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Neurotoxicity

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https://www.readbyqxmd.com/read/28934392/nceh-1-modulates-cholesterol-metabolism-and-protects-against-%C3%AE-synuclein-toxicity-in-a-c-elegans-model-of-parkinson-s-disease
#1
Siyuan Zhang, Samantha A Glukhova, Kim A Caldwell, Guy A Caldwell
Parkinson's disease (PD) is an aging-associated neurodegenerative disease affecting millions worldwide. Misfolding, oligomerization and accumulation of the human α-synuclein protein is a key pathological hallmark of PD and is associated with the progressive loss of dopaminergic neurons over the course of aging. Lifespan extension via the suppression of IGF-1/insulin-like signaling (IIS) offers a possibility to retard disease onset through induction of metabolic changes that provide neuroprotection. The nceh-1 gene of Caenorhabditis elegans encodes an ortholog of neutral cholesterol ester hydrolase 1 (NCEH-1), an IIS downstream protein that was identified in a screen as a modulator of α-synuclein accumulation in vivo...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28934390/protein-phosphatase-1-regulates-huntingtin-exon-1-aggregation-and-toxicity
#2
Joana Branco-Santos, Federico Herrera, Gonçalo M Poças, Yolanda Pires-Afonso, Flaviano Giorgini, Pedro M Domingos, Tiago F Outeiro
Huntington's disease is neurodegenerative disorder caused by a polyglutamine expansion in the N-terminal region of the huntingtin protein (N17). Here, we analysed the relative contribution of each phosphorylatable residue in the N17 region (T3, S13 and S16) towards huntingtin exon 1 (HTTex1) oligomerization, aggregation and toxicity in human cells and Drosophila neurons. We used bimolecular fluorescence complementation to show that expression of single phosphomimic mutations completely abolished HTTex1 aggregation in human cells...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28934387/mutations-in-tgm6-induce-the-unfolded-protein-response-in-sca35
#3
Debasmita Tripathy, Beatrice Vignoli, Nandini Ramesh, Maria Jose Polanco, Marie Coutelier, Christopher D Stephen, Marco Canossa, Marie-Lorraine Monin, Pascale Aeschlimann, Shannon Turberville, Daniel Aeschlimann, Jeremy D Schmahmann, Marios Hadjivassiliou, Alexandra Durr, Udai B Pandey, Maria Pennuto, Manuela Basso
Spinocerebellar ataxia type 35 (SCA35) is a rare autosomal-dominant neurodegenerative disease caused by mutations in the TGM6 gene, which codes for transglutaminase 6 (TG6). Mutations in TG6 induce cerebellar degeneration by an unknown mechanism. We identified seven patients bearing new mutations in TGM6. To gain insights into the molecular basis of mutant TG6-induced neurotoxicity, we analyzed all the seven new TG6 mutants and the five TG6 mutants previously linked to SCA35. We found that the wild-type (TG6-WT) protein mainly localized to the nucleus and perinuclear area, whereas five TG6 mutations showed nuclear depletion, increased accumulation in the perinuclear area, insolubility and loss of enzymatic function...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28933786/pink1-interacts-with-%C3%AE-synuclein-and-abrogates-%C3%AE-synuclein-induced-neurotoxicity-by-activating-autophagy
#4
Jia Liu, Xue Wang, Yongquan Lu, Chunli Duan, Ge Gao, Lingling Lu, Hui Yang
Parkinson's disease (PD) is one of the most common neurodegenerative diseases, characterized by degeneration of dopaminergic neurons in the substantia nigra. α-synuclein (α-syn) and PTEN-induced putative kinase (PINK)1 are two critical proteins associated with the pathogenesis of PD. α-syn induces mitochondrial deficits and apoptosis, PINK1 was found to alleviate α-syn-induced toxicity, but the mechanistic details remain obscure. Here, we show that PINK1 interacts with α-syn mainly in the cytoplasm, where it initiates autophagy...
September 21, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28931341/the-neurotoxic-effects-of-prenatal-gabapentin-and-oxcarbazepine-exposure-on-newborn-rats
#5
Zuleyha Erisgin, Bulent Ayas, Jens R Nyengaard, N Ercument Beyhun, Yuksel Terzi
Teratogenicity is a problematic issue for pregnant women because of x-ray radiation, drugs, genetic and unknown variables. First generation antiepileptic drugs (AED) like valproic acid are well-known teratogens for developing foetuses. However, their usage is necessary in order to prevent maternal seizures. The underlying mechanism of birth defects associated with AED exposure remains unclear and information about the neurotoxic effects of prenatal exposure to AED is still limited. Oxcarbazepine (OXC) and gabapentin (GBP) are second generation antiepileptic drugs...
September 20, 2017: Journal of Maternal-fetal & Neonatal Medicine
https://www.readbyqxmd.com/read/28931287/enhanced-capture-of-bacteria-and-endotoxin-by-antimicrobial-wlbu2-peptide-tethered-on-polyethylene-oxide-spacers
#6
Ramya Raman, Miranda A Raper, Erik Hahn, Kate F Schilke
Severe sepsis is a life threatening immune response that may be caused by endotoxins (lipopolysaccharides) in circulating bacterial cell wall fragments. Hemoperfusion through a sorbent column coated with the antimicrobial peptide polymyxin B (PMB) is a promising treatment for sepsis. However, PMB is cytotoxic and neurotoxic, and is a membrane disruptor that may fragment endotoxin vesicles. In addition, the blood is not protected from nonspecific interactions with the synthetic surface of the solid support. These effects may be responsible for the variety of undesirable clinical outcomes, including nonspecific adsorption of proteins, blood cell damage, platelet activation, and a lack of clear evidence of efficacy of the current hemoperfusion products...
September 20, 2017: Biointerphases
https://www.readbyqxmd.com/read/28930619/asiatic-acid-nullified-aluminium-toxicity-in-in-vitro-model-of-alzheimer-s-disease
#7
Mashoque Ahmad Rather, Arokiasamy Justin Thenmozhi, Thamilarasan Manivasagam, Jegadeesan Nataraj, Musthafa Mohamed Essa, Saravana Babu Chidambaram
Aluminium (Al) is a ubiquitously distributed environmental toxicant that lacks biological functions; however, its accumulation in the brain has been demonstrated to be linked to several neuropathological conditions particularly Alzheimer's disease (AD). Asiatic acid (AA), a triterpene extracted from Centella asiatica, has been reported to cross the blood brain barrier and also displayed antioxidant and neuroprotective activities. The present study was aimed to explore the neuroprotective effect of AA against aluminium maltolate (Al(mal)3) induced neurotoxicity by assessing cell viability, mitochondrial membrane potential, levels of reactive oxygen species (ROS), DNA damage and apoptosis (Hoechst and dual staining, comet assay; expressions of pro-apoptotic, anti-apoptotic and signaling indices) via AKT/GSK-3β signaling pathway in SH-SY 5Y  neuroblastoma cells...
January 1, 2018: Frontiers in Bioscience (Elite Edition)
https://www.readbyqxmd.com/read/28930615/role-for-apolipoprotein-e-in-neurodegeneration-and-mercury-intoxication
#8
Gabriela de Paula Fonseca Arrifano, Marcus Augusto de Oliveira, Jose Rogerio Souza-Monteiro, Ricardo Oliveira Paraense, Andrea Ribeiro-Dos-Santos, Jose Richardo Dos Santos Vieira, Artur Luis da Costa Silva, Barbarella de Matos Macchi, Jose Luiz Martins do Nascimento, Rommel Mario Rodriguez Burbano, Maria Elena Crespo-Lopez
Mercury intoxication is a serious public health problem and a worldwide concern. The Minamata Convention on Mercury has been signed by 128 countries and endorsed by the World Health Organization with the recommendation of promoting the management of epidemiological information. The Central Nervous System is the main target organ for mercury. Symptoms of intoxication include altered motor coordination, visual and tactile dysfunction and paralysis, caused by neurodegeneration with a key role for oxidative damage...
January 1, 2018: Frontiers in Bioscience (Elite Edition)
https://www.readbyqxmd.com/read/28930140/identification-of-phlogacantholide-c-as-a-novel-adam10-enhancer-from-traditional-chinese-medicinal-plants
#9
Myriam Meineck, Florian Schuck, Sara Abdelfatah, Thomas Efferth, Kristina Endres
Background: Alzheimer's disease is one of the most prevalent dementias in the elderly population with increasing numbers of patients. One pivotal hallmark of this disorder is the deposition of protein aggregates stemming from neurotoxic amyloid-beta peptides. Synthesis of those peptides has been efficiently prevented in AD model mice by activation of an enzyme called alpha-secretase. Therefore, drugs with the capability to increase the expression of this enzyme, named ADAM10, have been suggested as a valuable therapeutic medication...
December 5, 2016: Medicines (Basel, Switzerland)
https://www.readbyqxmd.com/read/28929435/neuroprotective-effects-of-galantamine-on-nerve-agent-induced-neuroglial-and-biochemical-changes
#10
RamaRao Golime, Meehir Palit, J Acharya, D K Dubey
Neuroprotection from nerve agent such as soman-induced neural damage is a major challenge for existing drugs. Nerve agent exposure can cause many neural effects in survivors arising mainly due to acetylcholinesterase (AChE) inhibition or death within minutes. Unraveling the mechanisms underlying the nerve agent-induced multiple neurological effects is useful to develop better and safe drugs. The present study aimed to understand the molecular response during soman exposure and to evaluate the neuroprotective efficacy of galantamine on nerve agent-induced neurotoxic changes...
September 19, 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/28929003/fatal-cobalt-toxicity-after-a-non-metal-on-metal-total-hip-arthroplasty
#11
Rinne M Peters, Pax Willemse, Paul C Rijk, Mels Hoogendoorn, Wierd P Zijlstra
This case illustrates the potential for systemic cobalt toxicity in non-metal-on-metal bearings and its potentially devastating consequences. We present a 71-year-old male with grinding sensations in his right hip following ceramic-on-ceramic total hip arthroplasty (THA). After diagnosing a fractured ceramic liner, the hip prosthesis was revised into a metal-on-polyethylene bearing. At one year postoperatively, X-rays and MARS-MRI showed a fixed reversed hybrid THA, with periarticular densities, flattening of the femoral head component, and a pattern of periarticular metal wear debris and pseudotumor formation...
2017: Case Reports in Orthopedics
https://www.readbyqxmd.com/read/28928969/morphine-pre-and-post-conditioning-exacerbates-apoptosis-in-rat-hippocampus-cells-in-a-model-of-homocysteine-induced-oxidative-stress
#12
Ahmad Karkhah, Ramin Ataee, Amin Ataie
Recent investigations indicated that morphine has protective effects in different ischemia/reperfusion models and may protect against neuronal cell death, while other evidence showed that morphine induces apoptosis in neurons. Therefore, the current study was conducted to investigate pre- and post-conditioning effects of morphine on hippocampal cell apoptosis in a rat model of homocysteine (Hcy)-induced oxidative stress. In the present study, 0.5 µmol/µl Hcy was injected into bilateral intrahipocampal in the rat brain and morphine at a therapeutic dose of 10 mg/kg was injected intraperitoneally 5 days before and after Hcy injection in rats...
October 2017: Biomedical Reports
https://www.readbyqxmd.com/read/28928905/fucoxanthin-a-marine-carotenoid-attenuates-%C3%AE-amyloid-oligomer-induced-neurotoxicity-possibly-via-regulating-the-pi3k-akt-and-the-erk-pathways-in-sh-sy5y-cells
#13
Jiajia Lin, Jie Yu, Jiaying Zhao, Ke Zhang, Jiachen Zheng, Jialing Wang, Chunhui Huang, Jingrong Zhang, Xiaojun Yan, William H Gerwick, Qinwen Wang, Wei Cui, Shan He
Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by neurofibrillary tangles, synaptic impairments, and loss of neurons. Oligomers of β-amyloid (Aβ) are widely accepted as the main neurotoxins to induce oxidative stress and neuronal loss in AD. In this study, we discovered that fucoxanthin, a marine carotenoid with antioxidative stress properties, concentration dependently prevented Aβ oligomer-induced increase of neuronal apoptosis and intracellular reactive oxygen species in SH-SY5Y cells...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28928740/microbiome-derived-lipopolysaccharide-enriched-in-the-perinuclear-region-of-alzheimer-s-disease-brain
#14
Yuhai Zhao, Lin Cong, Vivian Jaber, Walter J Lukiw
Abundant clinical, epidemiological, imaging, genetic, molecular, and pathophysiological data together indicate that there occur an unusual inflammatory reaction and a disruption of the innate-immune signaling system in Alzheimer's disease (AD) brain. Despite many years of intense study, the origin and molecular mechanics of these AD-relevant pathogenic signals are still not well understood. Here, we provide evidence that an intensely pro-inflammatory bacterial lipopolysaccharide (LPS), part of a complex mixture of pro-inflammatory neurotoxins arising from abundant Gram-negative bacilli of the human gastrointestinal (GI) tract, are abundant in AD-affected brain neocortex and hippocampus...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28926473/hydrogen-gas-attenuates-sevoflurane-neurotoxicity-through-inhibiting-nuclear-factor-%C3%AE%C2%BA-light-chain-enhancer-of-activated-b-cells-signaling-and-proinflammatory-cytokine-release-in-neonatal-rats
#15
Yiwei Shi, Gang Wang, Jinyuan Li, Wenli Yu
Anesthesia neurotoxicity in developing brain has gained increasing attention. However, knowledge regarding its mitigating strategies remains scant. Sevoflurane, a commonly used anesthetic, is responsible for learning and memory deficits in neonates. Molecular hydrogen is reported to be a potential neuroprotective agent because of its antioxidative and anti-inflammatory activities. This study aimed to investigate the effect of hydrogen gas on sevoflurane neurotoxicity. The newborn rats were treated with sevoflurane and/or hydrogen gas for 2 h...
September 18, 2017: Neuroreport
https://www.readbyqxmd.com/read/28925994/chimeric-antigen-receptor-t-cell-therapy-assessment-and-management-of-toxicities
#16
REVIEW
Sattva S Neelapu, Sudhakar Tummala, Partow Kebriaei, William Wierda, Cristina Gutierrez, Frederick L Locke, Krishna V Komanduri, Yi Lin, Nitin Jain, Naval Daver, Jason Westin, Alison M Gulbis, Monica E Loghin, John F de Groot, Sherry Adkins, Suzanne E Davis, Katayoun Rezvani, Patrick Hwu, Elizabeth J Shpall
Immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) is rapidly emerging as a promising new treatment for haematological and non-haematological malignancies. CAR-T-cell therapy can induce rapid and durable clinical responses, but is associated with unique acute toxicities, which can be severe or even fatal. Cytokine-release syndrome (CRS), the most commonly observed toxicity, can range in severity from low-grade constitutional symptoms to a high-grade syndrome associated with life-threatening multiorgan dysfunction; rarely, severe CRS can evolve into fulminant haemophagocytic lymphohistiocytosis (HLH)...
September 19, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28925253/novel-trimodal-maldi-imaging-mass-spectrometry-ims3-at-10-%C3%AE-m-reveals-spatial-lipid-and-peptide-correlates-implicated-in-a%C3%AE-plaque-pathology-in-alzheimer-s-disease
#17
Ibrahim Kaya, Dimitri Brinet, Wojciech Michno, Mehmet Baskurt, Henrik Zetterberg, Kaj Blennow, Jörg Hanrieder
Multimodal chemical imaging using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) can provide comprehensive molecular information in situ within the same tissue sections. This is of relevance for studying different brain pathologies such as Alzheimer's Disease (AD), where recent data suggest a critical relevance of co-localizing Aβ peptides and neuronal lipids. We here developed a novel trimodal, high-resolution (10µm) MALDI imaging MS (IMS) paradigm for negative- and positive ion mode lipid analysis and subsequent protein ion imaging on the same tissue section...
September 19, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28925030/drug-repurposing-may-generate-novel-approaches-to-treating-depression
#18
REVIEW
Mohamed Elsaed Ebada
OBJECTIVES: The breakthrough advancements in scientific medical research have greatly improved our understanding of the pathogenesis of depression, encouraging drug discoverers to take a shorter path than ever through drug repurposing to generate new antidepressant medications. In addition to reduced noradrenergic and serotonergic neurotransmission in the brain, other coincidence features such as glutamate neurotoxicity, inflammation and/or cerebrovascular insufficiency are implicated in the pathogenesis of major depressive disorder and late-life depression...
September 18, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28924167/a-toxic-conformer-of-a%C3%AE-42-with-a-turn-at-22-23-is-a-novel-therapeutic-target-for-alzheimer-s-disease
#19
Naotaka Izuo, Chihiro Kasahara, Kazuma Murakami, Toshiaki Kume, Masahiro Maeda, Kazuhiro Irie, Koutaro Yokote, Takahiko Shimizu
Immunotherapy targeting Aβ42 is drawing attention as a possible therapeutic approach for Alzheimer's disease (AD). Considering the significance of reported oligomerized Aβ42 species, selective targeting of the oligomer will increase the therapeutic efficacy. However, what kinds of oligomers are suitable targets for immunotherapy remains unclear. We previously identified a toxic conformer of Aβ42, which has a turn structure at 22-23 ("toxic turn"), among Aβ42 conformations. This toxic conformer of Aβ42 has been reported to show rapid oligomerization and to exhibit strong neurotoxicity and synaptotoxicity...
September 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28923922/trkb-neurotrophic-activities-are-blocked-by-%C3%AE-synuclein-triggering-dopaminergic-cell-death-in-parkinson-s-disease
#20
Seong Su Kang, Zhentao Zhang, Xia Liu, Fredric P Manfredsson, Matthew J Benskey, Xuebing Cao, Jun Xu, Yi E Sun, Keqiang Ye
BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson's disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase...
September 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
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