opioid receptor (MOR) ligand that may be a potential candidate for opioid use disorder treatment that produces less withdrawal signs than naltrexone. The efficacy of NAN was compared to varying efficacy ligands at the MOR, and determined at the δ opioid receptor (DOR) and κ opioid receptor (KOR)...
February 13, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30754968/direct-real-time-detection-of-adenosine-triphosphate-release-from-astrocytes-in-3-dimensional-culture-using-an-integrated-electrochemical-aptamer-based-sensor
#13
Mirelis Santos-Cancel, Laura Walker Simpson, Jennie B Leach, Ryan J White
In this manuscript, we describe the development and application of electrochemical, aptamer-based (E-AB) sensors directly interfaced with astrocytes in three-dimensional (3D) cell culture to monitor stimulated release of adenosine triphosphate (ATP). The aptamer-based sensor couples specific detection of ATP, selective performance directly in cell culture media, and seconds time resolution using squarewave voltammetry for quantitative ATP-release measurements. More specifically, we demonstrate the ability to quantitatively monitor ATP release into the extracellular environment after stimulation by the addition of calcium (Ca2+), ionomycin, and glutamate...
February 12, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30753053/neuroprotective-effect-of-swertiamain-on-cerebral-ischemia-reperfusion-injury-by-inducing-the-nrf2-protective-pathway
#14
Hui Wang, Wei Wei, Xiaobing Lan, Ning Liu, Yuxiang Li, Hanxiang Ma, Tao Sun, Xiaodong Peng, Chunlin Zhuang, Jian Qiang Yu
Oxidative stress plays a vital role in the development of cerebral ischemic/reperfusion (I/R). Targeting oxidative stress is proposed to be an effective strategy to treat cerebral I/R injury. Gentiana macrophylla Pall is reported to have potential protective effect against stroke. Swertiamarin (Swe), an active secoiridoid glycoside compound isolated from Gentiana macrophylla Pall, has been reported to possess the antioxidative potential. This study is to explore whether Swe could prevent brain from I/R injury and the related mechanisms of oxidative stress is also elucidated using mice middle cerebral artery occlusion (MCAO) model and primary hippocampal neurons oxygen-glucose deprivation/reperfusion (OGD/R) model...
February 12, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30694044/functional-interrogation-of-a-depression-related-serotonergic-single-nucleotide-polymorphism-rs6295-using-a-humanized-mouse-model
#15
Ashley M Cunningham, Tabia L Santos, Vanessa A Gutzeit, Heather Hamilton, René Hen, Zoe R Donaldson
The serotonin 1A receptor (5-HT1A) system has been extensively implicated in modulating mood and behavior. Notably, 5-HT1A levels in humans display remarkable variation, and differences in receptor levels have been linked with a variety of psychiatric disorders. Further, reduction of receptor levels by 30-50% in mice suggests that changes in receptor levels that model existing human variation are sufficient to drive behavioral alterations. As a result, genetic mechanisms that modulate human 5-HT1A levels may be important for explaining individual differences in mood and behavior, representing a potential source of psychiatric disease risk...
February 12, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30741526/cdh1-mediated-metabolic-switch-from-pentose-phosphate-pathway-to-glycolysis-contributes-to-sevoflurane-induced-neuronal-apoptosis-in-developing-brain
#16
Bin Liu, Wenjie Bai, Guoyao Ou, Jun Zhang
Cdh1 is a regulatory subunit of the anaphase promoting complex/cyclosome (APC/C), known to be involved in regulating neuronal survival. The role of Cdh1 in volatile anesthetics-induced neuronal apoptosis in the developing brain is unknown. In this study, we used postnatal day 7 (P7) and day 21 (P21) mice exposed to 2.3% sevoflurane for 6 h to investigate at which age and duration of exposure sevoflurane affects the expression of Cdh1 and glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and that of the pentose phosphate pathway (PPP) enzyme, Glucose-6-phosphate dehydrogenase (G6PD)...
February 11, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30698408/genetic-analyses-of-alzheimer-s-disease-in-china-achievements-and-perspectives
#17
Deng-Feng Zhang, Min Xu, Rui Bi, Yong-Gang Yao
Since 2010, the Chinese have become one of the most aged populations in the world, leading to a severe burden of neurodegenerative disorders. Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and has a high genetic heritability. In the past two decades, numerous genetic analyses, from linkage analyses and candidate gene studies to genome-wide association studies (GWASs) and next-generation sequencing studies, have identified dozens of AD susceptibility or causal genes. These studies have provided a comprehensive genetic view and contributed to the understanding of the pathological and molecular mechanisms of the disease...
February 8, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30726666/neuropeptide-pen-and-its-receptor-gpr83-distribution-signaling-and-regulation
#18
Seshat M Mack, Ivone Gomes, Lakshmi A Devi
Neuropeptides are peptide neuromodulators that are expressed by neurons and act on neural targets by activating neuropeptide receptors1. These receptors serve as therapeutic targets for the treatment of a number of pathophysiological conditions, including obesity, pain and addiction2-6. Major technological advances in the 1980s involving improved sensitivity of peptide purification methods and single neuron mRNA sequencing techniques have led to an explosion in the number of newly discovered neuropeptides7...
February 6, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30724553/the-curious-case-of-human-hippocampal-neurogenesis
#19
Sonu Gandhi, Jalaj Gupta, Prem Prakash Tripathi
Neurogenesis in the human brain has been validated to occur throughout adulthood. Recently, the human hippocampal neurogenesis field has been shaken by two significant reports that have been published with opposite reports, and these path-breaking studies have flipped the bandwagon of the neurogenesis field upside down, by questioning the existence of human hippocampal neurogenesis. Here, we discuss the findings by these two prominent papers, dissecting the potential reasons for conflicting results, insisting on the need to understand new observations critically, and further highlighting in what way the existing knowledge of adult hippocampal neurogenesis relates to the human...
February 6, 2019: ACS Chemical Neuroscience
https://read.qxmd.com/read/30721026/visualization-and-identification-of-neurotransmitters-in-crustacean-brain-via-multifaceted-mass-spectrometric-approaches
#20
Qinjingwen Cao, Yijia Wang, Bingming Chen, Fengfei Ma, Ling Hao, Gongyu Li, Chuanzi Ouyang, Lingjun Li
Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) has emerged as a label-free analytical tool for fast biomolecule profiling on tissue sections. Among various functional molecules, mapping neurotransmitters and related metabolites is of tremendous significance, as these compounds are critical to signaling and neuron communication in the central nervous system. Here, we demonstrated the use of both derivatization and reaction-free approaches that greatly reduced signal complexity and thus enabled complementary signaling molecule visualization on crab brain sections via MALDI-LTQ-Orbitrap XL platform...
February 5, 2019: ACS Chemical Neuroscience
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