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Sample records for abrogates lead-induced neurodegeneration

  1. Combinational chelation therapy abrogates lead-induced neurodegeneration in rats

    Lead, a ubiquitous and potent neurotoxicant causes oxidative stress which leads to numerous neurobehavioral and physiological alterations. The ability of lead to bind sulfhydryl groups or compete with calcium could be one of the reasons for its debilitating effects. In the present study, we addressed: i) if chelation therapy could circumvent the altered oxidative stress and prevent neuronal apoptosis in chronic lead-intoxicated rats, ii) whether chelation therapy could reverse biochemical and behavioral changes, and iii) if mono or combinational therapy with captopril (an antioxidant) and thiol chelating agents (DMSA/MiADMSA) is more effective than individual thiol chelator in lead-exposed rats. Results indicated that lead caused a significant increase in reactive oxygen species, nitric oxide, and intracellular free calcium levels along with altered behavioral abnormalities in locomotor activity, exploratory behavior, learning, and memory that were supported by changes in neurotransmitter levels. A fall in membrane potential, release of cytochrome c, and DNA damage indicated mitochondrial-dependent apoptosis. Most of these alterations showed significant recovery following combined therapy with captopril with MiADMSA and to a smaller extend with captopril + DMSA over monotherapy with these chelators. It could be concluded from our present results that co-administration of a potent antioxidant (like captopril) might be a better treatment protocol than monotherapy to counter lead-induced oxidative stress. The major highlight of the work is an interesting experimental evidence of the efficacy of combinational therapy using an antioxidant with a thiol chelator in reversing neurological dystrophy caused due to chronic lead exposure in rats.

  2. Oxidative Stress in Neurodegeneration

    Varsha Shukla

    2011-01-01

    Full Text Available It has been demonstrated that oxidative stress has a ubiquitous role in neurodegenerative diseases. Major source of oxidative stress due to reactive oxygen species (ROS is related to mitochondria as an endogenous source. Although there is ample evidence from tissues of patients with neurodegenerative disorders of morphological, biochemical, and molecular abnormalities in mitochondria, it is still not very clear whether the oxidative stress itself contributes to the onset of neurodegeneration or it is part of the neurodegenerative process as secondary manifestation. This paper begins with an overview of how oxidative stress occurs, discussing various oxidants and antioxidants, and role of oxidative stress in diseases in general. It highlights the role of oxidative stress in neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis. The last part of the paper describes the role of oxidative stress causing deregulation of cyclin-dependent kinase 5 (Cdk5 hyperactivity associated with neurodegeneration.

  3. Peroxiredoxins and Neurodegeneration

    S.H. Lee

    2006-01-01

    Full Text Available Peroxiredoxins (Prxs are a family of novel antioxidant proteins that are found in a variety of species and participate in a number of vital biological processes such as proliferation, differentiation, response to oxidative stress and intracellular signaling. It has been proposed that they might participate in these cellular processes by playing a role in eliminating or regulating the intracellular concentration of peroxides produced during metabolism as well as in the signaling cascades of growth factors and cytokines. Mammalian cells express six isoforms of Prx (Prx I to VI, which are classified into three subgroups (typical 2-Cys, atypical 2-Cys and 1-Cys based on the number and position of cysteine (Cys residues that participate in catalysis and on amino acid sequences and the immunological reactivity. Members of the typical 2-Cys subgroup include Prx I through Prx IV and contain an additional conserved cysteine in the carboxyl-terminal region, whereas Prx V and Prx VI, members of the atypical 2-Cys and 1-Cys subgroups, respectively, do not contain this second conserved Cys. On the other hand, Prxs activity can be regulated by phosphorylation and proteolysis processes in addition to overoxidation. Taken together, this study suggest that the generation of the oxidative stress which caused neurodegeneration may couple with produced Prxs and the reverse is true. However, this argument is still unclear on account of the difficulties of the direct observation of the reactive oxygen species due to their biological lifetime is short. Thus, experiments will be required to solve these problems and to comprehend the actual role of Prxs in neurodegeneration.

  4. Pantothenate Kinase-Associated Neurodegeneration

    Meitinger, Thomas; Prokisch, Holger; Hartig, Monika B.; Klopstock, Thomas

    2012-01-01

    Pantothenate kinase-associated neurodegeneration (PKAN) is a hereditary progressive disorder and the most frequent form of neurodegeneration with brain iron accumulation (NBIA). PKAN patients present with a progressive movement disorder, dysarthria, cognitive impairment and retinitis pigmentosa. In magnetic resonance imaging, PKAN patients exhibit the pathognonomic "eye of the tiger" sign in the globus pallidus which corresponds to iron accumulation and gliosis as shown in neuropathological e...

  5. "Abrogation of Rulings” Methodology: A Critique

    Gasser Auda

    2004-01-01

    Surveying the subject of abrogation (naskh) in the Qur’ān, ḥādīth and Islamic literature, it is clear that most abrogation cases were introduced after the Prophetic era in order to interpret certain Qur’ānic verses and Prophetic narrations (aḥādīth) that some scholars perceived as “conflicting.” Two striking examples are “The Verse of the Sword” (āyat al-saif) and “The Verse of the Barrier” (āyat al-ḥijāb). The Qur’ānic verses and aḥādīth,...

  6. Neurodegeneration in the diabetic eye

    Simó, Rafael; Hernández, Cristina; Bandello, F; Burks, D; Cunha-Vaz, J; Egan, C; Garcia-Arumi, J; Gibson, J; Harding, S; Karadeniz, S; Lang, G; Massin, P; Midena, E; Pontasi, B; Porta, M; Scanlon, P; Grauslund, Jakob; Valverde, AM

    2014-01-01

    Diabetic retinopathy (DR), one of the leading causes of preventable blindness, has been considered a microcirculatory disease of the retina. However, there is emerging evidence to suggest that retinal neurodegeneration is an early event in the pathogenesis of DR, which participates in the develop...

  7. Parkinson's disease managing reversible neurodegeneration.

    Hinz, Marty; Stein, Alvin; Cole, Ted; McDougall, Beth; Westaway, Mark

    2016-01-01

    Traditionally, the Parkinson's disease (PD) symptom course has been classified as an irreversible progressive neurodegenerative disease. This paper documents 29 PD and treatment-induced systemic depletion etiologies which cause and/or exacerbate the seven novel primary relative nutritional deficiencies associated with PD. These reversible relative nutritional deficiencies (RNDs) may facilitate and accelerate irreversible progressive neurodegeneration, while other reversible RNDs may induce previously undocumented reversible pseudo-neurodegeneration that is hiding in plain sight since the symptoms are identical to the symptoms being experienced by the PD patient. Documented herein is a novel nutritional approach for reversible processes management which may slow or halt irreversible progressive neurodegenerative disease and correct reversible RNDs whose symptoms are identical to the patient's PD symptoms. PMID:27103805

  8. Unconventional neurotransmitters, neurodegeneration and neuroprotection

    M. Leonelli; A.S. Torrão; L.R.G. Britto

    2009-01-01

    Neurotransmitters are also involved in functions other than conventional signal transfer between nerve cells, such as development, plasticity, neurodegeneration, and neuroprotection. For example, there is a considerable amount of data indicating developmental roles for the glutamatergic, cholinergic, dopaminergic, GABA-ergic, and ATP/adenosine systems. In this review, we discuss the existing literature on these "new" functions of neurotransmitters in relation to some unconventional neurotrans...

  9. Glioprotective Effects of Ashwagandha Leaf Extract against Lead Induced Toxicity

    Praveen Kumar

    2014-01-01

    Full Text Available Withania somnifera (Ashwagandha, also known as Indian Ginseng, is a well-known Indian medicinal plant due to its antioxidative, antistress, antigenotoxic, and immunomodulatory properties. The present study was designed to assess and establish the cytoprotective potential of Ashwagandha leaf aqueous extract against lead induced toxicity. Pretreatment of C6 cells with 0.1% Ashwagandha extract showed cytoprotection against 25 μM to 400 μM concentration of lead nitrate. Further pretreatment with Ashwagandha extract to lead nitrate exposed cells (200 μM resulted in normalization of glial fibrillary acidic protein (GFAP expression as well as heat shock protein (HSP70, mortalin, and neural cell adhesion molecule (NCAM expression. Further, the cytoprotective efficacy of Ashwagandha extract was studied in vivo. Administration of Ashwagandha extract provided significant protection to lead induced altered antioxidant defense that may significantly compromise normal cellular function. Ashwagandha also provided a significant protection to lipid peroxidation (LPx levels, catalase, and superoxide dismutase (SOD but not reduced glutathione (GSH contents in brain tissue as well as peripheral organs, liver and kidney, suggesting its ability to act as a free radical scavenger protecting cells against toxic insult. These results, thus, suggest that Ashwagandha water extract may have the potential therapeutic implication against lead poisoning.

  10. Nutritional abrogation of photoimmunosuppression: in vivo investigations.

    Pilkington, Suzanne M; Gibbs, Neil K; Friedmann, Peter S; Rhodes, Lesley E

    2014-01-01

    Skin cancer is a major public health concern, and the primary aetiological factor in the majority of skin cancers is ultraviolet radiation (UVR) exposure. UVR not only induces potentially mutagenic DNA damage but also suppresses cell-mediated immunity (CMI), allowing cancerous cells to escape destruction and progress to tumours. A considerable proportion of an individual's annual sun exposure is obtained outside the vacation period when topical and physical measures for photoprotection are irregularly used. Certain nutrients could provide an adjunctive protective role, and evidence is accruing from experimental studies to support their use in abrogation of photoimmunosuppression. Moreover, developments in clinical research methods to evaluate impact of solar-simulated radiation on cutaneous CMI allow the immune protective potential of nutritional agents to be examined in humans in vivo. This article summarises the mediation of CMI and its suppression by UVR, evaluates the methodology for quantitative assessment in vivo, reviews the human studies reported on nutritional abrogation of photoimmunosuppression including recent randomized controlled trials and discusses the mechanisms of photoprotection by the nutrients. This includes, in addition to antioxidants, novel studies of omega-3 polyunsaturated fatty acids and nicotinamide. PMID:24283330

  11. Pantothenate kinase-associated neurodegeneration.

    Hartig, Monika B; Prokisch, Holger; Meitinger, Thomas; Klopstock, Thomas

    2012-08-01

    Pantothenate kinase-associated neurodegeneration (PKAN) is a hereditary progressive disorder and the most frequent form of neurodegeneration with brain iron accumulation (NBIA). PKAN patients present with a progressive movement disorder, dysarthria, cognitive impairment and retinitis pigmentosa. In magnetic resonance imaging, PKAN patients exhibit the pathognonomic "eye of the tiger" sign in the globus pallidus which corresponds to iron accumulation and gliosis as shown in neuropathological examinations. The discovery of the disease causing mutations in PANK2 has linked the disorder to coenzyme A (CoA) metabolism. PANK2 is the only one out of four PANK genes encoding an isoform which localizes to mitochondria. At least two other NBIA genes (PLA2G6, C19orf12) encode proteins that share with PANK2 a mitochondrial localization and all are suggested to play a role in lipid homeostasis. With no causal therapy available for PKAN until now, only symptomatic treatment is possible. A multi-centre retrospective study with bilateral pallidal deep brain stimulation in patients with NBIA revealed a significant improvement of dystonia. Recently, studies in the PANK Drosophila model "fumble" revealed improvement by the compound pantethine which is hypothesized to feed an alternate CoA biosynthesis pathway. In addition, pilot studies with the iron chelator deferiprone that crosses the blood brain barrier showed a good safety profile and some indication of efficacy. An adequately powered randomized clinical trial will start in 2012. This review summarizes clinical presentation, neuropathology and pathogenesis of PKAN. PMID:22515741

  12. DNA repair deficiency in neurodegeneration

    Jeppesen, Dennis Kjølhede; Bohr, Vilhelm A; Stevnsner, Tinna V.

    2011-01-01

    Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive...... neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative...... base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby...

  13. Hydroalcoholic seed extract of Coriandrum sativum (Coriander) alleviates lead-induced oxidative stress in different regions of rat brain.

    Velaga, Manoj Kumar; Yallapragada, Prabhakara Rao; Williams, Dale; Rajanna, Sharada; Bettaiya, Rajanna

    2014-06-01

    Lead exposure is known to cause apoptotic neurodegeneration and neurobehavioral abnormalities in developing and adult brain by impairing cognition and memory. Coriandrum sativum is an herb belonging to Umbelliferae and is reported to have a protective effect against lead toxicity. In the present investigation, an attempt has been made to evaluate the protective activity of the hydroalcoholic extract of C. sativum seed against lead-induced oxidative stress. Male Wistar strain rats (100-120 g) were divided into four groups: control group: 1,000 mg/L of sodium acetate; exposed group: 1,000 mg/L lead acetate for 4 weeks; C. sativum treated 1 (CST1) group: 250 mg/kg body weight/day for seven consecutive days after 4 weeks of lead exposure; C. sativum treated 2 (CST2) group: 500 mg/kg body weight/day for seven consecutive days after 4 weeks of lead exposure. After the exposure and treatment periods, rats were sacrificed by cervical dislocation, and the whole brain was immediately isolated and separated into four regions: cerebellum, hippocampus, frontal cortex, and brain stem along with the control group. After sacrifice, blood was immediately collected into heparinized vials and stored at 4 °C. In all the tissues, reactive oxygen species (ROS), lipid peroxidation products (LPP), and total protein carbonyl content (TPCC) were estimated following standard protocols. An indicator enzyme for lead toxicity namely delta-amino levulinic acid dehydratase (δ-ALAD) activity was determined in the blood. A significant (p<0.05) increase in ROS, LPP, and TPCC levels was observed in exposed rat brain regions, while δ-ALAD showed a decrease indicating lead-induced oxidative stress. Treatment with the hydroalcoholic seed extract of C. sativum resulted in a tissue-specific amelioration of oxidative stress produced by lead. PMID:24793421

  14. The db/db mouse: a useful model for the study of diabetic retinal neurodegeneration.

    Patricia Bogdanov

    Full Text Available BACKGROUND: To characterize the sequential events that are taking place in retinal neurodegeneration in a murine model of spontaneous type 2 diabetes (db/db mouse. METHODS: C57BLKsJ-db/db mice were used as spontaneous type 2 diabetic animal model, and C57BLKsJ-db/+ mice served as the control group. To assess the chronological sequence of the abnormalities the analysis was performed at different ages (8, 16 and 24 weeks. The retinas were evaluated in terms of morphological and functional abnormalities [electroretinography (ERG]. Histological markers of neurodegeneration (glial activation and apoptosis were evaluated by immunohistochemistry. In addition glutamate levels and glutamate/aspartate transporter (GLAST expression were assessed. Furthermore, to define gene expression changes associated with early diabetic retinopathy a transcriptome analyses was performed at 8 week. Furthermore, an additional interventional study to lower blood glucose levels was performed. RESULTS: Glial activation was higher in diabetic than in non diabetic mice in all the stages (p<0.01. In addition, a progressive loss of ganglion cells and a significant reduction of neuroretinal thickness were also observed in diabetic mice. All these histological hallmarks of neurodegeneration were less pronounced at week 8 than at week 16 and 24. Significant ERG abnormalities were present in diabetic mice at weeks 16 and 24 but not at week 8. Moreover, we observed a progressive accumulation of glutamate in diabetic mice associated with an early downregulation of GLAST. Morphological and ERG abnormalities were abrogated by lowering blood glucose levels. Finally, a dysregulation of several genes related to neurotransmission and oxidative stress such as UCP2 were found at week 8. CONCLUSIONS: Our results suggest that db/db mouse reproduce the features of the neurodegenerative process that occurs in the human diabetic eye. Therefore, it seems an appropriate model for investigating the

  15. Parkinson’s disease managing reversible neurodegeneration

    Hinz, Marty; Stein, Alvin; Cole, Ted; McDougall, Beth; Westaway, Mark

    2016-01-01

    Traditionally, the Parkinson’s disease (PD) symptom course has been classified as an irreversible progressive neurodegenerative disease. This paper documents 29 PD and treatment-induced systemic depletion etiologies which cause and/or exacerbate the seven novel primary relative nutritional deficiencies associated with PD. These reversible relative nutritional deficiencies (RNDs) may facilitate and accelerate irreversible progressive neurodegeneration, while other reversible RNDs may induce previously undocumented reversible pseudo-neurodegeneration that is hiding in plain sight since the symptoms are identical to the symptoms being experienced by the PD patient. Documented herein is a novel nutritional approach for reversible processes management which may slow or halt irreversible progressive neurodegenerative disease and correct reversible RNDs whose symptoms are identical to the patient’s PD symptoms. PMID:27103805

  16. Biology and Genetics of Prions Causing Neurodegeneration

    Prusiner, SB

    2013-01-01

    Prions are proteins that acquire alternative conformations that become self-propagating. Transformation of proteins into prions is generally accompanied by an increase in β-sheet structure and a propensity to aggregate into oligomers. Some prions are beneficial and perform cellular functions, whereas others cause neurodegeneration. In mammals, more than a dozen proteins that become prions have been identified, and a similar number has been found in fungi. In both mammals and fungi, variations...

  17. Oral microbiome link to neurodegeneration in glaucoma.

    Konstantin Astafurov

    Full Text Available BACKGROUND: Glaucoma is a progressive optic nerve degenerative disease that often leads to blindness. Local inflammatory responses are implicated in the pathology of glaucoma. Although inflammatory episodes outside the CNS, such as those due to acute systemic infections, have been linked to central neurodegeneration, they do not appear to be relevant to glaucoma. Based on clinical observations, we hypothesized that chronic subclinical peripheral inflammation contributes to neurodegeneration in glaucoma. METHODS: Mouthwash specimens from patients with glaucoma and control subjects were analyzed for the amount of bacteria. To determine a possible pathogenic mechanism, low-dose subcutaneous lipopolysaccharide (LPS was administered in two separate animal models of glaucoma. Glaucomatous neurodegeneration was assessed in the retina and optic nerve two months later. Changes in gene expression of toll-like receptor 4 (TLR4 signaling pathway and complement as well as changes in microglial numbers and morphology were analyzed in the retina and optic nerve. The effect of pharmacologic blockade of TLR4 with naloxone was determined. FINDINGS: Patients with glaucoma had higher bacterial oral counts compared to control subjects (p<0.017. Low-dose LPS administration in glaucoma animal models resulted in enhancement of axonal degeneration and neuronal loss. Microglial activation in the optic nerve and retina as well as upregulation of TLR4 signaling and complement system were observed. Pharmacologic blockade of TLR4 partially ameliorated the enhanced damage. CONCLUSIONS: The above findings suggest that the oral microbiome contributes to glaucoma pathophysiology. A plausible mechanism by which increased bacterial loads can lead to neurodegeneration is provided by experiments in animal models of the disease and involves activation of microglia in the retina and optic nerve, mediated through TLR4 signaling and complement upregulation. The finding that commensal

  18. Alcohol-Related Neurodegeneration and Recovery

    Crews, Fulton T.

    2008-01-01

    Human studies have found alcoholics to have a smaller brain size than moderate drinkers; however, these studies are complicated by many uncontrollable factors, including timing and amount of alcohol use. Animal experiments, which can control many factors, have established that alcohol can cause damage to brain cells (i.e., neurons), which results in their loss of structure or function (i.e., neurodegeneration) in multiple brain regions, similar to the damage found in human alcoholics. In addi...

  19. Parkinson’s disease managing reversible neurodegeneration

    Hinz M

    2016-04-01

    Full Text Available Marty Hinz,1 Alvin Stein,2 Ted Cole,3 Beth McDougall,4 Mark Westaway5 1Clinical Research, NeuroResearch Clinics, Inc., Cape Coral, FL, 2Stein Orthopedic Associates, Plantation, FL, 3Cole Center for Healing, Cincinnati, OH, 4CLEARCenter of Health, Mill Valley, CA, USA; 5Four Pillars Health, Brendale, QLD, Australia Abstract: Traditionally, the Parkinson’s disease (PD symptom course has been classified as an irreversible progressive neurodegenerative disease. This paper documents 29 PD and treatment-induced systemic depletion etiologies which cause and/or exacerbate the seven novel primary relative nutritional deficiencies associated with PD. These reversible relative nutritional deficiencies (RNDs may facilitate and accelerate irreversible progressive neurodegeneration, while other reversible RNDs may induce previously undocumented reversible pseudo-neurodegeneration that is hiding in plain sight since the symptoms are identical to the symptoms being experienced by the PD patient. Documented herein is a novel nutritional approach for reversible processes management which may slow or halt irreversible progressive neurodegenerative disease and correct reversible RNDs whose symptoms are identical to the patient’s PD symptoms. Keywords: Parkinson’s disease, L-dopa, carbidopa, B6, neurodegeneration

  20. Neurodegeneration with Brain Iron Accumulation: An Overview

    Seyed Hassan TONEKABONI*

    2014-12-01

    Full Text Available How to Cite This Article: Tonekaboni SH, Mollamohammadi M. Neurodegeneration with Brain Iron Accumulation: An Overview. Iran J Child Neurol. 2014 Autumn;8(4: 1-8.AbstractObjectiveNeurodegeneration with brain iron accumulation (NBIA is a group of neurodegenerative disorder with deposition of iron in the brain (mainly Basal Ganglia leading to a progressive Parkinsonism, spasticity, dystonia, retinal degeneration, optic atrophy often accompanied by psychiatric manifestations and cognitive decline. 8 of the 10 genetically defined NBIA types are inherited as autosomal recessive and the remaining two by autosomal dominant and X-linked dominant manner. Brain MRI findings are almost specific and show abnormal brain iron deposition in basal ganglia some other related anatomicallocations. In some types of NBIA cerebellar atrophy is the major finding in MRI.ReferencesShevel M. Racial hygiene, activeeuthanasia, and Julius Hallervorden. Neurology 1992;42:2214-2219.HayflickSJ. Neurodegeneration with brain Iron accumulation: from genes to pathogenesis.Semin Pediatr Neurol 2006;13:182-185.Zhou B, Westawy SK, Levinson B, et al. A novel pantothenate kinase gene(PANK2 is defective in Hallervorden-Spatzsyndrome. Nat Genet 2001;28:345- 349.www.ncbi.nlm.nihgov/NBK111Y/university of Washington, seattle. Allison Gregory and Susan Hayflick.Paisan-Ruiz C, Li A, Schneider SA, et al. Widesread Levy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiol Aging 2012;33:814-823.Dick KJ, Eckhardt M, Paison-Ruiz C, et al. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia(SPG 35. Hum Mutat 31: E1251-E1260.Edvardson S, Hama H, Shaag A, et al. Mutation in the fatty acid 2-Hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. Am I Hum Genet 2008;83:647-648.Schneider SA, Aggarwal A, Bhatt m, et al. Severe tongue protrusion dystonia: clinical syndromes

  1. The role of tau in neurodegeneration

    Petrucelli Leonard

    2009-03-01

    Full Text Available Abstract Since the identification of tau as the main component of neurofibrillary tangles in Alzheimer's disease and related tauopathies, and the discovery that mutations in the tau gene cause frontotemporal dementia, much effort has been directed towards determining how the aggregation of tau into fibrillar inclusions causes neuronal death. As evidence emerges that tau-mediated neuronal death can occur even in the absence of tangle formation, a growing number of studies are focusing on understanding how abnormalities in tau (e.g. aberrant phosphorylation, glycosylation or truncation confer toxicity. Though data obtained from experimental models of tauopathies strongly support the involvement of pathologically modified tau and tau aggregates in neurodegeneration, the exact neurotoxic species remain unclear, as do the mechanism(s by which they cause neuronal death. Nonetheless, it is believed that tau-mediated neurodegeneration is likely to result from a combination of toxic gains of function as well as from the loss of normal tau function. To truly appreciate the detrimental consequences of aberrant tau function, a better understanding of all functions carried out by tau, including but not limited to the role of tau in microtubule assembly and stabilization, is required. This review will summarize what is currently known regarding the involvement of tau in the initiation and development of neurodegeneration in tauopathies, and will also highlight some of the remaining questions in need of further investigation.

  2. Antibody-mediated neutralization of virus is abrogated by mycoplasma.

    Dickson, C; Elkington, J; Hales, A.; Weiss, R.

    1980-01-01

    The ability of a mouse mammary tumor cell line to abrogate antibody neutralization of vesicular stomatitis virus was shown to be due to the presence of mycoplasma. The mycoplasma was isolated from the cell line and typed as Mycoplasma orale. Colonies of this mycoplasma were used to deliberately infect cell cultures which then gained the capacity to reactivate antibody-neutralized virus. The extent of the reactivation depended on the source of neutralizing antiserum. Other species of mycoplasm...

  3. Toll-like receptors in neurodegeneration

    Owens, Trevor

    2009-01-01

    Innate pattern recognition receptors are implicated in first-line defense against pathogens but also participate in maintenance of tissue homeostasis and response to injury. This chapter reviews the role of Toll-like receptors (TLRs) in neuronal and glial responses that are associated with...... neurodegeneration. Accompanying roles for infection and inflammation, involvement in clinical neurodegenerative disorders, and heterogeneity of glial response are discussed. A "strength of signal" hypothesis is advanced in an attempt to reconcile evolutionarily selected and therefore likely beneficial effects of...... TLR signaling in the nervous system with capability for neurotoxocity and gliotoxicity....

  4. Acetylcholinesterase from Human Erythrocytes as a Surrogate Biomarker of Lead Induced Neurotoxicity

    Vivek Kumar Gupta; Rajnish Pal; Nikhat Jamal Siddiqi; Bechan Sharma

    2015-01-01

    Lead induced neurotoxicity in the people engaged in different occupations has received wide attention but very little studies have been carried out to monitor occupational neurotoxicity directly due to lead exposure using biochemical methods. In the present paper an endeavour has been made in order to assess the lead mediated neurotoxicity by in vitro assay of the activity of acetylcholinesterase (AChE) from human erythrocytes in presence of different concentrations of lead. The results sugge...

  5. Neurodegeneration and Cancer: Where the Disorder Prevails.

    Klus, Petr; Cirillo, Davide; Botta Orfila, Teresa; Gaetano Tartaglia, Gian

    2015-01-01

    It has been reported that genes up-regulated in cancer are often down-regulated in neurodegenerative disorders and vice versa. The fact that apparently unrelated diseases share functional pathways suggests a link between their etiopathogenesis and the properties of molecules involved. Are there specific features that explain the exclusive association of proteins with either cancer or neurodegeneration? We performed a large-scale analysis of physico-chemical properties to understand what characteristics differentiate classes of diseases. We found that structural disorder significantly distinguishes proteins up-regulated in neurodegenerative diseases from those linked to cancer. We also observed high correlation between structural disorder and age of onset in Frontotemporal Dementia, Parkinson's and Alzheimer's diseases, which strongly supports the role of protein unfolding in neurodegenerative processes. PMID:26493371

  6. Insights into Mechanisms of Chronic Neurodegeneration

    Abigail B. Diack

    2016-01-01

    Full Text Available Chronic neurodegenerative diseases such as Alzheimer’s disease (AD, Parkinson’s disease (PD, and prion diseases are characterised by the accumulation of abnormal conformers of a host encoded protein in the central nervous system. The process leading to neurodegeneration is still poorly defined and thus development of early intervention strategies is challenging. Unique amongst these diseases are Transmissible Spongiform Encephalopathies (TSEs or prion diseases, which have the ability to transmit between individuals. The infectious nature of these diseases has permitted in vivo and in vitro modelling of the time course of the disease process in a highly reproducible manner, thus early events can be defined. Recent evidence has demonstrated that the cell-to-cell spread of protein aggregates by a “prion-like mechanism” is common among the protein misfolding diseases. Thus, the TSE models may provide insights into disease mechanisms and testable hypotheses for disease intervention, applicable to a number of these chronic neurodegenerative diseases.

  7. The relationship between hyperhomocysteinemia and neurodegeneration.

    Bonetti, Francesco; Brombo, Gloria; Zuliani, Giovanni

    2016-04-01

    Homocysteine (Hcy) is a key junction in methionine metabolism. In inherited forms of hyperhomocysteinemia patients develop early vascular damage and cognitive decline. Hyperhomocysteinemia is a common consequence of dietary, behavioral and pathological conditions and is epidemiologically related to different diseases, among them neurodegenerative ones are receiving progressively more attention in the last years. Several detrimental mechanisms that see in Hcy a possible promoter seem to be implicated in neurodegeneration (protein structural and functional modifications, oxidative stress, cellular metabolic derangements, epigenetic modifications, pathological aggregates deposition, endothelial damage and atherothrombosis). Interventional studies exploring B group vitamins administration in terms of prevention of Hcy-related cognitive decline and cerebrovascular involvement have shown scant results. In this review, current and possible alternative/complementary approaches are discussed. PMID:27033101

  8. Withania somnifera ameliorates lead-induced augmentation of adrenergic response in rat portal vein

    Subrata Kumar Hore

    2013-01-01

    Full Text Available Objectives: Present study was undertaken to elucidate the ameliorating potential of Withania somnifera root extract (WRE against lead-induced augmentation of adrenergic response in rat portal vein. Materials and Methods: In-vitro studies were conducted on effect of lead alone and lead+WRE on rat-isolated portal vein while in-vivo studies were done in three groups of 12 rats each; Group-II and III received 0.5% lead acetate and 1.0% WRE + 0.5% lead acetate, respectively, in drinking water for 12 weeks whereas group-I served as control. Adrenaline and noradrenaline levels in brain and blood were determined by HPLC assay while vascular reactivity of portal vein to lead and WRE was determined by measuring the isometric tension. Results: Following in-vitro exposure, lead did not alter the contractile effect of phenylephrine. In-vivo studies revealed that contractile effect of lead on portal vein was significantly potentiated and it was antagonized by prazosin (10 -7 M and WRE (1%. WRE treatment significantly reduced elevated blood noradrenaline (37.80% and restored noradrenaline level in brain (39.39% in lead-exposed animals. These values were almost comparable to the control group. But it failed to significantly affect the blood and brain adrenaline levels. Conclusions: Results suggest that following pre-exposure of rats to WRE, lead-induced augmentation of alpha 1 -adrenoceptors mediated response was reversed possibly by regulating catecholamine release from nerve endings. Thus, WRE may be useful in therapeutic management of lead-induced hypertension.

  9. Trimethyltin-induced hippocampal neurodegeneration: A mechanism-based review.

    Lee, Sueun; Yang, Miyoung; Kim, Jinwook; Kang, Sohi; Kim, Juhwan; Kim, Jong-Choon; Jung, Chaeyong; Shin, Taekyun; Kim, Sung-Ho; Moon, Changjong

    2016-07-01

    Trimethyltin (TMT), a toxic organotin compound, induces neurodegeneration selectively involving the limbic system and especially prominent in the hippocampus. Neurodegeneration-associated behavioral abnormalities, such as hyperactivity, aggression, cognitive deficits, and epileptic seizures, occur in both exposed humans and experimental animal models. Previously, TMT had been used generally in industry and agriculture, but the use of TMT has been limited because of its dangers to people. TMT has also been used to make a promising in vivo rodent model of neurodegeneration because of its region-specific characteristics. Several studies have demonstrated that TMT-treated animal models of epileptic seizures can be used as tools for researching hippocampus-specific neurotoxicity as well as the molecular mechanisms leading to hippocampal neurodegeneration. This review summarizes the in vivo and in vitro underlying mechanisms of TMT-induced hippocampal neurodegeneration (oxidative stress, inflammatory responses, and neuronal death/survival). Thus, the present review may be helpful to provide general insights into TMT-induced neurodegeneration and approaches to therapeutic interventions for neurodegenerative diseases, including temporal lobe epilepsy. PMID:27450702

  10. Nucleotide Salvage Deficiencies, DNA Damage and Neurodegeneration

    Michael Fasullo

    2015-04-01

    Full Text Available Nucleotide balance is critically important not only in replicating cells but also in quiescent cells. This is especially true in the nervous system, where there is a high demand for adenosine triphosphate (ATP produced from mitochondria. Mitochondria are particularly prone to oxidative stress-associated DNA damage because nucleotide imbalance can lead to mitochondrial depletion due to low replication fidelity. Failure to maintain nucleotide balance due to genetic defects can result in infantile death; however there is great variability in clinical presentation for particular diseases. This review compares genetic diseases that result from defects in specific nucleotide salvage enzymes and a signaling kinase that activates nucleotide salvage after DNA damage exposure. These diseases include Lesch-Nyhan syndrome, mitochondrial depletion syndromes, and ataxia telangiectasia. Although treatment options are available to palliate symptoms of these diseases, there is no cure. The conclusions drawn from this review include the critical role of guanine nucleotides in preventing neurodegeneration, the limitations of animals as disease models, and the need to further understand nucleotide imbalances in treatment regimens. Such knowledge will hopefully guide future studies into clinical therapies for genetic diseases.

  11. Oxidative and nitrative stress in neurodegeneration.

    Cobb, Catherine A; Cole, Marsha P

    2015-12-01

    Aerobes require oxygen for metabolism and normal free radical formation. As a result, maintaining the redox homeostasis is essential for brain cell survival due to their high metabolic energy requirement to sustain electrochemical gradients, neurotransmitter release, and membrane lipid stability. Further, brain antioxidant levels are limited compared to other organs and less able to compensate for reactive oxygen and nitrogen species (ROS/RNS) generation which contribute oxidative/nitrative stress (OS/NS). Antioxidant treatments such as vitamin E, minocycline, and resveratrol mediate neuroprotection by prolonging the incidence of or reversing OS and NS conditions. Redox imbalance occurs when the antioxidant capacity is overwhelmed, consequently leading to activation of alternate pathways that remain quiescent under normal conditions. If OS/NS fails to lead to adaptation, tissue damage and injury ensue, resulting in cell death and/or disease. The progression of OS/NS-mediated neurodegeneration along with contributions from microglial activation, dopamine metabolism, and diabetes comprise a detailed interconnected pathway. This review proposes a significant role for OS/NS and more specifically, lipid peroxidation (LPO) and other lipid modifications, by triggering microglial activation to elicit a neuroinflammatory state potentiated by diabetes or abnormal dopamine metabolism. Subsequently, sustained stress in the neuroinflammatory state overwhelms cellular defenses and prompts neurotoxicity resulting in the onset or amplification of brain damage. PMID:26024962

  12. Methylenedioxymethamphetamine (MDMA, 'Ecstasy': Neurodegeneration versus Neuromodulation

    Elena Puerta

    2011-07-01

    Full Text Available The amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’ is widely abused as a recreational drug due to its unique psychological effects. Of interest, MDMA causes long-lasting deficits in neurochemical and histological markers of the serotonergic neurons in the brain of different animal species. Such deficits include the decline in the activity of tryptophan hydroxylase in parallel with the loss of 5-HT and its main metabolite 5-hydoxyindoleacetic acid (5-HIAA along with a lower binding of specific ligands to the 5-HT transporters (SERT. Of concern, reduced 5-HIAA levels in the CSF and SERT density have also been reported in human ecstasy users, what has been interpreted to reflect the loss of serotonergic fibers and terminals. The neurotoxic potential of MDMA has been questioned in recent years based on studies that failed to show the loss of the SERT protein by western blot or the lack of reactive astrogliosis after MDMA exposure. In addition, MDMA produces a long-lasting down-regulation of SERT gene expression; which, on the whole, has been used to invoke neuromodulatory mechanisms as an explanation to MDMA-induced 5-HT deficits. While decreased protein levels do not necessarily reflect neurodegeneration, the opposite is also true, that is, neuroregulatory mechanisms do not preclude the existence of 5-HT terminal degeneration.

  13. Effects of hypothalamic neurodegeneration on energy balance.

    Allison Wanting Xu

    2005-12-01

    Full Text Available Normal aging in humans and rodents is accompanied by a progressive increase in adiposity. To investigate the role of hypothalamic neuronal circuits in this process, we used a Cre-lox strategy to create mice with specific and progressive degeneration of hypothalamic neurons that express agouti-related protein (Agrp or proopiomelanocortin (Pomc, neuropeptides that promote positive or negative energy balance, respectively, through their opposing effects on melanocortin receptor signaling. In previous studies, Pomc mutant mice became obese, but Agrp mutant mice were surprisingly normal, suggesting potential compensation by neuronal circuits or genetic redundancy. Here we find that Pomc-ablation mice develop obesity similar to that described for Pomc knockout mice, but also exhibit defects in compensatory hyperphagia similar to what occurs during normal aging. Agrp-ablation female mice exhibit reduced adiposity with normal compensatory hyperphagia, while animals ablated for both Pomc and Agrp neurons exhibit an additive interaction phenotype. These findings provide new insight into the roles of hypothalamic neurons in energy balance regulation, and provide a model for understanding defects in human energy balance associated with neurodegeneration and aging.

  14. Post-translational modifications in neurodegeneration

    Federico Benetti

    2015-12-01

    Full Text Available Post-translational modifications increase proteome functionality for managing all aspects of normal cell biology. They are based on the covalent attachment of functional groups, leading to phosphorylation, acetylation, glycosylation, acylation, ubiquitination, SUMOylation and oxidation of protein targets. Post-translational modifications occur at any step of protein life cycle, modulating in time and space protein folding, subcellular localization and activity. Aberrant post-translational modifications of one or more culprit proteins may lead to neurodegeneration, as shown in paradigmatic neurological disorders such as Alzheimer’s, Parkinson’s and prion diseases. In this review, we report the most important post-translational modifications found in neurodegenerative disorders, illustrating the pathophysiological mechanisms in which they are involved. This work highlights the lack of a global framework of post-translational modifications in terms of complexity and regulation. Therefore, in the next future many efforts are required to describe the interplay existing between post-translational modifications and their combinatorial patterns on protein targets.

  15. Acetylcholinesterase from Human Erythrocytes as a Surrogate Biomarker of Lead Induced Neurotoxicity

    Vivek Kumar Gupta

    2015-01-01

    Full Text Available Lead induced neurotoxicity in the people engaged in different occupations has received wide attention but very little studies have been carried out to monitor occupational neurotoxicity directly due to lead exposure using biochemical methods. In the present paper an endeavour has been made in order to assess the lead mediated neurotoxicity by in vitro assay of the activity of acetylcholinesterase (AChE from human erythrocytes in presence of different concentrations of lead. The results suggested that the activity of this enzyme was localized in membrane bound fraction and it was found to be highly stable up to 30 days when stored at −20°C in phosphate buffer (50 mM, pH 7.4 containing 0.2% Triton X-100. The erythrocyte’s AChE exhibited Km for acetylcholinesterase to be 0.1 mM. Lead caused sharp inhibition of the enzyme and its IC50 value was computed to be 1.34 mM. The inhibition of the enzyme by lead was found to be of uncompetitive type (Ki value, 3.6 mM which negatively influenced both the Vmax and the enzyme-substrate binding affinity. Taken together, these results indicate that AChE from human erythrocytes could be exploited as a surrogate biomarker of lead induced neurotoxicity particularly in the people occupationally exposed to lead.

  16. Recovery of lead-induced suppressed reproduction in male rats by testosterone.

    Reshma Anjum, M; Sreenivasula Reddy, P

    2015-06-01

    The objective of the present study was to investigate the effects of testosterone in recuperation of lead-induced suppressed reproduction in adult male rats. Lead acetate was administered orally to adult male rats (95 ± 5 days) at dosage level of 0.05 and 0.15% for 55 days through drinking water and injected intraperitoneally with either testoviron depot at a dose of 4.16 mg kg(-1) body weight or vehicle alone on days 1, 7 and 14 respectively. At the end of treatment, control and treated males were cohabited with untreated normal-cycling females. After cohabitation for 5 days, all the male rats were killed and weights of reproductive organs were determined. Significant increase in the indices of testis, epididymis, seminal vesicles, vas deferens and prostate glands was observed in testosterone (T)-treated rats when compared to those of lead-exposed rats. Testosterone treatment significantly increased epididymal sperm count, motile spermatozoa, viable spermatozoa and HOS tail-coiled spermatozoa and also the activity levels of testicular 3β- and 17β-hydroxysteroid dehydrogenases when compared to those of lead-exposed males. From the results, it can be hypothesised that supplementation of testosterone mitigated lead-induced suppressed reproduction in male rats. PMID:24909355

  17. Ameliorative potential of stem bromelain on lead-induced toxicity in Wistar rats.

    Al-Otaibi, Wedad Refaiea; Virk, Promy; Elobeid, Mai

    2015-06-01

    The present study investigates the protective efficacy of stem bromelain against lead-induced toxicity in male Wistar rats. There were six experimental groups; Group I was negative control, Group II was administered only 20 mg/kg of stem bromelain. Group III and V were orally exposed to 30 mg/kg/day and 60 mg/kg/day of lead acetate, respectively. Group IV and Group VI were exposed to both low and high dose of lead acetate, respectively, and treated with 20 mg/kg stem bromelain. The experimental period was 21 days. The end points evaluated were, lead accumulation in kidney, liver and spleen, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, serum malonaldehyde (MDA) cholesterol and triglycerides levels. Co-administration of stem bromelain with lead markedly reduced the lead accumulation in the kidney and spleen. The treatment of stem bromelain also reduced the serum MDA levels in the group exposed to lower dose of lead and serum triglyceride level in the group exposed to higher dose of lead. The lead-induced modulated levels of serum ALT and AST were also alleviated by bromelain treatment. Our key findings suggest a chelating potential of stem bromelain for combating lead toxicity and oxidative stress. Bromelain represents a novel approach to the treatment of metal toxicity and metabolic disorders with a limited therapeutic window. PMID:26081271

  18. Lipoic acid in combination with a chelator ameliorates lead-induced peroxidative damages in rat kidney

    Sivaprasad, R.; Nagaraj, M.; Varalakshmi, P. [Department of Medical Biochemistry, University of Madras (Taramani), Chennai 600 113 (India)

    2002-08-01

    The deleterious effect of lead has been attributed to lead-induced oxidative stress with the consequence of lipid peroxidation. The present study was designed to investigate the combined effect of DL-{alpha}-lipoic acid (LA) and meso-2,3-dimercaptosuccinic acid (DMSA) on lead-induced peroxidative damages in rat kidney. The increase in peroxidated lipids in lead-poisoned rats was accompanied by alterations in antioxidant defence systems. Lead acetate (Pb, 0.2%) was administered in drinking water for 5 weeks to induce lead toxicity. LA (25 mg/kg body weight per day i.p) and DMSA (20 mg/kg body weight per day i.p) were administered individually and also in combination during the sixth week. Nephrotoxic damage was evident from decreases in the activities of {gamma}-glutamyl transferase and N-acetyl {beta}-D-glucosaminidase, which were reversed upon combined treatment with LA and DMSA. Rats subjected to lead intoxication showed a decline in the thiol capacity of the cell, accompanied by high malondialdehyde levels along with lowered activities of catalase, superoxide dismutase, glutathione peroxidase and glutathione metabolizing enzymes (glutathione reductase, glucose-6-phosphate dehydrogenase, glutathione-S-transferase). Supplementation with LA as a sole agent showed considerable changes over oxidative stress parameters. The study has highlighted the combined effect of both drugs as being more effective in reversing oxidative damage by bringing about an improvement in the reductive status of the cell. (orig.)

  19. Curcumin and folic acid abrogated methotrexate induced vascular endothelial dysfunction.

    Sankrityayan, Himanshu; Majumdar, Anuradha S

    2016-01-01

    Methotrexate, an antifolate drug widely used in rheumatoid arthritis, psoriasis, and cancer, is known to cause vascular endothelial dysfunction by causing hyperhomocysteinemia, direct injury to endothelium or by increasing the oxidative stress (raising levels of 7,8-dihydrobiopterin). Curcumin is a naturally occurring polyphenol with strong antioxidant and anti-inflammatory action and therapeutic spectra similar to that of methotrexate. This study was performed to evaluate the effects of curcumin on methotrexate induced vascular endothelial dysfunction and also compare its effect with that produced by folic acid (0.072 μg·g(-1)·day(-1), p.o., 2 weeks) per se and in combination. Male Wistar rats were exposed to methotrexate (0.35 mg·kg(-1)·day(-1), i.p.) for 2 weeks to induce endothelial dysfunction. Methotrexate exposure led to shedding of endothelium, decreased vascular reactivity, increased oxidative stress, decreased serum nitrite levels, and increase in aortic collagen deposition. Curcumin (200 mg·kg(-1)·day(-1) and 400 mg·kg(-1)·day(-1), p.o.) for 4 weeks prevented the increase in oxidative stress, decrease in serum nitrite, aortic collagen deposition, and also vascular reactivity. The effects were comparable with those produced by folic acid therapy. The study shows that curcumin, when concomitantly administered with methotrexate, abrogated its vascular side effects by preventing an increase in oxidative stress and abating any reduction in physiological nitric oxide levels. PMID:26571019

  20. Neurodegeneration and Neuroprotection in Diabetic Retinopathy

    Abdullah S. Alhomida

    2013-01-01

    Full Text Available Diabetic retinopathy is widely considered to be a neurovascular disease. This is in contrast to its previous identity as solely a vascular disease. Early in the disease progression of diabetes, the major cells in the neuronal component of the retina consist of retinal ganglion cells and glial cells, both of which have been found to be compromised. A number of retinal function tests also indicated a functional deficit in diabetic retina, which further supports dysfunction of neuronal cells. As an endocrinological disorder, diabetes alters metabolism both systemically and locally in several body organs, including the retina. A growing body of evidences indicates increased levels of excitotoxic metabolites, including glutamate, branched chain amino acids and homocysteine in cases of diabetic retinopathy. Also present, early in the disease, are decreased levels of folic acid and vitamin-B12, which are potential metabolites capable of damaging neurons. These altered levels of metabolites are found to activate several metabolic pathways, leading to increases in oxidative stress and decreases in the level of neurotrophic factors. As a consequence, they may damage retinal neurons in diabetic patients. In this review, we have discussed those potential excitotoxic metabolites and their implications in neuronal damage. Possible therapeutic targets to protect neurons are also discussed. However, further research is needed to understand the exact molecular mechanism of neurodegeneration so that effective neuroprotection strategies can be developed. By protecting retinal neurons early in diabetic retinopathy cases, damage of retinal vessels can be protected, thereby helping to ameliorate the progression of diabetic retinopathy, a leading cause of blindness worldwide.

  1. Lead-induced SCC of alloy 600 in plausible steam generator crevice environments

    Laboratory stress corrosion cracking (SCC) test environments developed to simulate representative BNGS-A steam generator (SG) crevice chemistries have been used to determine the susceptibility of Alloy 600 to lead-induced SCC under plausible SG conditions. Test environments were based on plant SG hideout return data and analysis of removed tubes and deposits. Deviations from the normal near neutral crevice pH environment were considered to simulate possible faulted excursion crevice chemistry and to bound the postulated crevice pH range of 3-9 (at temperature). The effect of lead contamination up to 1000 ppm, but with an emphasis on the 100 to 500 ppm range, was determined. SCC susceptibility was investigated using constant extension rate tensile (CERT) tests and encapsulated C-ring tests. CERT tests were performed at 305 degrees C on tubing representative of BNGS-A SG U-bends. The C-ring test method allowed a wider test matrix covering three temperatures (280, 304 and 315 degrees C), three strain levels (0.2%, 2% and 4%) and tubing representative of U-bends plus tubing given a simulated stress relief to represent material at the tubesheet. The results of this test program confirmed that in the absence of lead contamination, cracking does not occur in these concentrated, 3.3 to 8.9 pH range, crevice environments. Also, it appears that the concentrated crevice environments suppress lead-induced cracking relative to that seen in all-volatile-treatment (AVT) water. For the (static) C-ring tests, lead-induced SCC was only produced in the near-neutral crevice environment and was more severe at 500 ppm than 100 ppm PbO. This trend was also observed in CERT tests but some cracking/grain boundary attack occurred in acidic (pH 3.3) and alkaline (pH 8.9) environments. The C-ring tests indicated that a certain amount of resistance to cracking was imparted by simulated stress relief of the tubing. This heat treatment, confirmed to have resulted in sensitization, promoted

  2. Lead-induced stress-corrosion cracking of alloy 600 in plausible steam generator crevice environments

    Laboratory stress-corrosion cracking (SCC) test environments were developed to simulate crevice chemistries representative of Bruce Nuclear Generating Station A (BNPD A) steam generators (SGs); these test environments were used to determine the susceptibility of Alloy 600 to lead-induced SCC under plausible SG conditions. Test environments were based on plant SG hideout return data and analysis of removed tubes and deposits. Deviations from the normal near-neutral crevice pH environment were considered to simulate possible faulted excursion crevice chemistry and to bound the postulated crevice pH range of 3 to 9 (at temperature). The effect of lead contamination up to 1000 ppm, but with an emphasis on the 100- to 500-ppm range, was determined. SCC susceptibility was investigated using constant extension rate tensile (CERT) tests and encapsulated C-ring tests. CERT tests were performed at 305 degrees C on tubing representative of BNPD A SG U-bends. The C-ring test method allowed a wider test matrix, covering 3 temperatures (280 degrees C, 304 degrees C and 315 degrees C), 3 strain levels (0.2%, 2% and 4%), and tubing representative of U-bends plus tubing given a simulated stress relief to represent material at the tube sheet. The results of this test program confirmed that in the absence of lead contamination, cracking does not occur in these concentrated, 3.3 to 8.9 pH range, crevice environments. Also, it appears that the concentrated crevice environments suppress lead-induced cracking relative to that seen in all-volatile-treatment (AVT) water. For the (static) C-ring tests, lead-induced SCC was only produced in the near-neutral crevice environment and was more severe at 500 ppm than at 100 ppm PbO. This trend was also observed in CERT tests, but some cracking-grain boundary attack occurred in acidic (pH 3.3) and alkaline (pH 8.9) environments. The C-ring tests indicated that a certain amount of resistance to cracking was imparted by simulated stress relief of

  3. Characterization of kidney sulfotransferases during lead-induced nephrotoxicity in rats

    Templer, L.A.; Kong, J.; Ronis, M.J.J.; Ringer, D.P. [Univ. Arkansas Medical School, Little Rock, AR (United States)

    1996-03-08

    Kidney sulfotransferases (ST) have been shown to be involved in the biotransformation of steroid and thyroid hormones as well as xenobiotics varying from carcinogenic heterocyclic amines to drugs such as acetaminophen. In order to examine the impact of lead-induced nephrotoxicity on kidney aryl, estrogen and DHEA STs during growth and development, time-impregnated female Sprague-Dawley rats were exposed ad libitum to lead acetate (0.6%) in drinking water from gestational day 5 and continuing in male and female pups until they were sacrificed at day 85. Cytosols from male rat kidneys showed levels of estrogen ST activity (59% of females) that were significantly lowered (P{le}0.05) after lead exposure (6-20% of male). Aryl ST activity was relatively unchanged in male rats after rat kidney cytosol. Immunochemical analysis of cytosols from normal males and females with the antiserums to the three STs substantiated the presence of only the aryl and estrogen STs. Immunohistochemical techniques localized the aryl and estrogen STs primarily to the S3 section of the proximal tubules. These findings indicate that kidney STs may be differently modulated during lead exposure.

  4. Chromosome 13 dementia syndromes as models of neurodegeneration

    Ghiso, J.; Revesz, T.; Holton, J.;

    2001-01-01

    Two hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the central nervous system and neurodegeneration. The two amyloid proteins, ABri and ADan, are degradation products of the same precursor molecule BriPP bearing...

  5. The Chemistry of Neurodegeneration: Kinetic Data and Their Implications.

    Pavlin, Matic; Repič, Matej; Vianello, Robert; Mavri, Janez

    2016-07-01

    We collected experimental kinetic rate constants for chemical processes responsible for the development and progress of neurodegeneration, focused on the enzymatic and non-enzymatic degradation of amine neurotransmitters and their reactive and neurotoxic metabolites. A gross scheme of neurodegeneration on the molecular level is based on two pathways. Firstly, reactive species oxidise heavy atom ions, which enhances the interaction with alpha-synuclein, thus promoting its folding to the beta form and giving rise to insoluble amyloid plaques. The latter prevents the function of vesicular transport leading to gradual neuronal death. In the second pathway, radical species, OH(·) in particular, react with the methylene groups of the apolar part of the lipid bilayer of either the cell or mitochondrial wall, resulting in membrane leakage followed by dyshomeostasis, loss of resting potential and neuron death. Unlike all other central neural system (CNS)-relevant biogenic amines, dopamine and noradrenaline are capable of a non-enzymatic auto-oxidative reaction, which produces hydrogen peroxide. This reaction is not limited to the mitochondrial membrane where scavenging enzymes, such as catalase, are located. On the other hand, dopamine and its metabolites, such as dopamine-o-quinone, dopaminechrome, 5,6-dihydroxyindole and indo-5,6-quinone, also interact directly with alpha-synuclein and reversibly inhibit plaque formation. We consider the role of the heavy metal ions, selected scavengers and scavenging enzymes, and discuss the relevance of certain foods and food supplements, including curcumin, garlic, N-acetyl cysteine, caffeine and red wine, as well as the long-term administration of non-steroid anti-inflammatory drugs and occasional tobacco smoking, that could all act toward preventing neurodegeneration. The current analysis can be employed in developing strategies for the prevention and treatment of neurodegeneration, and, hopefully, aid in the building of an overall

  6. Lead phytotoxicity in soils and nutrient solutions is related to lead induced phosphorus deficiency

    This study was set up to relate lead (Pb) bioavailability with its toxicity to plants in soils. Tomato and barley seedlings were grown in six different PbCl2 spiked soils (pH: 4.7–7.4; eCEC: 4.2–41.7 cmolc/kg). Soils were leached and pH corrected after spiking to exclude confounding factors. Plant growth was halved at 1600–6500 mg Pb/kg soil for tomato and at 1900–8300 mg Pb/kg soil for barley. These soil Pb threshold were unrelated to soil pH, organic carbon, texture or eCEC and neither soil solution Pb nor Pb2+ ion activity adequately explained Pb toxicity among soils. Shoot phosphorus (P) concentrations significantly decreased with increasing soil Pb concentrations. Tomato grown in hydroponics at either varying P supply or at increasing Pb (equal initial P) illustrated that shoot P explained growth response in both scenarios. The results suggest that Pb toxicity is partially related to Pb induced P deficiency, likely due to lead phosphate precipitation. - Highlights: ► Tomato and barley shoot growth was affected by Pb toxicity in six different soils. ► Soil properties did not explain differences in plant Pb toxicity among soils. ► Neither soil solution Pb nor Pb2+ ion activity explained Pb toxicity among soils. ► Shoot phosphorus concentration decreased with increasing soil Pb concentrations. ► Lead induced a P deficiency in plants, likely due to lead phosphate precipitation. - Soil properties did not explain differences in plant lead toxicity among different soils. Shoot phosphorus concentration decreased with increasing soil lead concentrations.

  7. Haemoprotective effects of Emblica officinalis Linn. against radiation and lead induced toxicity in Swiss albino mice

    Radiation is known to cause cell death, mainly due to its ability to produce reactive oxygen species in cells. Lead is a serious public health problem in many parts of the world. Emblica officinalis is closely linked to its protective properties against free radicals attack. The hematopoietic system plays an important role in maintaining the vitality of animals. Therefore, the purpose of present study was haemoprotective effects of Emblica officinalis Linn. against radiation and lead induced toxicity in Swiss albino mice. For the study, Animals were divided into seven groups. The Emblica was administered seven days prior to irradiation or lead acetate treatment. The animals were autopsied from all the experimental groups at each post treatment intervals of 1, 2, 4, 7, 14 and 28 days. The value of RBC, WBC, PCV, haemoglobin were found to decrease up to day-14 in non-drug treated groups (II, III and IV), thereafter it increased on day-28. In Emblica treated groups (V, VI and VII) the value decreased up to day-7 then it increased up to day-28. The decrease in values was lesser in Emblica treated groups. The value of MCV also showed an increasing trend. The increase in the value of MCR was lesser in Emblica treated groups as compared to non-drug treated groups. Besides this values of MCRC decreased in all the groups at various intervals but the values were lower in the Emblica treated groups. Thus, it may be concluded that Emblica has the ability of inhibiting oxidative stress and substantially protect blood from radiation and heavy metal toxicity. (author)

  8. Gamma-Glutamyl Cysteine Attenuates Tissue Damage and Enhances Tissue Regeneration in a rat Model of Lead-Induced Nephrotoxicity.

    Salama, Samir A; Arab, Hany H; Maghrabi, Ibrahim A; Hassan, Memy H; AlSaeed, Mohammed S

    2016-09-01

    Lead is a biohazardous metal that is commonly involved in human illness including renal injury. Although it is a non-redox reactive metal, lead-induced renal injury is largely based on oxidative stress. The current work aimed at exploring the possible protective effect of γ-glutamyl cysteine (γGC) against lead-induced renal injury. Rats were allocated to normal and γGC control groups, lead-treated group, and lead and γGC-treated group. γGC alleviated lead-induced renal injury as evidenced by attenuation of histopathological aberration, amelioration of oxidative injury as demonstrated by significant reduction in lipid and protein oxidation, elevation of total antioxidant capacity, and glutathione level. The activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) was significantly elevated. γGC significantly decreased levels of the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β and the activity of the apoptotic marker caspase-3. In addition, γGC reduced kidney lead content, enhanced weight gain, and improved renal function as demonstrated by reduced serum levels of urea and creatinine. Importantly, γGC upregulated proliferating cell nuclear antigen (PCNA) expression, denoting enhanced renal regenerative capacity. Together, our findings highlight evidence for alleviating effects of γGC against lead-induced renal injury that is potentially mediated through diminution of oxidative tissue injury, reduction of inflammatory response, attenuation of apoptosis, and enhancement of renal regenerative capacity. PMID:26767370

  9. The relation between inflammation and neurodegeneration in multiple sclerosis brains

    Frischer, J.M.; Bramow, S.; Dal-Bianco, A.;

    2009-01-01

    Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occur independently from inflammation. The aim of our study was to analyse the interdependence of inflammation, neurodegeneration and disease progression in various multiple sclerosis stages in relation to...... disease or brain lesions. We found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease. T- and B-cell infiltrates correlated with the activity of demyelinating lesions, while plasma cell...... infiltrates were most pronounced in patients with secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS) and even persisted, when T- and B-cell infiltrates declined to levels seen in age matched controls. A highly significant association between inflammation and...

  10. Microglial cell dysregulation in brain aging and neurodegeneration

    von Bernhardi, Rommy; Eugenín-von Bernhardi, Laura; Eugenín, Jaime

    2015-01-01

    Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergoes phenotypic changes compatible with their activation. Glial activation can lead to neuroinflammation, which is increasingly accepted as part of the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). We hypothesize that in aging, aberrant microglia activation leads to a deleterious environment and neurodegeneration. In aged mice, microglia exhibit an increased expression of c...

  11. Protection of MPTP-induced neuroinflammation and neurodegeneration by Pycnogenol

    Khan, Mohammad Moshahid; Kempuraj, Duraisamy; Thangavel, Ramasamy; Zaheer, Asgar

    2013-01-01

    Oxidative stress and inflammation play a crucial role in Parkinson’s disease (PD) pathogenesis and may represent a target for treatment. Current PD drugs provide only symptomatic relief and have limitations in terms of adverse effects and inability to prevent neurodegeneration. Flavonoids have been suggested to exert human health benefits by its anti-oxidant and anti-inflammatory properties. Therefore, in the present study, using 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydro pyridine (MPTP)-induced...

  12. Neurodegeneration in Schizophrenia: Evidence from In Vivo Neuroimaging Studies

    Csernansky, John G.

    2007-01-01

    Although schizophrenia is primarily considered to be a neurodevelopmental disorder, there is a growing consensus that the disorder may also involve neurodegeneration. Recent research using non-invasive neuroimaging techniques, such as magnetic resonance imaging, suggests that some patients with schizophrenia show progressive losses of gray matter in the frontal and temporal lobes of the brain. The cellular mechanisms responsible for such gray matter losses are unknown, but have been hypothesi...

  13. Emerging nexus between RAB GTPases, autophagy and neurodegeneration.

    Jain, Navodita; Ganesh, Subramaniam

    2016-05-01

    The RAB class of small GTPases includes the major regulators of intracellular communication, which are involved in vesicle generation through fusion and fission, and vesicular trafficking. RAB proteins also play an imperative role in neuronal maintenance and survival. Recent studies in the field of neurodegeneration have also highlighted the process of autophagy as being essential for neuronal maintenance. Here we review the emerging roles of RAB proteins in regulating macroautophagy and its impact in the context of neurodegenerative diseases. PMID:26985808

  14. Genetics and inflammation in nerve injury-induced neurodegeneration

    Lidman, Olle

    2003-01-01

    Neurodegeneration and inflammation are characteristic of many diseases of the central nervous system (CNS) and understanding the molecular networks that regulate these processes is of central importance for the development of effective therapies. Although the CNS has traditionally been regarded as an immuno privileged organ, immune reactions, including components of both local innate and systemic immunity, do occur in this tissue. Animal models can provide powerful tools for...

  15. Neurodegeneration in Schizophrenia: Evidence from In Vivo Neuroimaging Studies

    John G. Csernansky

    2007-01-01

    Full Text Available Although schizophrenia is primarily considered to be a neurodevelopmental disorder, there is a growing consensus that the disorder may also involve neurodegeneration. Recent research using non-invasive neuroimaging techniques, such as magnetic resonance imaging, suggests that some patients with schizophrenia show progressive losses of gray matter in the frontal and temporal lobes of the brain. The cellular mechanisms responsible for such gray matter losses are unknown, but have been hypothesized to involve abnormal increases in apoptosis.

  16. TDP-43 Aggregation In Neurodegeneration: Are Stress Granules The Key?

    Dewey, Colleen M.; Cenik, Basar; Sephton, Chantelle F.; Johnson, Brett A.; Herz, Joachim; Yu, Gang

    2012-01-01

    The RNA-binding protein TDP-43 is strongly linked to neurodegeneration. Not only are mutations in the gene encoding TDP-43 associated with ALS and FTLD, but this protein is also a major constituent of pathological intracellular inclusions in these diseases. Recent studies have significantly expanded our understanding of TDP-43 physiology. TDP-43 is now known to play important roles in neuronal RNA metabolism. It binds to and regulates the splicing and stability of numerous RNAs encoding prote...

  17. The multiple sclerosis visual pathway cohort: understanding neurodegeneration in MS

    Martínez-Lapiscina, Elena H; Fraga-Pumar, Elena; Gabilondo, Iñigo; Martínez-Heras, Eloy; Torres-Torres, Ruben; Ortiz-Pérez, Santiago; Llufriu, Sara; Tercero, Ana; Andorra, Magi; Roca, Marc Figueras; Lampert, Erika; Zubizarreta, Irati; Saiz, Albert; Sanchez-Dalmau, Bernardo; Villoslada, Pablo

    2014-01-01

    Background Multiple Sclerosis (MS) is an immune-mediated disease of the Central Nervous System with two major underlying etiopathogenic processes: inflammation and neurodegeneration. The latter determines the prognosis of this disease. MS is the main cause of non-traumatic disability in middle-aged populations. Findings The MS-VisualPath Cohort was set up to study the neurodegenerative component of MS using advanced imaging techniques by focusing on analysis of the visual pathway in a middle-...

  18. Maintaining the Brain: Insight into Human Neurodegeneration From Drosophila Mutants

    Lessing, Derek; Bonini, Nancy M.

    2009-01-01

    The fruit fly Drosophila melanogaster has brought significant advances to research in neurodegenerative disease, notably in the identification of genes that are required to maintain the structural integrity of the brain, defined by recessive mutations that cause adult-onset neurodegeneration. Here, we survey these genes in the fly and classify them according to five key cell biological processes. Over half of these genes have counterparts in mouse or human that are also associated with neurod...

  19. Mechanisms of neurodegeneration in Alzheimer’s disease

    Jovanović Zorica

    2012-01-01

    Introduction. Recent research into mechanisms of neurodegeneration in Alzheimer’s disease has lead to a dramatic increase in our understanding of the mechanisms of cell death and neuroprotection. Alzheimer’s disease is a complex disease with multiple etiological factors involved in disease pathogenesis. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Amyloid-β peptide toxicity is mediated at least in part by oxidative stress. Amyloid-β peptide directly generates r...

  20. The culture of referendum in Albania: Technical and theoritecal reflections on the abrogative referendum

    Valbona Pajo Bala

    2014-01-01

    The aim of this paper is to analyse the Albanian constitutional and legal framework on referenda, in general, focusing special attention to the abrogative referenda of a law or part thereof. Given the absence of any concrete case of an abrogative referenda held in Albania, which does not creates very much room for discussion in that regard, the paper, through a comparative approach on the referenda culture in other european states, aims at offering to the reader a more complete view on the me...

  1. Protective effects of chitosan and its water-soluble derivatives against lead-induced oxidative stress in mice.

    Wang, Zhihua; Yan, Yongbin; Yu, Xiaohua; Li, Wei; Li, Bojie; Qin, Caiqin

    2016-02-01

    Lead-induced oxidative stress was generated in mice under lead exposure, and the antioxidant activity of chitosan (CS) and its water-soluble derivatives was compared in vivo. The results indicated that there was significant difference (Pchitosan (HPCS) and quaternary ammonium salt of chitosan (HACC). And the changed biochemical variables showed recovery with different degrees, which indicated that CS and its derivatives were helpful for alleviating lead-induced oxidation damage in vivo. But the antioxidant activity for different CS was different, followed by HPCS>HACC>carboxymethyl chitosan (CMCS)>CS, which was in close with the introduction of different substituent groups. In particular, for the dietary of HPCS, there was significant recovery for the changed biochemical variables (P<0.05) in mice after lead exposure, except GSSG in kidney and MDA in brain. PMID:26454108

  2. Meeting report: 2009 international conference on molecular neurodegeneration May 18-20, 2009, Xiamen, China

    Owens Lisa; Zhang Yunwu; Bu Guojun

    2009-01-01

    Abstract Age-related neurodegenerative diseases are great challenges as the aging population grows. To promote neurodegeneration research and to share recent progress in understanding molecular mechanisms underlying these devastating diseases, the journal Molecular Neurodegeneration and Institute for Biomedical Research, Xiamen University co-organized the 2009 International Conference on Molecular Neurodegeneration in Xiamen, China on May 18-20, 2009. The objectives of this meeting were to (1...

  3. Huntingtin interacting proteins are genetic modifiers of neurodegeneration.

    Linda S Kaltenbach

    2007-05-01

    Full Text Available Huntington's disease (HD is a fatal neurodegenerative condition caused by expansion of the polyglutamine tract in the huntingtin (Htt protein. Neuronal toxicity in HD is thought to be, at least in part, a consequence of protein interactions involving mutant Htt. We therefore hypothesized that genetic modifiers of HD neurodegeneration should be enriched among Htt protein interactors. To test this idea, we identified a comprehensive set of Htt interactors using two complementary approaches: high-throughput yeast two-hybrid screening and affinity pull down followed by mass spectrometry. This effort led to the identification of 234 high-confidence Htt-associated proteins, 104 of which were found with the yeast method and 130 with the pull downs. We then tested an arbitrary set of 60 genes encoding interacting proteins for their ability to behave as genetic modifiers of neurodegeneration in a Drosophila model of HD. This high-content validation assay showed that 27 of 60 orthologs tested were high-confidence genetic modifiers, as modification was observed with more than one allele. The 45% hit rate for genetic modifiers seen among the interactors is an order of magnitude higher than the 1%-4% typically observed in unbiased genetic screens. Genetic modifiers were similarly represented among proteins discovered using yeast two-hybrid and pull-down/mass spectrometry methods, supporting the notion that these complementary technologies are equally useful in identifying biologically relevant proteins. Interacting proteins confirmed as modifiers of the neurodegeneration phenotype represent a diverse array of biological functions, including synaptic transmission, cytoskeletal organization, signal transduction, and transcription. Among the modifiers were 17 loss-of-function suppressors of neurodegeneration, which can be considered potential targets for therapeutic intervention. Finally, we show that seven interacting proteins from among 11 tested were able to

  4. Sporadic ALS/MND: a global neurodegeneration with retroviral involvement?

    Westarp, M E; Ferrante, P; Perron, H; Bartmann, P; Kornhuber, H H

    1995-05-01

    Sporadic amyotrophic lateral sclerosis may be an aetiologically heterogenous disease. We confirmed elevated circulating IgG immune complexes, and altered IgG seroreactivities against human retroviral antigens (HIV-2 and HTLV immunoblots) in overlapping subgroups of patients. Together with preliminary findings of a positive polymerase chain reactivity for human T-lymphotropic virus (HTLV.tax/rex) in blood leukocytes of 5 out of 14 sALS patients, we interpret this as evidence for a retroviral involvement in this relentlessly progressive, often asymmetrically spreading neurodegeneration. The possibility of a secondary phenomenon seems unlikely, yet cannot be completely ruled out. PMID:7595609

  5. Neurodegeneration with Brain Iron Accumulation: Diagnosis and Management

    Penelope Hogarth

    2015-01-01

    Full Text Available Neurodegeneration with brain iron accumulation (NBIA encompasses a group of inherited disorders that share the clinical features of an extrapyramidal movement disorder accompanied by varying degrees of intellectual disability and abnormal iron deposition in the basal ganglia. The genetic basis of ten forms of NBIA is now known. The clinical features of NBIA range from rapid global neurodevelopmental regression in infancy to mild parkinsonism with minimal cognitive impairment in adulthood, with wide variation seen between and within the specific NBIA sub-type. This review describes the clinical presentations, imaging findings, pathologic features, and treatment considerations for this heterogeneous group of disorders.

  6. Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease.

    Nelson, Amy R; Sweeney, Melanie D; Sagare, Abhay P; Zlokovic, Berislav V

    2016-05-01

    Vascular insults can initiate a cascade of molecular events leading to neurodegeneration, cognitive impairment, and dementia. Here, we review the cellular and molecular mechanisms in cerebral blood vessels and the pathophysiological events leading to cerebral blood flow dysregulation and disruption of the neurovascular unit and the blood-brain barrier, which all may contribute to the onset and progression of dementia and Alzheimer's disease (AD). Particularly, we examine the link between neurovascular dysfunction and neurodegeneration including the effects of AD genetic risk factors on cerebrovascular functions and clearance of Alzheimer's amyloid-β peptide toxin, and the impact of vascular risk factors, environment, and lifestyle on cerebral blood vessels, which in turn may affect synaptic, neuronal, and cognitive functions. Finally, we examine potential experimental treatments for dementia and AD based on the neurovascular model, and discuss some critical questions to be addressed by future studies. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26705676

  7. Does a loss of TDP-43 function cause neurodegeneration?

    Xu Zuo-Shang

    2012-06-01

    Full Text Available Abstract In 2006, TAR-DNA binding protein 43 kDa (TDP-43 was discovered to be in the intracellular aggregates in the degenerating cells in amyotrophic lateral sclerosis (ALS and frontotemporal lobar degeneration (FTLD, two fatal neurodegenerative diseases [1,2]. ALS causes motor neuron degeneration leading to paralysis [3,4]. FTLD causes neuronal degeneration in the frontal and temporal cortices leading to personality changes and a loss of executive function [5]. The discovery triggered a flurry of research activity that led to the discovery of TDP-43 mutations in ALS patients and the widespread presence of TDP-43 aggregates in numerous neurodegenerative diseases. A key question regarding the role of TDP-43 is whether it causes neurotoxicity by a gain of function or a loss of function. The gain-of-function hypothesis has received much attention primarily based on the striking neurodegenerative phenotypes in numerous TDP-43-overexpression models. In this review, I will draw attention to the loss-of-function hypothesis, which postulates that mutant TDP-43 causes neurodegeneration by a loss of function, and in addition, by exerting a dominant-negative effect on the wild-type TDP-43 allele. Furthermore, I will discuss how a loss of function can cause neurodegeneration in patients where TDP-43 is not mutated, review the literature in model systems to discuss how the current data support the loss-of-function mechanism and highlight some key questions for testing this hypothesis in the future.

  8. Supramolecular Inhibition of Neurodegeneration by a Synthetic Receptor.

    Li, Shengke; Chen, Huanxian; Yang, Xue; Bardelang, David; Wyman, Ian W; Wan, Jianbo; Lee, Simon M Y; Wang, Ruibing

    2015-12-10

    Cucurbit[7]uril (CB[7]) was found in vitro to sequester the neurotoxins MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP(+) (N-methyl-4-phenylpyridine). The CB[7]/neurotoxin host-guest complexes were studied in detail with (1)H NMR, electrospray ionization mass spectrometry, UV-visible spectroscopic titration, and molecular modeling by density functional theory. The results supported the macrocyclic encapsulation of MPTP and MPP(+), respectively, by CB[7] in aqueous solutions with relatively strong affinities and 1:1 host-guest binding stoichiometries in both cases. More importantly, the progression of MPTP/MPP(+) induced neurodegeneration (often referred to as a Parkinson's disease model) was observed to be strongly inhibited in vivo by the synthetic CB[7] receptor, as shown in zebrafish models. These results show that a supramolecular approach could lead to a new preventive and/or therapeutic strategy for counteracting the deleterious effects of some neurotoxins leading to neurodegeneration. PMID:26713100

  9. In Vitro Metabolomic Approach to Hippocampal Neurodegeneration Induced by Trimethyltin.

    Gasparova, Zdenka; Pronayova, Nada; Stara, Veronika; Liptaj, Tibor

    2016-04-01

    Search for indicators of neurodegenerative disorders is a hot topic where much research remains to be done. Our aim was to determine proton nuclear magnetic resonance ((1)H-NMR) spectra of brain metabolites in the trimethyltin (TMT) model of neurodegeneration. Male Wistar rats were subjected to TMT or saline and were sacrificed on day 3 or 24 after administration. (1)H-NMR spectrum was measured on the 600 MHz Varian VNMRS spectrometer in nano-probe in the volume of 40 μl of hippocampal extracts. TMT administration resulted in reduction of the hippocampal weight on day 24. Of the sixteen identified metabolite spectra, decreased aspartate and increased glutamine contents were observed in the initial asymptomatic stage of neurodegeneration on day 3 in hippocampal extracts of TMT exposed rats compared to sham animals. Increased myo-inositol content was observed on day 24. The presented data provide further knowledge about this experimental model and putative indicators of neuronal damage. PMID:26482153

  10. Protective role of ginger on lead induced derangement in plasma testosterone and luteinizing hormone levels of male sprague dawley rats

    Background: Lead is one of the most serious environmental threats to human health especially in developing countries. It damages multiple body systems including the reproductive system. Ginger's antioxidant and androgenic activity is reported in multiple animal studies. The aim of this study was to investigate the ameliorative effect of Zingiber officinale (ginger) on lead induced derangement in plasma testosterone and luteinizing hormone (LH) levels of male rats. Methods: Sixty adult male Sprague Dawley rats were used in this study in four groups. Group A served as normal control, Group B received 0.3% lead acetate in drinking water, Group C and group D received supplementary 0.5 and 1 gm/Kg bodyweight of ginger respectively along with lead acetate in drinking water. Five rats from each group were sacrificed at the end of 2nd, 4th and 6th weeks. Serum testosterone and LH levels were analysed using ELISA technique. Results: After co administration with different doses of ginger, serum testosterone level which was significantly decreased in lead treated group, showed a significant rise as compared to lead treated group. LH levels which had exhibited no significant change by lead treatment, after co administration with different doses of ginger, again showed no significant change. Conclusion: Oral administration of ginger ameliorated lead induced testicular toxicity in male rats by increasing serum testosterone level at all durations which might be a product of both its androgenic and antioxidant properties. (author)

  11. TLR4 initiated and cAMP mediated abrogation of bacterial invasion of the bladder

    Song, Jeongmin; Bishop, Brian L.; Li, Guojie; Duncan, Matthew J.; Abraham, Soman N

    2007-01-01

    The remarkable resistance of the urinary tract to infection has been attributed to its physical properties and the innate immune responses triggered by pattern recognition receptors lining the tract. We report a distinct TLR4 mediated mechanism in bladder epithelial cells (BECs) that abrogates bacterial invasion, a necessary step for successful infection. Compared to controls, uropathogenic type 1 fimbriated Escherichia coli and Klebsiella pneumoniae invaded BECs of TLR4 mutant mice in 10-fol...

  12. Puerarin protects rat kidney from lead-induced apoptosis by modulating the PI3K/Akt/eNOS pathway

    Liu, Chan-Min, E-mail: lcm9009@126.com [School of Life Science, Xuzhou Normal University, No.101, Shanghai Road, Tangshan New Area, Xuzhou City 221116, Xuzhou City, Jiangsu Province (China); Ma, Jie-Qiong [School of Chemical Engineering, China University of Mining and Technology, Xuzhou 221008, Xuzhou City, Jiangsu Province (China); Sun, Yun-Zhi [School of Life Science, Xuzhou Normal University, No.101, Shanghai Road, Tangshan New Area, Xuzhou City 221116, Xuzhou City, Jiangsu Province (China)

    2012-02-01

    Puerarin (PU), a natural flavonoid, has been reported to have many benefits and medicinal properties. However, its protective effects against lead (Pb) induced injury in kidney have not been clarified. The aim of the present study was to investigate the effects of puerarin on renal oxidative stress and apoptosis in rats exposed to Pb. Wistar rats were exposed to lead acetate in the drinking water (500 mg Pb/l) with or without puerarin co-administration (100, 200, 300 and 400 mg PU/kg intragastrically once daily) for 75 days. Our data showed that puerarin significantly prevented Pb-induced nephrotoxicity in a dose-dependent manner, indicated by both diagnostic indicators of kidney damage (serum urea, uric acid and creatinine) and histopathological analysis. Moreover, Pb-induced profound elevation of reactive oxygen species (ROS) production and oxidative stress, as evidenced by increasing of lipid peroxidation level and depleting of intracellular reduced glutathione (GSH) level in kidney, were suppressed by treatment with puerarin. Furthermore, TUNEL assay showed that Pb-induced apoptosis in rat kidney was significantly inhibited by puerarin. In exploring the underlying mechanisms of puerarin action, we found that activities of caspase-3 were markedly inhibited by the treatment of puerarin in the kidney of Pb-treated rats. Puerarin increased phosphorylated Akt, phosphorylated eNOS and NO levels in kidney, which in turn inactivated pro-apoptotic signaling events including inhibition of mitochondria cytochrome c release and restoration of the balance between pro- and anti-apoptotic Bcl-2 proteins in kidney of Pb-treated rats. In conclusion, these results suggested that the inhibition of Pb-induced apoptosis by puerarin is due at least in part to its antioxidant activity and its ability to modulate the PI3K/Akt/eNOS signaling pathway. Highlights: ► Puerarin prevented lead-induced nephrototoxicity. ► Puerarin reduced lead-induced increase in ROS and TBARS production

  13. Strategies for clinical approach to neurodegeneration in Amyotrophic lateral sclerosis.

    Carlesi, Cecilia; Pasquali, Livia; Piazza, Selina; Lo Gerfo, Annalisa; Caldarazzo Ienco, Elena; Alessi, Rosaria; Fornai, Francesco; Siciliano, Gabriele

    2011-03-01

    Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disorder of unknown aetiology that involves the loss of upper and lower motor neurons in the cerebral cortex, brainstem and spinal cord. Significant progress in understanding the cellular mechanisms of motor neuron degeneration in ALS has not been matched with the development of therapeutic strategies to prevent disease progression, and riluzole remains the only available therapy, with only marginal effects on disease survival. More recently alterations of mRNA processing in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations have provided important insights into the molecular networks implicated in the disease pathogenesis. Here we review some of the recent progress in promoting therapeutic strategies for neurodegeneration. PMID:21412722

  14. Self-mutilation in neurodegeneration with brain iron accumulation

    Sadanandavalli Retnaswami Chandra

    2015-01-01

    Full Text Available Neurodegeneration with brain iron accumulation (NBIA is the term applied to a heterogeneous group of disorders resulting in iron deposition in the basal ganglia. Well-known phenotypic features are progressive regression with extra pyramidal involvement and a variable course. A 10-year-old child born to consanguineous parents presented with progressive generalized opisthotonic dystonia, retrocollis, oromandibular dyskinesias, apraxia for swallowing, optic atrophy and severe self-mutilation of lips. MR imaging showed brain iron accumulation. Other causes of self-mutilation were excluded. Early infantile onset, ophisthotonic dystonia with oromandibular dyskinesias and characteristic MR images are suggestive of NBIA. There is only one case reported in the literature of self-mutilation in this condition.

  15. Implications of mitochondrial dynamics on neurodegeneration and on hypothalamic dysfunction

    Antonio eZorzano

    2015-06-01

    Full Text Available Mitochondrial dynamics is a term that encompasses the movement of mitochondria along the cytoskeleton, regulation of their architecture, and connectivity mediated by tethering and fusion/fission. The importance of these events in cell physiology and pathology has been partially unraveled with the identification of the genes responsible for the catalysis of mitochondrial fusion and fission. Mutations in two mitochondrial fusion genes (MFN2 and OPA1 cause neurodegenerative diseases, namely Charcot-Marie Tooth type 2A and autosomal dominant optic atrophy. Alterations in mitochondrial dynamics may be involved in the pathophysiology of prevalent neurodegenerative conditions. Moreover, impairment of the activity of mitochondrial fusion proteins dysregulates the function of hypothalamic neurons, leading to alterations in food intake and in energy homeostasis. Here we review selected findings in the field of mitochondrial dynamics and their relevance for neurodegeneration and hypothalamic dysfunction.

  16. Protection of MPTP-induced neuroinflammation and neurodegeneration by Pycnogenol.

    Khan, Mohammad Moshahid; Kempuraj, Duraisamy; Thangavel, Ramasamy; Zaheer, Asgar

    2013-03-01

    Oxidative stress and inflammation play a crucial role in Parkinson's disease (PD) pathogenesis and may represent a target for treatment. Current PD drugs provide only symptomatic relief and have limitations in terms of adverse effects and inability to prevent neurodegeneration. Flavonoids have been suggested to exert human health benefits by its anti-oxidant and anti-inflammatory properties. Therefore, in the present study, using 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP)-induced mouse model of Parkinsonism, we investigated the neuroprotective potential of bioflavonoid compound Pycnogenol® (PYC), an extract of Pinus maritime bark. MPTP injected mice developed significantly severe oxidative stress and impaired motor coordination at day 1 and day 7 postinjection. This was associated with significantly increased inflammatory responses of astrocyte and microglia as assessed by ionized calcium binding adaptor molecule 1 (Iba 1) and glial fibrillary acidic protein (GFAP) immunohistochemistry, and nuclear transcription factor-κB (NF-κB), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in the striata by Western blot. Additionally, there was significant upregulation of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) expression in the striata of MPTP injected mice compared to saline controls. The MPTP-induced neuroinflammation, neurodegeneration and behavioral impairments were markedly repudiated by treatment with PYC. These results suggest that PYC protects dopaminergic neurons from MPTP-induced toxicity in the mouse model of PD. Thus, the present finding of PYC-induced adaptation to oxidative stress and inflammation could suggest a novel avenue for clinical intervention in neurodegenerative diseases including PD. PMID:23391521

  17. Linking pathways in the developing and aging brain with neurodegeneration.

    Kovacs, G G; Adle-Biassette, H; Milenkovic, I; Cipriani, S; van Scheppingen, J; Aronica, E

    2014-06-01

    The molecular and cellular mechanisms, which coordinate the critical stages of brain development to reach a normal structural organization with appropriate networks, are progressively being elucidated. Experimental and clinical studies provide evidence of the occurrence of developmental alterations induced by genetic or environmental factors leading to the formation of aberrant networks associated with learning disabilities. Moreover, evidence is accumulating that suggests that also late-onset neurological disorders, even Alzheimer's disease, might be considered disorders of aberrant neural development with pathological changes that are set up at early stages of development before the appearance of the symptoms. Thus, evaluating proteins and pathways that are important in age-related neurodegeneration in the developing brain together with the characterization of mechanisms important during brain development with relevance to brain aging are of crucial importance. In the present review we focus on (1) aspects of neurogenesis with relevance to aging; (2) neurodegenerative disease (NDD)-associated proteins/pathways in the developing brain; and (3) further pathways of the developing or neurodegenerating brains that show commonalities. Elucidation of complex pathogenetic routes characterizing the earliest stage of the detrimental processes that result in pathological aging represents an essential first step toward a therapeutic intervention which is able to reverse these pathological processes and prevent the onset of the disease. Based on the shared features between pathways, we conclude that prevention of NDDs of the elderly might begin during the fetal and childhood life by providing the mothers and their children a healthy environment for the fetal and childhood development. PMID:24699227

  18. Abrogation of the Transactivation Activity of p53 by BCCIP Down-regulation*

    Meng, Xiangbing; Yue, Jingyin; Liu, Zhihe; Shen, Zhiyuan

    2006-01-01

    The tumor suppression function of p53 is mostly conferred by its transactivation activity, which is inactivated by p53 mutations in ~50% of human cancers. In cancers harboring wild type p53, the p53 transactivation activity may be compromised by other mechanisms. Identifying the mechanisms by which wild type p53 transactivation activity can be abrogated may provide insights into the molecular etiology of cancers harboring wild type p53. In this report, we show that BCCIP, a BRCA2 and CDKN1A-i...

  19. Early limited nitrosamine exposures exacerbate high fat diet-mediated type 2 diabetes and neurodegeneration

    Longato Lisa

    2010-03-01

    Full Text Available Abstract Background Type 2 diabetes mellitus (T2DM and several types of neurodegeneration, including Alzheimer's, are linked to insulin-resistance, and chronic high dietary fat intake causes T2DM with mild neurodegeneration. Intra-cerebral Streptozotocin, a nitrosamine-related compound, causes neurodegeneration, whereas peripheral treatment causes DM. Hypothesis Limited early exposures to nitrosamines that are widely present in the environment, enhance the deleterious effects of high fat intake in promoting T2DM and neurodegeneration. Methods Long Evans rat pups were treated with N-nitrosodiethylamine (NDEA by i.p. injection, and upon weaning, they were fed with high fat (60%; HFD or low fat (5%; LFD chow for 8 weeks. Cerebella were harvested to assess gene expression, and insulin and insulin-like growth factor (IGF deficiency and resistance in the context of neurodegeneration. Results HFD ± NDEA caused T2DM, neurodegeneration with impairments in brain insulin, insulin receptor, IGF-2 receptor, or insulin receptor substrate gene expression, and reduced expression of tau and choline acetyltransferase (ChAT, which are regulated by insulin and IGF-1. In addition, increased levels of 4-hydroxynonenal and nitrotyrosine were measured in cerebella of HFD ± NDEA treated rats, and overall, NDEA+HFD treatment reduced brain levels of Tau, phospho-GSK-3β (reflecting increased GSK-3β activity, glial fibrillary acidic protein, and ChAT to greater degrees than either treatment alone. Finally, pro-ceramide genes, examined because ceramides cause insulin resistance, oxidative stress, and neurodegeneration, were significantly up-regulated by HFD and/or NDEA exposure, but the highest levels were generally present in brains of HFD+NDEA treated rats. Conclusions Early limited exposure to nitrosamines exacerbates the adverse effects of later chronic high dietary fat intake in promoting T2DM and neurodegeneration. The mechanism involves increased generation of

  20. White Matter Integrity on DTI, Amyloid Load, and Neurodegeneration in Non-demented Elderly

    Kantarci, Kejal; Schwarz, Christopher G.; Reid, Robert; Przybelski, Scott A.; Lesnick, Timothy; Zuk, Samantha M.; Senjem, Matthew L.; Gunter, Jeffrey L.; Lowe, Val; Machulda, Mary M.; Knopman, David S.; Petersen, Ronald C.; Jack, Clifford R.

    2016-01-01

    Importance Pathophysiologic mechanisms leading to loss of white matter (WM) integrity and the temporal positioning of biomarkers of WM integrity relative to the biomarkers of gray matter (GM) neurodegeneration and amyloid load in the course of AD are poorly understood. Objective To investigate the effects of Alzheimer’s disease (AD)-related GM neurodegeneration and high β-amyloid on white matter (WM) microstructure in non-demented older adults. Design Longitudinal cohort study Setting Population-based Mayo Clinic Study of Aging. Participants Participants (n=701) with MRI/DTI and PET studies diagnosed as cognitively normal (CN; n=570) or mild cognitive impairment (MCI; n=131) were included. CN and MCI subjects were divided into biomarker-negative, amyloid- positive only, neurodegeneration- positive only, and amyloid plus neurodegeneration-positive groups based on their amyloid load on 11C-Pittsburgh compound-B PET, AD hypometabolic pattern on 18F-fluorodeoxyglucose PET and/or hippocampal atrophy on MRI. Main Outcome Measure Fractional anisotrophy (FA) from diffusion tensor imaging (DTI) Results No FA alterations were observed in biomarker-negative MCI, and amyloid-positive only CN and MCI groups. Conversely, neurodegeneration-positive only and amyloid plus neurodegeneration- positive CN and MCI groups consistently had decreased FA in the fornix, which correlated with cognitive performance (Rho=0.38; pPatients with MCI had more extensive WM involvement than CN subjects, and greatest FA decreases were observed in the amyloid plus neurodegeneration-positive MCI group. Conclusions and Relevance High amyloid load does not influence DTI-based measures of WM integrity in the absence of co-existent GM neurodegeneration in non-demented older adults. PMID:25347157

  1. Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

    Ahmad, Saif; Bhatia, Kanchan; Kannan, Annapoorna; Gangwani, Laxman

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA. PMID:27042141

  2. Selective neurodegeneration, neuropathology and symptom profiles in Huntington's disease.

    Waldvogel, Henry J; Thu, Doris; Hogg, Virginia; Tippett, Lynette; Faull, Richard L M

    2012-01-01

    Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease caused by a CAG repeat expansion in exon 1 of the Huntington gene (HD) also known as IT15. Despite the disease being caused by dysfunction ofa single gene, expressed as an expanded polyglutamine in the huntingtin protein, there is a major variability in the symptom profile of patients with Huntington's disease as well as great variability in the neuropathology. The symptoms vary throughout the course of the disease and vary greatly between cases. These symptoms present as varying degrees of involuntary movements, mood, personality changes, cognitive changes and dementia. To determine whether there is a morphological basis for this symptom variability, recent studies have investigated the cellular and neurochemical changes in the striatum and cerebral cortex in the human brain to determine whether there is a link between the pathology in these regions and the symptomatology shown by individual cases. These studies together revealed that cases showing mainly mood symptom profiles correlated with marked degeneration in the striosomal compartment of the striatum, or in the anterior cingulate gyrus of the cerebral cortex. In contrast, in cases with mainly motor symptoms neurodegeneration was especially marked in the primary motor cortex with variable degeneration in both the striosomes and matrix compartments of the striatum. These studies suggest that the variable degeneration of the striatum and cerebral cortex correlates with the variable profiles of Huntington's disease. PMID:23560309

  3. Application of medical cannabis in patients with the neurodegeneration disorders

    Lidia Kotuła

    2014-04-01

    Full Text Available Medical cannabis is the dried flowers of the female Cannabis sativa L. plant. Cannabis contains a number of active elements, including dronabinol (THC and cannabidiol (CBD. Dronabinol is usually the main ingredient. The body’s own cannabinoid system has been identified. The discovery of this system, which comprises endocannabinoids and receptors, confirmed that cannabis has a positive effect on certain illnesses and conditions. Two types of cannabinoid receptors have been identified: CB1 and CB2 receptors. The first type CB1 is mostly found in the central nervous system, modulate pain. It also has an anti-emetic effect, and has influence on the memory and the motor system. The second type of receptors CB2 is peripheral, and it is primarily found in immune system cells and it is responsible for the immunomodulatory effects of cannabinoids. Medical cannabis can help in cases of the neurodegeneration disorders, for example Parkinson’s disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis. Patients generally tolerate medical cannabis well.

  4. Aging and Neurodegeneration: A Tangle of Models and Mechanisms.

    Chakrabarti, Sasanka; Mohanakumar, Kochupurackal P

    2016-03-01

    The research on aging and age-related diseases, especially the neurodegenerative diseases, is on the fast track. However, the results have so far not been translated to actual benefit for the patients in terms of treatment or diagnosis of age-related degenerative diseases including those of the CNS. As far as the prevention of the cognitive decline during non-pathological aging is concerned, there is nothing much to offer other than calorie restriction and physical exercise. Needless to say, the benefits are not up to our expectations. However, over the years at the experimental level it has been possible to identify several cellular and molecular mechanisms that are intricately associated with aging in general and neurodegenerative diseases in particular. These include oxidative stress and altered redox-signaling, mitochondrial dysfunction, inflammation, proteotoxicity and altered gene expressions. These inter-dependent pathways mediate cellular senescence and often culminate in programmed cell death like apoptosis and autophagy, and in the context of brain these changes are manifested clinically as cognitive decline and pathologically as neurodegeneration. This special issue provides the readers with glimpses of this complex scenario from different angles primarily in the context of brain and also attempts to identify the potential drug targets against neurodegenerative diseases. PMID:27114843

  5. Oxidative damage and neurodegeneration in manganese-induced neurotoxicity

    Exposure to excessive manganese (Mn) levels results in neurotoxicity to the extrapyramidal system and the development of Parkinson's disease (PD)-like movement disorder, referred to as manganism. Although the mechanisms by which Mn induces neuronal damage are not well defined, its neurotoxicity appears to be regulated by a number of factors, including oxidative injury, mitochondrial dysfunction and neuroinflammation. To investigate the mechanisms underlying Mn neurotoxicity, we studied the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates (HEP), neuroinflammation mediators and associated neuronal dysfunctions both in vitro and in vivo. Primary cortical neuronal cultures showed concentration-dependent alterations in biomarkers of oxidative damage, F2-isoprostanes (F2-IsoPs) and mitochondrial dysfunction (ATP), as early as 2 h following Mn exposure. Treatment of neurons with 500 μM Mn also resulted in time-dependent increases in the levels of the inflammatory biomarker, prostaglandin E2 (PGE2). In vivo analyses corroborated these findings, establishing that either a single or three (100 mg/kg, s.c.) Mn injections (days 1, 4 and 7) induced significant increases in F2-IsoPs and PGE2 in adult mouse brain 24 h following the last injection. Quantitative morphometric analyses of Golgi-impregnated striatal sections from mice exposed to single or three Mn injections revealed progressive spine degeneration and dendritic damage of medium spiny neurons (MSNs). These findings suggest that oxidative stress, mitochondrial dysfunction and neuroinflammation are underlying mechanisms in Mn-induced neurodegeneration.

  6. Emerging targets in neurodegeneration: new opportunities for Alzheimer's disease treatment?

    Rampa, Angela; Gobbi, Silvia; Belluti, Federica; Bisi, Alessandra

    2013-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the brain associated with memory impairment, progressive cognitive decline and changes in personality and behavior, with rising incidence among elderly people. Reflecting the world population ageing, the scenario is expected to worsen in the next decades if novel drugs or mechanisms that help to counteract neurodegeneration will not be identified. The complex neuropathology of AD is characterized by cholinergic loss, extracellular deposition of amyloid-β plaques, formation of intracellular neurofibrillary tangles, chronic brain inflammation and oxidative damage. To date, there are no effective treatments that can slow or halt the disease, and currently approved drugs only seem to act as palliative by temporary ameliorating cognitive impairment. On the other hand, the role played by other biological systems in the pathogenetic process is now clearly growing and, as knowledge on how AD develops and triggers brain damage proceeds, drug discovery attempts to identify new potential therapeutic targets. This review will focus on these emerging strategies, some of which could open new therapeutic perspectives in Alzheimer's disease, adding new elements for the medicinal chemist to handle and combine for the design of novel multi-target-directed ligands able to simultaneously modulate 'old classic' and newly identified targets. PMID:23931436

  7. Influence of minerals on lead-induced alterations in liver function in rats exposed to long-term lead exposure

    The objective of this study was to evaluate the role of minerals on lead-induced effect on the liver. Differentiation of minerals and heavy metals pose an inherent problem due to certain common properties shared by them. With this approach to the problem of heavy metal toxicity, in the present study two groups of male Wistar albino rats, one group (well-nourished) fed on mineral rich diet and other group (undernourished) fed on diet without mineral supplements were used. Both the groups of rats were subjected to long-term lead exposure. The diet of well-nourished group was supplemented with calcium (Ca); 1.2%, phosphorous (P); 0.6%, iron (Fe); 90 mg/kg, zinc (Zn); 50 mg/kg, magnesium (Mg); 0.08%, manganese (Mn); 70 mg/kg, selenium (Se); 0.2 mg/kg, copper (Cu); 5 mg/kg, molybdenum (Mo); 0.8 mg/kg, iodine (I); 0.6 mg/kg, cobalt (Co); 3.0 mg/kg. Their blood lead and parameters of liver function were monitored periodically. Results of the study showed a very high statistically significant increase (p < 0.001) in the blood lead (PbB) levels and liver function test parameters in the undernourished subjects compared to the well-nourished subjects. Nutritional management of lead poisoning is of importance since essential elements and toxic heavy metals may interact to minimize the absorption of lead.

  8. Therapeutic Effects of Allium sativum on Lead-induced Biochemical changes in Soft tissues of Swiss Albino Mice

    Arti Sharma

    2009-01-01

    Full Text Available Allium sativum (Meaning pungent belongs to the Alliaceae family and genus Allium, is generally known in the developing world for its characteristic flavor, a medicinal plant and a source of vegetable oil. Besides, the plant is reported to have various biological activities including hypocholesterolemic, antiatherosclerotic, anticoagulant, antibacterial, antifungal, anti-diabetic, anti-tumor agent; used for treating various disease such as inflammation, cardiovascular and liver diseases. The objective of this study is to investigate the therapeutic effects of Allium sativum on lead induced toxicity in mice. Chronic dose of lead (2 mg/Kg body weight, i.p., showed significant decrease in antioxidant enzymes such as superoxide dismutase (SOD, catalase (CAT and the nonenzymatic antioxidant as glutathione (GSH and total protein content in the liver, kidney and brain. This decrease was accompanied with significant increase in lipid peroxidation and cholesterol level. Also, there were disturbances in the liver, kidney and brain functions manifested by significant changes in their functional markers. Efficacy of garlic to reduce tissue lead concentration was also evaluated. Mostly, all of the investigated parameters were restored nearly to the normal values after raw garlic extract treatment. In conclusion, garlic exerts its effects not only as an antioxidant but also as a sulfur donor. So, garlic has a promising role and it is worth to be considered as a natural chelating agent for lead intoxication.

  9. Influence of p53 abrogation on penclomedine and radiation-induced cell kill

    Purpose: Penclomedine [(3.5-dichloro-2,4-dimethoxy-6-trichloromethyl)pyridine], a synthetic pyridine derivative, has documented activity against human and murine tumor cells and is currently being investigated in Phase I clinical trials. Cells exposed to Penclomedine reveal abundant chromosomal aberrations suggesting that its mechanism of action may be through DNA alkylation. Since p53 is considered to be a DNA damage responsive element, we investigated the influence of p53 abrogation on Penclomedine sensitivity, on sensitivity to ionizing radiation and to both modalities combined. Material and Methods: Three malignant cell lines, derived from a human colorectal carcinoma, were used in this study: RKO cells which contain wild-type p53 alleles, RKO cells transfected with an over expressed mutant p53 transgene (p53.13) and RKO cells transfected with an over expressed HPV-16 E6 gene (RC 10.03) resulting in abrogation of normal p53 function. Cells were exposed to increasing concentrations of Penclomedine (0-120 μg/ml) for variable periods of time (4, 6, 8, 12, 24 hours) as well as to graded doses of ionizing radiation (0-8 Gy), either alone or following 24 hour exposure to Penclomedine. Cell viability was monitored by the colony-forming assay and Trypan blue exclusion. Cell numbers were counted using a hemocytometer and Coulter counter. Both asynchronous and synchronized cell populations were studied with synchrony attained by mitotic shake off. S phase cell determination was by anti-BrdU immuno labeling. Results: Each cell line exhibited a dose and time-dependent reduction in cell viability following Penclomedine treatment. However, RC 10.03 cells showed a dramatic enhancement in cell kill compared to the parental RKO cells (P<0.05). No significant difference in radiation sensitivity amongst the 3 cell lines was observed when cells were exposed either as an asynchronous population or in early G1. Conclusion: The results of this study suggest that radiation

  10. Protective efficacy of Emblica against radiation and lead induced changes in the Jejunum of Swiss Albino mice

    Recently, increased interest has developed on search for potential drugs of plant origin which can quench the radiation induced free radicals and eliminate oxygen with minimum side effects. In view of the fact, present study was planned to evaluate the protective efficacy of Emblica against radiation and lead induced changes in jejunum of mice. For the purpose, six to eight weeks old male Swiss albino mice were selected and divided into seven groups on the basis of radiation, lead, combined treatment and drug treated. The values of total proteins, cholesterol, acid phosphatase activity, alkaline phosphatase activity, DNA and RNA were estimated. The values of total proteins, cholesterol, DNA and RNA decreased whereas acid phosphatase and alkaline phosphatase activity increased. After irradiation with various doses of gamma rays, histological changes depend upon the dose of radiation delivered. The important radio-lesions were looseness of musculatrue, hydropic degeneration in submucosa and lamina propria, hyperaemia and haemorrhage in submucosa, pyknotic cells, cytoplasmic degranulation and vacuolation, abnormal mitotic figures. Karyolysis, karyorrhexis and chromatolysis were also observed in crypt cells. Shortening and breaking of villus tips, leucocytic infiltration in lamina propria and cell debris in intestinal lumen were also noted. The number of goblet cells per crypt section also decreased in all the experimental groups. The value of the experimental groups was significantly lower than that of the control group. The biochemical finding indicated the drug treated section of living tissue showed slightly/no degenerative changes. The drug treated groups demonstrating the ability of Aloe vera to inhibit oxidative stress thus preventing tissue injury. (author)

  11. Protective efficacy of Emblica against radiation and lead induced biochemical changes in the kidney of Swiss albino mice

    Ionizing radiation kills cells in the area being treated (the target tissue) as well as other surrounding healthy cells. The damaging effects of ionizing radiation on healthy tissue create a major barrier in effective treatment of common human cancers. Thus there is a need to find a safe and highly effective avenue to reduce normal cell damage during cancer therapy, plants have been used in the traditional healthcare system from time immemorial, and phyto products continue to play an essential role in medicine. Emblica, is reported to have an excellent radio protective activity, antioxidant and a free radical scavenger. In light of above, the present study was aimed to evaluate the protective effect of Emblica against radiation and lead induced biochemical alterations in the kidney of Swiss albino mice. The animals were exposed to 6.0 Gy of gamma rays with or without Lead acetate treatment. The Emblica was administered seven days prior to irradiation or Lead Acetate treatment. The animals from all experimental groups were sacrificed by cervical dislocation at each post treatment intervals of 1, 2, 4, 7, 14 and 28 days. After sacrificing the animals, pieces of the kidney were taken out and kept at - 20 deg C for different biochemical parameters. For the study the animals were exposed to 6.0 Gy of gamma rays with or without Lead acetate treatments. In the experimental groups the Emblica juice was given seven days prior to the radiation or lead acetate treatment. The various biochemical parameters viz, total proteins, glycogen, cholesterol, acid phosphatase and alkaline phosphatase activities, DNA and RNA were estimated. The values were observed in the form of increase or decrease. After combined treatment of radiation and lead acetate the changes were more severe showing synergistic effect of both the agent. An early and fast recovery was also noticed in Emblica pre-treated animals. Thus it appears that Emblica is potent enough to check Lead and Radiation induced

  12. A study of chemopreventive effects of Emblica officinalis Linn. against radiation and lead induced haematological changes in Swiss albino mice

    The vast potential of radiant energy opens vistas of new horizons as its use in various fields of science, technology, therapeutics and diagnosis. However its also exposes the global population to the hazards of nuclear accidents and radiation injury. In this era of nuclear science it has become a prerequisite to know the effects of radiation on mankind and to develop effective countermeasures for minimizing the damages of radiation exposure. Heavy metals like lead can cause deleterious effects when its concentration goes beyond the limit in ecosystem. The combined effects of radiation and lead further increases the causation of damages to organs and tissues. Amla is found to be a non toxic, inexpensive, easily available herbal drug. Therefore present study was pertain to evaluate the chemo preventive role of Amla against radiation and lead induced changes in blood of Swiss albino mice. The animals were exposed to 6.0 Gy of gamma rays and with or without lead acetate which was given to them adlibitum. The Emblica was administered seven days prior to irradiation or lead acetate treatment. Three animals were sacrificed from all the experimental group at each post treatment intervals of 1, 2, 4, 7, 14 and 28 days by cervical dislocation . The blood was collected in heparinised tube for estimating various haematological parameters. The value of RBC, WBC, PCV, Hemoglobin, and MCV decreased up to day-14 in non drug treated groups and day-7 in drug treated groups, thereafter the value increased. When the animals treated with radiation and lead simultaneously synergistic effects were observed. The Amla treated groups showed early and fast recovery thus, it may deduce from above observation that Amla has potential to check the alteration produced by radiation and lead in the blood of Swiss albino mice. (author)

  13. Brain mitochondrial dysfunction in aging, neurodegeneration and Parkinson's disease

    Ana Navarro

    2010-09-01

    Full Text Available Brain senescence and neurodegeneration occur with a mitochondrial dysfunction characterized by impaired electron transfer and by oxidative damage. Brain mitochondria of old animals show decreased rates of electron transfer in complexes I and IV, decreased membrane potential, increased content of the oxidation products of phospholipids and proteins and increased size and fragility. This impairment, with complex I inactivation and oxidative damage, is named “complex I syndrome” and is recognized as characteristic of mammalian brain aging and of neurodegenerative diseases. Mitochondrial dysfunction is more marked in brain areas as rat hippocampus and frontal cortex, in human cortex in Parkinson’s disease and dementia with Lewy bodies, and in substantia nigra in Parkinson’s disease. The molecular mechanisms involved in complex I inactivation include the synergistic inactivations produced by ONOO- mediated reactions, by reactions with free radical intermediates of lipid peroxidation and by amine-aldehyde adduction reactions. The accumulation of oxidation products prompts the idea of antioxidant therapies. High doses of vitamin E produce a significant protection of complex I activity and mitochondrial function in rats and mice, and with improvement of neurological functions and increased median life span in mice. Mitochondria-targeted antioxidants, as the Skulachev cations covalently attached to vitamin E, ubiquinone and PBN and the SS tetrapeptides, are negatively charged and accumulate in mitochondria where they exert their antioxidant effects. Activation of the cellular mechanisms that regulate mitochondrial biogenesis is another potential therapeutic strategy, since the process generates organelles devoid of oxidation products and with full enzymatic activity and capacity for ATP production.

  14. Mechanisms of neurodegeneration in Alzheimer’s disease

    Jovanović Zorica

    2012-01-01

    Full Text Available Introduction. Recent research into mechanisms of neurodegeneration in Alzheimer’s disease has lead to a dramatic increase in our understanding of the mechanisms of cell death and neuroprotection. Alzheimer’s disease is a complex disease with multiple etiological factors involved in disease pathogenesis. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Amyloid-β peptide toxicity is mediated at least in part by oxidative stress. Amyloid-β peptide directly generates reactive oxygen species in the presence of redox-active metal ions. In Alzheimer’s disease, oxidative stress is present early in pathogenesis and contributes to disease pathogenesis. Unlike other organs, the brain is especially vulnerable to reactive oxygen species due to neurons having relatively low levels of endogenous antioxidants. Overly abundant oxygen radicals cause the destruction of cellular macromolecules and participate in signaling mechanisms that result in apoptotic cell death. Microglial activation and nicotinamide adenine dinucleotide phosphate oxidase in Alzheimer’s disease. There is a wealth of evidence demonstrating that microglia, the resident innate immune cells in the brain, can become deleterious and damage neurons. Microglial activation causes neuron damage through the production of neurotoxic factors, such as reactive oxygen species and cytokines that are toxic to neurons. The neuron also has strong homeostatic mechanisms that can delay or prevent activation of apoptosis and necrosis. Insulin resistance and Alzheimer’s disease. Insulin plays a role in Alzheimer’s disease, as it is involved in the metabolism of β-amyloid. Hyperinsulinemia and type-2 diabetes mellitus results in an increased risk of developing Alzheimer’s disease, but its implications when the disease is already well established remain unknown. Treatment of central insulin resistance may be a promising avenue, not only in metabolic syndrom, but also in

  15. Abrogation of Early Apoptosis Does Not Alter Late Inhibition of Hippocampal Neurogenesis After Irradiation

    Purpose: Irradiation of the adult brain results in acute apoptosis of neural progenitors and vascular endothelial cells, as well as late dysfunction of neural progenitors and inhibition of neurogenesis. We sought to determine whether the early apoptotic response has a causative role in late inhibition of neurogenesis after cranial irradiation. Methods and Materials: Using a genetic approach with p53 and smpd1 transgenic mice and a pharmacologic approach with basic fibroblast growth factor (bFGF) to abrogate the early apoptotic response, we evaluated the late inhibition of neurogenesis in the hippocampal dentate gyrus after cranial irradiation. Results: In dentate gyrus, subgranular neural progenitors underwent p53-dependent apoptosis within 24 h after irradiation. Despite a near abrogation of neural progenitor apoptosis in p53-/- mice, the reduction in newborn neurons in dentate gyrus at 9 weeks after irradiation in p53-/- mice was not different from that observed in wildtype controls. Endothelial cell apoptosis after radiation is mediated by membrane damage initiated by activation of acid sphingomyelinase (ASMase). Deletion of the smpd1 gene (which encodes ASMase) attenuated the apoptotic response of endothelial cells. At 9 weeks after irradiation, the inhibition of hippocampal neurogenesis was not rescued by ASMase deficiency. Intravenous administration of bFGF protected both endothelial cells and neural progenitors against radiation-induced apoptosis. There was no protection against inhibition of neurogenesis at 9 weeks after irradiation in bFGF-treated mice. Conclusion: Early apoptotic death of neural progenitors, endothelial cells, or both does not have a causative association with late inhibition of neurogenesis after irradiation.

  16. HCV NS5A abrogates p53 protein function by interfering with p53-DNA binding

    Guo-Zhong Gong; Yong-Fang Jiang; Yan He; Li-Ying Lai; Ying-Hua Zhu; Xian-Shi Su

    2004-01-01

    AIM: To evaluate the inhibition effect of HCV NS5A on p53 transactivation on p21 promoter and explore its possible mechanism for influencing p53 function.METHODS: p53 function of transactivation on p21 promoter was studied with a luciferase reporter system in which the luciferase gene is driven by p21 promoter, and the p53-DNA binding ability was observed with the use of electrophoretic mobility-shift assay (EMSA). Lipofectin mediated p53 or HCV NS5A expression vectors were used to transfect hepatoma cell lines to observe whether HCV NS5A could abrogate the binding ability of p53 to its specific DNA sequence and p53 transactivation on p21 promoter.Western blot experiment was used for detection of HCV NS5A and p53 proteins expression.RESULTS: Relative luciferase activity driven by p21 promoter increased significantly in the presence of endogenous p53 protein. Compared to the control group, exogenous p53 protein also stimulated p21 promoter driven luciferase gene expression in a dose-dependent way. HCV NS5A protein gradually inhibited both endogenous and exogenous p53 transactivation on p21 promoter with increase of the dose of HCV NS5A expression plasmid. By the experiment of EMSA, we could find p53 binding to its specific DNA sequence and, when co-transfected with increased dose of HCV NS5A expression vector, the p53 binding affinity to its DNA gradually decreased and finally disappeared. Between the Huh 7 cells transfected with p53 expression vector alone or co-transfected with HCV NS5A expression vector, there was no difference in the p53 protein expression.CONCLUSION: HCV NS5A inhibits p53 transactivation on p21 promoter through abrogating p53 binding affinity to its specific DNA sequence. It does not affect p53 protein expression.

  17. Protective potential of Emblica Officinalis Linn. against radiation and lead induced hepatic lesion in Swiss albino mice

    Exposure of living systems to ionizing radiation causes a variety of damages to DNA and membranes due to generation of free radicals and reactive oxygen species. So there is a need of hour is to search for an ideal radioprotector which could minimize the deleterious and damaging effects caused by ionizing radiation. Radioprotectors are agents which reduce the radiation effects on cell when applied prior to exposure of radiation. The aim of this study was to access the efficacy of Emblica officinalis in reducing radiation and lead induced changes in mice liver. For the present experiment, healthy male Swiss albino mice (6-8 weeks) were selected and maintained under standard conditions of temperature and light. Fruit extract of Emblica was fed orally at the dose of 0.01 ml/animal/day.The animal were divided into seven groups according to the treatment i.e. lead acetate solution as drinking water (group-II) or exposed to 3.5 or 7.0 Gy gamma radiation (group-III) or combined treatment of radiation and lead acetate (group-IV). The animals of experimental groups were administered Emblica extract seven days prior to radiation or lead acetate treatment (group V, VI and VII) respectively. The animals from all the groups were sacrificed by cervical dislocation at each post-treatment intervals of 1, 2, 4, 7, 14 and 28 days. After sacrificing the animals pieces of liver were taken out and some of them were kept at -20℃ for different biochemical parameters. The histopathological changes included cytoplasmic degranulation, vacuolation, hyperaemia, pycnotic and crenated nuclei. The changes observed in the control groups were compared with the respective experimental groups. An increase in the value of total proteins, glycogen, acid phosphatase, alkaline phosphatase activity and RNA was observed up to day - 14 in the non drug treated group and day 7 in the Emblica treated groups, thereafter value declined up to day - 28 without reaching to normal. Whereas the value of

  18. 15. Sensitivity in visualizing vegetations in cardiac lead-induced endocarditis: A comparative study between transesophageal vs. transthoracic echocardiography

    A. AlFagih

    2016-07-01

    Full Text Available Despite advancement in sterile cardiac device implantation techniques, wound infections and/or bacteremia remain a significant problem. The presence of a vegetation in lead-induced endocarditis (LIE is a critical factor that determines the management. Transthoracic (TTE and Transesophageal (TEE Echocardiography are two different cardiac modalities that are used for the detection of lead vegetation. However, it is not yet clear which of the two has the highest diagnostic accuracy. We aim to identify which of the two has the highest sensitivity. In addition, we aim to correlate the existence of a vegetation with blood and wound culture results. We conducted a chart review in 113 patients whom underwent lead extraction at Prince Sultan Cardiac Center in Saudi Arabia during the period of Jan, 2002 to Jul, 2015. Six patients underwent lead extraction twice, increasing the number to be a total of 119 cases. Out of the study cohort, we include 38 patients who had both TTE and TEE done prior to lead extraction. Data regarding TTE, TEE, as well as blood and wound cultures were collected from echocardiography and microbiology lab reports using a well-structured case report form.Of the study population, 21 patients (55.3% had lead vegetations visualized either by TTE or TEE. Nineteen patients had vegetations detected by TEE, compared to 6 patients only when TTE was used. The sensitivity of TEE and TTE were 90.5% (CI: 69.6–98.8% and 28.5% (95% CI: 11.3–52.1%, respectively. Blood and wound culture results showed that in the presence of a vegetation, blood cultures were positive in 55% of the cases (P = 0.036 while only 44.4% of those with vegetations had a positive wound culture (P = 0.347. TEE has higher sensitivity in detecting vegetations compared to TTE in LIE. The presence of a vegetation is more likely to be associated with a positive blood culture than a positive wound culture. Further studies ought to measure the accuracy of different

  19. Vascular Changes and Neurodegeneration in the Early Stages of Diabetic Retinopathy

    Jonsson, Karoline Boegeberg; Frydkjaer-Olsen, Ulrik; Grauslund, Jakob

    2016-01-01

    patients without or with early DR, and to examine whether neurodegeneration precedes visible vasculopathy in the pathogenesis of DR. METHODS: A systematic literature search was performed to identify studies which used optical coherence tomography (OCT) or multifocal electroretinography (mfERG) to detect...... neurodegeneration in patients with no or mild DR as compared to healthy controls. Outcome measures were mean retinal thickness (RT), mean retinal nerve fiber layer (RNFL) thickness and ganglion cell layer (GCL) thickness. Also, mfERG amplitude and implicit time were analyzed. RESULTS: Eleven studies which used mfERG...... and/or OCT to detect neurodegeneration were included. Two OCT studies found significant thinning of RT, 2 found thinning of RNFL, whereas 1 found thickening of RT, RNFL and GCL in patients without DR. Two mfERG studies found a significant delay of implicit time in the same patient group. Retinal...

  20. Cause or Effect: Misregulation of MicroRNA Pathways in Neurodegeneration

    Fen-BiaoGao

    2012-04-01

    Full Text Available During normal aging or neurodegenerative diseases, neuronal survival and function depend on protein homeostasis, which is regulated by multiple mechanisms, including the microRNA (miRNA pathway. In different cells types, the absence of Dicer, a key miRNA processing enzyme, leads to neurodegeneration through cell-autonomous and non-cell-autonomous mechanisms. Loss of certain miRNAs also causes neurodegeneration in some model organisms. On the other hand, miRNA expression is misregulated in patients with different neurodegenerative diseases. Thus, the miRNA pathway appears to be essential in the pathogenesis of several age-dependent neurodegenerative conditions; however, our understanding of the underlying mechanism remains rudimentary. The precise causal relationships between specific miRNAs and neurodegeneration in humans need to be further investigated.

  1. Herpesvirus telomerase RNA (vTR with a mutated template sequence abrogates herpesvirus-induced lymphomagenesis.

    Benedikt B Kaufer

    2011-10-01

    Full Text Available Telomerase reverse transcriptase (TERT and telomerase RNA (TR represent the enzymatically active components of telomerase. In the complex, TR provides the template for the addition of telomeric repeats to telomeres, a protective structure at the end of linear chromosomes. Human TR with a mutation in the template region has been previously shown to inhibit proliferation of cancer cells in vitro. In this report, we examined the effects of a mutation in the template of a virus encoded TR (vTR on herpesvirus-induced tumorigenesis in vivo. For this purpose, we used the oncogenic avian herpesvirus Marek's disease virus (MDV as a natural virus-host model for lymphomagenesis. We generated recombinant MDV in which the vTR template sequence was mutated from AATCCCAATC to ATATATATAT (vAU5 by two-step Red-mediated mutagenesis. Recombinant viruses harboring the template mutation replicated with kinetics comparable to parental and revertant viruses in vitro. However, mutation of the vTR template sequence completely abrogated virus-induced tumor formation in vivo, although the virus was able to undergo low-level lytic replication. To confirm that the absence of tumors was dependent on the presence of mutant vTR in the telomerase complex, a second mutation was introduced in vAU5 that targeted the P6.1 stem loop, a conserved region essential for vTR-TERT interaction. Absence of vTR-AU5 from the telomerase complex restored virus-induced lymphoma formation. To test if the attenuated vAU5 could be used as an effective vaccine against MDV, we performed vaccination-challenge studies and determined that vaccination with vAU5 completely protected chickens from lethal challenge with highly virulent MDV. Taken together, our results demonstrate 1 that mutation of the vTR template sequence can completely abrogate virus-induced tumorigenesis, likely by the inhibition of cancer cell proliferation, and 2 that this strategy could be used to generate novel vaccine candidates

  2. Tetrandrine: A Potent Abrogator of G2 Checkpoint Function in Tumor Cells and Its Mechanism

    2007-01-01

    Objective To assess the ability of tetrandrine (Tet) to enhance the sensitivity to irradiation and its mechanism in cell lines of human breast cancer p53-mutant MCF-7/ADR, p53-wild-type MCF-7 and human colon carcinoma p53-mutant HT-29 as well as in C26 colorectal carcinoma-bearing BALB/c mice. Methods MCF-7/ADR, HT-29 and MCF-7 cells were exposed to irradiation in the absence or presence of tetrandrine. The effect of Tet on the cytotoxicity of X-irradiation in these three cells was determined and the effect of tetrandrine on cell cycle arrest induced by irradiation in its absence or presence was studied by flow cytometry, Moreover, mitotic index measurement determined mitosis of cells to enter mitosis. Western blotting was employed to detect cyclin B1 and Cdc2 proteins in extracts from irradiated or non-irradiated cells of MCF-7/ADR, HT-29 and MCF-7 treated with tetrandrine at various concentrations. Tumor growth delay assay was conducted to determine the radio-sensitization of tetrandrine in vivo. Results Clonogenic assay showed that tetrandrine markedly enhanced the lethal effect of X-rays on p53-mutant MCF-7/ADR and HT-29 cells and the sensitization enhancement ratio (SER) of tetrandrine was 1.51 and 1.63, but its SER was only 1.1 in p53-wt MCF-7 cells. Irradiated p53-mutant MCF-7/ADR and HT-29 cells were only arrested in G2/M phase while MCF-7 cells were arrested in G1 and G2/M phases. Radiation-induced G2 phase arrests were abrogated by tetrandrine in a concentration-dependent manner in MCF-7/ADR and HT-29 cells,whereas redistribution within MCF-7 cell cycle changed slightly. The proportion of cells in M phase increased from 1.3% to 14.7% in MCF-7/ADR cells, and from 1.5% to 13.2% in HT-29 cells, but 2.4% to 7.1% in MCF-7 cells. Furthermore, the levels of cyclin B 1 and Cdc2 expression decreased after X-irradiation in MCF-7/ADR and HT-29 cells, and the mitotic index was also lower. Tet could reverse the decrease and induce the irradiated cells to enter mitosis

  3. Relaxin requires the angiotensin II type 2 receptor to abrogate renal interstitial fibrosis.

    Chow, Bryna S Man; Kocan, Martina; Bosnyak, Sanja; Sarwar, Mohsin; Wigg, Belinda; Jones, Emma S; Widdop, Robert E; Summers, Roger J; Bathgate, Ross A D; Hewitson, Tim D; Samuel, Chrishan S

    2014-07-01

    Fibrosis is a hallmark of chronic kidney disease, for which there is currently no effective cure. The hormone relaxin is emerging as an effective antifibrotic therapy; however, its mechanism of action is poorly understood. Recent studies have shown that relaxin disrupts the profibrotic actions of transforming growth factor-β1 (TGF-β1) by its cognate receptor, relaxin family peptide receptor 1 (RXFP1), extracellular signal-regulated kinase phosphorylation, and a neuronal nitric oxide synthase-dependent pathway to abrogate Smad2 phosphorylation. Since angiotensin II also inhibits TGF-β1 activity through its AT2 receptor (AT2R), we investigated the extent to which relaxin interacts with the AT2R. The effects of the AT2R antagonist, PD123319, on relaxin activity were examined in primary rat kidney myofibroblasts, and in kidney tissue from relaxin-treated male wild-type and AT2R-knockout mice subjected to unilateral ureteric obstruction. Relaxin's antifibrotic actions were significantly blocked by PD123319 in vitro and in vivo, or when relaxin was administered to AT2R-knockout mice. While heterodimer complexes were formed between RXFP1 and AT2Rs independent of ligand binding, relaxin did not directly bind to AT2Rs but signaled through RXFP1-AT2R heterodimers to induce its antifibrotic actions. These findings highlight a hitherto unrecognized interaction that may be targeted to control fibrosis progression. PMID:24429402

  4. JAK Kinase Inhibition Abrogates STAT3 Activation and Head and Neck Squamous Cell Carcinoma Tumor Growth

    Malabika Sen

    2015-03-01

    Full Text Available Aberrant activation of the Janus kinase (JAK/signal transducer and activator of transcription (STAT 3 has been implicated in cell proliferation and survival of many cancers including head and neck squamous cell carcinoma (HNSCC. AZD1480, an orally active pharmacologic inhibitor of JAK1/JAK2, has been tested in several cancer models. In the present study, the in vitro and in vivo effects of AZD1480 were evaluated in HNSCC preclinical models to test the potential use of JAK kinase inhibition for HNSCC therapy. AZD1480 treatment decreased HNSCC proliferation in HNSCC cell lines with half maximal effective concentration (EC50 values ranging from 0.9 to 4 μM in conjunction with reduction of pSTAT3Tyr705 expression. In vivo antitumor efficacy of AZD1480 was demonstrated in patient-derived xenograft (PDX models derived from two independent HNSCC tumors. Oral administration of AZD1480 reduced tumor growth in conjunction with decreased pSTAT3Tyr705 expression that was observed in both PDX models. These findings suggest that the JAK1/2 inhibitors abrogate STAT3 signaling and may be effective in HNSCC treatment approaches.

  5. Arsenic induces apoptosis in mouse liver is mitochondria dependent and is abrogated by N-acetylcysteine

    Arsenicosis, caused by arsenic contamination of drinking water supplies, is a major public health problem in India and Bangladesh. Chronic liver disease, often with portal hypertension occurs in chronic arsenicosis, contributes to the morbidity and mortality. The early cellular events that initiate liver cell injury due to arsenicosis have not been studied. Our aim was to identify the possible mechanisms related to arsenic-induced liver injury in mice. Liver injury was induced in mice by arsenic treatment. The liver was used for mitochondrial oxidative stress, mitochondrial permeability transition (MPT). Evidence of apoptosis was sought by TUNEL test, caspase assay and histology. Pretreatment with N-acetyl-L-cysteine (NAC) was done to modulate hepatic GSH level. Arsenic treatment in mice caused liver injury associated with increased oxidative stress in liver mitochondria and alteration of MPT. Altered MPT facilitated cytochrome c release in the cytosol, activation of caspase 9 and caspase 3 activities and apoptotic cell death. Pretreatment of NAC to arsenic-treated mice abrogated all these alteration suggesting a glutathione (GSH)-dependent mechanism. Oxidative stress in mitochondria and inappropriate MPT are important in the pathogenesis of arsenic induced apoptotic liver cell injury. The phenomenon is GSH dependent and supplementation of NAC might have beneficial effects

  6. Beclin1-induced autophagy abrogates radioresistance of lung cancer cells by suppressing osteopontin

    Osteopontin (OPN) serves as an indicator of resistance to radiotherapy. However, the role of OPN in the development of acquired radioresistance in human lung cancer cells has not yet been fully elucidated. Therefore, the potential importance of OPN as a marker of lung cancer with a potential significant role in the development of radioresistance against repeated radiotherapy has prompted us to define the pathways by which OPN regulates lung cancer cell growth. In addition, autophagy has been reported to play a key role in the radiosensitization of cancer cells. Here, we report that increased OPN expression through induction of nuclear p53 following irradiation was inhibited by exogenous beclin-1 (BECN1). Our results clearly show that BECN1 gene expression led to induction of autophagy and inhibition of cancer cell growth and angiogenesis. Our results suggest that the induction of autophagy abrogated the radioresistance of the cancer cells. Interestingly, we showed that knockdown of OPN by lentivirus-mediated shRNA induced the autophagy of human lung cancer cell. Taken together, these results suggest that OPN and BECN1 can be molecular targets for overcoming radioresistance by controlling autophagy. (author)

  7. miR-143 interferes with ERK5 signaling, and abrogates prostate cancer progression in mice.

    Cyrielle Clapé

    Full Text Available BACKGROUND: Micro RNAs are small, non-coding, single-stranded RNAs that negatively regulate gene expression at the post-transcriptional level. Since miR-143 was found to be down-regulated in prostate cancer cells, we wanted to analyze its expression in human prostate cancer, and test the ability of miR-43 to arrest prostate cancer cell growth in vitro and in vivo. RESULTS: Expression of miR-143 was analyzed in human prostate cancers by quantitative PCR, and by in situ hybridization. miR-143 was introduced in cancer cells in vivo by electroporation. Bioinformatics analysis and luciferase-based assays were used to determine miR-143 targets. We show in this study that miR-143 levels are inversely correlated with advanced stages of prostate cancer. Rescue of miR-143 expression in cancer cells results in the arrest of cell proliferation and the abrogation of tumor growth in mice. Furthermore, we show that the effects of miR-143 are mediated, at least in part by the inhibition of extracellular signal-regulated kinase-5 (ERK5 activity. We show here that ERK5 is a miR-143 target in prostate cancer. CONCLUSIONS: miR-143 is as a new target for prostate cancer treatment.

  8. Abrogation of plasminogen activator inhibitor-1-vitronectin interaction ameliorates acute kidney injury in murine endotoxemia.

    Kamlesh K Gupta

    Full Text Available Sepsis-induced acute kidney injury (AKI contributes to the high mortality and morbidity in patients. Although the pathogenesis of AKI during sepsis is poorly understood, it is well accepted that plasminogen activator inhibitor-1 (PAI-1 and vitronectin (Vn are involved in AKI. However, the functional cooperation between PAI-1 and Vn in septic AKI has not been completely elucidated. To address this issue, mice were utilized lacking either PAI-1 (PAI-1-/- or expressing a PAI-1-mutant (PAI-1R101A/Q123K in which the interaction between PAI-1 and Vn is abrogated, while other functions of PAI-1 are retained. It was found that both PAI-1-/- and PAI-1R101A/Q123K mice are associated with decreased renal dysfunction, apoptosis, inflammation, and ERK activation as compared to wild-type (WT mice after LPS challenge. Also, PAI-1-/- mice showed attenuated fibrin deposition in the kidneys. Furthermore, a lack of PAI-1 or PAI-1-Vn interaction was found to be associated with an increase in activated Protein C (aPC in plasma. These results demonstrate that PAI-1, through its interaction with Vn, exerts multiple deleterious mechanisms to induce AKI. Therefore, targeting of the PAI-1-Vn interaction in kidney represents an appealing therapeutic strategy for the treatment of septic AKI by not only altering the fibrinolytic capacity but also regulating PC activity.

  9. Abrogation of Plasminogen Activator Inhibitor-1-Vitronectin Interaction Ameliorates Acute Kidney Injury in Murine Endotoxemia

    Gupta, Kamlesh K.; Donahue, Deborah L.; Sandoval-Cooper, Mayra J.; Castellino, Francis J.; Ploplis, Victoria A.

    2015-01-01

    Sepsis-induced acute kidney injury (AKI) contributes to the high mortality and morbidity in patients. Although the pathogenesis of AKI during sepsis is poorly understood, it is well accepted that plasminogen activator inhibitor-1 (PAI-1) and vitronectin (Vn) are involved in AKI. However, the functional cooperation between PAI-1 and Vn in septic AKI has not been completely elucidated. To address this issue, mice were utilized lacking either PAI-1 (PAI-1−/−) or expressing a PAI-1-mutant (PAI-1R101A/Q123K) in which the interaction between PAI-1 and Vn is abrogated, while other functions of PAI-1 are retained. It was found that both PAI-1−/− and PAI-1R101A/Q123K mice are associated with decreased renal dysfunction, apoptosis, inflammation, and ERK activation as compared to wild-type (WT) mice after LPS challenge. Also, PAI-1−/− mice showed attenuated fibrin deposition in the kidneys. Furthermore, a lack of PAI-1 or PAI-1-Vn interaction was found to be associated with an increase in activated Protein C (aPC) in plasma. These results demonstrate that PAI-1, through its interaction with Vn, exerts multiple deleterious mechanisms to induce AKI. Therefore, targeting of the PAI-1-Vn interaction in kidney represents an appealing therapeutic strategy for the treatment of septic AKI by not only altering the fibrinolytic capacity but also regulating PC activity. PMID:25799354

  10. Potentiation of lead-induced cell death in PC12 cells by glutamate: Protection by N-acetylcysteine amide (NACA), a novel thiol antioxidant

    Oxidative stress has been implicated as an important factor in many neurological diseases. Oxidative toxicity in a number of these conditions is induced by excessive glutamate release and subsequent glutamatergic neuronal stimulation. This, in turn, causes increased generation of reactive oxygen species (ROS), oxidative stress, excitotoxicity, and neuronal damage. Recent studies indicate that the glutamatergic neurotransmitter system is involved in lead-induced neurotoxicity. Therefore, this study aimed to (1) investigate the potential effects of glutamate on lead-induced PC12 cell death and (2) elucidate whether the novel thiol antioxidant N-acetylcysteine amide (NACA) had any protective abilities against such cytotoxicity. Our results suggest that glutamate (1 mM) potentiates lead-induced cytotoxicity by increased generation of ROS, decreased proliferation (MTS), decreased glutathione (GSH) levels, and depletion of cellular adenosine-triphosphate (ATP). Consistent with its ability to decrease ATP levels and induce cell death, lead also increased caspase-3 activity, an effect potentiated by glutamate. Exposure to glutamate and lead elevated the cellular malondialdehyde (MDA) levels and phospholipase-A2 (PLA2) activity and diminished the glutamine synthetase (GS) activity. NACA protected PC12 cells from the cytotoxic effects of glutamate plus lead, as evaluated by MTS assay. NACA reduced the decrease in the cellular ATP levels and restored the intracellular GSH levels. The increased levels of ROS and MDA in glutamate-lead treated cells were significantly decreased by NACA. In conclusion, our data showed that glutamate potentiated the effects of lead-induced PC12 cell death by a mechanism involving mitochondrial dysfunction (ATP depletion) and oxidative stress. NACA had a protective role against the combined toxic effects of glutamate and lead by inhibiting lipid peroxidation and scavenging ROS, thus preserving intracellular GSH

  11. Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration

    Rana, Anil; Seinen, Erwin; Siudeja, Katarzyna; Muntendam, Remco; Srinivasan, Balaji; van der Want, Johannes J.; Hayflick, Susan; Reijngoud, Dirk-Jan; Kayser, Oliver; Sibon, Ody C. M.

    2010-01-01

    Pantothenate kinase-associated neurodegeneration (PKAN), a progressive neurodegenerative disorder, is associated with impairment of pantothenate kinase function. Pantothenate kinase is the first enzyme required for de novo synthesis of CoA, an essential metabolic cofactor. The pathophysiology of PKA

  12. Clinical Heterogeneity of Atypical Pantothenate Kinase-Associated Neurodegeneration in Koreans

    Jae-Hyeok Lee

    2016-01-01

    Full Text Available Objective Neurodegeneration with brain iron accumulation (NBIA represents a group of inherited movement disorders characterized by iron accumulation in the basal ganglia. Recent advances have included the identification of new causative genes and highlighted the wide phenotypic variation between and within the specific NBIA subtypes. This study aimed to investigate the current status of NBIA in Korea. Methods We collected genetically confirmed NBIA patients from twelve nationwide referral hospitals and from a review of the literature. We conducted a study to describe the phenotypic and genotypic characteristics of Korean adults with atypical pantothenate kinase-associated neurodegeneration (PKAN. Results Four subtypes of NBIA including PKAN (n = 30, PLA2G6-related neurodegeneration (n = 2, beta-propeller protein-associated neurodegeneration (n = 1, and aceruloplasminemia (n = 1 have been identified in the Korean population. The clinical features of fifteen adults with atypical PKAN included early focal limb dystonia, parkinsonism-predominant feature, oromandibular dystonia, and isolated freezing of gait (FOG. Patients with a higher age of onset tended to present with parkinsonism and FOG. The p.R440P and p.D378G mutations are two major mutations that represent approximately 50% of the mutated alleles. Although there were no specific genotype-phenotype correlations, most patients carrying the p.D378G mutation had a late-onset, atypical form of PKAN. Conclusions We found considerable phenotypic heterogeneity in Korean adults with atypical PKAN. The age of onset may influence the presentation of extrapyramidal symptoms.

  13. Cognitive Functioning in Children with Pantothenate-Kinase-Associated Neurodegeneration Undergoing Deep Brain Stimulation

    Mahoney, Rachel; Selway, Richard; Lin, Jean-Pierre

    2011-01-01

    Aim: To examine the cognitive functioning of young people with pantothenate-kinase-associated neurodegeneration (PKAN) after pallidal deep brain stimulation (DBS). PKAN is characterized by progressive generalized dystonia and has historically been associated with cognitive decline. With growing evidence that DBS can improve motor function in…

  14. Activation of mTOR ameliorates fragile X premutation rCGG repeat-mediated neurodegeneration.

    Yunting Lin

    Full Text Available Fragile X associated tremor/ataxia syndrome (FXTAS is a late onset neurodegenerative disorder caused by aberrant expansion of CGG repeats in 5' UTR of FMR1 gene. The elevated mRNA confers a toxic gain-of-function thought to be the critical event of pathogenesis. Expressing rCGG90 repeats of the human FMR1 5'UTR in Drosophila is sufficient to induce neurodegeneration. Rapamycin has been demonstrated to attenuate neurotoxicity by inducing autophagy in various animal models of neurodegenerative diseases. Surprisingly, we observed rapamycin exacerbated rCGG90-induced neurodegenerative phenotypes through an autophagy-independent mechanism. CGG90 expression levels of FXTAS flies exposed to rapamycin presented no significant differences. We further demonstrated that activation of the mammalian target of rapamycin (mTOR signaling could suppress neurodegeneration of FXTAS. These findings indicate that rapamycin will exacerbate neurodegeneration, and that enhancing autophagy is insufficient to alleviate neurotoxicity in FXTAS. Moreover, these results suggest mTOR and its downstream molecules as new therapeutic targets for FXTAS by showing significant protection against neurodegeneration.

  15. Chrysin, an anti-inflammatory molecule, abrogates renal dysfunction in type 2 diabetic rats

    Diabetic nepropathy (DN) is considered as the leading cause of end-stage renal disease (ESRD) worldwide, but the current available treatments are limited. Recent experimental evidences support the role of chronic microinflammation in the development of DN. Therefore, the tumor necrosis factor-alpha (TNF-α) pathway has emerged as a new therapeutic target for the treatment of DN. We investigated the nephroprotective effects of chrysin (5, 7-dihydroxyflavone) in a high fat diet/streptozotocin (HFD/STZ)-induced type 2 diabetic Wistar albino rat model. Chrysin is a potent anti-inflammatory compound that is abundantly found in plant extracts, honey and bee propolis. The treatment with chrysin for 16 weeks post induction of diabetes significantly abrogated renal dysfunction and oxidative stress. Chrysin treatment considerably reduced renal TNF-α expression and inhibited the nuclear transcription factor-kappa B (NF-kB) activation. Furthermore, chrysin treatment improved renal pathology and suppressed transforming growth factor-beta (TGF-β), fibronectin and collagen-IV protein expressions in renal tissues. Chrysin also significantly reduced the serum levels of pro-inflammatory cytokines, interleukin-1beta (IL-1β) and IL-6. Moreover, there were no appreciable differences in fasting blood glucose and serum insulin levels between the chrysin treated groups compared to the HFD/STZ-treated group. Hence, our results suggest that chrysin prevents the development of DN in HFD/STZ-induced type 2 diabetic rats through anti-inflammatory effects in the kidney by specifically targeting the TNF-α pathway. - Highlights: • Chrysin reduced renal oxidative stress and inflammation in diabetic rats. • Chrysin reduced serum levels of pro-inflammatory in diabetic rats. • Chrysin exhibited renal protective effect by suppressing the TNF-α pathway

  16. Selenium deficiency abrogates inflammation-dependent plasma cell tumors in mice.

    Felix, Klaus; Gerstmeier, Simone; Kyriakopoulos, Antonios; Howard, O M Zack; Dong, Hui-Fang; Eckhaus, Michael; Behne, Dietrich; Bornkamm, Georg W; Janz, Siegfried

    2004-04-15

    The role of the micronutrient, selenium, in human cancers associated with chronic inflammations and persistent infections is poorly understood. Peritoneal plasmacytomas (PCTs) in strain BALB/c (C), the premier experimental model of inflammation-dependent plasma cell transformation in mice, may afford an opportunity to gain additional insights into the significance of selenium in neoplastic development. Here, we report that selenium-depleted C mice (n = 32) maintained on a torula-based low-selenium diet (5-8 micro g of selenium/kg) were totally refractory to pristane induction of PCT. In contrast, 11 of 26 (42.3%) control mice maintained on a selenium adequate torula diet (300 micro g of selenium/kg) and 15 of 40 (37.5%) control mice fed standard Purina chow (440 micro g of selenium/kg) developed PCT by 275 days postpristane. Abrogation of PCT was caused in part by the striking inhibition of the formation of the inflammatory tissue in which PCT develop (pristane granuloma). This was associated with the reduced responsiveness of selenium-deficient inflammatory cells (monocytes and neutrophils) to chemoattractants, such as thioredoxin and chemokines. Selenium-deficient C mice exhibited little evidence of disturbed redox homeostasis and increased mutant frequency of a transgenic lacZ reporter gene in vivo. These findings implicate selenium, via the selenoproteins, in the promotion of inflammation-induced PCT and suggest that small drug inhibitors of selenoproteins might be useful for preventing human cancers linked with chronic inflammations and persistent infections. PMID:15087411

  17. Chrysin, an anti-inflammatory molecule, abrogates renal dysfunction in type 2 diabetic rats

    Ahad, Amjid [Lipid Metabolism Laboratory, Department of Biochemistry, Faculty of Science, Jamia Hamdard, Hamdard Nagar, New Delhi 110062 (India); Ganai, Ajaz Ahmad [Department of Biotechnology, Faculty of Science, Jamia Hamdard, Hamdard Nagar, New Delhi 110062 (India); Mujeeb, Mohd [Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi 110062 (India); Siddiqui, Waseem Ahmad, E-mail: was.sid121@gmail.com [Lipid Metabolism Laboratory, Department of Biochemistry, Faculty of Science, Jamia Hamdard, Hamdard Nagar, New Delhi 110062 (India)

    2014-08-15

    Diabetic nepropathy (DN) is considered as the leading cause of end-stage renal disease (ESRD) worldwide, but the current available treatments are limited. Recent experimental evidences support the role of chronic microinflammation in the development of DN. Therefore, the tumor necrosis factor-alpha (TNF-α) pathway has emerged as a new therapeutic target for the treatment of DN. We investigated the nephroprotective effects of chrysin (5, 7-dihydroxyflavone) in a high fat diet/streptozotocin (HFD/STZ)-induced type 2 diabetic Wistar albino rat model. Chrysin is a potent anti-inflammatory compound that is abundantly found in plant extracts, honey and bee propolis. The treatment with chrysin for 16 weeks post induction of diabetes significantly abrogated renal dysfunction and oxidative stress. Chrysin treatment considerably reduced renal TNF-α expression and inhibited the nuclear transcription factor-kappa B (NF-kB) activation. Furthermore, chrysin treatment improved renal pathology and suppressed transforming growth factor-beta (TGF-β), fibronectin and collagen-IV protein expressions in renal tissues. Chrysin also significantly reduced the serum levels of pro-inflammatory cytokines, interleukin-1beta (IL-1β) and IL-6. Moreover, there were no appreciable differences in fasting blood glucose and serum insulin levels between the chrysin treated groups compared to the HFD/STZ-treated group. Hence, our results suggest that chrysin prevents the development of DN in HFD/STZ-induced type 2 diabetic rats through anti-inflammatory effects in the kidney by specifically targeting the TNF-α pathway. - Highlights: • Chrysin reduced renal oxidative stress and inflammation in diabetic rats. • Chrysin reduced serum levels of pro-inflammatory in diabetic rats. • Chrysin exhibited renal protective effect by suppressing the TNF-α pathway.

  18. Targeting ILK and β4 integrin abrogates the invasive potential of ovarian cancer

    Highlights: ► The potential of targeting ILK and integrins for highly aggressive ovarian cancer. ► Unanticipated synergistic effect for the combination of ILK/β4 integrin. ► Combination of ILK/β4 integrin effectively inhibited the PI3K/Akt/Rac1 cascade. ► Targeting of β4 integrin/ILK had potent inhibitory effects in ovarian cancer. -- Abstract: Integrins and integrin-linked kinase (ILK) are essential to cancerous invasion because they mediate physical interactions with the extracellular matrix, and regulate oncogenic signaling pathways. The purpose of our study is to determine whether deletion of β1 and β4 integrin and ILK, alone or in combination, has antitumoral effects in ovarian cancer. Expression of β1 and β4 integrin and ILK was analyzed by immunohistochemistry in 196 ovarian cancer tissue samples. We assessed the effects of depleting these molecules with shRNAs in ovarian cancer cells by Western blot, conventional RT-PCR, cell proliferation, migration, invasion, and in vitro Rac1 activity assays, and in vivo xenograft formation assays. Overexpression of β4 integrin and ILK in human ovarian cancer specimens was found to correlate with tumor aggressiveness. Depletion of these targets efficiently suppresses ovarian cancer cell proliferation, migration, and invasion in vitro and xenograft tumor formation in vivo. We also demonstrated that single depletion of ILK or combination depletion of β4 integrin/ILK inhibits phosphorylation of downstream signaling targets, p-Ser 473 Akt and p-Thr202/Tyr204 Erk1/2, and activation of Rac1, as well as reduce expression of MMP-2 and MMP-9 and increase expression of caspase-3 in vitro. In conclusion, targeting β4 integrin combined with ILK can instigate the latent tumorigenic potential and abrogate the invasive potential in ovarian cancer.

  19. The human leukemia oncogene bcr-abl abrogates the anchorage requirement but not the growth factor requirement for proliferation.

    Renshaw, M W; McWhirter, J R; Wang, J Y

    1995-01-01

    Proliferation of normal cells in a multicellular organism requires not only growth factors but also the proper attachment to the extracellular matrix. A hallmark of neoplastic transformation is the loss of anchorage dependence which usually accompanies the loss of growth factor requirement. The Bcr-Abl tyrosine kinase of human leukemias is shown here to abrogate only the anchorage, not the growth factor, requirement. Bcr-Abl-transformed cells grow in soft agar but do not proliferate in serum-...

  20. Are we ready to abrogate compulsory vaccinations for children?: The opinion of apulian family pediatricians; Italy, 2013

    Martinelli, Domenico; Tafuri, Silvio; Fortunato, Francesca; Cozza, Vanessa; Germinario, Cinzia A; Prato, Rosa

    2014-01-01

    In Italy, vaccination against diphtheria, tetanus, polio and hepatitis B is compulsory for infants countrywide, except in Veneto region where since 2007 Health Authorities have experimented the suspension of mandatory vaccination. In light of the recent discussion on the potential abrogation in other regions, we explored the opinion of family pediatricians who play a crucial role in promoting immunization programmes in Italy. In November 2009, we interviewed by phone the family pediatricians ...

  1. KNK437, abrogates hypoxia-induced radioresistance by dual targeting of the AKT and HIF-1{alpha} survival pathways

    Oommen, Deepu, E-mail: oommen1978@gmail.com [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast, Northern Ireland (United Kingdom); Prise, Kevin M. [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast, Northern Ireland (United Kingdom)

    2012-05-11

    Highlights: Black-Right-Pointing-Pointer KNK437, a benzylidene lactam compound, is a novel radiosensitizer. Black-Right-Pointing-Pointer KNK437 inhibits AKT signaling and abrogates the accumulation of HIF-1{alpha} under hypoxia. Black-Right-Pointing-Pointer KNK437 abrogates hypoxia induced resistance to radiation. -- Abstract: KNK437 is a benzylidene lactam compound known to inhibit stress-induced synthesis of heat shock proteins (HSPs). HSPs promote radioresistance and play a major role in stabilizing hypoxia inducible factor-1{alpha} (HIF-1{alpha}). HIF-1{alpha} is widely responsible for tumor resistance to radiation under hypoxic conditions. We hypothesized that KNK437 sensitizes cancer cells to radiation and overrides hypoxia-induced radioresistance via destabilizing HIF-1{alpha}. Treatment of human cancer cells MDA-MB-231 and T98G with KNK437 sensitized them to ionizing radiation (IR). Surprisingly, IR did not induce HSPs in these cell lines. As hypothesized, KNK437 abrogated the accumulation of HIF-1{alpha} in hypoxic cells. However, there was no induction of HSPs under hypoxic conditions. Moreover, the proteosome inhibitor MG132 did not restore HIF-1{alpha} levels in KNK437-treated cells. This suggested that the absence of HIF-1{alpha} in hypoxic cells was not due to the enhanced protein degradation. HIF-1{alpha} is mainly regulated at the level of post-transcription and AKT is known to modulate the translation of HIF-1{alpha} mRNA. Interestingly, pre-treatment of cells with KNK437 inhibited AKT signaling. Furthermore, down regulation of AKT by siRNA abrogated HIF-1{alpha} levels under hypoxia. Interestingly, KNK437 reduced cell survival in hypoxic conditions and inhibited hypoxia-induced resistance to radiation. Taken together, these data suggest that KNK437 is an effective radiosensitizer that targets multiple pro-survival stress response pathways.

  2. KNK437, abrogates hypoxia-induced radioresistance by dual targeting of the AKT and HIF-1α survival pathways

    Highlights: ► KNK437, a benzylidene lactam compound, is a novel radiosensitizer. ► KNK437 inhibits AKT signaling and abrogates the accumulation of HIF-1α under hypoxia. ► KNK437 abrogates hypoxia induced resistance to radiation. -- Abstract: KNK437 is a benzylidene lactam compound known to inhibit stress-induced synthesis of heat shock proteins (HSPs). HSPs promote radioresistance and play a major role in stabilizing hypoxia inducible factor-1α (HIF-1α). HIF-1α is widely responsible for tumor resistance to radiation under hypoxic conditions. We hypothesized that KNK437 sensitizes cancer cells to radiation and overrides hypoxia-induced radioresistance via destabilizing HIF-1α. Treatment of human cancer cells MDA-MB-231 and T98G with KNK437 sensitized them to ionizing radiation (IR). Surprisingly, IR did not induce HSPs in these cell lines. As hypothesized, KNK437 abrogated the accumulation of HIF-1α in hypoxic cells. However, there was no induction of HSPs under hypoxic conditions. Moreover, the proteosome inhibitor MG132 did not restore HIF-1α levels in KNK437-treated cells. This suggested that the absence of HIF-1α in hypoxic cells was not due to the enhanced protein degradation. HIF-1α is mainly regulated at the level of post-transcription and AKT is known to modulate the translation of HIF-1α mRNA. Interestingly, pre-treatment of cells with KNK437 inhibited AKT signaling. Furthermore, down regulation of AKT by siRNA abrogated HIF-1α levels under hypoxia. Interestingly, KNK437 reduced cell survival in hypoxic conditions and inhibited hypoxia-induced resistance to radiation. Taken together, these data suggest that KNK437 is an effective radiosensitizer that targets multiple pro-survival stress response pathways.

  3. N-Acetyl-L-Cysteine Affords Protection against Lead-Induced Cytotoxicity and Oxidative Stress in Human Liver Carcinoma (HepG2 Cells

    Paul B. Tchounwou

    2007-06-01

    Full Text Available Although lead exposure has declined in recent years as a result of change to lead-free gasoline, several epidemiological have pointed out that it represents a medical and public health emergency, especially in young children consuming high amounts of lead-contaminated flake paints. A previous study in our laboratory indicated that lead exposure induces cytotoxicity in human liver carcinoma cells. In the present study, we evaluated the role of oxidative stress in lead-induced toxicity, and the protective effect of the anti-oxidant n-acetyl-l-cysteine (NAC. We hypothesized that oxidative stress plays a role in lead-induced cytotoxicity, and that NAC affords protection against this adverse effect. To test this hypothesis, we performed the MTT [3-(4, 5-dimethylthiazol-2-yl-2, 5-diphenyltetrazolium bromide] assay and the trypan blue exclusion test for cell viability. We also performed the thiobarbituric acid test for lipid peroxidation. Data obtained from the MTT assay indicated that NAC significantly increased the viability of HepG2 cells in a dosedependent manner upon 48 hours of exposure. Similar trend was obtained with the trypan blue exclusion test. Data generated from the thiobarbituric acid test showed a significant (p ≤ 0.05 increase of MDA levels in lead nitrate-treated HepG2 cells compared to control cells. Interestingly, the addition of NAC to lead nitrate-treated HepG2 cells significantly decreased cellular content of reactive oxygen species (ROS, as evidenced by the decrease in lipid peroxidation byproducts. Overall, findings from this study suggest that NAC inhibits lead nitrate-induced cytotoxicity and oxidative stress in HepG2 cells. Hence, NAC may be used as a salvage therapy for lead-induced toxicity in exposed persons.

  4. Genistein abrogates G2 arrest induced by curcumin in p53 deficient T47D cells

    2012-01-01

    Background The high cost and low level of cancer survival urge the finding of new drugs having better mechanisms. There is a high trend of patients to be “back to nature” and use natural products as an alternative way to cure cancer. The fact is that some of available anticancer drugs are originated from plants, such as taxane, vincristine, vinblastine, pacitaxel. Curcumin (diferuloylmethane), a dietary pigment present in Curcuma longa rizhome is reported to induce cell cycle arrest in some cell lines. Other study reported that genistein isolated from Glycine max seed inhibited phosphorylation of cdk1, gene involved during G2/M transition and thus could function as G2 checkpoint abrogator. The inhibition of cdk1 phosphorylation is one of alternative strategy which could selectively kill cancer cells and potentially be combined with DNA damaging agent such as curcumin. Methods T47D cell line was treated with different concentrations of curcumin and genistein, alone or in combination; added together or with interval time. Flow Cytometry and MTT assay were used to evaluate cell cycle distribution and viability, respectively. The presence of apoptotic cells was determined using acridine orange-ethidium bromide staining. Results In this study curcumin induced G2 arrest on p53 deficient T47D cells at the concentration of 10 μM. Increasing concentration up to 30 μM increased the number of cell death. Whilst genistein alone at low concentration (≤10 μM) induced cell proliferation, addition of genistein (20 μM) 16 h after curcumin resulted in more cell death (89%), 34% higher than that administered at the same time (56%). The combination treatment resulted in apoptotic cell death. Combining curcumin with high dose of genistein (50 μM) induced necrotic cells. Conclusions Genistein increased the death of curcumin treated T47D cells. Appropriate timing of administration and concentration of genistein determine the outcome of treatment and this method

  5. Role of Ca+2 and other second messengers in excitatory amino acid receptor mediated neurodegeneration: clinical perspectives

    Schousboe, A; Belhage, B; Frandsen, A

    1997-01-01

    Neurodegeneration associated with neurological disorders such as epilepsy, Huntington's Chorea, Alzheimer's disease, and olivoponto cerebellar atrophy or with energy failure such as ischemia, hypoxia, and hypoglycemia proceeds subsequent to overexposure of neurons to excitatory amino acids of which...

  6. Metallothionein prevents neurodegeneration and central nervous system cell death after treatment with gliotoxin 6-aminonicotinamide

    Penkowa, Milena; Quintana, Albert; Carrasco, Javier;

    2004-01-01

    Transgenic expression of interleukin-6 (IL-6) in the CNS under the control of the glial fibrillary acidic protein (GFAP) gene promoter (GFAP-IL6 mice) induces significant inflammation and neurodegeneration but also affords neuroprotection against acute traumatic brain injury. This neuroprotection......-IL6 mice crossed with TgMT mice (GFAP-IL6 x TgMT). 6-AN caused acute damage of brainstem gray matter areas identified by necrosis of astrocytes, followed by inflammatory responses. After 6-AN-induced toxicity, secondary damage was observed, consisting of oxidative stress, neurodegeneration, and...... apoptotic cell death. We hereby show that the primary injury caused by 6-AN was comparable in wild-type and GFAP-IL6 mice, but MT-I overexpression could significantly protect the brain tissue. As expected, GFAP-IL6 mice showed increased CNS inflammation with more gliosis, macrophages, and lymphocytes...

  7. Optic Atrophy in a Patient With Atypical Pantothenate Kinase-Associated Neurodegeneration.

    Han, Jinu; Kim, Do Wook; Lee, Chul-Ho; Han, Sueng-Han

    2016-06-01

    Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive neurodegeneration with brain iron accumulation and characterized by extrapyramidal signs, vision loss, and intellectual decline. PKAN is caused by mutations in the PANK2 gene, which codes for a mitochondrial enzyme that phosphorylates vitamin B5 in the first reaction of the coenzyme A biosynthetic pathway. Visual failure in this disorder is typically due to pigmentary retinopathy. Yet our patient, a 13-year-old girl with PKAN, developed bilateral optic atrophy and the appearance of the retina and electroretinography were normal. Optic atrophy is a rare finding in patients with PKAN. It is important for the clinician to consider PKAN in the differential diagnosis of patients presenting with signs of extrapyramidal dysfunction, cognitive decline, and vision loss because of optic atrophy. PMID:26828840

  8. Correlated Inflammatory Responses and Neurodegeneration in Peptide-Injected Animal Models of Alzheimer’s Disease

    McLarnon, James G

    2014-01-01

    Animal models of Alzheimer's disease (AD) which emphasize activation of microglia may have particular utility in correlating proinflammatory activity with neurodegeneration. This paper reviews injection of amyloid- β (A β ) into rat brain as an alternative AD animal model to the use of transgenic animals. In particular, intrahippocampal injection of Aβ 1-42 peptide demonstrates prominent microglial mobilization and activation accompanied by a significant loss of granule cell neurons. Furtherm...

  9. Analysis of axonal transport and molecular chaperones during neurodegeneration in drosophila

    Sinadinos, Christopher

    2010-01-01

    Neuronal dysfunction and cell death occurs during neurodegeneration. Animal models that express human disease genes and show neurodegenerative-like pathologies are widely used to study particular molecular systems in early neurodegenerative changes. Axonal transport (AT) is perturbed in several prevalent neurodegenerative diseases. The development of a Huntington’s Disease (HD) model in Drosophila melanogaster larvae is described, in which disease gene expression is directed to motor neurons ...

  10. Pantethine rescues a Drosophila model for pantothenate kinase–associated neurodegeneration

    Rana, Anil; Seinen, Erwin; Siudeja, Katarzyna; Muntendam, Remco; Srinivasan, Balaji; Van der Want, Johannes J.; Hayflick, Susan; Reijngoud, Dirk-Jan; Kayser, Oliver; Sibon, Ody C.M

    2010-01-01

    Pantothenate kinase–associated neurodegeneration (PKAN), a progressive neurodegenerative disorder, is associated with impairment of pantothenate kinase function. Pantothenate kinase is the first enzyme required for de novo synthesis of CoA, an essential metabolic cofactor. The pathophysiology of PKAN is not understood, and there is no cure to halt or reverse the symptoms of this devastating disease. Recently, we and others presented a PKAN Drosophila model, and we demonstrated that impaired f...

  11. Human embryonic stem cell-derived neurons as a tool for studying neuroprotection and neurodegeneration

    Hardingham, G. E.; Patani, R; Baxter, P.; Wyllie, David; Chandran, S

    2010-01-01

    The capacity to generate myriad differentiated cell types, including neurons, from human embryonic stem (hES) cell lines offers great potential for developing cell-based therapies and also for increasing our understanding of human developmental mechanisms. In addition, the emerging development of this technology as an experimental tool represents a potential opportunity for neuroscientists interested in mechanisms of neuroprotection and neurodegeneration. Potentially unlimited generation of w...

  12. Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice

    Li Li; Meng Xu; Bo Shen; Man Li; Qian Gao; Shou-gang Wei

    2016-01-01

    D-galactose has been widely used in aging research because of its efficacy in inducing senescence and accelerating aging in animal models. The present study investigated the benefits of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-galactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected ...

  13. Traumatic stress, oxidative stress and posttraumatic stress disorder: neurodegeneration and the accelerated-aging hypothesis

    Miller, Mark W.; Sadeh, Naomi

    2014-01-01

    Posttraumatic stress disorder (PTSD) is associated with elevated risk for a variety of age-related diseases and neurodegeneration. In this paper, we review evidence relevant to the hypothesis that chronic PTSD constitutes a form of persistent life stress that potentiates oxidative stress (OXS) and accelerates cellular aging. We provide an overview of empirical studies that have examined the effects of psychological stress on OXS, discuss the stress-perpetuating characteristics of PTSD, and th...

  14. Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis

    Hampton, David W; Serio, Andrea; Pryce, Gareth; Al-Izki, Sarah; Franklin, Robin Jm; Giovannoni, Gavin; Baker, David; Chandran, Siddharthan

    2013-01-01

    BackgoundMultiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered qu...

  15. Oxidative Stress Mechanisms Underlying Parkinson’s Disease-Associated Neurodegeneration in C. elegans

    Sudipta Chakraborty; Julia Bornhorst; Nguyen, Thuy T; Michael Aschner

    2013-01-01

    Oxidative stress is thought to play a significant role in the development and progression of neurodegenerative diseases. Although it is currently considered a hallmark of such processes, the interweaving of a multitude of signaling cascades hinders complete understanding of the direct role of oxidative stress in neurodegeneration. In addition to its extensive use as an aging model, some researchers have turned to the invertebrate model Caenorhabditis elegans (C. elegans) in order to further i...

  16. Microglial AGE-Albumin Is Critical in Promoting Alcohol-Induced Neurodegeneration in Rats and Humans

    Byun, Kyunghee; Bayarsaikhan, Delger; Bayarsaikhan, Enkhjargal; Son, Myeongjoo; Oh, Seyeon; Lee, Jaesuk; Son, Hye-in; Won, Moo-Ho; Seung U. Kim; Song, Byoung-Joon; Lee, Bonghee

    2014-01-01

    Alcohol is a neurotoxic agent, since long-term heavy ingestion of alcohol can cause various neural diseases including fetal alcohol syndrome, cerebellar degeneracy and alcoholic dementia. However, the molecular mechanisms of alcohol-induced neurotoxicity are still poorly understood despite numerous studies. Thus, we hypothesized that activated microglial cells with elevated AGE-albumin levels play an important role in promoting alcohol-induced neurodegeneration. Our results revealed that micr...

  17. Early intranasal insulin therapy halts progression of neurodegeneration: progress in Alzheimer’s disease therapeutics

    de la Monte, Suzanne M

    2012-01-01

    Evaluation of Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial. Arch Neurol. 2011 Sep 12. Alzheimer’s disease is associated with brain insulin deficiency and insulin resistance, similar to the problems in diabetes. If insulin could be supplied to the brain in the early stages of Alzheimer’s, subsequent neurodegeneration might be prevented. ...

  18. Modeling and imaging cardiac sympathetic neurodegeneration in Parkinson’s disease

    Joers, Valerie; Emborg, Marina E.

    2014-01-01

    Parkinson’s disease (PD) is currently recognized as a multisystem disorder affecting several components of the central and peripheral nervous system. This new understanding of PD helps explain the complexity of the patients’ symptoms while challenges researchers to identify new diagnostic and therapeutic strategies. Cardiac neurodegeneration and dysautonomia affect PD patients and are associated with orthostatic hypotension, fatigue, and abnormal control of electrical heart activity. They can...

  19. Soil processes and tree growth at shooting ranges in a boreal forest reflect contamination history and lead-induced changes in soil food webs.

    Selonen, Salla; Setälä, Heikki

    2015-06-15

    The effects of shooting-derived lead (Pb) on the structure and functioning of a forest ecosystem, and the recovery of the ecosystem after range abandonment were studied at an active shotgun shooting range, an abandoned shooting range where shooting ceased 20 years earlier and an uncontaminated control site. Despite numerous lead-induced changes in the soil food web, soil processes were only weakly related to soil food web composition. However, decomposition of Scots pine (Pinus sylvestris) needle litter was retarded at the active shooting range, and microbial activity, microbial biomass and the rate of decomposition of Pb-contaminated grass litter decreased with increasing soil Pb concentrations. Tree (P. sylvestris) radial growth was suppressed at the active shooting range right after shooting activities started. In contrast, the growth of pines improved at the abandoned shooting range after the cessation of shooting, despite reduced nitrogen and phosphorus contents of the needles. Higher litter degradation rates and lower Pb concentrations in the topmost soil layer at the abandoned shooting range suggest gradual recovery after range abandonment. Our findings suggest that functions in lead-contaminated coniferous forest ecosystems depend on the successional stage of the forest as well as the time since the contamination source has been eliminated, which affects, e.g., the vertical distribution of the contaminant in the soil. However, despite multiple lead-induced changes throughout the ecosystem, the effects were rather weak, indicating high resistance of coniferous forest ecosystems to this type of stress. PMID:25770944

  20. Long non-coding RNA MALAT1 regulates retinal neurodegeneration through CREB signaling.

    Yao, Jin; Wang, Xiao-Qun; Li, Yu-Jie; Shan, Kun; Yang, Hong; Wang, Yang-Ning-Zhi; Yao, Mu-Di; Liu, Chang; Li, Xiu-Miao; Shen, Yi; Liu, Jing-Yu; Cheng, Hong; Yuan, Jun; Zhang, Yang-Yang; Jiang, Qin; Yan, Biao

    2016-01-01

    The nervous and vascular systems, although functionally different, share many common regulators of function maintenance. Long non-coding RNAs (lncRNAs) are important players in many biological processes and human disorders. We previously identified a role of MALAT1 in microvascular dysfunction. However, its role in neurodegeneration is still unknown. Here, we used the eye as the model to investigate the role of MALAT1 in retinal neurodegeneration. We show that MALAT1 expression is significantly up-regulated in the retinas, Müller cells, and primary retinal ganglion cells (RGCs) upon stress. MALAT1 knockdown reduces reactive gliosis, Müller cell activation, and RGC survival in vivo and in vitro MALAT1-CREB binding maintains CREB phosphorylation by inhibiting PP2A-mediated dephosphorylation, which leads to continuous CREB signaling activation. Clinical and animal experimentation suggests that MALAT1 dysfunction is implicated in neurodegenerative processes and several human disorders. Collectively, this study reveals that MALAT1 might regulate the development of retinal neurodegeneration through CREB signaling. PMID:26964565

  1. Mitochondrial optic neuropathy: In vivo model of neurodegeneration and neuroprotective strategies

    Julio C Rojas

    2010-03-01

    Full Text Available Julio C Rojas, Francisco Gonzalez-LimaDepartments of Psychology, Pharmacology and Toxicology, University of Texas at Austin, Austin, TX, USAAbstract: This review summarizes the characteristics of a rodent toxicologic model of optic neuropathy induced by the mitochondrial complex I inhibitor rotenone. This model has been developed to fulfill the demand for a drug-screening tool providing a sound mechanistic context to address the role of mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders. It features biochemical, structural, and functional retinal deficits that resemble those of patients with Leber’s hereditary optic neuropathy, a mitochondrial disease characterized by selective degeneration of retinal ganglion cells, and for which an environmental component is believed to play a major triggering role. The available data support the efficiency, sensitivity, and versatility of the model for providing insights into the mechanisms of neurodegeneration, including mitochondrial dysfunction, oxidative stress and excitotoxicity. Screening work with this model has provided proof-of-principle that interventions targeting the electron transport chain, such as USP methylene blue and near-infrared light therapy, are effective at preventing neurodegeneration induced by mitochondrial dysfunction in vivo. Prospective developments of this model include the use of neuronal reporter genes for in vivo non-invasive assessment of retinal degeneration at different time points, and its combination with genetic approaches to elucidate the synergism of environmental and genetic factors in neurodegeneration.Keywords: animal model, neuroprotection, mitochondrial dysfunction, visual function, oxidative stress, cytochrome oxidase

  2. Metal and Microelement Biomarkers of Neurodegeneration in Early Life Permethrin-Treated Rats

    Cinzia Nasuti

    2016-01-01

    Full Text Available Hair is a non-invasive biological material useful in the biomonitoring of trace elements because it is a vehicle for substance excretion from the body, and it permits evaluating long-term metal exposure. Here, hair from an animal model of neurodegeneration, induced by early life permethrin treatment from the sixth to 21th day of life, has been analyzed with the aim to assess if metal and microelement content could be used as biomarkers. A hair trace element assay was performed by the ICP-MS technique in six- and 12-month-old rats. A significant increase of As, Mg, S and Zn was measured in the permethrin-treated group at 12 months compared to six months, while Si and Cu/Zn were decreased. K, Cu/Zn and S were increased in the treated group compared to age-matched controls at six and 12 months, respectively. Cr significantly decreased in the treated group at 12 months. PCA analysis showed both a best difference between treated and age-matched control groups at six months. The present findings support the evidence that the Cu/Zn ratio and K, measured at six months, are the best biomarkers for neurodegeneration. This study supports the use of hair analysis to identify biomarkers of neurodegeneration induced by early life permethrin pesticide exposure.

  3. Evidence that a panel of neurodegeneration biomarkers predicts vasospasm, infarction, and outcome in aneurysmal subarachnoid hemorrhage.

    Robert Siman

    Full Text Available Biomarkers for neurodegeneration could be early prognostic measures of brain damage and dysfunction in aneurysmal subarachnoid hemorrhage (aSAH with clinical and medical applications. Recently, we developed a new panel of neurodegeneration biomarkers, and report here on their relationships with pathophysiological complications and outcomes following severe aSAH. Fourteen patients provided serial cerebrospinal fluid samples for up to 10 days and were evaluated by ultrasonography, angiography, magnetic resonance imaging, and clinical examination. Functional outcomes were assessed at hospital discharge and 6-9 months thereafter. Eight biomarkers for acute brain damage were quantified: calpain-derived α-spectrin N- and C-terminal fragments (CCSntf and CCSctf, hypophosphorylated neurofilament H,14-3-3 β and ζ, ubiquitin C-terminal hydrolase L1, neuron-specific enolase, and S100β. All 8 biomarkers rose up to 100-fold in a subset of patients. Better than any single biomarker, a set of 6 correlated significantly with cerebral vasospasm, brain infarction, and poor outcome. Furthermore, CSF levels of 14-3-3β, CCSntf, and NSE were early predictors of subsequent moderate-to-severe vasospasm. These data provide evidence that a panel of neurodegeneration biomarkers may predict lasting brain dysfunction and the pathophysiological processes that lead to it following aSAH. The panel may be valuable as surrogate endpoints for controlled clinical evaluation of treatment interventions and for guiding aSAH patient care.

  4. Neuroprotective Effects of Citicoline in in Vitro Models of Retinal Neurodegeneration

    Andrea Matteucci

    2014-04-01

    Full Text Available In recent years, citicoline has been the object of remarkable interest as a possible neuroprotectant. The aim of this study was to investigate if citicoline affected cell survival in primary retinal cultures and if it exerted neuroprotective activity in conditions modeling retinal neurodegeneration. Primary retinal cultures, obtained from rat embryos, were first treated with increasing concentrations of citicoline (up to 1000 µM and analyzed in terms of apoptosis and caspase activation and characterized by immunocytochemistry to identify neuronal and glial cells. Subsequently, excitotoxic concentration of glutamate or High Glucose-containing cell culture medium (HG was administered as well-known conditions modeling neurodegeneration. Glutamate or HG treatments were performed in the presence or not of citicoline. Neuronal degeneration was evaluated in terms of apoptosis and loss of synapses. The results showed that citicoline did not cause any damage to the retinal neuroglial population up to 1000 µM. At the concentration of 100 µM, it was able to counteract neuronal cell damage both in glutamate- and HG-treated retinal cultures by decreasing proapoptotic effects and contrasting synapse loss. These data confirm that citicoline can efficiently exert a neuroprotective activity. In addition, the results suggest that primary retinal cultures, under conditions inducing neurodegeneration, may represent a useful system to investigate citicoline neuroprotective mechanisms.

  5. Bioactive peptide carnosin protects against lead acetate-induced hepatotoxicity by abrogation of oxidative stress in rats.

    Hasanein, Parisa; Kazemian-Mahtaj, Azam; Khodadadi, Iraj

    2016-08-01

    Context Oxidative stress is a common mechanism of liver injury. Carnosine is a dipeptide having strong antioxidant effects. Objectives We investigated the effects of carnosine on lead-induced hepatotoxicity and oxidative stress in rats. Materials and methods Animals received an aqueous solution of lead acetate (500 mg Pb/L in the drinking water) and/or daily oral gavage of carnosine (10 mg/kg) for 8 weeks. Rats were then weighed and used for the biochemical (commercial kits), molecular (standard chemical methods) and histological (microscopic) evaluations. Results Lead-induced oxidative stress in liver tissue was indicated by a significant increase in the level of malondialdehyde (MDA) (8.25 ± 0.15 nmol/mg) as well as decrease in the level of total antioxidant capacity (TAC) (1.72 ± 0.25 μmol/g) and total thiol (SH) groups) 1.9 ± 0.22 μmol/g). Carnosine treatment decreased MDA (4 ± 0.08 nmol/mg), whereas it increased the contents of total thiol (3.25 ± 0.04 μmol/g) and TAC (3.44 ± 0.32 μmol/g) in the lead group. Carnosine also prevented the decreased body weight (p carnosine attenuates liver damage by decreasing necrosis and infiltration of inflammatory cells. Conclusion Carnosine prevented lead-induced hepatotoxicity, indicated by molecular, biochemical and histopathological analyses through inhibiting lipid peroxidation and enhancing antioxidant defence systems. Therefore, carnosine makes a good candidate to protect against the deleterious effect of chronic lead intoxication. PMID:26808926

  6. Repulsive Guidance Molecule-a Is Involved in Th17-Cell-Induced Neurodegeneration in Autoimmune Encephalomyelitis

    Shogo Tanabe

    2014-11-01

    Full Text Available Multiple sclerosis (MS is a chronic autoimmune disease characterized by inflammation, demyelination, and neurodegeneration in the CNS. Although it is important to prevent neurodegeneration for alleviating neurological disability, the molecular mechanism of neurodegeneration remains largely unknown. Here, we report that repulsive guidance molecule-a (RGMa, known to regulate axonal growth, is associated with neurodegeneration in experimental autoimmune encephalomyelitis (EAE, a mouse model of MS. RGMa is highly expressed in interleukin-17-producing CD4+ T cells (Th17 cells. We induced EAE by adoptive transfer of myelin oligodendrocyte glycoprotein (MOG-specific Th17 cells and then inhibited RGMa with a neutralizing antibody. Inhibition of RGMa improves EAE scores and reduces neuronal degeneration without altering immune or glial responses. Th17 cells induce cultured cortical neuron death through RGMa-neogenin and Akt dephosphorylation. Our results demonstrate that RGMa is involved in Th17-cell-mediated neurodegeneration and that RGMa-specific antibody may have a therapeutic effect in MS.

  7. The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-Stage Alzheimer-Type Tauopathy.

    Robert Siman

    Full Text Available The perforant pathway projection from layer II of the entorhinal cortex to the hippocampal dentate gyrus is especially important for long-term memory formation, and is preferentially vulnerable to developing a degenerative tauopathy early in Alzheimer's disease (AD that may spread over time trans-synaptically. Despite the importance of the perforant pathway to the clinical onset and progression of AD, a therapeutic has not been identified yet that protects it from tau-mediated toxicity. Here, we used an adeno-associated viral vector-based mouse model of early-stage AD-type tauopathy to investigate effects of the mTOR inhibitor and autophagy stimulator rapamycin on the tau-driven loss of perforant pathway neurons and synapses. Focal expression of human tau carrying a P301L mutation but not eGFP as a control in layer II of the lateral entorhinal cortex triggered rapid degeneration of these neurons, loss of lateral perforant pathway synapses in the dentate gyrus outer molecular layer, and activation of neuroinflammatory microglia and astroglia in the two locations. Chronic systemic rapamycin treatment partially inhibited phosphorylation of a mechanistic target of rapamycin substrate in brain and stimulated LC3 cleavage, a marker of autophagic flux. Compared with vehicle-treated controls, rapamycin protected against the tau-induced neuronal loss, synaptotoxicity, reactive microgliosis and astrogliosis, and activation of innate neuroimmunity. It did not alter human tau mRNA or total protein levels. Finally, rapamycin inhibited trans-synaptic transfer of human tau expression to the dentate granule neuron targets for the perforant pathway, likely by preventing the synaptic spread of the AAV vector in response to pathway degeneration. These results identify systemic rapamycin as a treatment that protects the entorhinal cortex and perforant pathway projection from tau-mediated neurodegeneration, axonal and synapse loss, and neuroinflammatory reactive

  8. Dimethyl fumarate attenuates intracerebroventricular streptozotocin-induced spatial memory impairment and hippocampal neurodegeneration in rats.

    Majkutewicz, Irena; Kurowska, Ewelina; Podlacha, Magdalena; Myślińska, Dorota; Grembecka, Beata; Ruciński, Jan; Plucińska, Karolina; Jerzemowska, Grażyna; Wrona, Danuta

    2016-07-15

    Intracerebroventricular (ICV) injection of streptozotocin (STZ) is a widely-accepted animal model of sporadic Alzheimer's disease (sAD). The present study evaluated the ability of dimethyl fumarate (DMF), an agent with antioxidant and anti-inflammatory properties, to prevent spatial memory impairments and hippocampal neurodegeneration mediated by ICV injection of STZ in 4-month-old rats. Rodent chow containing DMF (0.4%) or standard rodent chow was made available on day 0. Rat body weight and food intake were measured daily for whole the experiment (21days). STZ or vehicle (SHAM) ICV injections were performed on days 2 and 4. Spatial reference and working memory were evaluated using the Morris water maze on days 14-21. Cells containing Fluoro-Jade B (neurodegeneration marker), IL-6, IL-10 were quantified in the hippocampus and choline acetyltransferase (ChAT) in the basal forebrain. The disruption of spatial memory and a high density of hippocampal CA1-3 cells labeled with Fluoro-Jade B or containing IL-6 or IL-10 were observed in the STZ group but not in the STZ+DMF group, as compared to the SHAM or SHAM+DMF groups. STZ vs. STZ+DMF differences were found: worse reference memory acquisition, fewer ChAT-positive neurons in the medial septum (Ch1), more Fluoro-Jade-positive CA1 hippocampal cells in STZ rats. DMF therapy in a rodent model of sAD prevented the disruption of spatial reference and working memory, loss of Ch1 cholinergic cells and hippocampal neurodegeneration as well as the induction of IL-6 and IL-10 in CA1. These beneficial cognitive and molecular effects validate the anti-inflammatory and neuroprotective properties of DMF in the hippocampus. PMID:27083302

  9. Complement is dispensable for neurodegeneration in Niemann-Pick disease type C

    Lopez Manuel E

    2012-09-01

    Full Text Available Abstract Background The immune system has been implicated in neurodegeneration during development and disease. In various studies, the absence of complement (that is, C1q deficiency impeded the elimination of apoptotic neurons, allowing survival. In the genetic lysosomal storage disease Niemann-Pick C (NPC, caused by loss of NPC1 function, the expression of complement system components, C1q especially, is elevated in degenerating brain regions of Npc1-/- mice. Here we test whether complement is mediating neurodegeneration in NPC disease. Findings In normal mature mice, C1q mRNA was found in neurons, particularly cerebellar Purkinje neurons (PNs. In Npc1-/- mice, C1q mRNA was additionally found in activated microglia, which accumulate during disease progression and PN loss. Interestingly, C1q was not enriched on or near degenerating neurons. Instead, C1q was concentrated in other brain regions, where it partially co-localized with a potential C1q inhibitor, chondroitin sulfate proteoglycan (CSPG. Genetic deletion of C1q, or of the downstream complement pathway component C3, did not significantly alter patterned neuron loss or disease progression. Deletion of other immune response factors, a Toll-like receptor, a matrix metalloprotease, or the apoptosis facilitator BIM, also failed to alter neuron loss. Conclusion We conclude that complement is not involved in the death and clearance of neurons in NPC disease. This study supports a view of neuroinflammation as a secondary response with non-causal relationship to neuron injury in the disease. This disease model may prove useful for understanding the conditions in which complement and immunity do contribute to neurodegeneration in other disorders.

  10. Tetraspanin (TSP-17 protects dopaminergic neurons against 6-OHDA-induced neurodegeneration in C. elegans.

    Neda Masoudi

    2014-12-01

    Full Text Available Parkinson's disease (PD, the second most prevalent neurodegenerative disease after Alzheimer's disease, is linked to the gradual loss of dopaminergic neurons in the substantia nigra. Disease loci causing hereditary forms of PD are known, but most cases are attributable to a combination of genetic and environmental risk factors. Increased incidence of PD is associated with rural living and pesticide exposure, and dopaminergic neurodegeneration can be triggered by neurotoxins such as 6-hydroxydopamine (6-OHDA. In C. elegans, this drug is taken up by the presynaptic dopamine reuptake transporter (DAT-1 and causes selective death of the eight dopaminergic neurons of the adult hermaphrodite. Using a forward genetic approach to find genes that protect against 6-OHDA-mediated neurodegeneration, we identified tsp-17, which encodes a member of the tetraspanin family of membrane proteins. We show that TSP-17 is expressed in dopaminergic neurons and provide genetic, pharmacological and biochemical evidence that it inhibits DAT-1, thus leading to increased 6-OHDA uptake in tsp-17 loss-of-function mutants. TSP-17 also protects against toxicity conferred by excessive intracellular dopamine. We provide genetic and biochemical evidence that TSP-17 acts partly via the DOP-2 dopamine receptor to negatively regulate DAT-1. tsp-17 mutants also have subtle behavioral phenotypes, some of which are conferred by aberrant dopamine signaling. Incubating mutant worms in liquid medium leads to swimming-induced paralysis. In the L1 larval stage, this phenotype is linked to lethality and cannot be rescued by a dop-3 null mutant. In contrast, mild paralysis occurring in the L4 larval stage is suppressed by dop-3, suggesting defects in dopaminergic signaling. In summary, we show that TSP-17 protects against neurodegeneration and has a role in modulating behaviors linked to dopamine signaling.

  11. Minocycline Rescues from Zinc-Induced Nigrostriatal Dopaminergic Neurodegeneration: Biochemical and Molecular Interventions.

    Kumar, Vinod; Singh, Brajesh Kumar; Chauhan, Amit Kumar; Singh, Deepali; Patel, Devendra Kumar; Singh, Chetna

    2016-07-01

    Accumulation of zinc (Zn) in dopaminergic neurons is implicated in Parkinson's disease (PD), and microglial activation plays a critical role in toxin-induced Parkinsonism. Oxidative stress is accused in Zn-induced dopaminergic neurodegeneration; however, its connection with microglial activation is still not known. This study was undertaken to elucidate the role and underlying mechanism of microglial activation in Zn-induced nigrostriatal dopaminergic neurodegeneration. Male Wistar rats were treated intraperitoneally with/without zinc sulphate (20 mg/kg) in the presence/absence of minocycline (30 mg/kg), a microglial activation inhibitor, for 2-12 weeks. While neurobehavioral and biochemical indexes of PD and number of dopaminergic neurons were reduced, the number of microglial cells was increased in the substantia nigra of the Zn-exposed animals. Similarly, Zn elevated lipid peroxidation (LPO) and activities of superoxide dismutase (SOD) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; however, catalase activity was reduced. Besides, Zn increased an association of NADPH oxidase subunit p67(phox) with membrane, cytochrome c release from the mitochondria and cleavage of pro-caspase 3. Zn attenuated the expression of tyrosine hydroxylase (TH) and vesicular monoamine transporter-2 (VMAT-2) while augmented the expression of dopamine transporter (DAT) and heme oxygenase-1 (HO-1). Minocycline alleviated Zn-induced behavioural impairments, loss of TH-positive neurons, activated microglial cells and biochemical indexes and modulated the expression of studied genes/proteins towards normalcy. The results demonstrate that minocycline reduces the number of activated microglial cells and oxidative stress, which rescue from Zn-induced changes in the expression of monoamine transporter and nigrostriatal dopaminergic neurodegeneration. PMID:25764516

  12. Investigating bacterial sources of toxicity as an environmental contributor to dopaminergic neurodegeneration.

    Kim A Caldwell

    Full Text Available Parkinson disease (PD involves progressive neurodegeneration, including loss of dopamine (DA neurons from the substantia nigra. Select genes associated with rare familial forms of PD function in cellular pathways, such as the ubiquitin-proteasome system (UPS, involved in protein degradation. The misfolding and accumulation of proteins, such as alpha-synuclein, into inclusions termed Lewy Bodies represents a clinical hallmark of PD. Given the predominance of sporadic PD among patient populations, environmental toxins may induce the disease, although their nature is largely unknown. Thus, an unmet challenge surrounds the discovery of causal or contributory neurotoxic factors that could account for the prevalence of sporadic PD. Bacteria within the order Actinomycetales are renowned for their robust production of secondary metabolites and might represent unidentified sources of environmental exposures. Among these, the aerobic genera, Streptomyces, produce natural proteasome inhibitors that block protein degradation and may potentially damage DA neurons. Here we demonstrate that a metabolite produced by a common soil bacterium, S. venezuelae, caused DA neurodegeneration in the nematode, Caenorhabditis elegans, which increased as animals aged. This metabolite, which disrupts UPS function, caused gradual degeneration of all neuronal classes examined, however DA neurons were particularly vulnerable to exposure. The presence of DA exacerbated toxicity because neurodegeneration was attenuated in mutant nematodes depleted for tyrosine hydroxylase (TH, the rate-limiting enzyme in DA production. Strikingly, this factor caused dose-dependent death of human SH-SY5Y neuroblastoma cells, a dopaminergic line. Efforts to purify the toxic activity revealed that it is a highly stable, lipophilic, and chemically unique small molecule. Evidence of a robust neurotoxic factor that selectively impacts neuronal survival in a progressive yet moderate manner is consistent

  13. Eugenia jambolana Lam. Increases lifespan and ameliorates experimentally induced neurodegeneration in C. elegans

    Maria de Fátima Bezerra

    2014-09-01

    Full Text Available Summary. Type-2 diabetes mellitus (T2DM, dyslipidemia (DL and inflammation (IF are associated with reduced lifespan (LS and increased risk of neurodegenerative diseases (NDG. Dysregulation in insulin/insulin-like growth factor-1 (IGF-1 (IIS signaling, forkhead box O transcription factor (FOXO and Silent Information Regulators or Sirtuins (SIRT may be responsible. We investigated the effect of spray dried Jambolan (Eugenia jambolana Lam. fruit in Caenorhabditis elegans model for lifespan, amyloid b1-42 (Ab1-42 aggregation induced paralysis and MPP+ (1-methyl-4-phenylpyridinium induced neurodegeneration. Effect on modulating critical genes involved signaling pathways important in IIS, LS and NDG were also studied in C. elegans. Results show suggest statistically significant increase in lifespan (9-22.7% coupled with a delay in Ab1-42 induced paralysis (11.5% and MPP+ induced paralysis (38-43%. Gene expression studies indicated a significant upregulation in expression of  C. elegans homologs of foxo, sirt1, dopamine D1 receptor and suggested a non-FOXO mediated mechanism of action.Industrial relevance. Jambolan is a bioactive-rich tropical fruit with high colorant potential. Despite this fact, its perishability has hampered its market and industrial use beyond the countries where it is cultivated. Considering that drying is a popular technique able to extend fruits shelf life and concentrate their natural bioactive compounds, this research investigates the health relevance of spray dried jambolan. Here we addressed the potential of dried Jambolan fruit to extend lifespan and inhibit the progression of experimentally induced neurodegeneration using the C. elegans model. We demonstrated that this convenient fruit product was able to increase the lifespan of C. elegans. The jambolan extracts also influenced some critical genes of signaling pathways relevant to metabolic diseases, aging and neurodegeneration. Based on our results, some insight about

  14. Frontal lobe neurodegeneration - Use of songs in the music therapy setting

    Ridder, Hanne Mette Ochsner

    2005-01-01

    When the frontal lobes are damaged by neurodegeneration certain qualities of psychosocial functioning are changed. The person might show lack of initiative, poor social judgment, and loss of personal and social awareness. When these symptoms co-occur with other cortical degeneration (e.g. in...... vascular or frontotemporal dementia) it is difficult to avoid secondary symptoms of the brain damage that is caused by missing communicative abilities and difficulties in fulfilment of psychosocial needs. Songs are used to build up the music therapy setting with this client group. The songs function as...

  15. The db/db Mouse: A Useful Model for the Study of Diabetic Retinal Neurodegeneration

    Bogdanov, Patricia; Corraliza, Lidia; A. Villena, Josep; Carvalho, Andrea R.; Garcia-Arumí, José; Ramos, David; Ruberte, Jesús; Simó, Rafael; Hernández, Cristina

    2014-01-01

    Background To characterize the sequential events that are taking place in retinal neurodegeneration in a murine model of spontaneous type 2 diabetes (db/db mouse). Methods C57BLKsJ-db/db mice were used as spontaneous type 2 diabetic animal model, and C57BLKsJ-db/+ mice served as the control group. To assess the chronological sequence of the abnormalities the analysis was performed at different ages (8, 16 and 24 weeks). The retinas were evaluated in terms of morphological and functional abnor...

  16. May “Mitochondrial Eve” and Mitochondrial Haplogroups Play a Role in Neurodegeneration and Alzheimer's Disease?

    Elena Caldarazzo Ienco

    2011-01-01

    Full Text Available Mitochondria, the powerhouse of the cell, play a critical role in several metabolic processes and apoptotic pathways. Multiple evidences suggest that mitochondria may be crucial in ageing-related neurodegenerative diseases. Moreover, mitochondrial haplogroups have been linked to multiple area of medicine, from normal ageing to diseases, including neurodegeneration. Polymorphisms within the mitochondrial genome might lead to impaired energy generation and to increased amount of reactive oxygen species, having either susceptibility or protective role in several diseases. Here, we highlight the role of the mitochondrial haplogroups in the pathogenetic cascade leading to diseases, with special attention to Alzheimer's disease.

  17. Induction of cell stress in neurons from transgenic mice expressing yellow fluorescent protein: implications for neurodegeneration research.

    Laura H Comley

    Full Text Available BACKGROUND: Mice expressing fluorescent proteins in neurons are one of the most powerful tools in modern neuroscience research and are increasingly being used for in vivo studies of neurodegeneration. However, these mice are often used under the assumption that the fluorescent proteins present are biologically inert. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that thy1-driven expression of yellow fluorescent protein (YFP in neurons triggers multiple cell stress responses at both the mRNA and protein levels in vivo. The presence of YFP in neurons also subtly altered neuronal morphology and modified the time-course of dying-back neurodegeneration in experimental axonopathy, but not in Wallerian degeneration triggered by nerve injury. CONCLUSIONS/SIGNIFICANCE: We conclude that fluorescent protein expressed in thy1-YFP mice is not biologically inert, modifies molecular and cellular characteristics of neurons in vivo, and has diverse and unpredictable effects on neurodegeneration pathways.

  18. Intestinal microbiota shifts towards elevated commensal Escherichia coli loads abrogate colonization resistance against Campylobacter jejuni in mice.

    Lea-Maxie Haag

    Full Text Available BACKGROUND: The zoonotic pathogen Campylobacter jejuni is a leading cause of bacterial foodborne enterocolitis in humans worldwide. The understanding of immunopathology underlying human campylobacteriosis is hampered by the fact that mice display strong colonization resistance against the pathogen due to their host specific gut microbiota composition. METHODOLOGY/PRINCIPAL FINDINGS: Since the microbiota composition changes significantly during intestinal inflammation we dissected factors contributing to colonization resistance against C. jejuni in murine ileitis, colitis and in infant mice. In contrast to healthy animals C. jejuni could stably colonize mice suffering from intestinal inflammation. Strikingly, in mice with Toxoplasma gondii-induced acute ileitis, C. jejuni disseminated to mesenteric lymphnodes, spleen, liver, kidney, and blood. In infant mice C. jejuni infection induced enterocolitis. Mice suffering from intestinal inflammation and C. jejuni susceptible infant mice displayed characteristical microbiota shifts dominated by increased numbers of commensal Escherichia coli. To further dissect the pivotal role of those distinct microbiota shifts in abrogating colonization resistance, we investigated C. jejuni infection in healthy adult mice in which the microbiota was artificially modified by feeding live commensal E. coli. Strikingly, in animals harboring supra-physiological intestinal E. coli loads, colonization resistance was significantly diminished and C. jejuni infection induced enterocolitis mimicking key features of human campylobacteriosis. CONCLUSION/SIGNIFICANCE: Murine colonization resistance against C. jejuni is abrogated by changes in the microbiota composition towards elevated E. coli loads during intestinal inflammation as well as in infant mice. Intestinal inflammation and microbiota shifts thus represent potential risk factors for C. jejuni infection. Corresponding interplays between C. jejuni and microbiota might

  19. Abrogation of Age-Induced MicroRNA-195 Rejuvenates the Senescent Mesenchymal Stem Cells by Reactivating Telomerase.

    Okada, Motoi; Kim, Ha Won; Matsu-ura, Kaoru; Wang, Yi-Gang; Xu, Meifeng; Ashraf, Muhammad

    2016-01-01

    Previously, we reported that a novel subpopulation of young mesenchymal stem cells (YMSCs) existed in old bone marrow, which possessed high antiaging properties as well as excellent efficacy for cardiac repair. MicroRNAs (miRNAs) have emerged as key regulators in post-transcriptional gene expression programs, and however, it is unknown whether miRNAs directly control stem cell senescence. Here we present the first evidence that miR-195 overexpressed in old MSCs (OMSCs) induces stem cell senescence deteriorating their regenerative ability by directly deactivating telomerase reverse transcriptase (Tert), and abrogation of miR-195 can reverse stem cell aging. MiRNAs profiling analysis in YMSCs and OMSCs by microarray showed that miR-140, miR-146a/b, and miR-195 were significantly upregulated in OMSCs, which led us to hypothesize that these are age-induced miRNAs involved in stem cell senescence. Of these miRNAs, we found miR-195 directly targeted 3'-untranslated region of Tert gene by computational target prediction analysis and luciferase assay, and knockdown of miR-195 significantly increased Tert expression in OMSCs. Strikingly, miR-195 inhibition significantly induced telomere relengthening in OMSCs along with reduced expression of senescence-associated β-galactosidase. Moreover, silencing miR-195 in OMSCs by transfection of miR-195 inhibitor significantly restored antiaging factors expression including Tert and Sirt1 as well as phosphorylation of Akt and FOXO1. Notably, abrogation of miR-195 markedly restored proliferative abilities in OMSCs. Transplantation of OMSCs with knocked out miR-195 reduced infarction size and improved LV function. In conclusion, rejuvenation of aged stem cells by miR-195 inhibition would be a promising autologous therapeutic strategy for cardiac repair in the elderly patients. PMID:26390028

  20. Abrogation of prostaglandin E-EP4 signaling in osteoblasts prevents the bone destruction induced by human prostate cancer metastases.

    Watanabe, Kenta; Tominari, Tsukasa; Hirata, Michiko; Matsumoto, Chiho; Maruyama, Takayuki; Murphy, Gillian; Nagase, Hideaki; Miyaura, Chisato; Inada, Masaki

    2016-09-01

    The metastasis of tumors to bone is known to be promoted by prostaglandin E2 (PGE2) produced by the tumor host stromal tissue. Although bone metastases frequently occur in prostate cancer patients, the significance of PGE2 in stromal responses to the tumor is not known. In this study, we report that PGE2 and its receptor EP4 play a pivotal role in bone destruction and metastasis in an experimental metastasis model of prostate cancer in nude mice. Using human prostate cancer PC-3 cells that are stably transfected with luciferase, we showed that the development of bone metastasis was accompanied by increased osteoclastic bone resorption in the bone metastasis microenvironment, and could be abrogated by an EP4 receptor antagonist. The growth of PC-3 cells in vitro was not influenced by PGE2 or by the EP4 receptor. However, cell-cell interactions between fixed PC-3 cells and host osteoblasts induced PGE2 production and RANKL expression in the osteoblasts. Addition of an EP4 antagonist suppressed both PGE2 and RANKL expression induced by the PC3-osteoblast interaction, which would have consequent effects on osteoclast activation and osteolysis. These results indicate that the blockage of PGE2-EP4 signaling prevents the bone destruction required for prostate cancer metastases, and that this is, in part due to the abrogation of bone cell responses. The study provides further evidence that an EP4 antagonist is a candidate for the treatment of prostate cancer in the blockade of bone metastasis. PMID:27450806

  1. CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome.

    Todd, Peter K; Oh, Seok Yoon; Krans, Amy; He, Fang; Sellier, Chantal; Frazer, Michelle; Renoux, Abigail J; Chen, Kai-chun; Scaglione, K Matthew; Basrur, Venkatesha; Elenitoba-Johnson, Kojo; Vonsattel, Jean P; Louis, Elan D; Sutton, Michael A; Taylor, J Paul; Mills, Ryan E; Charlet-Berguerand, Nicholas; Paulson, Henry L

    2013-05-01

    Fragile X-associated tremor ataxia syndrome (FXTAS) results from a CGG repeat expansion in the 5' UTR of FMR1. This repeat is thought to elicit toxicity as RNA, yet disease brains contain ubiquitin-positive neuronal inclusions, a pathologic hallmark of protein-mediated neurodegeneration. We explain this paradox by demonstrating that CGG repeats trigger repeat-associated non-AUG-initiated (RAN) translation of a cryptic polyglycine-containing protein, FMRpolyG. FMRpolyG accumulates in ubiquitin-positive inclusions in Drosophila, cell culture, mouse disease models, and FXTAS patient brains. CGG RAN translation occurs in at least two of three possible reading frames at repeat sizes ranging from normal (25) to pathogenic (90), but inclusion formation only occurs with expanded repeats. In Drosophila, CGG repeat toxicity is suppressed by eliminating RAN translation and enhanced by increased polyglycine protein production. These studies expand the growing list of nucleotide repeat disorders in which RAN translation occurs and provide evidence that RAN translation contributes to neurodegeneration. PMID:23602499

  2. Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice

    Li Li; Meng Xu; Bo Shen; Man Li; Qian Gao; Shou-gang Wei

    2016-01-01

    D-galactose has been widely used in aging research because of its efifcacy in inducing senescence and accelerating aging in animal models. The present study investigated the beneifts of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-ga-lactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected to exercise training by running on a treadmill for 6 days a week. Shortened escape latency in a Morris water maze test indicated that exercise improved learning and memory in aging mice. The ameliorative changes were likely induced by an upregulation of Bcl-2 and brain-derived neurotrophic factor, the repression of apop-tosis factors such as Fas and Bax, and an increase in the activity of glucose transporters-1 and 4. The data suggest moderate exercise may retard or inhibit neurodegeneration in D-galactose-induced aging mice.

  3. Network Neurodegeneration in Alzheimer’s Disease via MRI based Shape Diffeomorphometry and High Field Atlasing

    Michael I Miller

    2015-05-01

    Full Text Available This paper examines MRI analysis of neurodegeneration in Alzheimer’s Disease (AD in a network of structures within the medial temporal lobe using diffeomorphometry methods coupled with high-field atlasing in which the entorhinal cortex is partitioned into nine subareas. The morphometry markers for three groups of subjects (controls, preclinical AD and symptomatic AD are indexed to template coordinates measured with respect to these nine subareas. The location and timing of changes are examined within the subareas as it pertains to the classic Braak and Braak staging by comparing the three groups. We demonstrate that the earliest preclinical changes in the population occur in the lateral most sulcal extent in the entorhinal cortex (alluded to as trans entorhinal cortex by Braak and Braak, and then proceeds medially which is consistent with the Braak and Braak staging. We use high field 11T atlasing to demonstrate that the network changes are occurring at the junctures of the substructures in this medial temporal lobe network. Temporal progression of the disease through the network is also examined via changepoint analysis demonstrating earliest changes in entorhinal cortex. The differential expression of rate of atrophy with progression signaling the changepoint time across the network is demonstrated to be signaling in the intermediate caudal subarea of the entorhinal cortex, which has been noted to be proximal to the hippocampus. This coupled to the findings of the nearby basolateral involvement in amygdala demonstrates the selectivity of neurodegeneration in early AD.

  4. Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites.

    Breda, Carlo; Sathyasaikumar, Korrapati V; Sograte Idrissi, Shama; Notarangelo, Francesca M; Estranero, Jasper G; Moore, Gareth G L; Green, Edward W; Kyriacou, Charalambos P; Schwarcz, Robert; Giorgini, Flaviano

    2016-05-10

    Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway-kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites. However, it is not clear if TDO inhibition is protective via a similar mechanism or if this is instead due to increased levels of TRP-the substrate of TDO. Here, we find that increased levels of KYNA relative to 3-HK are likely central to the protection conferred by TDO inhibition in a fruit fly model of Huntington's disease and that TRP treatment strongly reduces neurodegeneration by shifting KP flux toward KYNA synthesis. In fly models of Alzheimer's and Parkinson's disease, we provide genetic evidence that inhibition of TDO or KMO improves locomotor performance and ameliorates shortened life span, as well as reducing neurodegeneration in Alzheimer's model flies. Critically, we find that treatment with a chemical TDO inhibitor is robustly protective in these models. Consequently, our work strongly supports targeting of the KP as a potential treatment strategy for several major neurodegenerative disorders and suggests that alterations in the levels of neuroactive KP metabolites could underlie several therapeutic benefits. PMID:27114543

  5. Insulin and Insulin-Sensitizing Drugs in Neurodegeneration: Mitochondria as Therapeutic Targets

    Paula I. Moreira

    2009-12-01

    Full Text Available Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria are intracellular organelles that despite playing a critical role in cellular metabolism are also one of the major sources of reactive oxygen species. Mitochondrial dysfunction, oxidative stress and neuroinflammation, hallmarks of neurodegeneration, can result from impaired insulin signaling. Insulin-sensitizing drugs such as the thiazolidinediones are a new class of synthetic compounds that potentiate insulin action in the target tissues and act as specific agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ. Recently, several PPAR agonists have been proposed as novel and possible therapeutic agents for neurodegenerative disorders. Indeed, the literature shows that these agents are able to protect against mitochondrial dysfunction, oxidative damage, inflammation and apoptosis. This review discusses the role of mitochondria and insulin signaling in normal brain function and in neurodegeneration. Furthermore, the potential protective role of insulin and insulin sensitizers in Alzheimer´s, Parkinson´s and Huntington´s diseases and amyotrophic lateral sclerosis will be also discussed.

  6. Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice.

    Li, Li; Xu, Meng; Shen, Bo; Li, Man; Gao, Qian; Wei, Shou-Gang

    2016-05-01

    D-galactose has been widely used in aging research because of its efficacy in inducing senescence and accelerating aging in animal models. The present study investigated the benefits of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-galactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected to exercise training by running on a treadmill for 6 days a week. Shortened escape latency in a Morris water maze test indicated that exercise improved learning and memory in aging mice. The ameliorative changes were likely induced by an upregulation of Bcl-2 and brain-derived neurotrophic factor, the repression of apoptosis factors such as Fas and Bax, and an increase in the activity of glucose transporters-1 and 4. The data suggest moderate exercise may retard or inhibit neurodegeneration in D-galactose-induced aging mice. PMID:27335566

  7. A deficiency of ceramide biosynthesis causes cerebellar purkinje cell neurodegeneration and lipofuscin accumulation.

    Lihong Zhao

    2011-05-01

    Full Text Available Sphingolipids, lipids with a common sphingoid base (also termed long chain base backbone, play essential cellular structural and signaling functions. Alterations of sphingolipid levels have been implicated in many diseases, including neurodegenerative disorders. However, it remains largely unclear whether sphingolipid changes in these diseases are pathological events or homeostatic responses. Furthermore, how changes in sphingolipid homeostasis shape the progression of aging and neurodegeneration remains to be clarified. We identified two mouse strains, flincher (fln and toppler (to, with spontaneous recessive mutations that cause cerebellar ataxia and Purkinje cell degeneration. Positional cloning demonstrated that these mutations reside in the Lass1 gene. Lass1 encodes (dihydroceramide synthase 1 (CerS1, which is highly expressed in neurons. Both fln and to mutations caused complete loss of CerS1 catalytic activity, which resulted in a reduction in sphingolipid biosynthesis in the brain and dramatic changes in steady-state levels of sphingolipids and sphingoid bases. In addition to Purkinje cell death, deficiency of CerS1 function also induced accumulation of lipofuscin with ubiquitylated proteins in many brain regions. Our results demonstrate clearly that ceramide biosynthesis deficiency can cause neurodegeneration and suggest a novel mechanism of lipofuscin formation, a common phenomenon that occurs during normal aging and in some neurodegenerative diseases.

  8. The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration

    Costanza Savino

    2013-01-01

    Full Text Available Mitochondrial-mediated oxidative stress and apoptosis play a crucial role in neurodegenerative disease and aging. Both mitochondrial permeability transition (PT and swelling of mitochondria have been involved in neurodegeneration. Indeed, knockout mice for cyclophilin-D (Cyc-D, a key regulatory component of the PT pore (PTP that triggers mitochondrial swelling, resulted to be protected in preclinical models of multiple sclerosis (MS, Parkinson’s disease (PD, and amyotrophic lateral sclerosis (ALS. However, how neuronal stress is transduced into mitochondrial oxidative stress and swelling is unclear. Recently, the aging determinant p66Shc that generates H2O2 reacting with cytochrome c and induces oxidation of PTP and mitochondrial swelling was found to be involved in MS and ALS. To investigate the role of p66Shc/PTP pathway in neurodegeneration, we performed experimental autoimmune encephalomyelitis (EAE experiments in p66Shc knockout mice (p66Shc−/−, knock out mice for cyclophilin-D (Cyc-D−/−, and p66Shc Cyc-D double knock out (p66Shc/Cyc-D−/− mice. Results confirm that deletion of p66Shc protects from EAE without affecting immune response, whereas it is not epistatic to the Cyc-D mutation. These findings demonstrate that p66Shc contributes to EAE induced neuronal damage most likely through the opening of PTP suggesting that p66Shc/PTP pathway transduces neurodegenerative stresses.

  9. Microglial AGE-albumin is critical in promoting alcohol-induced neurodegeneration in rats and humans.

    Byun, Kyunghee; Bayarsaikhan, Delger; Bayarsaikhan, Enkhjargal; Son, Myeongjoo; Oh, Seyeon; Lee, Jaesuk; Son, Hye-In; Won, Moo-Ho; Kim, Seung U; Song, Byoung-Joon; Lee, Bonghee

    2014-01-01

    Alcohol is a neurotoxic agent, since long-term heavy ingestion of alcohol can cause various neural diseases including fetal alcohol syndrome, cerebellar degeneracy and alcoholic dementia. However, the molecular mechanisms of alcohol-induced neurotoxicity are still poorly understood despite numerous studies. Thus, we hypothesized that activated microglial cells with elevated AGE-albumin levels play an important role in promoting alcohol-induced neurodegeneration. Our results revealed that microglial activation and neuronal damage were found in the hippocampus and entorhinal cortex following alcohol treatment in a rat model. Increased AGE-albumin synthesis and secretion were also observed in activated microglial cells after alcohol exposure. The expressed levels of receptor for AGE (RAGE)-positive neurons and RAGE-dependent neuronal death were markedly elevated by AGE-albumin through the mitogen activated protein kinase pathway. Treatment with soluble RAGE or AGE inhibitors significantly diminished neuronal damage in the animal model. Furthermore, the levels of activated microglial cells, AGE-albumin and neuronal loss were significantly elevated in human brains from alcoholic indivisuals compared to normal controls. Taken together, our data suggest that increased AGE-albumin from activated microglial cells induces neuronal death, and that efficient regulation of its synthesis and secretion is a therapeutic target for preventing alcohol-induced neurodegeneration. PMID:25140518

  10. Abrogation of Chk1-mediated S/G2 checkpoint by UCN-01 enhances ara-C-induced cytotoxicity in human colon cancer cells

    Rong-guang SHAO; Chun-Xia CAO; Yves POMMIER

    2004-01-01

    AIM: To investigate whether 7-hydroxystaurosporine (UCN-01) affects cell cycle progression in arabinosylcytosine (ara-C) treated human colon carcinoma HT-29 cells. METHODS: Cytotoxicity, DNA synthesis, cell cycle distribution,protein level, and kinase activity were determined by clonogenic assay, flow cytometry, DNA synthesis assay,immunoblotting, and kinase assays, respectively. RESULTS: UCN-01 abrogated an S/G2-phase checkpoint in HT29 cells treated with ara-C. When UCN-01 was added after treatment with ara-C, the rate of recovery of DNA synthesis was enhanced and colony-forming ability diminished. Thus, premature recovery of DNA synthesis was associated with increased cytotoxicity. Measurements of cyclin A and B protein levels, Cdk2 and Cdc2 kinase activities, Cdc25C phosphorylation, and Chkl kinase activity were consistent with UCN-01-induced abrogation of the S/G2-phase checkpoint in ara-C treated cells. CONCLUSION: The abrogation of the S/G2 checkpoint may be due to inhibition of Chkl kinase by UCN-01. The enhanced cytotoxicity produced when UCN-01 was combined with ara-C suggested a rationale for the use of this drug combination for tumors that might be susceptible to cell cycle checkpoint abrogation.

  11. Impaired Coenzyme A metabolism affects histone and tubulin acetylation in Drosophila and human cell models of pantothenate kinase associated neurodegeneration

    Siudeja, Katarzyna; Srinivasan, Balaji; Xu, Lanjun; Rana, Anil; de Jong, Jannie; Nollen, Ellen A. A.; Jackowski, Suzanne; Sanford, Lynn; Hayflick, Susan; Sibon, Ody C. M.

    2011-01-01

    Pantothenate kinase-associated neurodegeneration (PKAN is a neurodegenerative disease with unresolved pathophysiology. Previously, we observed reduced Coenzyme A levels in a Drosophila model for PKAN. Coenzyme A is required for acetyl-Coenzyme A synthesis and acyl groups from the latter are transfer

  12. A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration

    Gräff, Johannes; Kahn, Martin; Samiei, Alireza; Gao, Jun; Ota, Kristie T.; Rei, Damien; Tsai, Li-Huei

    2013-01-01

    Caloric restriction (CR) is a dietary regimen known to promote lifespan by slowing down the occurrence of age-dependent diseases. The greatest risk factor for neurodegeneration in the brain is age, from which follows that CR might also attenuate the progressive loss of neurons that is often associated with impaired cognitive capacities. In this study, we used a transgenic mouse model that allows for a temporally and spatially controlled onset of neurodegeneration to test the potentially beneficial effects of CR. We found that in this model, CR significantly delayed the onset of neurodegeneration, synaptic loss and dysfunction, and thereby preserved cognitive capacities. Mechanistically, CR induced the expression of the known lifespan-regulating protein SIRT1, prompting us to test whether a pharmacological activation of SIRT1 might recapitulate CR. We found that oral administration of a SIRT1-activating compound essentially replicated the beneficial effects of CR. Thus, SIRT1-activating compounds might provide a pharmacological alternative to the regimen of CR against neurodegeneration and its associated ailments. PMID:23699506

  13. Neurodegeneration in drop-dead mutant drosophila melanogaster is associated with the respiratory system but not with Hypoxia.

    Sansone, Christine Lynn; Blumenthal, Edward M

    2013-01-01

    Mutations in the gene drop-dead (drd) cause diverse phenotypes in adult Drosophila melanogaster including early lethality, neurodegeneration, tracheal defects, gut dysfunction, reduced body mass, and female sterility. Despite the identification of the drd gene itself, the causes of early lethality and neurodegeneration in the mutant flies remain unknown. To determine the pattern of drd expression associated with the neurodegenerative phenotype, knockdown of drd with various Gal4 drivers was performed. Early adult lethality and neurodegeneration were observed upon knockdown of drd in the tracheal system with two independent insertions of the breathless-Gal4 driver and upon knockdown in the tracheal system and elsewhere with the DJ717-Gal4 driver. Surprisingly, rescue of drd expression exclusively in the tracheae in otherwise mutant flies rescued the neurodegenerative phenotype but not adult lethality. Gut dysfunction, as measured by defecation rate, was not rescued in these flies, and gut function appeared normal upon tracheal-specific knockdown of drd. Finally, the hypothesis that tracheal dysfunction in drd mutants results in hypoxia was tested. Hypoxia-sensitive reporter transgenes (LDH-Gal4 and LDH-LacZ) were placed on a drd mutant background, but enhanced expression of these reporters was not observed. In addition, manipulation of drd expression in the tracheae did not affect expression of the hypoxia-induced genes LDH, tango, and similar. Overall, these results indicate that there are at least two causes of adult lethality in drd mutants, that gut dysfunction and neurodegeneration are independent phenotypes, and that neurodegeneration is associated with tracheal expression of drd but not with hypoxia. PMID:23874488

  14. Beta-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation

    Hayflick, Susan J.; Kruer, Michael C.; Gregory, Allison; Haack, Tobias B.; Kurian, Manju A.; Houlden, Henry H.; Anderson, James; Boddaert, Nathalie; Sanford, Lynn; Harik, Sami I.; Dandu, Vasuki H.; Nardocci, Nardo; Zorzi, Giovanna; Dunaway, Todd; Tarnopolsky, Mark; Skinner, Steven; Holden, Kenton R.; Frucht, Steven; Hanspal, Era; Schrander-Stumpel, Connie; Mignot, Cyril; Héron, Delphine; Saunders, Dawn E.; Kaminska, Margaret; Lin, Jean-Pierre; Lascelles, Karine; Cuno, Stephan M.; Meyer, Esther; Garavaglia, Barbara; Bhatia, Kailash; de Silva, Rajith; Crisp, Sarah; Lunt, Peter; Carey, Martyn; Hardy, John; Meitinger, Thomas; Prokisch, Holger; Hogarth, Penelope

    2013-01-01

    Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a ‘halo’ of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features. PMID:23687123

  15. Neurodegeneration in drop-dead mutant drosophila melanogaster is associated with the respiratory system but not with Hypoxia.

    Christine Lynn Sansone

    Full Text Available Mutations in the gene drop-dead (drd cause diverse phenotypes in adult Drosophila melanogaster including early lethality, neurodegeneration, tracheal defects, gut dysfunction, reduced body mass, and female sterility. Despite the identification of the drd gene itself, the causes of early lethality and neurodegeneration in the mutant flies remain unknown. To determine the pattern of drd expression associated with the neurodegenerative phenotype, knockdown of drd with various Gal4 drivers was performed. Early adult lethality and neurodegeneration were observed upon knockdown of drd in the tracheal system with two independent insertions of the breathless-Gal4 driver and upon knockdown in the tracheal system and elsewhere with the DJ717-Gal4 driver. Surprisingly, rescue of drd expression exclusively in the tracheae in otherwise mutant flies rescued the neurodegenerative phenotype but not adult lethality. Gut dysfunction, as measured by defecation rate, was not rescued in these flies, and gut function appeared normal upon tracheal-specific knockdown of drd. Finally, the hypothesis that tracheal dysfunction in drd mutants results in hypoxia was tested. Hypoxia-sensitive reporter transgenes (LDH-Gal4 and LDH-LacZ were placed on a drd mutant background, but enhanced expression of these reporters was not observed. In addition, manipulation of drd expression in the tracheae did not affect expression of the hypoxia-induced genes LDH, tango, and similar. Overall, these results indicate that there are at least two causes of adult lethality in drd mutants, that gut dysfunction and neurodegeneration are independent phenotypes, and that neurodegeneration is associated with tracheal expression of drd but not with hypoxia.

  16. Correlated Inflammatory Responses and Neurodegeneration in Peptide-Injected Animal Models of Alzheimer’s Disease

    James G. McLarnon

    2014-01-01

    Full Text Available Animal models of Alzheimer’s disease (AD which emphasize activation of microglia may have particular utility in correlating proinflammatory activity with neurodegeneration. This paper reviews injection of amyloid-β (Aβ into rat brain as an alternative AD animal model to the use of transgenic animals. In particular, intrahippocampal injection of Aβ1-42 peptide demonstrates prominent microglial mobilization and activation accompanied by a significant loss of granule cell neurons. Furthermore, pharmacological inhibition of inflammatory reactivity is demonstrated by a broad spectrum of drugs with a common endpoint in conferring neuroprotection in peptide-injected animals. Peptide-injection models provide a focus on glial cell responses to direct peptide injection in rat brain and offer advantages in the study of the mechanisms underlying neuroinflammation in AD brain.

  17. STRUCTURAL AND FUNCTIONAL HETEROGENEITY OF ASTROCYTES IN THE BRAIN: ROLE IN NEURODEGENERATION AND NEUROINFLAMMATION

    A. V. Morgun

    2014-01-01

    Full Text Available The review covers the current concepts on structural and functional heterogeneity of brain astrocytes that serve for numerous (pathophysiological processes in the central nervous system. Astrocytes from various subpopulations demonstrate different sensitivity to the action of pathogenic factors, varied behaviors in reactive processes and within the local immune response. Key functions of astrocytes like neurogenesis, neuron-astroglia metabolic coupling, glial control of local blood flow greatly depend on the origin and characteristics of astroglial cells. Changes at the initial stages of neurodegeneration or in neurodevelopmental disorders are associated with significant alterations in astroglial structural and functional properties, thus suggesting new approaches to therapeutic strategies implementing astroglia-expressing molecules and targets for effective

  18. Nanomedicine and nanotoxicology: the pros and cons for neurodegeneration and brain cancer.

    Catalan-Figueroa, Johanna; Palma-Florez, Sujey; Alvarez, Gonzalo; Fritz, Hans F; Jara, Miguel O; Morales, Javier O

    2016-01-01

    Current strategies for brain diseases are mostly symptomatic and noncurative. Nanotechnology has the potential to facilitate the transport of drugs across the blood-brain barrier and to enhance their pharmacokinetic profile. However, to reach clinical application, an understanding of nanoneurotoxicity in terms of oxidative stress and inflammation is required. Emerging evidence has also shown that nanoparticles have the ability to alter autophagy, which can induce inflammation and oxidative stress, or vice versa. These effects may increase neurodegenerative processes damage, but on the other hand, they may have benefits for brain cancer therapies. In this review, we emphasize how nanomaterials may induce neurotoxic effects focusing on neurodegeneration, and how these effects could be exploited toward brain cancer treatment. PMID:26653284

  19. Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus.

    Sharma, D R; Wani, W Y; Sunkaria, A; Kandimalla, R J; Sharma, R K; Verma, D; Bal, A; Gill, K D

    2016-06-01

    Aluminum is a light weight and toxic metal present ubiquitously on earth, which has gained considerable attention due to its neurotoxic effects. It also has been linked ecologically and epidemiologically to several neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Guamanian-Parkinsonian complex and Amyotrophic lateral sclerosis (ALS). The mechanism of aluminum neurotoxicity is poorly understood, but it is well documented that aluminum generates reactive oxygen species (ROS). Enhanced ROS production leads to disruption of cellular antioxidant defense systems and release of cytochrome c (cyt-c) from mitochondria to cytosol resulting in apoptotic cell death. Quercetin (a natural flavonoid) protects it from oxidative damage and has been shown to decrease mitochondrial damage in various animal models of oxidative stress. We hypothesized that if oxidative damage to mitochondria does play a significant role in aluminum-induced neurodegeneration, and then quercetin should ameliorate neuronal apoptosis. Administration of quercetin (10mg/kg body wt/day) reduced aluminum (10mg/kg body wt/day)-induced oxidative stress (decreased ROS production, increased mitochondrial superoxide dismutase (MnSOD) activity). In addition, quercetin also prevents aluminum-induced translocation of cyt-c, and up-regulates Bcl-2, down-regulates Bax, p53, caspase-3 activation and reduces DNA fragmentation. Quercetin also obstructs aluminum-induced neurodegenerative changes in aluminum-treated rats as seen by Hematoxylin and Eosin (H&E) staining. Further electron microscopic studies revealed that quercetin attenuates aluminum-induced mitochondrial swelling, loss of cristae and chromatin condensation. These results indicate that treatment with quercetin may represent a therapeutic strategy to attenuate the neuronal death against aluminum-induced neurodegeneration. PMID:26944603

  20. Increased RhoA prenylation in the loechrig (loe mutant leads to progressive neurodegeneration.

    Mandy Cook

    Full Text Available The Drosophila mutant loechrig (loe shows age-dependent degeneration of the nervous system and is caused by the loss of a neuronal isoform of the AMP-activated protein kinase (AMPK γ-subunit (also known as SNF4Aγ. The trimeric AMPK complex is activated by low energy levels and metabolic insults and regulates multiple important signal pathways that control cell metabolism. A well-known downstream target of AMPK is hydroxyl-methylglutaryl-CoA reductase (HMGR, a key enzyme in isoprenoid synthesis, and we have previously shown that HMGR genetically interacts with loe and affects the severity of the degenerative phenotype. Prenylation of proteins like small G-proteins is an important posttranslational modification providing lipid moieties that allow the association of these proteins with membranes, thereby facilitating their subsequent activation. Rho proteins have been extensively studied in neuronal outgrowth, however, much less is known about their function in neuronal maintenance. Here we show that the loe mutation interferes with isoprenoid synthesis, leading to increased prenylation of the small GTPase Rho1, the fly orthologue of vertebrate RhoA. We also demonstrate that increased prenylation and Rho1 activity causes neurodegeneration and aggravates the behavioral and degenerative phenotypes of loe. Because we cannot detect defects in the development of the central nervous system in loe, this suggests that loe only interferes with the function of the RhoA pathway in maintaining neuronal integrity during adulthood. In addition, our results show that alterations in isoprenoids can result in progressive neurodegeneration, supporting findings in vertebrates that prenylation may play a role in neurodegenerative diseases like Alzheimer's Disease.

  1. Ninjin'yoeito and ginseng extract prevent oxaliplatin-induced neurodegeneration in PC12 cells.

    Suzuki, Toshiaki; Yamamoto, Ayano; Ohsawa, Masahiro; Motoo, Yoshiharu; Mizukami, Hajime; Makino, Toshiaki

    2015-10-01

    Ninjin'yoeito (NYT) is a formula of Japanese traditional kampo medicine composed of 12 crude drugs, and is designed to improve the decline in constitution after recovery from disease, fatigue, anemia, anorexia, perspiration during sleep, cold limbs, slight fever, chills, persistent cough, malaise, mental disequilibrium, insomnia, and constipation. Oxaliplatin (L-OHP) is a platinum-based anticancer drug used to treat colorectal, pancreatic, and stomach cancers. However, it often causes acute and chronic peripheral neuropathies including cold allodynia and mechanical hyperalgesia. In this study, we investigated the preventive effects of NYT on neuronal degeneration caused by L-OHP using PC12 cells, which are derived from the rat adrenal medulla and differentiate into nerve-like cells after exposure to nerve growth factor. L-OHP treatment decreased the elongation of neurite-like projection outgrowths in differentiated PC12 cells. When PC12 cells were treated with NYT hot water extract, neurodegeneration caused by L-OHP was significantly prevented in a concentration-dependent manner. Among the 12 crude drugs composing NYT, the extract of Ginseng (the root of Panax ginseng) exhibited the strongest preventive effects on neurodegeneration in differentiated PC12 cells. By activity-guided fractionation, we found that the fraction containing ginsenosides displayed preventive activity and, among several ginsenosides, ginsenoside F2 exhibited significant preventive effects on L-OHP-induced decreases in neurite-like outgrowths in differentiated PC12 cells. These results suggest that NYT and ginseng are promising agents for preventing L-OHP-induced neuropathies and present ginsenoside F2 as one of the active ingredients in ginseng. PMID:26014046

  2. Huntington's Disease (HD): Neurodegeneration of Brodmann's Primary Visual Area 17 (BA17).

    Rüb, Udo; Seidel, Kay; Vonsattel, Jean Paul; Lange, Herwig W; Eisenmenger, Wolfgang; Götz, Monika; Del Turco, Domenico; Bouzrou, Mohamed; Korf, Horst-Werner; Heinsen, Helmut

    2015-11-01

    Huntington's disease (HD), an autosomal dominantly inherited polyglutamine or CAG repeat disease along with somatomotor, oculomotor, psychiatric and cognitive symptoms, presents clinically with impairments of elementary and complex visual functions as well as altered visual-evoked potentials (VEPs). Previous volumetric and pathoanatomical post-mortem investigations pointed to an involvement of Brodmann's primary visual area 17 (BA17) in HD. Because the involvement of BA17 could be interpreted as an early onset brain neurodegeneration, we further characterized this potential primary cortical site of HD-related neurodegeneration neuropathologically and performed an unbiased estimation of the absolute nerve cell number in thick gallocyanin-stained frontoparallel tissue sections through the striate area of seven control individuals and seven HD patients using Cavalieri's principle for volume and the optical disector for nerve and glial cell density estimations. This investigation showed a reduction of the estimated absolute nerve cell number of BA17 in the HD patients (71,044,037 ± 12,740,515 nerve cells) of 32% in comparison with the control individuals (104,075,067 ± 9,424,491 nerve cells) (Mann-Whitney U-test; P < 0.001). Additional pathoanatomical studies showed that nerve cell loss was most prominent in the outer pyramidal layer III, the inner granular layers IVa and IVc as well as in the multiform layer VI of BA17 of the HD patients. Our neuropathological results in BA17 confirm and extend previous post-mortem, biochemical and in vivo neuroradiological HD findings and offer suitable explanations for the elementary and complex visual dysfunctions, as well as for the altered VEP observed in HD patients. PMID:25495445

  3. The aliens inside human DNA: HERV-W/MSRV/syncytin-1 endogenous retroviruses and neurodegeneration.

    Dolei, Antonina; Uleri, Elena; Ibba, Gabriele; Caocci, Maurizio; Piu, Claudia; Serra, Caterina

    2015-06-01

    The human genome contains remnants of ancestral retroviruses now endogenously transmitted, called human endogenous retroviruses (HERVs). HERVs can be variably expressed, and both beneficial and detrimental effects have described. This review focuses on the MSRV and syncytin-1 HERV-W elements in relationship to neurodegeneration in view of their neuro-pathogenic and immune-pathogenic properties. Multiple sclerosis (MS) and a neurodegenerative disease (neuroAIDS) are reported in this review. In vivo studies in patients and controls for molecular epidemiology and follow-up studies are reviewed, along with in vitro cellular studies of the effects of treatments and of molecular mechanisms. HERV-W/MSRV has been repeatedly found in MS patients (in blood, spinal fluid, and brain samples), and MRSV presence/load strikingly parallels MS stages and active/remission phases, as well as therapy outcome. The DNA of MS patients has increased MSRVenv copies, while syncytin-1 copies are unchanged in controls. Presence of MSRV in the spinal fluid predicted the worst MS progression, ten years in advance. The Epstein-Barr virus (EBV) activates HERV-W/MSRV both in vitro and in vivo. With respect to neuroAIDS, the HIV transactivator of transcription (Tat) protein activates HERV-W/MSRV in monocytes/macrophages and astrocytes indirectly by interaction with TLR4 and induction of TNFa. HERV-W/MSRV can be considered a biomarker for MS behavior and therapy outcome. Regarding MS pathogenesis, we postulate the possibility for EBV of an initial trigger of future MS, years later, and for MSRV of a direct role of effector of neuropathogenesis during MS. Additionally, HERV-W/MSR/syncytin-1 activation by HIV Tat could contribute to the HIV-related neurodegeneration. PMID:26142666

  4. Mitochondrial dysfunction and defects in lipid homeostasis as therapeutic targets in neurodegeneration with brain iron accumulation

    Kinghorn, Kerri J.; Castillo-Quan, Jorge Iván

    2016-01-01

    ABSTRACT The PLA2G6 gene encodes a group VIA calcium independent phospholipase A2 (iPLA2β), which hydrolyses glycerophospholipids to release fatty acids and lysophospholipids. Mutations in PLA2G6 are associated with a number of neurodegenerative disorders including neurodegeneration with brain iron accumulation (NBIA), infantile neuroaxonal dystrophy (INAD), and dystonia parkinsonism, collectively known as PLA2G6-associated neurodegeneration (PLAN). Recently Kinghorn et al. demonstrated in Drosophila and PLA2G6 mutant fibroblasts that loss of normal PLA2G6 activity is associated with mitochondrial dysfunction and mitochondrial lipid peroxidation. Furthermore, they were able to show the beneficial effects of deuterated polyunsaturated fatty acids (D-PUFAs), which reduce lipid peroxidation. D-PUFAs were able to rescue the locomotor deficits of flies lacking the fly ortholog of PLA2G6 (iPLA2-VIA), as well as the mitochondrial abnormalities in PLA2G6 mutant fibroblasts. This work demonstrated that the iPLA2-VIA knockout fly is a useful organism to dissect the mechanisms of pathogenesis of PLAN, and that further investigation is required to determine the therapeutic potential of D-PUFAs in patients with PLA2G6 mutations. The fruit fly has also been used to study some of the other genetic causes of NBIA, and here we also describe what is known about the mechanisms of pathogenesis of these NBIA variants. Mitochondrial dysfunction, defects in lipid metabolism, as well as defective Coenzyme A (CoA) biosynthesis, have all been implicated in some genetic forms of NBIA, including PANK2, CoASY, C12orf19 and FA2H.

  5. Potential of GRID2 receptor gene for preventing TNF-induced neurodegeneration in autism.

    Kalkan, Zeynep; Durasi, İlknur Melis; Sezerman, Ugur; Atasever-Arslan, Belkis

    2016-05-01

    Autism is one of the most common subtypes of autism spectrum disorder (ASD). Recent studies suggested a relationship between immune-dependent coding genes and ASD, indicating that long term neuroimmunological anomalies affect brain development and synaptic transmission among neural networks. Furthermore, various studies focused on biomarker potential of TNF-α in autism. Ionotropic receptors are also studied as potential marker for autism since altered gene expression levels are observed in autistic patients. GRID2 is a candidate ionotropic receptor which is involved glutamate transfer. In this study, to propose TNF-α dependent cellular processes involved in autism aetiology in relation to GRID2 we performed a bioinformatic network analysis and identified potential pathways and genes that are involved in TNF-α induced changes at GRID2 receptor levels. As a result, we ascertained the GRID2 receptor gene as a candidate gene and further studied the association between GRID2 expression levels and TNF-induced neurodegeneration. Our bioinformatic analyses and experimental results revealed that TNF-α regulates GRID2 gene expression by activating Cdc42 and GOPC genes. Moreover, increased TNF-α levels leads to increase of caspase-3 protein levels triggering neuronal apoptosis leading to neuronal deficiency, which is one of the major symptoms of autism. The study is the first to show the role of TNF-α in regulation of GRID2 gene expression and its signalling pathway. As a result, GRID2 gene can be a suppressor in TNF-induced neurodegeneration which may help to understand the main factors leading to autism. PMID:27019035

  6. Glycine inhibits ethanol-induced oxidative stress, neuroinflammation and apoptotic neurodegeneration in postnatal rat brain.

    Amin, Faiz Ul; Shah, Shahid Ali; Kim, Myeong Ok

    2016-06-01

    Here we investigated for the first time the inhibitory potential of Glycine (Gly) against ethanol-induced oxidative stress, neuroinflammation and apoptotic neurodegeneration in human neuroblastoma SH-SY5Y cells and in the developing rat brain. The Gly co-treatment significantly increased the cell viability, inhibited the expression of phospho-Nuclear Factor kappa B (p-NF-kB) and caspase-3 and reduced the oxidative stress in ethanol-treated SH-SY5Y cells in a PI3K-dependent manner. Seven days old male rat pups were injected with ethanol (5 g/kg subcutaneously, prepared in a 20% saline solution) and Gly (1 g/kg). Gly co-treatment stimulated the PI3K/Akt signaling pathway to limit the ethanol induced reactive oxygen species (ROS) production in the developing rat brain. It lowered the ethanol-elevated levels of phospho-c Jun N terminal kinase (p-JNK) and its various downstream apoptotic markers, including Bax, cytochrome C, caspase-3 and PARP-1. Additionally, the Gly treatment upregulated antiapoptotic Bcl-2 proteins and prevented ethanol-induced neurodegeneration as assessed by Fluoro-Jade-B (FJB) and Nissl staining. Furthermore, the Gly administration caused significant reduction in the ethanol-induced neuroinflammation by inhibiting the expression of inflammatory markers such as p-NF-kB, cyclooxygenase 2 (COX2) and tumor necrosis factor-α (TNF-α) and reversed the ethanol-induced synaptic protein markers expression. The results suggest that acute Gly treatment reduces ethanol-induced oxidative stress and neuronal cell loss in SH-SY5Y cells and in the developing rat brain. Therefore, Gly may be considered as potential treatment in ethanol-intoxicated newborns and infants. PMID:27058626

  7. Mutations Abrogating VP35 Interaction with Double-Stranded RNA Render Ebola Virus Avirulent in Guinea Pigs

    Prins, Kathleen C.; Delpeut, Sebastien; Leung, Daisy W.; Reynard, Olivier; Volchkova, Valentina A.; Reid, St. Patrick; Ramanan, Parameshwaran; Cárdenas, Washington B.; Amarasinghe, Gaya K.; Volchkov, Viktor E.; Basler, Christopher F. (CNRS-INSERM); (Mount Sinai Hospital); (LB-Ecuador); (Iowa State)

    2010-10-11

    Ebola virus (EBOV) protein VP35 is a double-stranded RNA (dsRNA) binding inhibitor of host interferon (IFN)-{alpha}/{beta} responses that also functions as a viral polymerase cofactor. Recent structural studies identified key features, including a central basic patch, required for VP35 dsRNA binding activity. To address the functional significance of these VP35 structural features for EBOV replication and pathogenesis, two point mutations, K319A/R322A, that abrogate VP35 dsRNA binding activity and severely impair its suppression of IFN-{alpha}/{beta} production were identified. Solution nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography reveal minimal structural perturbations in the K319A/R322A VP35 double mutant and suggest that loss of basic charge leads to altered function. Recombinant EBOVs encoding the mutant VP35 exhibit, relative to wild-type VP35 viruses, minimal growth attenuation in IFN-defective Vero cells but severe impairment in IFN-competent cells. In guinea pigs, the VP35 mutant virus revealed a complete loss of virulence. Strikingly, the VP35 mutant virus effectively immunized animals against subsequent wild-type EBOV challenge. These in vivo studies, using recombinant EBOV viruses, combined with the accompanying biochemical and structural analyses directly correlate VP35 dsRNA binding and IFN inhibition functions with viral pathogenesis. Moreover, these studies provide a framework for the development of antivirals targeting this critical EBOV virulence factor.

  8. Silencing of poly(ADP-ribose) glycohydrolase sensitizes lung cancer cells to radiation through the abrogation of DNA damage checkpoint

    Nakadate, Yusuke [Shien-Lab, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Department of Bioengineering, Graduate School of Engineering, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585 (Japan); Kodera, Yasuo; Kitamura, Yuka [Shien-Lab, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Tachibana, Taro [Department of Bioengineering, Graduate School of Engineering, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585 (Japan); Tamura, Tomohide [Division of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Koizumi, Fumiaki, E-mail: fkoizumi@ncc.go.jp [Division of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan)

    2013-11-29

    Highlights: •Radiosensitization by PARG silencing was observed in multiple lung cancer cells. •PAR accumulation was enhanced by PARG silencing after DNA damage. •Radiation-induced G2/M arrest and checkpoint activation were impaired by PARG siRNA. -- Abstract: Poly(ADP-ribose) glycohydrolase (PARG) is a major enzyme that plays a role in the degradation of poly(ADP-ribose) (PAR). PARG deficiency reportedly sensitizes cells to the effects of radiation. In lung cancer, however, it has not been fully elucidated. Here, we investigated whether PARG siRNA contributes to an increased radiosensitivity using 8 lung cancer cell lines. Among them, the silencing of PARG induced a radiosensitizing effect in 5 cell lines. Radiation-induced G2/M arrest was largely suppressed by PARG siRNA in PC-14 and A427 cells, which exhibited significantly enhanced radiosensitivity in response to PARG knockdown. On the other hand, a similar effect was not observed in H520 cells, which did not exhibit a radiosensitizing effect. Consistent with a cell cycle analysis, radiation-induced checkpoint signals were not well activated in the PC-14 and A427 cells when treated with PARG siRNA. These results suggest that the increased sensitivity to radiation induced by PARG knockdown occurs through the abrogation of radiation-induced G2/M arrest and checkpoint activation in lung cancer cells. Our findings indicate that PARG could be a potential target for lung cancer treatments when used in combination with radiotherapy.

  9. A Molecular Switch Abrogates Glycoprotein 100 (gp100) T-cell Receptor (TCR) Targeting of a Human Melanoma Antigen*

    Bianchi, Valentina; Bulek, Anna; Fuller, Anna; Lloyd, Angharad; Attaf, Meriem; Rizkallah, Pierre J.; Dolton, Garry; Sewell, Andrew K.; Cole, David K.

    2016-01-01

    Human CD8+ cytotoxic T lymphocytes can mediate tumor regression in melanoma through the specific recognition of HLA-restricted peptides. Because of the relatively weak affinity of most anti-cancer T-cell receptors (TCRs), there is growing emphasis on immunizing melanoma patients with altered peptide ligands in order to induce strong anti-tumor immunity capable of breaking tolerance toward these self-antigens. However, previous studies have shown that these immunogenic designer peptides are not always effective. The melanocyte differentiation protein, glycoprotein 100 (gp100), encodes a naturally processed epitope that is an attractive target for melanoma immunotherapies, in particular peptide-based vaccines. Previous studies have shown that substitutions at peptide residue Glu3 have a broad negative impact on polyclonal T-cell responses. Here, we describe the first atomic structure of a natural cognate TCR in complex with this gp100 epitope and highlight the relatively high affinity of the interaction. Alanine scan mutagenesis performed across the gp100280–288 peptide showed that Glu3 was critically important for TCR binding. Unexpectedly, structural analysis demonstrated that the Glu3 → Ala substitution resulted in a molecular switch that was transmitted to adjacent residues, abrogating TCR binding and T-cell recognition. These findings help to clarify the mechanism of T-cell recognition of gp100 during melanoma responses and could direct the development of altered peptides for vaccination. PMID:26917722

  10. Fibronectin induction abrogates the BRAF inhibitor response of BRAF V600E/PTEN-null melanoma cells.

    Fedorenko, I V; Abel, E V; Koomen, J M; Fang, B; Wood, E R; Chen, Y A; Fisher, K J; Iyengar, S; Dahlman, K B; Wargo, J A; Flaherty, K T; Sosman, J A; Sondak, V K; Messina, J L; Gibney, G T; Smalley, K S M

    2016-03-10

    The mechanisms by which some melanoma cells adapt to Serine/threonine-protein kinase B-Raf (BRAF) inhibitor therapy are incompletely understood. In the present study, we used mass spectrometry-based phosphoproteomics to determine how BRAF inhibition remodeled the signaling network of melanoma cell lines that were BRAF mutant and PTEN null. Short-term BRAF inhibition was associated with marked changes in fibronectin-based adhesion signaling that were PTEN dependent. These effects were recapitulated through BRAF siRNA knockdown and following treatment with chemotherapeutic drugs. Increased fibronectin expression was also observed in mouse xenograft models as well as specimens from melanoma patients undergoing BRAF inhibitor treatment. Analysis of a melanoma tissue microarray showed loss of PTEN expression to predict for a lower overall survival, with a trend for even lower survival being seen when loss of fibronectin was included in the analysis. Mechanistically, the induction of fibronectin limited the responses of these PTEN-null melanoma cell lines to vemurafenib, with enhanced cytotoxicity observed following the knockdown of either fibronectin or its receptor α5β1 integrin. This in turn abrogated the cytotoxic response to BRAF inhibition via increased AKT signaling, which prevented the induction of cell death by maintaining the expression of the pro-survival protein Mcl-1. The protection conveyed by the induction of FN expression could be overcome through combined treatment with a BRAF and PI3K inhibitor. PMID:26073081

  11. Surgical Stress Abrogates Pre-Existing Protective T Cell Mediated Anti-Tumor Immunity Leading to Postoperative Cancer Recurrence.

    Ananth, Abhirami A; Tai, Lee-Hwa; Lansdell, Casey; Alkayyal, Almohanad A; Baxter, Katherine E; Angka, Leonard; Zhang, Jiqing; Tanese de Souza, Christiano; Stephenson, Kyle B; Parato, Kelley; Bramson, Jonathan L; Bell, John C; Lichty, Brian D; Auer, Rebecca C

    2016-01-01

    Anti-tumor CD8+ T cells are a key determinant for overall survival in patients following surgical resection for solid malignancies. Using a mouse model of cancer vaccination (adenovirus expressing melanoma tumor-associated antigen (TAA)-dopachrome tautomerase (AdDCT) and resection resulting in major surgical stress (abdominal nephrectomy), we demonstrate that surgical stress results in a reduction in the number of CD8+ T cell that produce cytokines (IFNγ, TNFα, Granzyme B) in response to TAA. This effect is secondary to both reduced proliferation and impaired T cell function following antigen binding. In a prophylactic model, surgical stress completely abrogates tumor protection conferred by vaccination in the immediate postoperative period. In a clinically relevant surgical resection model, vaccinated mice undergoing a positive margin resection with surgical stress had decreased survival compared to mice with positive margin resection alone. Preoperative immunotherapy with IFNα significantly extends survival in surgically stressed mice. Importantly, myeloid derived suppressor cell (MDSC) population numbers and functional impairment of TAA-specific CD8+ T cell were altered in surgically stressed mice. Our observations suggest that cancer progression may result from surgery-induced suppression of tumor-specific CD8+ T cells. Preoperative immunotherapies aimed at targeting the prometastatic effects of cancer surgery will reduce recurrence and improve survival in cancer surgery patients. PMID:27196057

  12. An exon 53 frameshift mutation in CUBN abrogates cubam function and causes Imerslund-Gräsbeck syndrome in dogs.

    Fyfe, John C; Hemker, Shelby L; Venta, Patrick J; Fitzgerald, Caitlin A; Outerbridge, Catherine A; Myers, Sherry L; Giger, Urs

    2013-08-01

    Cobalamin malabsorption accompanied by selective proteinuria is an autosomal recessive disorder known as Imerslund-Gräsbeck syndrome in humans and was previously described in dogs due to amnionless (AMN) mutations. The resultant vitamin B12 deficiency causes dyshematopoiesis, lethargy, failure to thrive, and life-threatening metabolic disruption in the juvenile period. We studied 3 kindreds of border collies with cobalamin malabsorption and mapped the disease locus in affected dogs to a 2.9Mb region of homozygosity on canine chromosome 2. The region included CUBN, the locus encoding cubilin, a peripheral membrane protein that in concert with AMN forms the functional intrinsic factor-cobalamin receptor expressed in ileum and a multi-ligand receptor in renal proximal tubules. Cobalamin malabsorption and proteinuria comprising CUBN ligands were demonstrated by radiolabeled cobalamin uptake studies and SDS-PAGE, respectively. CUBN mRNA and protein expression were reduced ~10 fold and ~20 fold, respectively, in both ileum and kidney of affected dogs. DNA sequencing demonstrated a single base deletion in exon 53 predicting a translational frameshift and early termination codon likely triggering nonsense mediated mRNA decay. The mutant allele segregated with the disease in the border collie kindred. The border collie disorder indicates that a CUBN mutation far C-terminal from the intrinsic factor-cobalamin binding site can abrogate receptor expression and cause Imerslund-Gräsbeck syndrome. PMID:23746554

  13. ERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation

    de Jong, Petrus R.; Taniguchi, Koji; Harris, Alexandra R.; Bertin, Samuel; Takahashi, Naoki; Duong, Jen; Campos, Alejandro D.; Powis, Garth; Corr, Maripat; Karin, Michael; Raz, Eyal

    2016-01-01

    The ERK1/2 MAPK signalling module integrates extracellular cues that induce proliferation and differentiation of epithelial lineages, and is an established oncogenic driver, particularly in the intestine. However, the interrelation of the ERK1/2 module relative to other signalling pathways in intestinal epithelial cells and colorectal cancer (CRC) is unclear. Here we show that loss of Erk1/2 in intestinal epithelial cells results in defects in nutrient absorption, epithelial cell migration and secretory cell differentiation. However, intestinal epithelial cell proliferation is not impeded, implying compensatory mechanisms. Genetic deletion of Erk1/2 or pharmacological targeting of MEK1/2 results in supraphysiological activity of the ERK5 pathway. Furthermore, targeting both pathways causes a more effective suppression of cell proliferation in murine intestinal organoids and human CRC lines. These results suggest that ERK5 provides a common bypass route in intestinal epithelial cells, which rescues cell proliferation upon abrogation of ERK1/2 signalling, with therapeutic implications in CRC. PMID:27187615

  14. Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model

    Brunetti, Dario; Dusi, Sabrina; Giordano, Carla; Lamperti, Costanza; Morbin, Michela; Fugnanesi, Valeria; Marchet, Silvia; Fagiolari, Gigliola; Sibon, Ody; Moggio, Maurizio; d'Amati, Giulia; Tiranti, Valeria

    2014-01-01

    Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2,

  15. Dithiothreitol abrogates the effect of arsenic trioxide on normal rat liver mitochondria and human hepatocellular carcinoma cells

    Arsenic trioxide (ATO) is a known environmental toxicant and a potent chemotherapeutic agent. Significant correlation has been reported between consumption of arsenic-contaminated water and occurrence of liver cancer; moreover, ATO-treated leukemia patients also suffers from liver toxicity. Hence, modulation of ATO action may help to prevent populations suffering from arsenic toxicity as well as help reduce the drug-related side effects. Dithiothreitol (DTT) is a well-known dithiol agent reported to modulate the action of ATO. Controversial reports exist regarding the effect of DTT on ATO-induced apoptosis in leukemia cells. To the best of our knowledge, no report illustrates the modulatory effect of DTT on ATO-induced liver toxicity, the prime target for arsenic. Mitochondria serve as the doorway to apoptosis and have been implicated in ATO-induced cell death. Hence, we attempted to study the modulatory effect of DTT on ATO-induced dysfunction of mammalian liver mitochondria and human hepatocellular carcinoma cell line (Hep3B). We, for the first time, report that ATO produces complex I-mediated electron transfer inhibition, reactive oxygen species (ROS) generation, respiration inhibition, and ATO-induced ROS-mediated mitochondrial permeability transition (MPT) opening. DTT at low concentration (100 μM and less) prevents the effect of ATO-induced complex I-malfunctions. DTT protects mitochondria from ATO-mediated opening of MPT and membrane potential depolarization. DTT also prevented ATO-induced Hep3B cell death. Thus, at low concentrations DTT abrogates the effect of ATO on rat liver mitochondria and Hep3B cell line. Therefore, the present result suggests, that use of low concentration of dithiols as food supplement may prevent arsenic toxicity in affected population

  16. Combined inhibition of p38 and Akt signaling pathways abrogates cyclosporine A-mediated pathogenesis of aggressive skin SCCs

    Highlights: ► p38 and Akt are the crucial molecular targets in the pathogenesis of SCCs in OTRs. ► Combined inhibition of these targets diminished tumor growth by 90%. ► Inhibition of these targets act through downregulating mTOR signaling pathway. -- Abstract: Non-melanoma skin cancers (NMSCs) are the most common neoplasm in organ transplant recipients (OTRs). These cancers are more invasive and metastatic as compared to those developed in normal cohorts. Previously, we have shown that immunosuppressive drug, cyclosporine A (CsA) directly alters tumor phenotype of cutaneous squamous cell carcinomas (SCCs) by activating TGF-β and TAK1/TAB1 signaling pathways. Here, we identified novel molecular targets for the therapeutic intervention of these SCCs. We observed that combined blockade of Akt and p38 kinases-dependent signaling pathways in CsA-promoted human epidermoid carcinoma A431 xenograft tumors abrogated their growth by more than 90%. This diminution in tumor growth was accompanied by a significant decrease in proliferation and an increase in apoptosis. The residual tumors following the combined treatment with Akt inhibitor triciribine and p38 inhibitors SB-203580 showed significantly diminished expression of phosphorylated Akt and p38 and these tumors were less invasive and highly differentiated. Diminished tumor invasiveness was associated with the reduced epithelial–mesenchymal transition as ascertained by the enhanced E-cadherin and reduced vimentin and N-cadherin expression. Consistently, these tumors also manifested reduced MMP-2/9. The decreased p-Akt expression was accompanied by a significant reduction in p-mTOR. These data provide first important combinatorial pharmacological approach to block the pathogenesis of CsA-induced highly aggressive cutaneous neoplasm in OTRs.

  17. Mutations that abrogate transactivational activity of the feline leukemia virus long terminal repeat do not affect virus replication

    The U3 region of the LTR of oncogenic Moloney murine leukemia virus (Mo-MuLV) and feline leukemia viruses (FeLV) have been previously reported to activate expression of specific cellular genes in trans, such as MHC class I, collagenase IV, and MCP-1, in an integration-independent manner. It has been suggested that transactivation of these specific cellular genes by leukemia virus U3-LTR may contribute to the multistage process of leukemogenesis. The U3-LTR region, necessary for gene transactivational activity, also contains multiple transcription factor-binding sites that are essential for normal virus replication. To dissect the promoter activity and the gene transactivational activity of the U3-LTR, we conducted mutational analysis of the U3-LTR region of FeLV-A molecular clone 61E. We identified minimal nucleotide substitution mutants on the U3 LTR that did not disturb transcription factor-binding sites but abrogated its ability to transactivate the collagenase gene promoter. To determine if these mutations actually have altered any uncharacterized important transcription factor-binding site, we introduced these U3-LTR mutations into the full-length infectious molecular clone 61E. We demonstrate that the mutant virus was replication competent but could not transactivate cellular gene expression. These results thus suggest that the gene transactivational activity is a distinct property of the LTR and possibly not related to its promoter activity. The cellular gene transactivational activity-deficient mutant FeLV generated in this study may also serve as a valuable reagent for testing the biological significance of LTR-mediated cellular gene activation in the tumorigenesis caused by leukemia viruses

  18. A combination of an anti-SLAMF6 antibody and ibrutinib efficiently abrogates expansion of chronic lymphocytic leukemia cells.

    Yigit, Burcu; Halibozek, Peter J; Chen, Shih-Shih; O'Keeffe, Michael S; Arnason, Jon; Avigan, David; Gattei, Valter; Bhan, Atul; Cen, Osman; Longnecker, Richard; Chiorazzi, Nicholas; Wang, Ninghai; Engel, Pablo; Terhorst, Cox

    2016-05-01

    The signaling lymphocyte activation molecule family [SLAMF] of cell surface receptors partakes in both the development of several immunocyte lineages and innate and adaptive immune responses in humans and mice. For instance, the homophilic molecule SLAMF6 (CD352) is in part involved in natural killer T cell development, but also modulates T follicular helper cell and germinal B cell interactions. Here we report that upon transplantation of a well-defined aggressive murine B220+CD5+ Chronic Lymphocytic Leukemia (CLL) cell clone, TCL1-192, into SCID mice one injection of a monoclonal antibody directed against SLAMF6 (αSlamf6) abrogates tumor progression in the spleen, bone marrow and blood. Similarly, progression of a murine B cell lymphoma, LMP2A/λMyc, was also eliminated by αSlamf6. But, surprisingly, αSLAMF6 neither eliminated TCL1-192 nor LMP2A/λMyc cells, which resided in the peritoneal cavity or omentum. This appeared to be dependent upon the tumor environment, which affected the frequency of sub-populations of the TCL1-192 clone or the inability of peritoneal macrophages to induce Antibody Dependent Cellular Cytotoxicity (ADCC). However, co-administering αSlamf6 with the Bruton tyrosine kinase (Btk) inhibitor, ibrutinib, synergized to efficiently eliminate the tumor cells in the spleen, bone marrow, liver and the peritoneal cavity. Because an anti-human SLAMF6 mAb efficiently killed human CLL cells in vitro and in vivo, we propose that a combination of αSlamf6 with ibrutinib should be considered as a novel therapeutic approach for CLL and other B cell tumors. PMID:27029059

  19. Combined inhibition of p38 and Akt signaling pathways abrogates cyclosporine A-mediated pathogenesis of aggressive skin SCCs

    Arumugam, Aadithya; Walsh, Stephanie B.; Xu, Jianmin; Afaq, Farrukh [Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019 (United States); Elmets, Craig A. [Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019 (United States); Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019 (United States); Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL 35294 (United States)

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer p38 and Akt are the crucial molecular targets in the pathogenesis of SCCs in OTRs. Black-Right-Pointing-Pointer Combined inhibition of these targets diminished tumor growth by 90%. Black-Right-Pointing-Pointer Inhibition of these targets act through downregulating mTOR signaling pathway. -- Abstract: Non-melanoma skin cancers (NMSCs) are the most common neoplasm in organ transplant recipients (OTRs). These cancers are more invasive and metastatic as compared to those developed in normal cohorts. Previously, we have shown that immunosuppressive drug, cyclosporine A (CsA) directly alters tumor phenotype of cutaneous squamous cell carcinomas (SCCs) by activating TGF-{beta} and TAK1/TAB1 signaling pathways. Here, we identified novel molecular targets for the therapeutic intervention of these SCCs. We observed that combined blockade of Akt and p38 kinases-dependent signaling pathways in CsA-promoted human epidermoid carcinoma A431 xenograft tumors abrogated their growth by more than 90%. This diminution in tumor growth was accompanied by a significant decrease in proliferation and an increase in apoptosis. The residual tumors following the combined treatment with Akt inhibitor triciribine and p38 inhibitors SB-203580 showed significantly diminished expression of phosphorylated Akt and p38 and these tumors were less invasive and highly differentiated. Diminished tumor invasiveness was associated with the reduced epithelial-mesenchymal transition as ascertained by the enhanced E-cadherin and reduced vimentin and N-cadherin expression. Consistently, these tumors also manifested reduced MMP-2/9. The decreased p-Akt expression was accompanied by a significant reduction in p-mTOR. These data provide first important combinatorial pharmacological approach to block the pathogenesis of CsA-induced highly aggressive cutaneous neoplasm in OTRs.

  20. Contact-dependent abrogation of bone marrow-derived plasmacytoid dendritic cell differentiation by murine mesenchymal stem cells.

    Hackstein, Holger; Tschipakow, Inna; Bein, Gregor; Nold, Philipp; Brendel, Cornelia; Baal, Nelli

    2016-07-15

    Plasmacytoid dendritic cells (pDCs) are rare central regulators of antiviral immunity and unsurpassed producers of interferon-α (IFN-α). Despite their crucial role as a link between innate and adaptive immunity, little is known about the modulation of pDC differentiation by other bone marrow (BM) cells. In this study, we investigated the modulation of pDC differentiation in Flt-3 ligand (Flt3L)-supplemented BM cultures, using highly purified mesenchymal stem cells (MSCs) that were FACS-isolated from murine BM based on surface marker expression and used after in vitro expansion. Initial analysis revealed an almost complete inhibition of BM-derived pDC expansion in the presence of >2% MSC. This inhibition was cell contact-dependent and soluble factor-independent, as indicated by trans-well experiments. The abrogation of functional pDC development by MSCs was confirmed after TLR9 stimulation, revealing a complete, contact-dependent suppression of the IFN-a producing capacity of pDCs in Flt3L MSC BM co-cultures. MSC selectively inhibited pDC development in contrast to myeloid DC development, as indicated by the significantly increased numbers of myeloid DC in Flt3L-supplemented BM cultures. The absence of significant MSC-mediated inhibitory effects on myeloid DC differentiation was confirmed by additional experiments in GM-CSF/IL-4-supplemented BM cultures. In summary, we describe a novel contact-dependent immunomodulatory mechanism of MSC that targets the BM-derived expansion of functional pDCs. PMID:27233615

  1. Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration

    Ramsay, Rona R.; Majekova, Magdalena; Medina, Milagros; Valoti, Massimo

    2016-01-01

    HIGHLIGHTS Compounds that interact with multiple targets but minimally with the cytochrome P450 system (CYP) address the many factors leading to neurodegeneration.Acetyl- and Butyryl-cholineEsterases (AChE, BChE) and Monoamine Oxidases A/B (MAO A, MAO B) are targets for Multi-Target Designed Ligands (MTDL).ASS234 is an irreversible inhibitor of MAO A >MAO B and has micromolar potency against the cholinesterases.ASS234 is a poor CYP substrate in human liver, yielding the depropargylated metabolite.SMe1EC2, a stobadine derivative, showed high radical scavenging property, in vitro and in vivo giving protection in head trauma and diabetic damage of endothelium.Control of mitochondrial function and morphology by manipulating fission and fusion is emerging as a target area for therapeutic strategies to decrease the pathological outcome of neurodegenerative diseases. Growing evidence supports the view that neurodegenerative diseases have multiple and common mechanisms in their aetiologies. These multifactorial aspects have changed the broadly common assumption that selective drugs are superior to “dirty drugs” for use in therapy. This drives the research in studies of novel compounds that might have multiple action mechanisms. In neurodegeneration, loss of neuronal signaling is a major cause of the symptoms, so preservation of neurotransmitters by inhibiting the breakdown enzymes is a first approach. Acetylcholinesterase (AChE) inhibitors are the drugs preferentially used in AD and that one of these, rivastigmine, is licensed also for PD. Several studies have shown that monoamine oxidase (MAO) B, located mainly in glial cells, increases with age and is elevated in Alzheimer (AD) and Parkinson's Disease's (PD). Deprenyl, a MAO B inhibitor, significantly delays the initiation of levodopa treatment in PD patients. These indications underline that AChE and MAO are considered a necessary part of multi-target designed ligands (MTDL). However, both of these targets are

  2. Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration.

    Ramsay, Rona R; Majekova, Magdalena; Medina, Milagros; Valoti, Massimo

    2016-01-01

    HIGHLIGHTS Compounds that interact with multiple targets but minimally with the cytochrome P450 system (CYP) address the many factors leading to neurodegeneration.Acetyl- and Butyryl-cholineEsterases (AChE, BChE) and Monoamine Oxidases A/B (MAO A, MAO B) are targets for Multi-Target Designed Ligands (MTDL).ASS234 is an irreversible inhibitor of MAO A >MAO B and has micromolar potency against the cholinesterases.ASS234 is a poor CYP substrate in human liver, yielding the depropargylated metabolite.SMe1EC2, a stobadine derivative, showed high radical scavenging property, in vitro and in vivo giving protection in head trauma and diabetic damage of endothelium.Control of mitochondrial function and morphology by manipulating fission and fusion is emerging as a target area for therapeutic strategies to decrease the pathological outcome of neurodegenerative diseases. Growing evidence supports the view that neurodegenerative diseases have multiple and common mechanisms in their aetiologies. These multifactorial aspects have changed the broadly common assumption that selective drugs are superior to "dirty drugs" for use in therapy. This drives the research in studies of novel compounds that might have multiple action mechanisms. In neurodegeneration, loss of neuronal signaling is a major cause of the symptoms, so preservation of neurotransmitters by inhibiting the breakdown enzymes is a first approach. Acetylcholinesterase (AChE) inhibitors are the drugs preferentially used in AD and that one of these, rivastigmine, is licensed also for PD. Several studies have shown that monoamine oxidase (MAO) B, located mainly in glial cells, increases with age and is elevated in Alzheimer (AD) and Parkinson's Disease's (PD). Deprenyl, a MAO B inhibitor, significantly delays the initiation of levodopa treatment in PD patients. These indications underline that AChE and MAO are considered a necessary part of multi-target designed ligands (MTDL). However, both of these targets are simply

  3. TGF-β1 induced epithelial to mesenchymal transition (EMT) in human bronchial epithelial cells is enhanced by IL-1β but not abrogated by corticosteroids

    Doerner, Astrid M; Zuraw, Bruce L

    2009-01-01

    Background Chronic persistent asthma is characterized by ongoing airway inflammation and airway remodeling. The processes leading to airway remodeling are poorly understood, and there is increasing evidence that even aggressive anti-inflammatory therapy does not completely prevent this process. We sought to investigate whether TGFβ1 stimulates bronchial epithelial cells to undergo transition to a mesenchymal phenotype, and whether this transition can be abrogated by corticosteroid treatment o...

  4. PLA2G6-associated neurodegeneration (PLAN): Further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease

    Illingworth, M.A.; Carr, L J; Kurian, M.A.; Meyer, E.; Chong, W.K.; Manzur, A.Y.; Younis, R.; Hardy, C; McDonald, F.; Childs, A. M.; Stewart, B.; Warren, D.; KNEEN, R; King, M.D.; Hayflick, S.J.

    2014-01-01

    Phospholipase A2 associated neurodegeneration (PLAN) is a major phenotype of autosomal recessive Neurodegeneration with Brain Iron Accumulation (NBIA). We describe the clinical phenotypes, neuroimaging features and PLA2G6 mutations in 5 children, of whom 4 presented with infantile neuroaxonal dystrophy (INAD). One other patient was diagnosed with the onset of PLAN in childhood, and our report highlights the diagnostic challenges associated with this atypical PLAN subtype. In this series, the ...

  5. Neural Stem Cells as Engraftable Packaging Lines Can Mediate Gene Delivery to Microglia: Evidence from Studying Retroviral env-Related Neurodegeneration

    Lynch, William P.; Sharpe, Arlene H.; Snyder, Evan Y.

    1999-01-01

    The induction of spongiform myeloencephalopathy by murine leukemia viruses is mediated primarily by infection of central nervous system (CNS) microglia. In this regard, we have previously shown that CasBrE-induced disease requires late, rather than early, virus replication events in microglial cells (W. P. Lynch et al., J. Virol. 70:8896–8907, 1996). Furthermore, neurodegeneration requires the presence of unique sequences within the viral env gene. Thus, the neurodegeneration-inducing events ...

  6. Cerebrospinal Fluid Markers of Neurodegeneration and Rates of Brain Atrophy in Early Alzheimer Disease

    Tarawneh, Rawan; Head, Denise; Allison, Samantha; Buckles, Virginia; Fagan, Anne M.; Ladenson, Jack H.; Morris, John C.; Holtzman, David M.

    2015-01-01

    IMPORTANCE Measures of neuronal loss are likely good surrogates for clinical and radiological disease progression in Alzheimer disease (AD). Cerebrospinal fluid (CSF) markers of neuronal injury or neurodegeneration may offer usefulness in predicting disease progression and guiding outcome assessments and prognostic decisions in clinical trials of disease-modifying therapies. Visinin-like protein 1 (VILIP-1) has demonstrated potential usefulness as a marker of neuronal injury in AD. OBJECTIVE To investigate the usefulness of CSF VILIP-1, tau, p-tau181, and Aβ42 levels in predicting rates of whole-brain and regional atrophy in early AD and cognitively normal control subjects over time. DESIGN, SETTING, AND PARTICIPANTS Longitudinal observational study of brain atrophy in participants with early AD and cognitively normal controls. Study participants had baseline CSF biomarker measurements and longitudinal magnetic resonance imaging assessments for a mean follow-up period of 2 to 3 years. Mixed linear models assessed the ability of standardized baseline CSF biomarker measures to predict rates of whole-brain and regional atrophy over the follow-up period. The setting was The Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine in St Louis. Participants (mean age, 72.6 years) were individuals with a clinical diagnosis of very mild AD (n = 23) and cognitively normal controls (n = 64) who were enrolled in longitudinal studies of healthy aging and dementia. The study dates were 2000 to 2010. MAIN OUTCOMES AND MEASURES Correlations between baseline CSF biomarker measures and rates of whole-brain or regional atrophy in the AD and control cohorts over the follow-up period. RESULTS Baseline CSF VILIP-1, tau, and p-tau181 levels (but not Aβ42 levels) predicted rates of whole-brain and regional atrophy in AD over the follow-up period. Baseline CSF VILIP-1 levels predicted whole-brain (P = .006), hippocampal (P = .01), and

  7. No parkinsonism in SCA2 and SCA3 despite severe neurodegeneration of the dopaminergic substantia nigra.

    Schöls, Ludger; Reimold, Matthias; Seidel, Kay; Globas, Christoph; Brockmann, Kathrin; Hauser, Till Karsten; Auburger, Georg; Bürk, Katrin; den Dunnen, Wilfred; Reischl, Gerald; Korf, Horst-Werner; Brunt, Ewout R; Rüb, Udo

    2015-11-01

    See Klockgether (doi:10.1093/awv253) for a scientific commentary on this article.The spinocerebellar ataxias types 2 (SCA2) and 3 (SCA3) are autosomal dominantly inherited cerebellar ataxias which are caused by CAG trinucleotide repeat expansions in the coding regions of the disease-specific genes. Although previous post-mortem studies repeatedly revealed a consistent neurodegeneration of the dopaminergic substantia nigra in patients with SCA2 and with SCA3, parkinsonian motor features evolve only rarely. As the pathophysiological mechanism how SCA2 and SCA3 patients do not exhibit parkinsonism is still enigmatic, we performed a positron emission tomography and a post-mortem study of two independent cohorts of SCA2 and SCA3 patients with and without parkinsonian features. Positron emission tomography revealed a significant reduction of dopamine transporter levels in the striatum as well as largely unaffected postsynaptic striatal D2 receptors. In spite of this remarkable pathology in the motor mesostriatal pathway, only 4 of 19 SCA2 and SCA3 patients suffered from parkinsonism. The post-mortem investigation revealed, in addition to an extensive neuronal loss in the dopaminergic substantia nigra of all patients with spinocerebellar ataxia, a consistent affection of the thalamic ventral anterior and ventral lateral nuclei, the pallidum and the cholinergic pedunculopontine nucleus. With the exception of a single patient with SCA3 who suffered from parkinsonian motor features during his lifetime, the subthalamic nucleus underwent severe neuronal loss, which was clearly more severe in its motor territory than in its limbic or associative territories. Our observation that lesions of the motor territory of the subthalamic nucleus were consistently associated with the prevention of parkinsonism in our SCA2 and SCA3 patients matches the clinical experience that selective targeting of the motor territory of the subthalamic nucleus by focal lesions or deep brain stimulation

  8. Cognitive Performance and Cerebrospinal Fluid Biomarkers of Neurodegeneration: A Study of Patients with Bipolar Disorder and Healthy Controls

    Sindre Rolstad; Joel Jakobsson; Carl Sellgren; Carl-Johan Ekman; Kaj Blennow; Henrik Zetterberg; Erik Pålsson; Mikael Landén

    2015-01-01

    The purpose of the present study was to investigate if cerebrospinal fluid (CSF) biomarkers of neurodegeneration are associated with cognition in bipolar disorder and healthy controls, respectively. CSF concentrations of total and phosphorylated tau, amyloid beta (Aβ)1-42, ratios of Aβ42/40 and Aβ42/38, soluble amyloid precursor protein α and β, and neurofilament light chain protein were analyzed in relation to neuropsychological performance in 82 euthymic bipolar disorder patients and 71 hea...

  9. Impaired Coenzyme A metabolism affects histone and tubulin acetylation in Drosophila and human cell models of pantothenate kinase associated neurodegeneration

    Siudeja, Katarzyna; Srinivasan, Balaji; Xu, Lanjun; Rana, Anil; de Jong, Jannie; Nollen, Ellen A. A.; Jackowski, Suzanne; Sanford, Lynn; Hayflick, Susan; Sibon, Ody C.M

    2011-01-01

    Pantothenate kinase-associated neurodegeneration (PKAN is a neurodegenerative disease with unresolved pathophysiology. Previously, we observed reduced Coenzyme A levels in a Drosophila model for PKAN. Coenzyme A is required for acetyl-Coenzyme A synthesis and acyl groups from the latter are transferred to lysine residues of proteins, in a reaction regulated by acetyltransferases. The tight balance between acetyltransferases and their antagonistic counterparts histone deacetylases is a well-kn...

  10. Exome Sequence Reveals Mutations in CoA Synthase as a Cause of Neurodegeneration with Brain Iron Accumulation

    Dusi, Sabrina; Valletta, Lorella; Haack, Tobias B.; Tsuchiya, Yugo; Venco, Paola; Pasqualato, Sebastiano; Goffrini, Paola; Tigano, Marco; Demchenko, Nikita; Wieland, Thomas; Schwarzmayr, Thomas; Strom, Tim M; Invernizzi, Federica; Garavaglia, Barbara; Gregory, Allison

    2014-01-01

    Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders with progressive extrapyramidal signs and neurological deterioration, characterized by iron accumulation in the basal ganglia. Exome sequencing revealed the presence of recessive missense mutations in COASY, encoding coenzyme A (CoA) synthase in one NBIA-affected subject. A second unrelated individual carrying mutations in COASY was identified by Sanger sequence analys...

  11. PGC-1 family coactivators and cell fate: roles in cancer, neurodegeneration, cardiovascular disease and retrograde mitochondria-nucleus signalling.

    Jones, A W; Z. Yao; Vicencio, J. M.; Karkucinska-Wieckowska, A.; Szabadkai, G.

    2012-01-01

    Over the past two decades, a complex nuclear transcriptional machinery controlling mitochondrial biogenesis and function has been described. Central to this network are the PGC-1 family coactivators, characterised as master regulators of mitochondrial biogenesis. Recent literature has identified a broader role for PGC-1 coactivators in both cell death and cellular adaptation under conditions of stress, here reviewed in the context of the pathology associated with cancer, neurodegeneration and...

  12. The Role of S-Nitrosylation and S-Glutathionylation of Protein Disulphide Isomerase in Protein Misfolding and Neurodegeneration

    M. Halloran

    2013-01-01

    Full Text Available Neurodegenerative diseases involve the progressive loss of neurons, and a pathological hallmark is the presence of abnormal inclusions containing misfolded proteins. Although the precise molecular mechanisms triggering neurodegeneration remain unclear, endoplasmic reticulum (ER stress, elevated oxidative and nitrosative stress, and protein misfolding are important features in pathogenesis. Protein disulphide isomerase (PDI is the prototype of a family of molecular chaperones and foldases upregulated during ER stress that are increasingly implicated in neurodegenerative diseases. PDI catalyzes the rearrangement and formation of disulphide bonds, thus facilitating protein folding, and in neurodegeneration may act to ameliorate the burden of protein misfolding. However, an aberrant posttranslational modification of PDI, S-nitrosylation, inhibits its protective function in these conditions. S-nitrosylation is a redox-mediated modification that regulates protein function by covalent addition of nitric oxide- (NO- containing groups to cysteine residues. Here, we discuss the evidence for abnormal S-nitrosylation of PDI (SNO-PDI in neurodegeneration and how this may be linked to another aberrant modification of PDI, S-glutathionylation. Understanding the role of aberrant S-nitrosylation/S-glutathionylation of PDI in the pathogenesis of neurodegenerative diseases may provide insights into novel therapeutic interventions in the future.

  13. An α2-Na/K ATPase/α-adducin complex in astrocytes triggers non–cell autonomous neurodegeneration

    Gallardo, Gilbert; Barowski, Jessica; Ravits, John; Siddique, Teepu; Lingrel, Jerry B; Robertson, Janice; Steen, Hanno; Bonni, Azad

    2015-01-01

    Perturbations of astrocytes trigger neurodegeneration in several diseases, but the glial cell–intrinsic mechanisms that induce neurodegeneration remain poorly understood. We found that a protein complex of α2-Na/K ATPase and α-adducin was enriched in astrocytes expressing mutant superoxide dismutase 1 (SOD1), which causes familial amyotrophic lateral sclerosis (ALS). Knockdown of α2-Na/K ATPase or α-adducin in mutant SOD1 astrocytes protected motor neurons from degeneration, including in mutant SOD1 mice in vivo. Heterozygous disruption of the α2-Na/K ATPase gene suppressed degeneration in vivo and increased the lifespan of mutant SOD1 mice. The pharmacological agent digoxin, which inhibits Na/K ATPase activity, protected motor neurons from mutant SOD1 astrocyte–induced degeneration. Notably, α2-Na/K ATPase and α-adducin were upregulated in spinal cord of sporadic and familial ALS patients. Collectively, our findings define chronic activation of the α2-Na/K ATPase/α-adducin complex as a critical glial cell–intrinsic mechanism of non–cell autonomous neurodegeneration, with implications for potential therapies for neurodegenerative diseases. PMID:25344630

  14. Molecular signatures of neurodegeneration in the cortex of PS1/PS2 double knockout mice

    Choi Se

    2008-10-01

    Full Text Available Abstract Background Familial Alzheimer's disease-linked variants of presenilin (PSEN1 and PSEN2 contribute to the pathophysiology of disease by both gain-of-function and loss-of-function mechanisms. Deletions of PSEN1 and PSEN2 in the mouse forebrain result in a strong and progressive neurodegenerative phenotype which is characterized by both anatomical and behavioral changes. Results To better understand the molecular changes associated with these morphological and behavioral phenotypes, we performed a DNA microarray transcriptome profiling of the hippocampus and the frontal cortex of the PSEN1/PSEN2 double knock-out mice and littermate controls at five different ages ranging from 2–8 months. Our data suggest that combined deficiencies of PSEN1 and PSEN2 results in a progressive, age-dependent transcriptome signature related to neurodegeneration and neuroinflammation. While these events may progress differently in the hippocampus and frontal cortex, the most critical expression signatures are common across the two brain regions, and involve a strong upregulation of cathepsin and complement system transcripts. Conclusion The observed neuroinflammatory expression changes are likely to be causally linked to the neurodegenerative phenotype observed in mice with compound deletions of PSEN1 and PSEN2. Furthermore, our results suggest that the evaluation of inhibitors of PS/γ-secretase activity for treatment of Alzheimer's Disease must include close monitoring for signs of calpain-cathepsin system activation.

  15. Intrathecal morphine therapy in the management of status dystonicus in neurodegeneration brain iron accumulation type 1.

    Lopez, William Omar Contreras; Kluge Schroeder, Humberto; Santana Neville, Iuri; Jacobsen Teixeira, Manoel; Costa Barbosa, Danilo; Assumpçao de Mônaco, Bernardo; Talamoni Fonoff, Erich

    2015-01-01

    Neurodegeneration with brain iron accumulation type 1 (NBIA-1) is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. NBIA-1 encompasses typical iron brain accumulation, mostly in the globus pallidus with secondary dementia, spasticity, rigidity, dystonia, and choreoathetosis. Treatment remains mostly symptomatic and is challenging. We present the case of a 14-year-old boy diagnosed with NBIA-1, presenting intractable progressive generalized dystonia leading to unresponsive status dystonicus (SD). The patient received a SynchroMed II (model 8637) programmable system pump (Medtronic®, Inc.) implant with an Ascenda intrathecal catheter for intrathecal morphine therapy (IMT). The initial dose of morphine was 1.0 mg/day. Overall, we observed no complications with IMT treatment and important improvement of the patient's motor function with stabilization of his incapacitating dystonia and his quality of life. On the Global Dystonia Severity Rating Scale, he presented 52% improvement, 30% improvement on the Unified Dystonia Rating Scale, and 38% improvement on the Fahn-Marsden Rating Scale after 10 months, when the dose was 1.7 mg/day. IMT should be considered as a potential palliative treatment in the management of intractable dystonia and SD secondary to NBIA-1. PMID:25896138

  16. Yeast proteinopathy models: a robust tool for deciphering the basis of neurodegeneration

    Amit Shrestha

    2015-11-01

    Full Text Available Protein quality control or proteostasis is an essential determinant of basic cell health and aging. Eukaryotic cells have evolved a number of proteostatic mechanisms to ensure that proteins retain functional conformation, or are rapidly degraded when proteins misfold or self-aggregate. Disruption of proteostasis is now widely recognized as a key feature of aging related illness, specifically neurodegenerative disease. For example, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis (ALS each target and afflict distinct neuronal cell subtypes, yet this diverse array of human pathologies share the defining feature of aberrant protein aggregation within the affected cell population. Here, we review the use of budding yeast as a robust proxy to study the intersection between proteostasis and neurodegenerative disease. The humanized yeast model has proven to be an amenable platform to identify both, conserved proteostatic mechanisms across eukaryotic phyla and novel disease specific molecular dysfunction. Moreover, we discuss the intriguing concept that yeast specific proteins may be utilized as bona fide therapeutic agents, to correct proteostasis errors across various forms of neurodegeneration.

  17. Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surf1 knockout mice.

    Dell'agnello, Carlotta; Leo, Sara; Agostino, Alessandro; Szabadkai, György; Tiveron, Cecilia; Zulian, Alessandra; Prelle, Alessandro; Roubertoux, Pierre; Rizzuto, Rosario; Zeviani, Massimo

    2007-02-15

    Leigh syndrome associated with cytochrome c oxidase (COX) deficiency is a mitochondrial disorder usually caused by mutations of SURF1, a gene encoding a putative COX assembly factor. We present here a Surf1-/- recombinant mouse obtained by inserting a loxP sequence in the open reading frame of the gene. The frequency of -/-, +/+ and +/- genotypes in newborn mice followed a mendelian distribution, indicating that the ablation of Surf1 is compatible with postnatal survival. The biochemical and assembly COX defect was present in Surf1(loxP)-/- mice, but milder than in humans. Surprisingly, not only these animals failed to show spontaneous neurodegeneration at any age, but they also displayed markedly prolonged lifespan, and complete protection from Ca(2+)-dependent neurotoxicity induced by kainic acid. Experiments on primary neuronal cultures showed markedly reduced rise of cytosolic and mitochondrial Ca(2+) in Surf1(loxP)-/- neurons, and reduced mortality, compared to controls. The mitochondrial membrane potential was unchanged in KO versus wild-type neurons, suggesting that the effects of the ablation of Surf1 on Ca(2+) homeostasis, and possibly on longevity, may be independent, at least in part, from those on COX assembly and mitochondrial bioenergetics. PMID:17210671

  18. Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration.

    Rana, Anil; Seinen, Erwin; Siudeja, Katarzyna; Muntendam, Remco; Srinivasan, Balaji; van der Want, Johannes J; Hayflick, Susan; Reijngoud, Dirk-Jan; Kayser, Oliver; Sibon, Ody C M

    2010-04-13

    Pantothenate kinase-associated neurodegeneration (PKAN), a progressive neurodegenerative disorder, is associated with impairment of pantothenate kinase function. Pantothenate kinase is the first enzyme required for de novo synthesis of CoA, an essential metabolic cofactor. The pathophysiology of PKAN is not understood, and there is no cure to halt or reverse the symptoms of this devastating disease. Recently, we and others presented a PKAN Drosophila model, and we demonstrated that impaired function of pantothenate kinase induces a neurodegenerative phenotype and a reduced lifespan. We have explored this Drosophila model further and have demonstrated that impairment of pantothenate kinase is associated with decreased levels of CoA, mitochondrial dysfunction, and increased protein oxidation. Furthermore, we searched for compounds that can rescue pertinent phenotypes of the Drosophila PKAN model and identified pantethine. Pantethine feeding restores CoA levels, improves mitochondrial function, rescues brain degeneration, enhances locomotor abilities, and increases lifespan. We show evidence for the presence of a de novo CoA biosynthesis pathway in which pantethine is used as a precursor compound. Importantly, this pathway is effective in the presence of disrupted pantothenate kinase function. Our data suggest that pantethine may serve as a starting point to develop a possible treatment for PKAN. PMID:20351285

  19. Pantethine rescues a Drosophila model for pantothenate kinase–associated neurodegeneration

    Rana, Anil; Seinen, Erwin; Siudeja, Katarzyna; Muntendam, Remco; Srinivasan, Balaji; van der Want, Johannes J.; Hayflick, Susan; Reijngoud, Dirk-Jan; Kayser, Oliver; Sibon, Ody C. M.

    2010-01-01

    Pantothenate kinase–associated neurodegeneration (PKAN), a progressive neurodegenerative disorder, is associated with impairment of pantothenate kinase function. Pantothenate kinase is the first enzyme required for de novo synthesis of CoA, an essential metabolic cofactor. The pathophysiology of PKAN is not understood, and there is no cure to halt or reverse the symptoms of this devastating disease. Recently, we and others presented a PKAN Drosophila model, and we demonstrated that impaired function of pantothenate kinase induces a neurodegenerative phenotype and a reduced lifespan. We have explored this Drosophila model further and have demonstrated that impairment of pantothenate kinase is associated with decreased levels of CoA, mitochondrial dysfunction, and increased protein oxidation. Furthermore, we searched for compounds that can rescue pertinent phenotypes of the Drosophila PKAN model and identified pantethine. Pantethine feeding restores CoA levels, improves mitochondrial function, rescues brain degeneration, enhances locomotor abilities, and increases lifespan. We show evidence for the presence of a de novo CoA biosynthesis pathway in which pantethine is used as a precursor compound. Importantly, this pathway is effective in the presence of disrupted pantothenate kinase function. Our data suggest that pantethine may serve as a starting point to develop a possible treatment for PKAN. PMID:20351285

  20. Neurodegeneration after mild and repetitive traumatic brain injury: Chronic traumatic encepalopathy

    Stanescu Ioana

    2015-09-01

    Full Text Available Repetitive brain trauma is associated with a progressive neurological deterioration, now termed as chronic traumatic encephalopathy (CTE. Although research on the long-term effects of TBI is advancing quickly, the incidence and prevalence of post-traumatic neurodegeneration and CTE are unknown. The incidence and prevalence of chronic traumatic encephalopathy and the genetic risk factors critical to its development are currently under research. CTE can be diagnosed only by post mortem neuropathological examination of the brain. Great efforts are being made to better understand the clinical signs and symptoms of CTE, obtained in most cases retrospectively from families of affected persons.Patients with CTE are described as having behavioral, mood, cognitive and motor impairments, occurring after a long latency from the traumatic events. Recent pathogenetic studies have provided new insights to CTE mechanisms, offering important clues in understanding neurodegenerative process and relations between physical factors and pathologic protein deposition. Further research is needed to better identify the genetic and environmental risk factors for CTE, as well as rehabilitation and treatment strategies.

  1. ROS effects on neurodegeneration in Alzheimer's disease and related disorders: on environmental stresses of ionizing radiation.

    Manton, Kenneth G; Volovik, Serge; Kulminski, Alexander

    2004-11-01

    Neurodegenerative processes associated with Alzheimer's disease are complex and involve many CNS tissue types, structures and biochemical processes. Factors believed involved in these processes are generation of Reactive Oxygen Species (ROS), associated inflammatory responses, and the bio-molecular and genetic damage they produce. Since oxidative processes are essential to energy production, and to other biological functions, such as cell signaling, the process is not one of risk exposure, as for cigarettes and cancer, but one where normal physiological processes operate out of normal ranges and without adequate control. Thus, it is necessary to study the ambiphilicity that allows the same molecule (e.g., beta amyloid) to behave in contradictory ways depending upon the physiological microenvironment. To determine ways to study this in human populations we review evidence on the effects of an exogenous generator of ROS, ionizing radiation, in major population events with radionuclides (e.g., Hiroshima and Nagasaki; Chernobyl Reactor accident; environmental contamination in Chelyabinsk (South Urals) where plutonium was produced, and in the nuclear weapons test area in Semipalatinsk, Kazakhstan). The age evolution, and traits, of neurodegenerative processes in human populations in these areas, may help us understand how IR affects the CNS. After reviewing human population evidence, we propose a model of neurodegeneration based upon the complexity of CNS functions. PMID:15975057

  2. The function of RNA-binding proteins at the synapse: implications for neurodegeneration.

    Sephton, Chantelle F; Yu, Gang

    2015-10-01

    The loss of synapses is a central event in neurodegenerative diseases. Synaptic proteins are often associated with disease neuropathology, but their role in synaptic loss is not fully understood. Of the many processes involved in sustaining the integrity of synapses, local protein translation can directly impact synaptic formation, communication, and maintenance. RNA-binding proteins and their association with RNA granules serve to regulate mRNA transportation and translation at synapses and in turn regulate the synapse. Genetic mutations in RNA-binding proteins FUS and TDP-43 have been linked with causing neurodegenerative diseases: amyotrophic lateral sclerosis and frontotemporal dementia. The observation that mutations in FUS and TDP-43 coincide with changes in RNA granules provides evidence that dysfunction of RNA metabolism may underlie the mechanism of synaptic loss in these diseases. However, we do not know how mutations in RNA-binding proteins would affect RNA granule dynamics and local translation, or if these alterations would cause neurodegeneration. Further investigation into this area will lead to important insights into how disruption of RNA metabolism and local translation at synapses can cause neurodegenerative diseases. PMID:26047658

  3. Use of Okadaic Acid to Identify Relevant Phosphoepitopes in Pathology: A Focus on Neurodegeneration

    Jesús Avila

    2013-05-01

    Full Text Available Protein phosphorylation is involved in the regulation of a wide variety of physiological processes and is the result of a balance between protein kinase and phosphatase activities. Biologically active marine derived compounds have been shown to represent an interesting source of novel compounds that could modify that balance. Among them, the marine toxin and tumor promoter, okadaic acid (OA, has been shown as an inhibitor of two of the main cytosolic, broad-specificity protein phosphatases, PP1 and PP2A, thus providing an excellent cell-permeable probe for examining the role of protein phosphorylation, and PP1 and PP2A in particular, in any physiological or pathological process. In the present work, we review the use of okadaic acid to identify specific phosphoepitopes mainly in proteins relevant for neurodegeneration. We will specifically highlight those cases of highly dynamic phosphorylation-dephosphorylation events and the ability of OA to block the high turnover phosphorylation, thus allowing the detection of modified residues that could be otherwise difficult to identify. Finally, its effect on tau hyperhosphorylation and its relevance in neurodegenerative pathologies such as Alzheimer’s disease and related dementia will be discussed.

  4. Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus.

    Sohn, Elliott H; van Dijk, Hille W; Jiao, Chunhua; Kok, Pauline H B; Jeong, Woojin; Demirkaya, Nazli; Garmager, Allison; Wit, Ferdinand; Kucukevcilioglu, Murat; van Velthoven, Mirjam E J; DeVries, J Hans; Mullins, Robert F; Kuehn, Markus H; Schlingemann, Reinier Otto; Sonka, Milan; Verbraak, Frank D; Abràmoff, Michael David

    2016-05-10

    Diabetic retinopathy (DR) has long been recognized as a microvasculopathy, but retinal diabetic neuropathy (RDN), characterized by inner retinal neurodegeneration, also occurs in people with diabetes mellitus (DM). We report that in 45 people with DM and no to minimal DR there was significant, progressive loss of the nerve fiber layer (NFL) (0.25 μm/y) and the ganglion cell (GC)/inner plexiform layer (0.29 μm/y) on optical coherence tomography analysis (OCT) over a 4-y period, independent of glycated hemoglobin, age, and sex. The NFL was significantly thinner (17.3 μm) in the eyes of six donors with DM than in the eyes of six similarly aged control donors (30.4 μm), although retinal capillary density did not differ in the two groups. We confirmed significant, progressive inner retinal thinning in streptozotocin-induced "type 1" and B6.BKS(D)-Lepr(db)/J "type 2" diabetic mouse models on OCT; immunohistochemistry in type 1 mice showed GC loss but no difference in pericyte density or acellular capillaries. The results suggest that RDN may precede the established clinical and morphometric vascular changes caused by DM and represent a paradigm shift in our understanding of ocular diabetic complications. PMID:27114552

  5. Protective Effects of AGE and Its Components on Neuroinflammation and Neurodegeneration.

    Qu, Zhe; Mossine, Valeri V; Cui, Jiankun; Sun, Grace Y; Gu, Zezong

    2016-09-01

    Garlic (Allium sativum) is used for culinary and medicinal purposes in diverse cultures worldwide. When fresh garlic is soaked in aqueous ethanol under ambient environment over 4 months or longer, the majority of irritating taste and odor is eliminated and the antioxidant profile in the resulting aged garlic extract (AGE) changes significantly. Recently, AGE and its components have been demonstrated to exert neuroprotective effects in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and cerebral ischemia. Because of its health supporting potential, there is increasing interest in understanding the antioxidant and anti-inflammatory properties and the underlying mechanisms for its protective effects in heath and disease. There is evidence for AGE to exert its action on distinct signaling pathways associated with oxidative stress and neuroinflammation, although the primary molecular mechanisms remain unclear. By utilizing quantitative proteomic approaches, we demonstrated that AGE and two of its major ingredients, S-allyl-L-cysteine and N (α)-(1-deoxy-D-fructos-1-yl)-L-arginine, can attenuate neuroinflammatory responses in microglial cells through modulation of Nrf2-mediated signaling as well as other oxidative stress-related pathways. These experimental data provide information for the molecular targets of AGE and its components to mitigate neurodegeneration and neuroinflammation and show a promising potential of these compounds as dietary supplements for health maintenance. PMID:27263111

  6. Genome-wide screen for modifiers of ataxin-3 neurodegeneration in Drosophila.

    Julide Bilen

    2007-10-01

    Full Text Available Spinocerebellar ataxia type-3 (SCA3 is among the most common dominantly inherited ataxias, and is one of nine devastating human neurodegenerative diseases caused by the expansion of a CAG repeat encoding glutamine within the gene. The polyglutamine domain confers toxicity on the protein Ataxin-3 leading to neuronal dysfunction and loss. Although modifiers of polyglutamine toxicity have been identified, little is known concerning how the modifiers function mechanistically to affect toxicity. To reveal insight into spinocerebellar ataxia type-3, we performed a genetic screen in Drosophila with pathogenic Ataxin-3-induced neurodegeneration and identified 25 modifiers defining 18 genes. Despite a variety of predicted molecular activities, biological analysis indicated that the modifiers affected protein misfolding. Detailed mechanistic studies revealed that some modifiers affected protein accumulation in a manner dependent on the proteasome, whereas others affected autophagy. Select modifiers of Ataxin-3 also affected tau, revealing common pathways between degeneration due to distinct human neurotoxic proteins. These findings provide new insight into molecular pathways of polyQ toxicity, defining novel targets for promoting neuronal survival in human neurodegenerative disease.

  7. KCa2 and KCa3 channels in learning and memory processes, and neurodegeneration

    Els F. E. Kuiper

    2012-06-01

    Full Text Available Calcium-activated potassium (KCa channels are present throughout the central nervous system as well as many peripheral tissues. Activation of KCa channels is essential for maintenance of the neuronal membrane potential and was shown to underlie the afterhyperpolarization (AHP that regulates action potential firing and limits the firing frequency of repetitive action potentials. Different subtypes of KCa channels were anticipated on the basis of their physiological and pharmacological profiles, and cloning revealed two well defined but phylogenetic distantly related groups of channels. The group subject of this review includes both the small-conductance KCa2 channels (KCa2.1, KCa2.2, and KCa2.3 and the intermediate-conductance (KCa3.1 channel. These channels are activated by submicromolar intracellular Ca2+ concentrations and are voltage independent. Of all KCa channels only the KCa2 channels can be potently but differentially blocked by the bee-venom apamin. In the past few years modulation of KCa channel activation revealed new roles for KCa2 channels in controlling dendritic excitability, synaptic functioning and synaptic plasticity. Furthermore, KCa2 channels appeared to be involved in neurodegeneration, and learning and memory processes. In this review, we focus on the role of KCa2 and KCa3 channels in these latter mechanisms with emphasis on learning and memory, Alzheimer’s disease and on the interplay between neuroinflammation and different neurotransmitters/neuromodulators, their signalling components and KCa channel activation.

  8. Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone.

    Zhao, Liangliang; Hadziahmetovic, Majda; Wang, Chenguang; Xu, Xueying; Song, Ying; Jinnah, H A; Wodzinska, Jolanta; Iacovelli, Jared; Wolkow, Natalie; Krajacic, Predrag; Weissberger, Alyssa Cwanger; Connelly, John; Spino, Michael; Lee, Michael K; Connor, James; Giasson, Benoit; Harris, Z Leah; Dunaief, Joshua L

    2015-12-01

    Brain iron accumulates in several neurodegenerative diseases and can cause oxidative damage, but mechanisms of brain iron homeostasis are incompletely understood. Patients with mutations in the cellular iron-exporting ferroxidase ceruloplasmin (Cp) have brain iron accumulation causing neurodegeneration. Here, we assessed the brains of mice with combined mutation of Cp and its homolog hephaestin. Compared to single mutants, brain iron accumulation was accelerated in double mutants in the cerebellum, substantia nigra, and hippocampus. Iron accumulated within glia, while neurons were iron deficient. There was loss of both neurons and glia. Mice developed ataxia and tremor, and most died by 9 months. Treatment with the oral iron chelator deferiprone diminished brain iron levels, protected against neuron loss, and extended lifespan. Ferroxidases play important, partially overlapping roles in brain iron homeostasis by facilitating iron export from glia, making iron available to neurons. Above: Iron (Fe) normally moves from capillaries to glia to neurons. It is exported from the glia by ferroportin (Fpn) with ferroxidases ceruloplasmin (Cp) and/or Hephaestin (Heph). Below: In mice with mutation of Cp and Heph, iron accumulates in glia, while neurons have low iron levels. Both neurons and glia degenerate and mice become ataxic unless given an iron chelator. PMID:26303407

  9. Retinal Vascular Fractals Correlate With Early Neurodegeneration in Patients With Type 2 Diabetes Mellitus

    Frydkjaer-Olsen, Ulrik; Soegaard Hansen, Rasmus; Pedersen, Knud;

    2015-01-01

    . In a randomly selected eye of each patient, Fd was calculated using SIVA-Fractal, a specialized semiautomatic software. Retinal neurodegeneration was evaluated by Topcon 3D OCT-2000 spectral-domain optical coherence tomography (OCT) and by a RETI-scan multifocal ERG (mf-ERG) system in rings one to...... ETDRS levels were 10 (42.7%), 20 (35.0%), and 35 (22.3%), respectively. Fd correlated inversely with mf-ERG implicit time of ring one (r = -0.25, P = 0.01) and present diabetic neuropathy (P = 0.02), and positively with OCT ganglion cell layer (GCL) thickness (r = 0.20, P = 0.04). In a multivariable...... linear regression model, Fd was associated with mf-ERG implicit time of ring one (coefficient -0.0021/ms, P = 0.040) and the presence of diabetic neuropathy (coefficient -0.0209 for neuropathy present versus absent, P = 0.041). Conclusions: In patients with T2DM and no or minimal DR, independent...

  10. Moringa oleifera Mitigates Memory Impairment and Neurodegeneration in Animal Model of Age-Related Dementia

    Chatchada Sutalangka

    2013-01-01

    Full Text Available To date, the preventive strategy against dementia is still essential due to the rapid growth of its prevalence and the limited therapeutic efficacy. Based on the crucial role of oxidative stress in age-related dementia and the antioxidant and nootropic activities of Moringa oleifera, the enhancement of spatial memory and neuroprotection of M. oleifera leaves extract in animal model of age-related dementia was determined. The possible underlying mechanism was also investigated. Male Wistar rats, weighing 180–220 g, were orally given M. oleifera leaves extract at doses of 100, 200, and 400 mg/kg at a period of 7 days before and 7 days after the intracerebroventricular administration of AF64A bilaterally. Then, they were assessed memory, neuron density, MDA level, and the activities of SOD, CAT, GSH-Px, and AChE in hippocampus. The results showed that the extract improved spatial memory and neurodegeneration in CA1, CA2, CA3, and dentate gyrus of hippocampus together with the decreased MDA level and AChE activity but increased SOD and CAT activities. Therefore, our data suggest that M. oleifera leaves extract is the potential cognitive enhancer and neuroprotectant. The possible mechanism might occur partly via the decreased oxidative stress and the enhanced cholinergic function. However, further explorations concerning active ingredient(s are still required.

  11. The effects of soluble Aβ oligomers on neurodegeneration in Alzheimer's disease.

    Brouillette, Jonathan

    2014-01-01

    The neurodegenerative process that defines Alzheimer''s disease (AD) is initially characterized by synaptic alterations followed by synapse loss and ultimately cell death. Decreased synaptic density that precedes neuronal death is the strongest pathological correlate of cognitive deficits observed in AD. Substantial synapse and neuron loss occur early in disease progression in the entorhinal cortex (EC) and the CA1 region of the hippocampus, when memory deficits become clinically detectable. Mounting evidence suggests that soluble amyloid-β (Aβ) oligomers trigger synapse dysfunction both in vitro and in vivo. However, the neurodegenerative effect of Aβ species observed on neuronal culture or organotypic brain slice culture has been more challenging to mimic in animal models. While most of the transgenic mice that overexpress Aβ show abundant amyloid plaque pathology and early synaptic alterations, these models have been less successful in recapitulating the spatiotemporal pattern of cell loss observed in AD. Recently we developed a novel animal model that revealed the neurodegenerative effect of soluble low-molecular-weight Aβ oligomers in vivo. This new approach may now serve to determine the molecular and cellular mechanisms linking soluble Aβ species to neurodegeneration in animals. In light of the low efficiency of AD therapies based on the amyloid cascade hypothesis, a novel framework, the aging factor cascade hypothesis, is proposed in an attempt to integrate the new data and concepts that emerged from recent research to develop disease modifying therapies. PMID:23859546

  12. Functional modulation of G-protein coupled receptors during Parkinson disease-like neurodegeneration.

    Jenkins, Bruce G; Zhu, Aijun; Poutiainen, Pekka; Choi, Ji-Kyung; Kil, Kun-Eek; Zhang, Zhaoda; Kuruppu, Darshini; Aytan, Nurgul; Dedeoglu, Alpaslan; Brownell, Anna-Liisa

    2016-09-01

    G-protein coupled dopamine and metabotropic glutamate receptors (mGlu) can modulate neurotransmission during Parkinson's disease (PD)-like neurodegeneration. PET imaging studies in a unilateral dopamine denervation model (6-OHDA) showed a significant inverse correlation of presynaptic mGlu4 and postsynaptic mGlu5 expression in the striatum and rapidly declining mGlu4 and enhanced mGlu5 expression in the hippocampus during progressive degeneration over time. Immunohistochemical studies verified the decreased mGlu4 expression in the hippocampus on the lesion side but did not show difference in mGlu5 expression between lesion and control side. Pharmacological MRI studies showed enhanced hemodynamic response in several brain areas on the lesion side compared to the control side after challenge with mGlu4 positive allosteric modulator or mGlu5 negative allosteric modulator. However, mGlu4 response was biphasic having short enhancement followed by negative response on both sides of brain. Studies in mGlu4 expressing cells demonstrated that glutamate induces cooperative increase in binding of mGlu4 ligands - especially at high glutamate levels consistent with in vivo concentration. This suggests that mGlu allosteric modulators as drug candidates will be highly sensitive to changes in glutamate concentration and hence metabolic state. These experiments demonstrate the importance of the longitudinal imaging studies to investigate temporal changes in receptor functions to obtain individual response for experimental drugs. PMID:26581500

  13. Phosphatidylinositol-glycan-phospholipase D is involved in neurodegeneration in prion disease.

    Jae-Kwang Jin

    Full Text Available PrPSc is formed from a normal glycosylphosphatidylinositol (GPI-anchored prion protein (PrPC by a posttranslational modification. Most GPI-anchored proteins have been shown to be cleaved by GPI phospholipases. Recently, GPI-phospholipase D (GPI-PLD was shown to be a strictly specific enzyme for GPI anchors. To investigate the involvement of GPI-PLD in the processes of neurodegeneration in prion diseases, we examined the mRNA and protein expression levels of GPI-PLD in the brains of a prion animal model (scrapie, and in both the brains and cerebrospinal fluids (CSF of sporadic and familial Creutzfeldt-Jakob disease (CJD patients. We found that compared with controls, the expression of GPI-PLD was dramatically down-regulated in the brains of scrapie-infected mice, especially in the caveolin-enriched membrane fractions. Interestingly, the observed decrease in GPI-PLD expression levels began at the same time that PrPSc began to accumulate in the infected brains and this decrease was also observed in both the brain and CSF of CJD patients; however, no differences in expression were observed in either the brains or CSF specimens from Alzheimer's disease patients. Taken together, these results suggest that the down-regulation of GPI-PLD protein may be involved in prion propagation in the brains of prion diseases.

  14. Review: Insights into molecular mechanisms of disease in neurodegeneration with brain iron accumulation: unifying theories.

    Arber, C E; Li, A; Houlden, H; Wray, S

    2016-04-01

    Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterized by dystonia, parkinsonism and spasticity. Iron accumulates in the basal ganglia and may be accompanied by Lewy bodies, axonal swellings and hyperphosphorylated tau depending on NBIA subtype. Mutations in 10 genes have been associated with NBIA that include Ceruloplasmin (Cp) and ferritin light chain (FTL), both directly involved in iron homeostasis, as well as Pantothenate Kinase 2 (PANK2), Phospholipase A2 group 6 (PLA2G6), Fatty acid hydroxylase 2 (FA2H), Coenzyme A synthase (COASY), C19orf12, WDR45 and DCAF17 (C2orf37). These genes are involved in seemingly unrelated cellular pathways, such as lipid metabolism, Coenzyme A synthesis and autophagy. A greater understanding of the cellular pathways that link these genes and the disease mechanisms leading to iron dyshomeostasis is needed. Additionally, the major overlap seen between NBIA and more common neurodegenerative diseases may highlight conserved disease processes. In this review, we will discuss clinical and pathological findings for each NBIA-related gene, discuss proposed disease mechanisms such as mitochondrial health, oxidative damage, autophagy/mitophagy and iron homeostasis, and speculate the potential overlap between NBIA subtypes. PMID:25870938

  15. Neuronal dark matter: The emerging role of microRNAs in neurodegeneration

    Emily Frances Goodall

    2013-10-01

    Full Text Available MicroRNAs (miRNAs are small, abundant RNA molecules that constitute part of the cell’s non-coding RNA dark matter. In recent years, the discovery of miRNAs has revolutionised the traditional view of gene expression and our understanding of miRNA biogenesis and function has expanded. Altered expression of miRNAs is increasingly recognised as a feature of many disease states, including neurodegeneration. Here, we review the emerging role for miRNA dysfunction in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease pathogenesis. We emphasise the complex nature of gene regulatory networks and the need for systematic studies, with larger sample cohorts than have so far been reported, to reveal the most important miRNA regulators in disease. Finally, miRNA diversity and their potential to target multiple pathways, offers novel clinical applications for miRNAs as biomarkers and therapeutic agents in neurodegenerative diseases.

  16. Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration.

    Brahmachari, Saurav; Ge, Preston; Lee, Su Hyun; Kim, Donghoon; Karuppagounder, Senthilkumar S; Kumar, Manoj; Mao, Xiaobo; Shin, Joo Ho; Lee, Yunjong; Pletnikova, Olga; Troncoso, Juan C; Dawson, Valina L; Dawson, Ted M; Ko, Han Seok

    2016-08-01

    Aggregation of α-synuclein contributes to the formation of Lewy bodies and neurites, the pathologic hallmarks of Parkinson disease (PD) and α-synucleinopathies. Although a number of human mutations have been identified in familial PD, the mechanisms that promote α-synuclein accumulation and toxicity are poorly understood. Here, we report that hyperactivity of the nonreceptor tyrosine kinase c-Abl critically regulates α-synuclein-induced neuropathology. In mice expressing a human α-synucleinopathy-associated mutation (hA53Tα-syn mice), deletion of the gene encoding c-Abl reduced α-synuclein aggregation, neuropathology, and neurobehavioral deficits. Conversely, overexpression of constitutively active c-Abl in hA53Tα-syn mice accelerated α-synuclein aggregation, neuropathology, and neurobehavioral deficits. Moreover, c-Abl activation led to an age-dependent increase in phosphotyrosine 39 α-synuclein. In human postmortem samples, there was an accumulation of phosphotyrosine 39 α-synuclein in brain tissues and Lewy bodies of PD patients compared with age-matched controls. Furthermore, in vitro studies show that c-Abl phosphorylation of α-synuclein at tyrosine 39 enhances α-synuclein aggregation. Taken together, this work establishes a critical role for c-Abl in α-synuclein-induced neurodegeneration and demonstrates that selective inhibition of c-Abl may be neuroprotective. This study further indicates that phosphotyrosine 39 α-synuclein is a potential disease indicator for PD and related α-synucleinopathies. PMID:27348587

  17. Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease.

    Nuber, Silke; Petrasch-Parwez, Elisabeth; Winner, Beate; Winkler, Jürgen; von Hörsten, Stephan; Schmidt, Thorsten; Boy, Jana; Kuhn, Melanie; Nguyen, Huu P; Teismann, Peter; Schulz, Jörg B; Neumann, Manuela; Pichler, Bernd J; Reischl, Gerald; Holzmann, Carsten; Schmitt, Ina; Bornemann, Antje; Kuhn, Wilfried; Zimmermann, Frank; Servadio, Antonio; Riess, Olaf

    2008-03-01

    Alpha-synuclein (alpha-syn) has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease. These disorders are characterized by various neurological and psychiatric symptoms based on progressive neuropathological alterations. Whether the neurodegenerative process might be halted or even reversed is presently unknown. Therefore, conditional mouse models are powerful tools to analyze the relationship between transgene expression and progression of the disease. To explore whether alpha-syn solely originates and further incites these alterations, we generated conditional mouse models by using the tet-regulatable system. Mice expressing high levels of human wild-type alpha-syn in midbrain and forebrain regions developed nigral and hippocampal neuropathology, including reduced neurogenesis and neurodegeneration in absence of fibrillary inclusions, leading to cognitive impairment and progressive motor decline. Turning off transgene expression in symptomatic mice halted progression but did not reverse the symptoms. Thus, our data suggest that approaches targeting alpha-syn-induced pathological pathways might be of benefit rather in early disease stages. Furthermore, alpha-syn-associated cytotoxicity is independent of filamentous inclusion body formation in our conditional mouse model. PMID:18322092

  18. Neurodegeneration in Friedreich’s Ataxia: From Defective Frataxin to Oxidative Stress

    Cláudio M. Gomes

    2013-01-01

    Full Text Available Friedreich’s ataxia is the most common inherited autosomal recessive ataxia and is characterized by progressive degeneration of the peripheral and central nervous systems and cardiomyopathy. This disease is caused by the silencing of the FXN gene and reduced levels of the encoded protein, frataxin. Frataxin is a mitochondrial protein that functions primarily in iron-sulfur cluster synthesis. This small protein with an α/β sandwich fold undergoes complex processing and imports into the mitochondria, generating isoforms with distinct N-terminal lengths which may underlie different functionalities, also in respect to oligomerization. Missense mutations in the FXN coding region, which compromise protein folding, stability, and function, are found in 4% of FRDA heterozygous patients and are useful to understand how loss of functional frataxin impacts on FRDA physiopathology. In cells, frataxin deficiency leads to pleiotropic phenotypes, including deregulation of iron homeostasis and increased oxidative stress. Increasing amount of data suggest that oxidative stress contributes to neurodegeneration in Friedreich’s ataxia.

  19. Chronic expression of H-ferritin in dopaminergic midbrain neurons results in an age-related expansion of the labile iron pool and subsequent neurodegeneration: implications for Parkinson’s disease

    Kaur, Deepinder; Rajagopalan, Subramanian; Andersen, Julie K.

    2009-01-01

    While ferritin elevation within dopaminergic (DA) neurons of the substantia nigra (SN) is protective against neurodegeneration elicited by two toxin models of Parkinson’s disease (PD), MPTP and paraquat, in young animals, its prolonged elevation results in a selective age-related neurodegeneration. A similar age-related neurodegeneration has been reported in iron regulatory protein 2-deficient (IRP2 −/−) mice coinciding with increased ferritin levels within degenerating neurons. This has been...

  20. Synergistic stress exacerbation in hippocampal neurons: Evidence favoring the dual-hit hypothesis of neurodegeneration.

    Heinemann, Scott D; Posimo, Jessica M; Mason, Daniel M; Hutchison, Daniel F; Leak, Rehana K

    2016-08-01

    The dual-hit hypothesis of neurodegeneration states that severe stress sensitizes vulnerable cells to subsequent challenges so that the two hits are synergistic in their toxic effects. Although the hippocampus is vulnerable to a number of neurodegenerative disorders, there are no models of synergistic cell death in hippocampal neurons in response to combined proteotoxic and oxidative stressors, the two major characteristics of these diseases. Therefore, a relatively high-throughput dual-hit model of stress synergy was developed in primary hippocampal neurons. In order to increase the rigor of the study and strengthen the interpretations, three independent, unbiased viability assays were employed at multiple timepoints. Stress synergy was elicited when hippocampal neurons were treated with the proteasome inhibitor MG132 followed by exposure to the oxidative toxicant paraquat, but only after 48 h. MG132 and paraquat only elicited additive effects 24 h after the final hit and even loss of heat shock protein 70 activity and glutathione did not promote stress synergy at this early timepoint. Dual hits of MG132 elicited modest glutathione loss and slightly synergistic toxic effects 48 h after the second hit, but only at some concentrations and only according to two viability assays (metabolic fitness and cytoskeletal integrity). The thiol N-acetyl cysteine protected hippocampal neurons against dual MG132/MG132 hits but not dual MG132/paraquat hits. These findings support the view that proteotoxic and oxidative stress propel and propagate each other in hippocampal neurons, leading to synergistically toxic effects, but not as the default response and only after a delay. The neuronal stress synergy observed here lies in contrast to astrocytic responses to dual hits, because astrocytes that survive severe proteotoxic stress resist additional cell loss following second hits. In conclusion, a new model of hippocampal vulnerability was developed for the testing of therapies

  1. Multivariate profiling of neurodegeneration-associated changes in a subcellular compartment of neurons via image processing

    Kumarasamy Saravana K

    2008-11-01

    differentiates all three bchs phenotypes (loss of function as well as overexpression from the wild type. Conclusion Our model demonstrates that neurodegeneration-associated endolysosomal defects can be detected, analyzed, and classified rapidly and accurately as a diagnostic imaging-based screening tool.

  2. Re-circulating Phagocytes Loaded with CNS Debris: A Potential Marker of Neurodegeneration in Parkinsons Disease?

    Vanessa J. White

    2015-02-01

    Full Text Available Diagnosis and monitoring of diseases by measurement of biochemical markers has most commonly been performed on samples of peripheral blood. However, no such markers are available for clinical use in the major diseases of the central nervous system (CNS. In Parkinson's disease circulating biomarkers would find clinical utility in early diagnosis and also monitoring of disease progression. Of particular interest is early diagnosis as this would create .a window of opportunity for treatment with neuroprotective drugs. We have developed a novel strategy for monitoring disease activity in the CNS based on the recognition that tissue injuries incite inflammation and recruitment of phagocytes that engulf debris. We postulated that some of these debris laden phagocytes may return to the peripheral blood and their cargo of CNS proteins could be measured. If CNS antigens can be measured in PBMCs it may be an indicator of active neurodegeneration as the debris engulfed by phagocytes is completely degraded within days. To make this approach more specific to Parkinson's disease we probed PBMC lysates for neuromelanin as a marker of degeneration within the substancia nigra. We performed a proof of principle study in ten subjects with early PD and ten age and sex matched controls. The biomarkers neuromelanin, Tau protein, UCH-L1 and HPCAL-1 were measured in PBMC lysates from these two groups. Neuromelanin and Tau protein mean levels were elevated in PD compared with controls and was extremely statistically significant in both cases. UCH-L1 and HPCAL-1 mean levels were elevated in PD over controls and were not quite significant in both cases. These results suggest that this is a promising new approach for diagnosis and monitoring of PD and potentially other CNS diseases.

  3. Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson's Disease.

    Ghosh, Anamitra; Langley, Monica R; Harischandra, Dilshan S; Neal, Matthew L; Jin, Huajun; Anantharam, Vellareddy; Joseph, Joy; Brenza, Timothy; Narasimhan, Balaji; Kanthasamy, Arthi; Kalyanaraman, Balaraman; Kanthasamy, Anumantha G

    2016-06-01

    Mitochondrial dysfunction, oxidative stress and neuroinflammation have been implicated as key mediators contributing to the progressive degeneration of dopaminergic neurons in Parkinson's disease (PD). Currently, we lack a pharmacological agent that can intervene in all key pathological mechanisms, which would offer better neuroprotective efficacy than a compound that targets a single degenerative mechanism. Herein, we investigated whether mito-apocynin (Mito-Apo), a newly-synthesized and orally available derivative of apocynin that targets mitochondria, protects against oxidative damage, glial-mediated inflammation and nigrostriatal neurodegeneration in cellular and animal models of PD. Mito-Apo treatment in primary mesencephalic cultures significantly attenuated the 1-methyl-4-phenylpyridinium (MPP(+))-induced loss of tyrosine hydroxylase (TH)-positive neuronal cells and neurites. Mito-Apo also diminished MPP(+)-induced increases in glial cell activation and inducible nitric oxide synthase (iNOS) expression. Additionally, Mito-Apo decreased nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE) levels in primary mesencephalic cultures. Importantly, we assessed the neuroprotective property of Mito-Apo in the MPTP mouse model of PD, wherein it restored the behavioral performance of MPTP-treated mice. Immunohistological analysis of nigral dopaminergic neurons and monoamine measurement further confirmed the neuroprotective effect of Mito-Apo against MPTP-induced nigrostriatal dopaminergic neuronal loss. Mito-Apo showed excellent brain bioavailability and also markedly attenuated MPTP-induced oxidative markers in the substantia nigra (SN). Furthermore, oral administration of Mito-Apo significantly suppressed MPTP-induced glial cell activation, upregulation of proinflammatory cytokines, iNOS and gp91phox in IBA1-positive cells of SN. Collectively, these results demonstrate that the novel mitochondria-targeted compound Mito-Apo exhibits profound neuroprotective effects in

  4. Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist

    Prophylactic agents acutely administered in response to anticholinesterases intoxication can prevent toxic symptoms, including fasciculations, seizures, convulsions and death. However, anticholinesterases also have long-term unknown pathophysiological effects, making rational prophylaxis/treatment problematic. Increasing evidence suggests that in addition to excessive cholinergic stimulation, organophosphate compounds such as diisopropylphosphorofluoridate (DFP) induce activation of glutamatergic neurons, generation of reactive oxygen (ROS) and nitrogen species (RNS), leading to neurodegeneration. The present study investigated multiple affectors of DFP exposure critical to cerebral oxidative damage and whether antioxidants and NMDA receptor antagonist memantine provide neuroprotection by preventing DFP-induced biochemical and morphometric changes in rat brain. Rats treated acutely with DFP (1.25 mg/kg, s.c.) developed onset of toxicity signs within 7-15 min that progressed to maximal severity of seizures and fasciculations within 60 min. At this time point, DFP caused significant (p 2-isoprostanes, F2-IsoPs; and F4-neuroprostanes, F4-NeuroPs), RNS (citrulline), and declines in high-energy phosphates (HEP) in rat cerebrum. At the same time, quantitative morphometric analysis of pyramidal neurons of the hippocampal CA1 region revealed significant (p 2-IsoPs, F4-NeuroPs, citrulline, and depletion of HEP were noted. Furthermore, attenuation in oxidative damage following antioxidants or memantine pretreatment was accompanied by rescue from dendritic degeneration of pyramidal neurons in the CA1 hippocampal area. These findings closely associated DFP-induced lipid peroxidation with dendritic degeneration of pyramidal neurons in the CA1 hippocampal area and point to possible interventions to limit oxidative injury and dendritic degeneration induced by anticholinesterase neurotoxicity.

  5. How the Wnt signaling pathway protects from neurodegeneration: the mitochondrial scenario

    Arrázola, Macarena S.; Silva-Alvarez, Carmen; Inestrosa, Nibaldo C.

    2015-01-01

    Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is characterized by progressive memory loss and cognitive decline. One of the hallmarks of AD is the overproduction of amyloid-beta aggregates that range from the toxic soluble oligomer (Aβo) form to extracellular accumulations in the brain. Growing evidence indicates that mitochondrial dysfunction is a common feature of neurodegenerative diseases and is observed at an early stage in the pathogenesis of AD. Reports indicate that mitochondrial structure and function are affected by Aβo and can trigger neuronal cell death. Mitochondria are highly dynamic organelles, and the balance between their fusion and fission processes is essential for neuronal function. Interestingly, in AD, the process known as “mitochondrial dynamics” is also impaired by Aβo. On the other hand, the activation of the Wnt signaling pathway has an essential role in synaptic maintenance and neuronal functions, and its deregulation has also been implicated in AD. We have demonstrated that canonical Wnt signaling, through the Wnt3a ligand, prevents the permeabilization of mitochondrial membranes through the inhibition of the mitochondrial permeability transition pore (mPTP), induced by Aβo. In addition, we showed that non-canonical Wnt signaling, through the Wnt5a ligand, protects mitochondria from fission-fusion alterations in AD. These results suggest new approaches by which different Wnt signaling pathways protect neurons in AD, and support the idea that mitochondria have become potential therapeutic targets for the treatment of neurodegenerative disorders. Here we discuss the neuroprotective role of the canonical and non-canonical Wnt signaling pathways in AD and their differential modulation of mitochondrial processes, associated with mitochondrial dysfunction and neurodegeneration. PMID:25999816

  6. Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders.

    McGuire, Jennifer L; Gill, Alexander J; Douglas, Steven D; Kolson, Dennis L

    2015-08-01

    HIV-associated neurocognitive disorders (HAND) affect up to 50 % of HIV-infected adults, independently predict HIV morbidity/mortality, and are associated with neuronal damage and monocyte activation. Cerebrospinal fluid (CSF) neurofilament subunits (NFL, pNFH) are sensitive surrogate markers of neuronal damage in several neurodegenerative diseases. In HIV, CSF NFL is elevated in individuals with and without cognitive impairment, suggesting early/persistent neuronal injury during HIV infection. Although individuals with severe cognitive impairment (HIV-associated dementia (HAD)) express higher CSF NFL levels than cognitively normal HIV-infected individuals, the relationships between severity of cognitive impairment, monocyte activation, neurofilament expression, and systemic infection are unclear. We performed a retrospective cross-sectional study of 48 HIV-infected adults with varying levels of cognitive impairment, not receiving antiretroviral therapy (ART), enrolled in the CNS Anti-Retroviral Therapy Effects Research (CHARTER) study. We quantified NFL, pNFH, and monocyte activation markers (sCD14/sCD163) in paired CSF/plasma samples. By examining subjects off ART, these correlations are not confounded by possible effects of ART on inflammation and neurodegeneration. We found that CSF NFL levels were elevated in individuals with HAD compared to cognitively normal or mildly impaired individuals with CD4+ T-lymphocyte nadirs ≤200. In addition, CSF NFL levels were significantly positively correlated to plasma HIV-1 RNA viral load and negatively correlated to plasma CD4+ T-lymphocyte count, suggesting a link between neuronal injury and systemic HIV infection. Finally, CSF NFL was significantly positively correlated with CSF pNFH, sCD163, and sCD14, demonstrating that monocyte activation within the CNS compartment is directly associated with neuronal injury at all stages of HAND. PMID:25776526

  7. Multiple sclerosis and fatigue: A review on the contribution of inflammation and immune-mediated neurodegeneration.

    Patejdl, Robert; Penner, Iris K; Noack, Thomas K; Zettl, Uwe K

    2016-03-01

    Multiple sclerosis (MS) is an immune mediated disease of the central nervous system (CNS) and the leading cause of non-traumatic disability among young and middle-aged adults in the western world. One of its most prevalent and debilitating symptoms is fatigue. Despite the general acceptance of the idea of an immune pathogenesis of MS itself, the role of autoimmunity in the course of MS-fatigue is a matter of debate. Both immune-related processes (acute inflammation, chronic inflammation, immune-mediated neurodegeneration, immune-mediated alterations of endocrine functions related to fatigue) and presumably non-immune-mediated disturbances and factors (sleep disturbances, depression, cognitive alterations, chronic infections, adverse effects of medications) contribute to the clinical picture. Data from in vitro and animal experiments has provided evidence for a role of cytokines as IL-1 and TNF-alpha. This association could not be verified directly in blood samples from humans whereas whole blood stimulation protocols gave some indirect evidence for a role of cytokines in MS-fatigue. MRI being able to detect acute and chronic immune mediated damage to the CNS could depict that global atrophy of gray or white matter does not correlate with fatigue. Rather, distinctive clusters of lesions and atrophy at different locations, mostly bifrontal or in subcortical structures, correlate specifically with fatigue. Regardless of the difficulties in pinpointing the immunogenesis of MS-fatigue, an important role of autoimmunity is strongly supported by an indirect route: A growing amount of data shows that the highly effective immunotherapeutics which have been introduced to MS-treatment over the last years effectively and sustainably stabilize and ameliorate fatigue in parallel to their dampening effects on the neuroinflammatory process. This review summarizes the existing data on the relation between inflammation, patterns of CNS-lesions and the effects of immunotherapeutics

  8. Microglia and regulation of inflammation-mediated neurodegeneration: Prevention and treatment by phytochemicals and metabolic nutrients

    Rajagopal Shanmuga Sundaram

    2012-01-01

    Full Text Available Inflammation, a common denominator among the diverse list of neurodegenerative diseases, has recently been implicated as a critical mechanism responsible for the progressive nature of neurodegeneration. Microglias are the resident innate immune cells in the central nervous system and produce a barrage of factors (ILs, TNF α, NO, PGs, SOD that are toxic to neurons. Evidence supports that the unregulated activation of microglia, in response to environmental toxins, endogenous proteins and neuronal death, results in the production of toxic factors that propagate neuronal injury. Herbal medicine has long been used to treat neural symptoms. Although the precise mechanisms of action of herbal drugs have yet to be determined, some of them have been shown to exert anti-inflammatory and / or antioxidant effects in a variety of peripheral systems. Now, as increasing evidence indicates that neuroglia-derived chronic inflammatory responses play a pathological role in the central nervous system, anti-inflammatory herbal medicine and its constituents are being proved to be potent neuroprotectors against various brain pathologies. Structural diversity of medicinal herbs makes them a valuable source of novel lead compounds against therapeutic targets that are newly discovered by genomics, proteomics and high-throughput screening. In the following review, we discuss the common thread of microglial activation across numerous neurodegenerative diseases, define current perceptions of how microglia are damaging neurons and explain how the microglial response to neuronal damage results in a self-propelling cycle of neuron death. This article synthesizes what we know about these destructive processes, while offering an insight into a new avenue of treatment involving phytochemicals and other nutrients.

  9. Bill project aiming at abrogating exclusive search permits for unconventional hydrocarbon searches, and at prohibiting their exploration and exploitation of the national territory

    After having briefly recalled the origin of shale gases, their extraction process and the evolution of their production in the USA, the authors outline the extremely negative environmental impacts of the fracking technique (hydraulic fracturing): water pollution, air pollution, soil pollution, existence of numerous drilling sites which would degrade landscapes, water and soil contamination risks. As some search permits have already been awarded, and while taking these negative consequences into account, the authors propose a bill project to prohibit these explorations, to abrogate the existing permits, and to ensure public information before bestowing such search permits and exploitation concessions

  10. Abrogation of donor T-cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD from GVL

    Hanash, Alan M.; Kappel, Lucy W.; Yim, Nury L.; Nejat, Rebecca A.; Goldberg, Gabrielle L.; Smith, Odette M.; Rao, Uttam K.; Dykstra, Lindsay; Na, Il-Kang; Holland, Amanda M.; Dudakov, Jarrod A.; Liu, Chen; Murphy, George F.; Leonard, Warren J.; Heller, Glenn

    2011-01-01

    IL-21 is a proinflammatory cytokine produced by Th17 cells. Abrogation of IL-21 signaling has recently been shown to reduce GVHD while retaining graft-versus-leukemia/lymphoma (GVL) responses. However, the mechanisms by which IL-21 may lead to a separation of GVHD and GVL remain incompletely understood. In a murine MHC-mismatched BM transplantation model, we observed that IL-21 receptor knockout (IL-21R KO) donor T cells mediate decreased systemic and gastrointestinal GVHD in recipients of a ...

  11. Anti-CD4 abrogates rejection and reestablishes long-term tolerance to syngeneic newborn hearts grafted in mice chronically infected with Trypanosoma cruzi

    1992-01-01

    The contribution of autoimmunity in the genesis of chronic Chagas' heart pathology is not clear. In the present study, we show that: (a) BALB/c mice chronically infected with Trypanosoma cruzi reject syngeneic newborn hearts; (b) in vivo treatment with anti-CD4 but not anti-CD8 monoclonal antibodies (mAbs) abrogates rejection; (c) CD4+ T cells from chronically infected mice proliferate in vitro to syngeneic myocardium antigens and induce heart graft destruction when injected in situ; (d) anti...

  12. Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model.

    Brunetti, Dario; Dusi, Sabrina; Giordano, Carla; Lamperti, Costanza; Morbin, Michela; Fugnanesi, Valeria; Marchet, Silvia; Fagiolari, Gigliola; Sibon, Ody; Moggio, Maurizio; d'Amati, Giulia; Tiranti, Valeria

    2014-01-01

    Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2, responsible for the phosphorylation of pantothenate or vitamin B5 in the biosynthesis of co-enzyme A. A Pank2 knockout (Pank2(-/-)) mouse model did not recapitulate the human disease but showed azoospermia and mitochondrial dysfunctions. We challenged this mouse model with a low glucose and high lipid content diet (ketogenic diet) to stimulate lipid use by mitochondrial beta-oxidation. In the presence of a shortage of co-enzyme A, this diet could evoke a general impairment of bioenergetic metabolism. Only Pank2(-/-) mice fed with a ketogenic diet developed a pantothenate kinase-associated neurodegeneration-like syndrome characterized by severe motor dysfunction, neurodegeneration and severely altered mitochondria in the central and peripheral nervous systems. These mice also showed structural alteration of muscle morphology, which was comparable with that observed in a patient with pantothenate kinase-associated neurodegeneration. We here demonstrate that pantethine administration can prevent the onset of the neuromuscular phenotype in mice suggesting the possibility of experimental treatment in patients with pantothenate kinase-associated neurodegeneration. PMID:24316510

  13. Neurodegeneration in Autoimmune Optic Neuritis Is Associated with Altered APP Cleavage in Neurons and Up-Regulation of p53.

    Sabine Herold

    Full Text Available Multiple Sclerosis (MS is a chronic autoimmune inflammatory disease of the central nervous system (CNS. Histopathological and radiological analysis revealed that neurodegeneration occurs early in the disease course. However, the pathological mechanisms involved in neurodegeneration are poorly understood. Myelin oligodendrocyte glycoprotein (MOG-induced experimental autoimmune encephalomyelitis (EAE in Brown Norway rats (BN-rats is a well-established animal model, especially of the neurodegenerative aspects of MS. Previous studies in this animal model indicated that loss of retinal ganglion cells (RGCs, the neurons that form the axons of the optic nerve, occurs in the preclinical phase of the disease and is in part independent of overt histopathological changes of the optic nerve. Therefore, the aim of this study was to identify genes which are involved in neuronal cell loss at different disease stages of EAE. Furthermore, genes that are highly specific for autoimmune-driven neurodegeneration were compared to those regulated in RGCs after optic nerve axotomy at corresponding time points. Using laser capture micro dissection we isolated RNA from unfixed RGCs and performed global transcriptome analysis of retinal neurons. In total, we detected 582 genes sequentially expressed in the preclinical phase and 1150 genes in the clinical manifest EAE (P 1.5. Furthermore, using ingenuity pathway analysis (IPA, we identified amyloid precursor protein (APP as a potential upstream regulator of changes in gene expression in the preclinical EAE but neither in clinical EAE, nor at any time point after optic nerve transection. Therefore, the gene pathway analysis lead to the hypothesis that altered cleavage of APP in neurons in the preclinical phase of EAE leads to the enhanced production of APP intracellular domain (AICD, which in turn acts as a transcriptional regulator and thereby initiates an apoptotic signaling cascade via up-regulation of the target gene p

  14. Neurodegeneration severity can be predicted from early microglia alterations monitored in vivo in a mouse model of chronic glaucoma

    Alejandra Bosco

    2015-05-01

    Full Text Available Microglia serve key homeostatic roles, and respond to neuronal perturbation and decline with a high spatiotemporal resolution. The course of all chronic CNS pathologies is thus paralleled by local microgliosis and microglia activation, which begin at early stages of the disease. However, the possibility of using live monitoring of microglia during early disease progression to predict the severity of neurodegeneration has not been explored. Because the retina allows live tracking of fluorescent microglia in their intact niche, here we investigated their early changes in relation to later optic nerve neurodegeneration. To achieve this, we used the DBA/2J mouse model of inherited glaucoma, which develops progressive retinal ganglion cell degeneration of variable severity during aging, and represents a useful model to study pathogenic mechanisms of retinal ganglion cell decline that are similar to those in human glaucoma. We imaged CX3CR1+/GFP microglial cells in vivo at ages ranging from 1 to 5 months by confocal scanning laser ophthalmoscopy (cSLO and quantified cell density and morphological activation. We detected early microgliosis at the optic nerve head (ONH, where axonopathy first manifests, and could track attenuation of this microgliosis induced by minocycline. We also observed heterogeneous and dynamic patterns of early microglia activation in the retina. When the same animals were aged and analyzed for the severity of optic nerve pathology at 10 months of age, we found a strong correlation with the levels of ONH microgliosis at 3 to 4 months. Our findings indicate that live imaging and monitoring the time course and levels of early retinal microgliosis and microglia activation in glaucoma could serve as indicators of future neurodegeneration severity.

  15. Exacerbation of CNS inflammation and neurodegeneration by systemic LPS treatment is independent of circulating IL-1 beta and IL-6

    Murray, Carol L

    2011-05-17

    Abstract Background Chronic neurodegeneration comprises an inflammatory response but its contribution to the progression of disease remains unclear. We have previously shown that microglial cells are primed by chronic neurodegeneration, induced by the ME7 strain of prion disease, to synthesize limited pro-inflammatory cytokines but to produce exaggerated responses to subsequent systemic inflammatory insults. The consequences of this primed response include exaggerated hypothermic and sickness behavioural responses, acute neuronal death and accelerated progression of disease. Here we investigated whether inhibition of systemic cytokine synthesis using the anti-inflammatory steroid dexamethasone-21-phosphate was sufficient to block any or all of these responses. Methods ME7 animals, at 18-19 weeks post-inoculation, were challenged with LPS (500 μg\\/kg) in the presence or absence of dexamethasone-21-phosphate (2 mg\\/kg) and effects on core-body temperature and systemic and CNS cytokine production and apoptosis were examined. Results LPS induced hypothermia and decreased exploratory activity. Dexamethasone-21-phosphate prevented this hypothermia, markedly suppressed systemic IL-1β and IL-6 secretion but did not prevent decreased exploration. Furthermore, robust transcription of cytokine mRNA occurred in the hippocampus of both ME7 and NBH (normal brain homogenate) control animals despite the effective blocking of systemic cytokine synthesis. Microglia primed by neurodegeneration were not blocked from the robust synthesis of IL-1β protein and endothelial COX-2 was also robustly synthesized. We injected biotinylated LPS at 100 μg\\/kg and even at this lower dose this could be detected in blood plasma. Apoptosis was acutely induced by LPS, despite the inhibition of the systemic cytokine response. Conclusions These data suggest that LPS can directly activate the brain endothelium even at relatively low doses, obviating the need for systemic cytokine stimulation to

  16. Mitochondrial defects and neurodegeneration in mice overexpressing wild-type or G399S mutant HtrA2.

    Casadei, Nicolas; Sood, Poonam; Ulrich, Thomas; Fallier-Becker, Petra; Kieper, Nicole; Helling, Stefan; May, Caroline; Glaab, Enrico; Chen, Jing; Nuber, Silke; Marcus, Katrin; Rapaport, Doron; Ott, Thomas; Riess, Olaf; Krüger, Rejko; Fitzgerald, Julia C

    2016-02-01

    The protease HtrA2 has a protective role inside mitochondria, but promotes apoptosis under stress. We previously identified the G399S HtrA2 mutation in Parkinson's disease (PD) patients and reported mitochondrial dysfunction in vitro. Mitochondrial dysfunction is a common feature of PD and related to neurodegeneration. Complete loss of HtrA2 has been shown to cause neurodegeneration in mice. However, the full impact of HtrA2 overexpression or the G399S mutation is still to be determined in vivo. Here, we report the first HtrA2 G399S transgenic mouse model. Our data suggest that the mutation has a dominant-negative effect. We also describe a toxic effect of wild-type (WT) HtrA2 overexpression. Only low overexpression of the G399S mutation allowed viable animals and we suggest that the mutant protein is likely unstable. This is accompanied by reduced mitochondrial respiratory capacity and sensitivity to apoptotic cell death. Mice overexpressing WT HtrA2 were viable, yet these animals have inhibited mitochondrial respiration and significant induction of apoptosis in the brain leading to motor dysfunction, highlighting the opposing roles of HtrA2. Our data further underscore the importance of HtrA2 as a key mediator of mitochondrial function and its fine regulatory role in cell fate. The location and abundance of HtrA2 is tightly controlled and, therefore, human mutations leading to gain- or loss of function could provide significant risk for PD-related neurodegeneration. PMID:26604148

  17. Inhibition of sodium glucose cotransporters following status epilepticus induced by intrahippocampal pilocarpine affects neurodegeneration process in hippocampus.

    Melo, Igor S; Santos, Yngrid M O; Costa, Maísa A; Pacheco, Amanda L D; Silva, Nívea K G T; Cardoso-Sousa, L; Pereira, U P; Goulart, L R; Garcia-Cairasco, Norberto; Duzzioni, Marcelo; Gitaí, Daniel L G; Tilelli, Cristiane Q; Sabino-Silva, Robinson; Castro, Olagide W

    2016-08-01

    Temporal lobe epilepsy (TLE) is characterized by spontaneous recurrent seizures, starting from secondary functional disorders due to several insults, including self-sustaining continuous seizures identified as status epilepticus (SE). Although hypoglycemia has been associated with SE, the effect of inhibition of the Na(+)/glucose cotransporters (SGLTs) on hippocampus during SE is still unknown. Here we evaluated the functional role of SGLT in the pattern of limbic seizures and neurodegeneration process after pilocarpine (PILO)-induced SE. Vehicle (VEH, 1μL) or phlorizin, a specific SGLT inhibitor (PZN, 1μL, 50μg/μL), was administered in the hippocampus of rats 30min before PILO (VEH+PILO or PZN+PILO, respectively). The limbic seizures were classified using the Racine's scale, and the amount of wet dog shakes (WDS) was quantified before and during SE. Neurodegeneration process was evaluated by Fluoro-Jade C (FJ-C), and FJ-C-positive neurons (FJ-C+) were counted 24h and 15days after SE. The PZN-treated rats showed higher (pclass 5 seizures repeated themselves more times (pclasses in the PZN group at 50min after SE induction. The PZN+PILO animals had a higher (p<0.05) number of FJ-C+ cells in the dentate gyrus (DG), hilus, and CA3 and CA1 of hippocampus, when compared with VEH+PILO. The PZN+PILO animals had a decreased number (p<0.05) of FJ-C+ cells in CA1 compared with VEH+PILO 15days after SE induction. Taken together, our data suggest that SGLT inhibition with PZN increased the severity of limbic seizures during SE and increased neurodegeneration in hippocampus 24h after SE, suggesting that SGLT1 and SGLT2 could participate in the modulation of earlier stages of epileptogenic processes. PMID:27429292

  18. Diabetes and overexpression of proNGF cause retinal neurodegeneration via activation of RhoA pathway.

    Mohammed M H Al-Gayyar

    Full Text Available Our previous studies showed positive correlation between accumulation of proNGF, activation of RhoA and neuronal death in diabetic models. Here, we examined the neuroprotective effects of selective inhibition of RhoA kinase in the diabetic rat retina and in a model that stably overexpressed the cleavage-resistance proNGF plasmid in the retina. Male Sprague-Dawley rats were rendered diabetic using streptozotocin or stably express cleavage-resistant proNGF plasmid. The neuroprotective effects of the intravitreal injection of RhoA kinase inhibitor Y27632 were examined in vivo. Effects of proNGF were examined in freshly isolated primary retinal ganglion cell (RGC cultures and RGC-5 cell line. Retinal neurodegeneration was assessed by counting TUNEL-positive and Brn-3a positive retinal ganglion cells. Expression of proNGF, p75(NTR, cleaved-PARP, caspase-3 and p38MAPK/JNK were examined by Western-blot. Activation of RhoA was assessed by pull-down assay and G-LISA. Diabetes and overexpression of proNGF resulted in retinal neurodegeneration as indicated by 9- and 6-fold increase in TUNEL-positive cells, respectively. In vitro, proNGF induced 5-fold cell death in RGC-5 cell line, and it induced >10-fold cell death in primary RGC cultures. These effects were associated with significant upregulation of p75(NTR and activation of RhoA. While proNGF induced TNF-α expression in vivo, it selectively activated RhoA in primary RGC cultures and RGC-5 cell line. Inhibiting RhoA kinase with Y27632 significantly reduced diabetes- and proNGF-induced activation of proapoptotic p38MAPK/JNK, expression of cleaved-PARP and caspase-3 and prevented retinal neurodegeneration in vivo and in vitro. Taken together, these results provide compelling evidence for a causal role of proNGF in diabetes-induced retinal neurodegeneration through enhancing p75(NTR expression and direct activation of RhoA and p38MAPK/JNK apoptotic pathways.

  19. Permissive role of cytosolic pH acidification in neurodegeneration: A closer look at its causes and consequences.

    Majdi, Alireza; Mahmoudi, Javad; Sadigh-Eteghad, Saeed; Golzari, Samad E J; Sabermarouf, Babak; Reyhani-Rad, Siamak

    2016-10-01

    The maintenance of cytosolic pH in its physiological range is required for normal neuronal activity, and even minor alterations can have serious consequences. This Review summarizes the current understanding of the conditions that are associated with cytosolic pH disruption and that lead to abnormal cytosolic acidification. Oxidative stress results in cytosolic acidification, and this plays a crucial role in the emergence of apoptosis in protein misfolding and excitotoxicity, ultimately leading to irreversible neuronal damage. Through the identification of mechanisms by which intraneuronal pH acidification promotes neurodegeneration, we may identify new approaches for preventing and treating neurodegenerative disorders. © 2016 Wiley Periodicals, Inc. PMID:27282491

  20. Nasal Administration of Quercetin Liposomes Improves Memory Impairment and Neurodegeneration in Animal Model of Alzheimer's Disease

    Terdthai Tong-un

    2010-01-01

    Full Text Available Problem statement: At present, the development of protective strategy against Alzheimer’s Disease (AD is increasing its importance due to the high prevalence of AD, a limitation of therapeutic efficacy and its high impacts on economic and social aspects. The development of the preventive and therapeutic strategy to protect against the path physiology induced by free radicals in AD from antioxidant has gained very much concentration. Quercetin, one of the flavonoids in fruits and vegetables, has a powerful antioxidant activity both in vitro and in vivo. However, poor absorption, rapid metabolism and limited ability to cross the blood-brain-barrier are obstacles to its use for treatment of AD. Liposome’s have been used as an effective delivery system to the brain. Advantages associated with the nasal administration over oral route include higher bioavailability due to no first pass hepatic metabolism and rapid absorption leading to shorter time to onset of effect. Based on all these points, the possible effects of quercetin liposomes via nasal route on improving cognitive behavior and neurodegeneration in animal model of Alzheimer’s disease were investigated. Approach: Male Wistar rats were pretreated with quercetin liposome’s, containing 0.5 mg of quercetin in 20 μL (dose = 20 μg, via intranasal route once daily continually for 2 weeks before and 1 week after AF64A administration. Learning and memory was evaluated using the Morris water maze test at 7 days after the AF64A administration and then the rats were sacrificed for determining the density of neurons and cholinergic neurons in hippocampus using histological and immunohistochemical techniques. Results: Nasal administration of quercetin liposome’s significantly prevented changes of spatial memory of AF64A treated rats. The cognitive enhancement of quercetin liposome’s was found to be related to its ability to inhibit the degeneration of neurons and cholinergic neurons in hippocampus

  1. Pantothenate kinase-associated neurodegeneration: altered mitochondria membrane potential and defective respiration in Pank2 knock-out mouse model.

    Brunetti, Dario; Dusi, Sabrina; Morbin, Michela; Uggetti, Andrea; Moda, Fabio; D'Amato, Ilaria; Giordano, Carla; d'Amati, Giulia; Cozzi, Anna; Levi, Sonia; Hayflick, Susan; Tiranti, Valeria

    2012-12-15

    Neurodegeneration with brain iron accumulation (NBIA) comprises a group of neurodegenerative disorders characterized by high brain content of iron and presence of axonal spheroids. Mutations in the PANK2 gene, which encodes pantothenate kinase 2, underlie an autosomal recessive inborn error of coenzyme A metabolism, called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia, dysarthria, rigidity and pigmentary retinal degeneration. The pathogenesis of this disorder is poorly understood and, although PANK2 is a mitochondrial protein, perturbations in mitochondrial bioenergetics have not been reported. A knock-out (KO) mouse model of PKAN exhibits retinal degeneration and azoospermia, but lacks any neurological phenotype. The absence of a clinical phenotype has partially been explained by the different cellular localization of the human and murine PANK2 proteins. Here we demonstrate that the mouse Pank2 protein localizes to mitochondria, similar to its human orthologue. Moreover, we show that Pank2-defective neurons derived from KO mice have an altered mitochondrial membrane potential, a defect further corroborated by the observations of swollen mitochondria at the ultra-structural level and by the presence of defective respiration. PMID:22983956

  2. Apolipoprotein E-mimetics inhibit neurodegeneration and restore cognitive functions in a transgenic Drosophila model of Alzheimer's disease.

    Svetlana Sarantseva

    Full Text Available BACKGROUND: Mutations of the amyloid precursor protein gene (APP are found in familial forms of Alzheimer's disease (AD and some lead to the elevated production of amyloid-beta-protein (Abeta. While Abeta has been implicated in the causation of AD, the exact role played by Abeta and its APP precursor are still unclear. PRINCIPAL FINDINGS: In our study, Drosophila melanogaster transgenics were established as a model to analyze AD-like pathology caused by APP overexpression. We demonstrated that age related changes in the levels and pattern of synaptic proteins accompanied progressive neurodegeneration and impairment of cognitive functions in APP transgenic flies, but that these changes may be independent from the generation of Abeta. Using novel peptide mimetics of Apolipoprotein-E, COG112 or COG133 proved to be neuroprotective and significantly improved the learning and memory of APP transgenic flies. CONCLUSIONS: The development of neurodegeneration and cognitive deficits was corrected by injections of COG112 or COG133, novel mimetics of apolipoprotein-E (apoE with neuroprotective activities.

  3. Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration

    Chen, Kuchuan; Lin, Guang; Haelterman, Nele A; Ho, Tammy Szu-Yu; Li, Tongchao; Li, Zhihong; Duraine, Lita; Graham, Brett H; Jaiswal, Manish; Yamamoto, Shinya; Rasband, Matthew N; Bellen, Hugo J

    2016-01-01

    Mutations in Frataxin (FXN) cause Friedreich’s ataxia (FRDA), a recessive neurodegenerative disorder. Previous studies have proposed that loss of FXN causes mitochondrial dysfunction, which triggers elevated reactive oxygen species (ROS) and leads to the demise of neurons. Here we describe a ROS independent mechanism that contributes to neurodegeneration in fly FXN mutants. We show that loss of frataxin homolog (fh) in Drosophila leads to iron toxicity, which in turn induces sphingolipid synthesis and ectopically activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2). Dampening iron toxicity, inhibiting sphingolipid synthesis by Myriocin, or reducing Pdk1 or Mef2 levels, all effectively suppress neurodegeneration in fh mutants. Moreover, increasing dihydrosphingosine activates Mef2 activity through PDK1 in mammalian neuronal cell line suggesting that the mechanisms are evolutionarily conserved. Our results indicate that an iron/sphingolipid/Pdk1/Mef2 pathway may play a role in FRDA. DOI: http://dx.doi.org/10.7554/eLife.16043.001 PMID:27343351

  4. Gene Expression Profiling as a Tool to Investigate the Molecular Machinery Activated during Hippocampal Neurodegeneration Induced by Trimethyltin (TMT Administration

    Maria Concetta Geloso

    2013-08-01

    Full Text Available Trimethyltin (TMT is an organotin compound exhibiting neurotoxicant effects selectively localized in the limbic system and especially marked in the hippocampus, in both experimental animal models and accidentally exposed humans. TMT administration causes selective neuronal death involving either the granular neurons of the dentate gyrus or the pyramidal cells of the Cornu Ammonis, with a different pattern of localization depending on the different species studied or the dosage schedule. TMT is broadly used to realize experimental models of hippocampal neurodegeneration associated with cognitive impairment and temporal lobe epilepsy, though the molecular mechanisms underlying the associated selective neuronal death are still not conclusively clarified. Experimental evidence indicates that TMT-induced neurodegeneration is a complex event involving different pathogenetic mechanisms, probably acting differently in animal and cell models, which include neuroinflammation, intracellular calcium overload, and oxidative stress. Microarray-based, genome-wide expression analysis has been used to investigate the molecular scenario occurring in the TMT-injured brain in different in vivo and in vitro models, producing an overwhelming amount of data. The aim of this review is to discuss and rationalize the state-of-the-art on TMT-associated genome wide expression profiles in order to identify comparable and reproducible data that may allow focusing on significantly involved pathways.

  5. Isolation of a cdc28 mutation that abrogates the dependence of S phase on completion of M phase of the budding yeast cell cycle

    Santanu Kumar Ghosh; Pratima Sinha

    2000-01-01

    We have isolated a mutation in the budding yeast Saccharomyces cerevisisae CDC28 gene that allows cdc13 cells, carrying damaged DNA, to continue with the cell division cycle. While cdc13 mutant cells are arrested as large-budded cells at the nonpermissive temperature 37°C, the cdc13 cdc28 double mutant culture showed cells with one or more buds, most of which showed apical growth. The additional buds emerged without the intervening steps of nuclear division and cell separation. We suggest that the cdc28 mutation abrogates a checkpoint function and allows cells with damaged or incompletely replicated DNA an entry to another round of cell cycle and bypasses the mitotic phase of the cell cycle.

  6. Amitriptyline Activates TrkA to Aid Neuronal Growth and Attenuate Anesthesia-Induced Neurodegeneration in Rat Dorsal Root Ganglion Neurons.

    Zheng, Xiaochun; Chen, Feng; Zheng, Ting; Huang, Fengyi; Chen, Jianghu; Tu, Wenshao

    2016-05-01

    Tricyclic antidepressant amitriptyline (AM) has been shown to exert neurotrophic activity on neurons. We thus explored whether AM may aid the neuronal development and protect anesthesia-induced neuro-injury in young spinal cord dorsal root ganglion (DRG) neurons.The DRG explants were prepared from 1-day-old rats. The effect of AM on aiding DRG neural development was examined by immunohistochemistry at dose-dependent manner. AM-induced changes in gene and protein expressions, and also phosphorylation states of tyrosine kinases receptor A (TrkA) and B (TrkB) in DRG, were examined by quantitative real-time polymerase chain reaction and western blot. The effect of AM on attenuating lidocaine-induced DRG neurodegeneration was examined by immunohistochemistry, and small interfering RNA (siRNA)-mediated TrkA/B down-regulation.Amitriptyline stimulated DRG neuronal development in dose-dependent manner, but exerted toxic effect at concentrations higher than 10 M. AM activated TrkA in DRG through phosphorylation, whereas it had little effect on TrkB-signaling pathway. AM reduced lidocaine-induced DRG neurodegeneration by regenerating neurites and growth cones. Moreover, the neuroprotection of AM on lidocaine-injured neurodegeneration was blocked by siRNA-mediated TrkA down-regulation, but not by TrkB down-regulation.Amitriptyline facilitated neuronal development and had protective effect on lidocaine-induced neurodegeneration, very likely through the activation of TrkA-signaling pathway in DRG. PMID:27149473

  7. Peroxisome proliferator-activated receptor γ is expressed in hippocampal neurons and its activation prevents β-amyloid neurodegeneration: role of Wnt signaling

    The molecular pathogenesis of Alzheimer's disease (AD) involves the participation of the amyloid-β-peptide (Aβ), which plays a critical role in the neurodegeneration that triggers the disease. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which are members of the nuclear receptor family. We report here that (1) PPARγ is present in rat hippocampal neurons in culture. (2) Activation of PPARγ by troglitazone and rosiglitazone protects rat hippocampal neurons against Aβ-induced neurodegeneration, as shown by the 3-[4,5 -2yl]-2,5-diphenyltetrazolium bromide (MTT) reduction assay, immunofluorescence using an anti-heavy neurofilament antibody, and quantitative electron microscopy. (3) Hippocampal neurons treated with several PPARγ agonists, including troglitazone, rosiglitazone, and ciglitazone, prevent the excitotoxic Aβ-induced rise in bulk-free Ca2+. (4) PPARγ activation results in the modulation of Wnt signaling components, including the inhibition of glycogen synthase kinase-3β (GSK-3β) and an increase of the cytoplasmic and nuclear β-catenin levels. We conclude that the activation of PPARγ prevents Aβ-induced neurodegeneration by a mechanism that may involve a cross talk between neuronal PPARγ and the Wnt signaling pathway. More important, the fact that the activation of PPARγ attenuated Aβ-dependent neurodegeneration opens the possibility to fight AD from a new therapeutic perspective

  8. Correlation between Retinal Vessel Calibre and Neurodegeneration in Patients with Type 2 Diabetes Mellitus in the European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR)

    Frydkjaer-Olsen, Ulrik; Soegaard Hansen, Rasmus; Simó, Rafael;

    2016-01-01

    PURPOSE: To investigate the correlation between retinal vessel calibre and measurements of neurodegeneration in patients with type 2 diabetes (T2D) and no or early diabetic retinopathy (DR). METHODS: Baseline data on 440 patients with T2D from the EUROCONDOR clinical trial were used. DR was grade...

  9. Bill project aiming at abrogating exclusive search permits for unconventional hydrocarbon searches, and at prohibiting their exploration and exploitation of the national territory; Proposition de Loi visant a abroger les permis exclusifs de recherches d'hydrocarbures non conventionnels et a interdire leur exploration et leur exploitation sur le territoire national

    NONE

    2011-07-01

    After having briefly recalled the origin of shale gases, their extraction process and the evolution of their production in the USA, the authors outline the extremely negative environmental impacts of the fracking technique (hydraulic fracturing): water pollution, air pollution, soil pollution, existence of numerous drilling sites which would degrade landscapes, water and soil contamination risks. As some search permits have already been awarded, and while taking these negative consequences into account, the authors propose a bill project to prohibit these explorations, to abrogate the existing permits, and to ensure public information before bestowing such search permits and exploitation concessions

  10. Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy.

    Haack, Tobias B; Ignatius, Erika; Calvo-Garrido, Javier; Iuso, Arcangela; Isohanni, Pirjo; Maffezzini, Camilla; Lönnqvist, Tuula; Suomalainen, Anu; Gorza, Matteo; Kremer, Laura S; Graf, Elisabeth; Hartig, Monika; Berutti, Riccardo; Paucar, Martin; Svenningsson, Per; Stranneheim, Henrik; Brandberg, Göran; Wedell, Anna; Kurian, Manju A; Hayflick, Susan A; Venco, Paola; Tiranti, Valeria; Strom, Tim M; Dichgans, Martin; Horvath, Rita; Holinski-Feder, Elke; Freyer, Christoph; Meitinger, Thomas; Prokisch, Holger; Senderek, Jan; Wredenberg, Anna; Carroll, Christopher J; Klopstock, Thomas

    2016-09-01

    SQSTM1 (sequestosome 1; also known as p62) encodes a multidomain scaffolding protein involved in various key cellular processes, including the removal of damaged mitochondria by its function as a selective autophagy receptor. Heterozygous variants in SQSTM1 have been associated with Paget disease of the bone and might contribute to neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Using exome sequencing, we identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families with a childhood- or adolescence-onset neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline. We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts and found evidence of a defect in the early response to mitochondrial depolarization and autophagosome formation. Our findings expand the SQSTM1-associated phenotypic spectrum and lend further support to the concept of disturbed selective autophagy pathways in neurodegenerative diseases. PMID:27545679

  11. Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice.

    Jérôme Ausseil

    Full Text Available BACKGROUND: In mucopolysaccharidosis type IIIB, a lysosomal storage disease causing early onset mental retardation in children, the production of abnormal oligosaccharidic fragments of heparan sulfate is associated with severe neuropathology and chronic brain inflammation. We addressed causative links between the biochemical, pathological and inflammatory disorders in a mouse model of this disease. METHODOLOGY/PRINCIPAL FINDINGS: In cell culture, heparan sulfate oligosaccharides activated microglial cells by signaling through the Toll-like receptor 4 and the adaptor protein MyD88. CD11b positive microglial cells and three-fold increased expression of mRNAs coding for the chemokine MIP1alpha were observed at 10 days in the brain cortex of MPSIIIB mice, but not in MPSIIIB mice deleted for the expression of Toll-like receptor 4 or the adaptor protein MyD88, indicating early priming of microglial cells by heparan sulfate oligosaccharides in the MPSIIIB mouse brain. Whereas the onset of brain inflammation was delayed for several months in doubly mutant versus MPSIIIB mice, the onset of disease markers expression was unchanged, indicating similar progression of the neurodegenerative process in the absence of microglial cell priming by heparan sulfate oligosaccharides. In contrast to younger mice, inflammation in aged MPSIIIB mice was not affected by TLR4/MyD88 deficiency. CONCLUSIONS/SIGNIFICANCE: These results indicate priming of microglia by HS oligosaccharides through the TLR4/MyD88 pathway. Although intrinsic to the disease, this phenomenon is not a major determinant of the neurodegenerative process. Inflammation may still contribute to neurodegeneration in late stages of the disease, albeit independent of TLR4/MyD88. The results support the view that neurodegeneration is primarily cell autonomous in this pediatric disease.

  12. In vivo treatment with diphenyl ditelluride induces neurodegeneration in striatum of young rats: Implications of MAPK and Akt pathways

    Heimfarth, Luana; Loureiro, Samanta Oliveira; Dutra, Márcio Ferreira; Andrade, Cláudia; Pettenuzzo, Letícia; Guma, Fátima T. Costa Rodrigues; Gonçalves, Carlos Alberto Saraiva [Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, RS (Brazil); Batista Teixeira da Rocha, João [Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, RS Brazil (Brazil); Pessoa-Pureur, Regina, E-mail: rpureur@ufrgs.br [Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, RS (Brazil)

    2012-10-15

    In the present report 15 day-old Wistar rats were injected with 0.3 μmol of diphenyl ditelluride (PhTe){sub 2}/kg body weight and parameters of neurodegeneration were analyzed in slices from striatum 6 days afterwards. We found hyperphosphorylation of intermediate filament (IF) proteins from astrocyte (glial fibrillary acidic protein—GFAP and vimentin) and from neuron (low-, medium- and high molecular weight neurofilament subunits: NF-L, NF-M and NF-H, respectively) and increased MAPK (Erk, JNK and p38MAPK) as well as PKA activities. The treatment induced reactive astrogliosis in the striatum, evidenced by increased GFAP and vimentin immunocontent as well as their mRNA overexpression. Also, (PhTe){sub 2} significantly increased the propidium iodide (PI) positive cells in NeuN positive population without altering PI incorporation into GFAP positive cells, indicating that in vivo exposure to (PhTe){sub 2} provoked neuronal damage. Immunohistochemistry showed a dramatic increase of GFAP staining characteristic of reactive astrogliosis. Moreover, increased caspase 3 in (PhTe){sub 2} treated striatal slices suggested apoptotic cell death. (PhTe){sub 2} exposure decreased Akt immunoreactivity, however phospho-GSK-3-β (Ser9) was unaltered, suggesting that this kinase is not directly implicated in the neurotoxicity of this compound. Therefore, the present results shed light into the mechanisms of (PhTe){sub 2}-induced neurodegeneration in rat striatum, evidencing a critical role for the MAPK and Akt signaling pathways and disruption of cytoskeletal homeostasis, which could be related with apoptotic neuronal death and astrogliosis. -- Highlights: ► Diphenyl ditelluride causes apoptotic neuronal death in the striatum of young rats. ► Diphenyl ditelluride causes reactive astrogliosis in the striatum of rats. ► Diphenyl ditelluride disrupts the homeostasis of the cytoskeleton of the striatum. ► The actions of diphenyl ditelluride are mediated by MAPK and Akt

  13. Maternal epileptic seizure induced by Pentylenetetrazol: Apoptotic neurodegeneration and decreased GABAB1 receptor expression in prenatal rat brain

    Naseer Muhammad

    2009-06-01

    Full Text Available Abstract Epilepsy is a prominent sign of neurological dysfunction in children with various fetal and maternal deficiencies. However, the detailed mechanism and influences underlying epileptic disorders are still unrevealed. The hippocampal neurons are vulnerable to epilepsy-induced pathologic changes and often manifests as neuronal death. The present study was designed to investigate the effect of maternal epileptic seizure on apoptotic neuronal death, modulation of GABAB1 receptor (R, and protein kinase A-α (PKA in prenatal rat hippocampal neurons at gestational days (GD 17.5. Seizure was induced in pregnant rat using intraperitoneal injection of pentylenetetrazol (PTZ (40 mg/kg for 15 days. To confirm the seizure electroencephalography (EEG data was obtained by the Laxtha EEG-monitoring device in the EEG recording room and EEG were monitored 5 min and 15 min after PTZ injection. The RT-PCR and Western blot results showed significant increased expression of cytochrome-c and caspases-3, while decreased levels of GABAB1R, and PKA protein expression upon ethanol, PTZ and ethanol plus PTZ exposure in primary neuronal cells cultured from PTZ-induced seizure model as compare to non-PTZ treated maternal group. Apoptotic neurodegeneration was further confirmed with Fluoro-Jade B and propidium iodide staining, where neurons were scattered and shrunken, with markedly condensed nuclei in PTZ treated group compared with control. This study for the first time indicate that PTZ-induced seizures triggered activation of caspases-3 to induce widespread apoptotic neuronal death and decreased GABAB1R expression in hippocampal neurons, providing a possible mechanistic link between maternal epilepsy induced neurodegeneration alteration of GABAB1R and PKA expression level during prenatal brain development. This revealed new aspects of PTZ and ethanol's modulation on GABAB1R, learning and memory. Further, explain the possibility that children delivered by epileptic

  14. Different susceptibility to neurodegeneration of dorsal and ventral hippocampal dentate gyrus: a study with transgenic mice overexpressing GSK3β.

    Almudena Fuster-Matanzo

    Full Text Available Dorsal hippocampal regions are involved in memory and learning processes, while ventral areas are related to emotional and anxiety processes. Hippocampal dependent memory and behaviour alterations do not always come out in neurodegenerative diseases at the same time. In this study we have tested the hypothesis that dorsal and ventral dentate gyrus (DG regions respond in a different manner to increased glycogen synthase kinase-3β (GSK3β levels in GSK3β transgenic mice, a genetic model of neurodegeneration. Reactive astrocytosis indicate tissue stress in dorsal DG, while ventral area does not show that marker. These changes occurred with a significant reduction of total cell number and with a significantly higher level of cell death in dorsal area than in ventral one as measured by fractin-positive cells. Biochemistry analysis showed higher levels of phosphorylated GSK3β in those residues that inactivate the enzyme in hippocampal ventral areas compared with dorsal area suggesting that the observed susceptibility is in part due to different GSK3 regulation. Previous studies carried out with this animal model had demonstrated impairment in Morris Water Maze and Object recognition tests point out to dorsal hippocampal atrophy. Here, we show that two tests used to evaluate emotional status, the light-dark box and the novelty suppressed feeding test, suggest that GSK3β mice do not show any anxiety-related disorder. Thus, our results demonstrate that in vivo overexpression of GSK3β results in dorsal but not ventral hippocampal DG neurodegeneration and suggest that both areas do not behave in a similar manner in neurodegenerative processes.

  15. A new in vivo model of pantothenate kinase-associated neurodegeneration reveals a surprising role for transcriptional regulation in pathogenesis.

    Varun ePandey

    2013-09-01

    Full Text Available Pantothenate Kinase-Associated Neurodegeneration (PKAN is a neurodegenerative disorder with a poorly understood molecular mechanism. It is caused by mutations in Pantothenate Kinase, the first enzyme in the Coenzyme A (CoA biosynthetic pathway. Here, we developed a Drosophila model of PKAN (tim-fbl flies that allows us to continuously monitor the modeled disease in the brain. In tim-fbl flies, downregulation of fumble, the Drosophila PanK homologue in the cells containing a circadian clock results in characteristic features of PKAN such as developmental lethality, hypersensitivity to oxidative stress, and diminished life span. Despite quasi-normal circadian transcriptional rhythms, tim-fbl flies display brain-specific aberrant circadian locomotor rhythms, and a unique transcriptional signature. Comparison with expression data from flies exposed to paraquat demonstrates that, as previously suggested, pathways others than oxidative stress are affected by PANK downregulation. Surprisingly we found a significant decrease in the expression of key components of the photoreceptor recycling pathways, which could lead to retinal degeneration, a hallmark of PKAN. Importantly, these defects are not accompanied by changes in structural components in eye genes suggesting that changes in gene expression in the eye precede and may cause the retinal degeneration. Indeed tim-fbl flies have diminished response to light transitions, and their altered day/night patterns of activity demonstrates defects in light perception. This suggest that retinal lesions are not solely due to oxidative stress and demonstrates a role for the transcriptional response to CoA deficiency underlying the defects observed in dPanK deficient flies. Moreover, in the present study we developed a new fly model that can be applied to other diseases and that allows the assessment of neurodegeneration in the brains of living flies.

  16. Knockdown of platinum-induced growth differentiation factor 15 abrogates p27-mediated tumor growth delay in the chemoresistant ovarian cancer model A2780cis

    Molecular mechanisms underlying the development of resistance to platinum-based treatment in patients with ovarian cancer remain poorly understood. This is mainly due to the lack of appropriate in vivo models allowing the identification of resistance-related factors. In this study, we used human whole-genome microarrays and linear model analysis to identify potential resistance-related genes by comparing the expression profiles of the parental human ovarian cancer model A2780 and its platinum-resistant variant A2780cis before and after carboplatin treatment in vivo. Growth differentiation factor 15 (GDF15) was identified as one of five potential resistance-related genes in the A2780cis tumor model. Although A2780-bearing mice showed a strong carboplatin-induced increase of GDF15 plasma levels, the basal higher GDF15 plasma levels of A2780cis-bearing mice showed no further increase after short-term or long-term carboplatin treatment. This correlated with a decreased DNA damage response, enhanced AKT survival signaling and abrogated cell cycle arrest in the carboplatin-treated A2780cis tumors. Furthermore, knockdown of GDF15 in A2780cis cells did not alter cell proliferation but enhanced cell migration and colony size in vitro. Interestingly, in vivo knockdown of GDF15 in the A2780cis model led to a basal-enhanced tumor growth, but increased sensitivity to carboplatin treatment as compared to the control-transduced A2780cis tumors. This was associated with larger necrotic areas, a lobular tumor structure and increased p53 and p16 expression of the carboplatin-treated shGDF15-A2780cis tumors. Furthermore, shRNA-mediated GDF15 knockdown abrogated p27 expression as compared to control-transduced A2780cis tumors. In conclusion, these data show that GDF15 may contribute to carboplatin resistance by suppressing tumor growth through p27. These data show that GDF15 might serve as a novel treatment target in women with platinum-resistant ovarian cancer

  17. The Thomsen-Friedenreich antigen-binding lectin jacalin interacts with desmoglein-1 and abrogates the pathogenicity of pemphigus foliaceus autoantibodies in vivo.

    Li, Ning; Park, Moonhee; Zhao, Minglang; Hilario-Vargas, Julio; McInnes, David M; Prisayanh, Phillip S; Liu, Zhi; Diaz, Luis A

    2010-12-01

    Pemphigus foliaceus (PF) is an autoimmune skin blistering disease mediated by pathogenic autoantibodies against the desmosomal core glycoprotein desmoglein-1 (Dsg1). This study demonstrated that the O-glycan-specific plant lectin jacalin binds Dsg1 and inhibits the interaction of Dsg1/PF IgG. N-glycosylation is not involved in the interaction of Dsg1/jacalin or Dsg1/PF IgG. Subcutaneous injection of jacalin into neonatal mice drastically reduced PF IgG deposition at the epidermal cell surface and blocked PF IgG-induced skin blisters, both clinically and histologically. Interestingly, another plant lectin, peanut agglutinin, which shares the same carbohydrate specificity toward the O-linked carbohydrate structure known as Thomsen-Friedenreich antigen (TF antigen, Galβ1-3GalNAcα-O-Ser/Thr), also bound Dsg1 and blocked the skin blistering. In contrast, the plant lectin vicia villosa-B4 (VVL-B4), which shares the carbohydrate specificity toward the O-linked monosaccharide known as Thomsen-nouveau antigen (GalNAc-α1-O-Ser/Thr), did not bind Dsg1 and did not show a protective effect against the disease induced by the autoantibodies. Collectively, these results suggest that the binding of jacalin to O-linked TF carbohydrate motifs on Dsg1 impairs the Dsg1/PF autoantibody interactions and abrogates its pathogenicity in vivo. TF-specific binding ligands may have a potential therapeutic value for PF. PMID:20631728

  18. PF573,228 inhibits vascular tumor cell growth, migration as well as angiogenesis, induces apoptosis and abrogates PRAS40 and S6RP phosphorylation.

    Mabeta, Peace

    2016-09-01

    PF573,228 is a compound that targets focal adhesion kinase (FAK), a non-receptor protein kinase, which is over-expressed in various tumors. The aim of this study was to evaluate the effects of PF573,228 on the cells derived from mouse vascular tumors, namely, endothelioma cells. The treatment of endothelioma cells with PF573,228 reduced their growth with an IC50 of approximately 4.6 μmol L-1 and inhibited cell migration with an IC50 of about 0.01 μmol L-1. Microscopic studies revealed morphological attributes of apoptosis. These observations were confirmed by ELISA, which showed increased caspase-3 activity. PF573,228 also inhibited angiogenesis in a dose-dependent manner, with an IC50 of approximately 3.7 μmol L-1, and abrogated the phosphorylation of cell survival proteins, proline-rich Akt substrate (PRAS40) and S6 ribosomal protein (S6RP). Array data further revealed that PF573,228 induced caspase-3 activation, thus promoting apoptosis. Since all the processes inhibited by PF573,228 provide important support to tumor survival and progression, the drug may have a potential role in the treatment of vascular tumors. PMID:27383888

  19. Y-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model.

    Siveen, Kodappully Sivaraman; Ahn, Kwang Seok; Ong, Tina H; Shanmugam, Muthu K; Li, Feng; Yap, Wei Ney; Kumar, Alan Prem; Fong, Chee Wai; Tergaonkar, Vinay; Hui, Kam M; Sethi, Gautam

    2014-04-15

    Angiogenesis is one of the key hallmarks of cancer. In this study, we investigated whether γ-tocotrienol can abrogate angiogenesis-mediated tumor growth in hepatocellular carcinoma (HCC) and if so, through what molecular mechanisms. We observed that γ-tocotrienol inhibited vascular endothelial growth factor (VEGF)-induced migration, invasion, tube formation and viability of HUVECs in vitro. Moreover, γ-tocotrienol reduced the number of capillary sprouts from matrigel embedded rat thoracic aortic ring in a dose-dependent manner. Also, in chick chorioallantoic membrane assay, γ-tocotrienol significantly reduced the blood vessels formation. We further noticed that γ-tocotrienol blocked angiogenesis in an in vivo matrigel plug assay. Furthermore, γ-tocotrienol inhibited VEGF-induced autophosphorylation of VEGFR2 in HUVECs and also suppressed the constitutive activation of AKT/mammalian target of rapamycin (mTOR) signal transduction cascades in HUVECs as well as in HCC cells. Interestingly, γ-tocotrienol was also found to significantly reduce the tumor growth in an orthotopic HCC mouse model and inhibit tumor-induced angiogenesis in HCC patient xenografts through the suppression of various biomarkers of proliferation and angiogenesis. Taken together, our findings strongly suggest that γ-tocotrienol might be a promising anti-angiogenic drug with significant antitumor activity in HCC. PMID:24722367

  20. Environmental exposure to lead induces oxidative stress and modulates the function of the antioxidant defense system and the immune system in the semen of males with normal semen profile

    We investigated the associations between environmental exposure to lead and a repertoire of cytokines in seminal plasma of males with normal semen profile according to the WHO criteria. Based on the median lead concentration in seminal plasma, 65 samples were divided into two groups: low (LE) and high exposure to lead (HE). Differences in semen volume and the pH, count, motility and morphology of sperm cells were not observed between the examined groups. The total oxidant status value and the level of protein sulfhydryl groups as well as the activities of manganese superoxide dismutase and catalase were significantly higher in the HE group, whereas the total antioxidant capacity value and the activities of glutathione reductase and glutathione-S-transferase were depressed. IL-7, IL-10, IL-12, and TNF-α levels were significantly higher in the HE group compared with the LE group. Environmental exposure to lead is sufficient to induce oxidative stress in seminal plasma and to modulate antioxidant defense system. - Highlights: • Lead induces oxidative stress in seminal plasma in human. • Lead modulates antioxidant defense system in seminal plasma in human. • Lead does not change a Th1/Th2 imbalance in seminal plasma in human

  1. Environmental exposure to lead induces oxidative stress and modulates the function of the antioxidant defense system and the immune system in the semen of males with normal semen profile

    Kasperczyk, Aleksandra; Dobrakowski, Michał [Dept. of Biochemistry, School of Medicine with the Division of Dentistry, Medical University of Silesia, Katowice, Jordana 19, 41-808 Zabrze (Poland); Czuba, Zenon P. [Dept. of Microbiology and Immunology, School of Medicine with the Division of Dentistry, Medical University of Silesia, Katowice, Jordana 19, 41-808 Zabrze (Poland); Horak, Stanisław [I-st Chair and Clin. Dept. of Gynecology, Obstetrics and Gynecological Oncology, School of Medicine with the Division of Dentistry, Medical University of Silesia, Katowice, Batorego 15, 41-902 Bytom (Poland); Kasperczyk, Sławomir, E-mail: kaslav@mp.pl [Dept. of Biochemistry, School of Medicine with the Division of Dentistry, Medical University of Silesia, Katowice, Jordana 19, 41-808 Zabrze (Poland)

    2015-05-01

    We investigated the associations between environmental exposure to lead and a repertoire of cytokines in seminal plasma of males with normal semen profile according to the WHO criteria. Based on the median lead concentration in seminal plasma, 65 samples were divided into two groups: low (LE) and high exposure to lead (HE). Differences in semen volume and the pH, count, motility and morphology of sperm cells were not observed between the examined groups. The total oxidant status value and the level of protein sulfhydryl groups as well as the activities of manganese superoxide dismutase and catalase were significantly higher in the HE group, whereas the total antioxidant capacity value and the activities of glutathione reductase and glutathione-S-transferase were depressed. IL-7, IL-10, IL-12, and TNF-α levels were significantly higher in the HE group compared with the LE group. Environmental exposure to lead is sufficient to induce oxidative stress in seminal plasma and to modulate antioxidant defense system. - Highlights: • Lead induces oxidative stress in seminal plasma in human. • Lead modulates antioxidant defense system in seminal plasma in human. • Lead does not change a Th1/Th2 imbalance in seminal plasma in human.

  2. Electron Transport Disturbances and Neurodegeneration: From Albert Szent-Györgyi's Concept (Szeged) till Novel Approaches to Boost Mitochondrial Bioenergetics

    Levente Szalárdy; Dénes Zádori; Péter Klivényi; József Toldi; László Vécsei

    2015-01-01

    Impaired function of certain mitochondrial respiratory complexes has long been linked to the pathogenesis of chronic neurodegenerative disorders such as Parkinson’s and Huntington’s diseases. Furthermore, genetic alterations of mitochondrial genome or nuclear genes encoding proteins playing essential roles in maintaining proper mitochondrial function can lead to the development of severe systemic diseases associated with neurodegeneration and vacuolar myelinopathy. At present, all of these di...

  3. Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model

    Brunetti, D.; Dusi, S.; C. Giordano; Lamperti, C; Morbin, M; Fugnanesi, V.; Marchet, S.; Fagiolari, G.; Sibon, O.; Moggio, M.; d'Amati, G.; TIRANTI, V.

    2013-01-01

    Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2, responsible for the phosphorylation of pantothenate or vitamin B5 in the biosynthesis of co-enzyme A. A Pank2 knockout (Pank2−/− ) mouse model did not recapitulate the human disease but showed azo...

  4. TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson¿s disease

    Rayaprolu, Sruti; Mullen, Bianca; Baker, Matt; Lynch, Timothy; Finger, Elizabeth; Seeley, William W.; Hatanpaa, Kimmo J.; Lomen-Hoerth, Catherine; Kertesz, Andrew; Bigio, Eileen H; Lippa, Carol; Josephs, Keith A.; Knopman, David S.; White, Charles L.; Caselli, Richard

    2013-01-01

    Abstract Background A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we s...

  5. Conditional Expression of Parkinson's Disease-Related R1441C LRRK2 in Midbrain Dopaminergic Neurons of Mice Causes Nuclear Abnormalities without Neurodegeneration

    Tsika, Elpida; Kannan, Meghna; Foo, Caroline Shi-Yan; Dikeman, Dustin; Glauser, Liliane; Gellhaar, Sandra; Galter, Dagmar; Knott, Graham W.; Ted M Dawson; Dawson, Valina L.; Moore, Darren J.

    2014-01-01

    Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant Parkinson's disease (PD). The clinical and neurochemical features of LRRK2-linked PD are similar to idiopathic disease although neuropathology is somewhat heterogeneous. Dominant mutations in LRRK2 precipitate neurodegeneration through a toxic gain-of-function mechanism which can be modeled in transgenic mice overexpressing human LRRK2 variants. A number of LRRK2 transgenic mouse models have been d...

  6. Diabetic Retinal Neurodegeneration Is Associated With Mitochondrial Oxidative Stress and Is Improved by an Angiotensin Receptor Blocker in a Model Combining Hypertension and Diabetes

    Silva, Kamila C.; Rosales, Mariana A.B.; Biswas, Subrata K.; Lopes de Faria, Jose B.; Lopes de Faria, Jacqueline M.

    2009-01-01

    OBJECTIVE Diabetic retinopathy displays the features of a neurodegenerative disease. Oxidative stress is involved in the pathogenesis of diabetic retinopathy. This investigation sought to determine whether hypertension exacerbates the oxidative stress, neurodegeneration, and mitochondrial dysfunction that exists in diabetic retinopathy and whether these changes could be minimized by the angiotensin II type 1 (AT1) receptor blocker (ARB) losartan. RESEARCH DESIGN AND METHODS Diabetes was induc...

  7. Protective effect of naringin on 3-nitropropionic acid-induced neurodegeneration through the modulation of matrix metalloproteinases and glial fibrillary acidic protein.

    Gopinath, Kulasekaran; Sudhandiran, Ganapasam

    2016-01-01

    Naringin (4',5,7-trihydroxy-flavonone-7-rhamnoglucoside), a flavonone present in grapefruit, has recently been reported to protect against neurodegeration, induced with 3-nitropropionic acid (3-NP), through its antioxidant, anti-inflammatory, and antiapoptotic properties. This study used a rat model of 3-NP-induced neurodegeneration to investigate the neuroprotective effects of naringin exerted by modulating the expression of matrix metalloproteinases and glial fibrillary acidic protein. Neurodegeneration was induced with 3-NP (10 mg/kg body mass, by intraperitoneal injection) once a day for 2 weeks, and induced rats were treated with naringin (80 mg/kg body mass, by oral gavage, once a day for 2 weeks). Naringin ameliorated the motor abnormalities caused by 3-NP, and reduced blood-brain barrier dysfunction by decreasing the expression of matrix metalloproteinases 2 and 9, along with increasing the expression of the tissue inhibitors of metalloproteinases 1 and 2 in 3-NP-induced rats. Further, naringin reduced 3-NP-induced neuroinflammation by decreasing the expression of nuclear factor-kappa B and glial fibrillary acidic protein. Thus, naringin exerts protective effects against 3-NP-induced neurodegeneration by ameliorating the expressions of matrix metalloproteinases and glial fibrillary acidic protein. PMID:26544788

  8. Interaction between misfolded PrP and the ubiquitin-proteasome system in prion-mediated neurodegeneration

    Zhu Lin; Deming Zhao; Lifeng Yang

    2013-01-01

    Prion diseases are associated with the conformational conversion of cellular prion protein (PrPC) to pathological β-sheet isoforms (PrpSc),which is the infectious agent beyond comprehension.Increasing evidence indicated that an unknown toxic gain of function of PrPSc underlies neuronal death.Conversely,strong evidence indicated that cellular prion protein might be directly cytotoxic by mediating neurotoxic signaling of β-sheet-rich conformers independent of prion replication.Furthermore,the common properties of β-sheet-rich isoform such as PrPSc and β amyloid protein become the lynchpin that interprets the general pathological mechanism of protein misfolding diseases.Dysfunction of the ubiquitin-proteasome system (UPS) has been implicated in various protein misfolding diseases.However,the mechanisms of this impairment remain unknown in many cases.In prion disease,prioninfected mouse brains have increased levels of ubiquitin conjugates,which correlate with decreased proteasome function.Both PrPC and PrPsc accumulate in cells after proteasome inhibition,which leads to increased cell death.A direct interaction between 20S core particle and PrP isoforms was demonstrated.Here we review the ability of misfolded PrP and UPS to affect each other,which might contribute to the pathological features of prion-mediated neurodegeneration.

  9. Cognitive performance and cerebrospinal fluid biomarkers of neurodegeneration: a study of patients with bipolar disorder and healthy controls.

    Sindre Rolstad

    Full Text Available The purpose of the present study was to investigate if cerebrospinal fluid (CSF biomarkers of neurodegeneration are associated with cognition in bipolar disorder and healthy controls, respectively. CSF concentrations of total and phosphorylated tau, amyloid beta (Aβ1-42, ratios of Aβ42/40 and Aβ42/38, soluble amyloid precursor protein α and β, and neurofilament light chain protein were analyzed in relation to neuropsychological performance in 82 euthymic bipolar disorder patients and 71 healthy controls. Linear regression models were applied to account for performance in five cognitive domains using the CSF biomarkers. In patients, the CSF biomarkers explained a significant proportion of the variance (15-36%, p=.002 - <.0005 in all cognitive domains independently of age, medication, disease status, and bipolar subtype I or II. However, the CSF biomarkers specifically mirroring Alzheimer-type brain changes, i.e., P-tau and Aβ1-42, did not contribute significantly. In healthy controls, CSF biomarkers did not explain the variance in cognitive performance. Selected CSF biomarkers of neurodegenerative processes accounted for cognitive performance in persons with bipolar disorder, but not for healthy controls. Specifically, the ratios of Aβ42/40 and Aβ42/38 were consistently associated with altered cognitive performance.

  10. Impaired Coenzyme A metabolism affects histone and tubulin acetylation in Drosophila and human cell models of pantothenate kinase associated neurodegeneration.

    Siudeja, Katarzyna; Srinivasan, Balaji; Xu, Lanjun; Rana, Anil; de Jong, Jannie; Nollen, Ellen A A; Jackowski, Suzanne; Sanford, Lynn; Hayflick, Susan; Sibon, Ody C M

    2011-12-01

    Pantothenate kinase-associated neurodegeneration (PKAN is a neurodegenerative disease with unresolved pathophysiology. Previously, we observed reduced Coenzyme A levels in a Drosophila model for PKAN. Coenzyme A is required for acetyl-Coenzyme A synthesis and acyl groups from the latter are transferred to lysine residues of proteins, in a reaction regulated by acetyltransferases. The tight balance between acetyltransferases and their antagonistic counterparts histone deacetylases is a well-known determining factor for the acetylation status of proteins. However, the influence of Coenzyme A levels on protein acetylation is unknown. Here we investigate whether decreased levels of the central metabolite Coenzyme A induce alterations in protein acetylation and whether this correlates with specific phenotypes of PKAN models. We show that in various organisms proper Coenzyme A metabolism is required for maintenance of histone- and tubulin acetylation, and decreased acetylation of these proteins is associated with an impaired DNA damage response, decreased locomotor function and decreased survival. Decreased protein acetylation and the concurrent phenotypes are partly rescued by pantethine and HDAC inhibitors, suggesting possible directions for future PKAN therapy development. PMID:21998097

  11. Systemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration.

    Sankowski, Roman; Mader, Simone; Valdés-Ferrer, Sergio Iván

    2015-01-01

    The nervous and immune systems have evolved in parallel from the early bilaterians, in which innate immunity and a central nervous system (CNS) coexisted for the first time, to jawed vertebrates and the appearance of adaptive immunity. The CNS feeds from, and integrates efferent signals in response to, somatic and autonomic sensory information. The CNS receives input also from the periphery about inflammation and infection. Cytokines, chemokines, and damage-associated soluble mediators of systemic inflammation can also gain access to the CNS via blood flow. In response to systemic inflammation, those soluble mediators can access directly through the circumventricular organs, as well as open the blood-brain barrier. The resulting translocation of inflammatory mediators can interfere with neuronal and glial well-being, leading to a break of balance in brain homeostasis. This in turn results in cognitive and behavioral manifestations commonly present during acute infections - including anorexia, malaise, depression, and decreased physical activity - collectively known as the sickness behavior (SB). While SB manifestations are transient and self-limited, under states of persistent systemic inflammatory response the cognitive and behavioral changes can become permanent. For example, cognitive decline is almost universal in sepsis survivors, and a common finding in patients with systemic lupus erythematosus. Here, we review recent genetic evidence suggesting an association between neurodegenerative disorders and persistent immune activation; clinical and experimental evidence indicating previously unidentified immune-mediated pathways of neurodegeneration; and novel immunomodulatory targets and their potential relevance for neurodegenerative disorders. PMID:25698933

  12. Systemic Inflammation and the Brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration.

    Roman Sankowski

    2015-02-01

    Full Text Available The nervous and immune systems have evolved in parallel from the early bilaterians, in which innate immunity and a central nervous system coexisted for the first time, to jawed vertebrates and the appearance of adaptive immunity. The central nervous system (CNS feeds from, and integrates efferent signals in response to, somatic and autonomic sensory information. The CNS receives input also from the periphery about inflammation and infection. Cytokines, chemokines, damage-associated soluble mediators of systemic inflammation can also gain access to the CNS via blood flow. In response to systemic inflammation, those soluble mediators can access directly through the circumventricular organs, as well as open the blood-brain barrier (BBB. The resulting translocation of inflammatory mediators can interfere with neuronal and glial well-being, leading to a break of balance in brain homeostasis. This in turn results in cognitive and behavioral manifestations commonly present during acute infections -including anorexia, malaise, depression, and decreased physical activity- collectively known as the sickness behavior (SB. While SB manifestations are transient and self-limited, under states of persistent systemic inflammatory response the cognitive and behavioral changes can become permanent. For example, cognitive decline is almost universal in sepsis survivors, and a common finding in patients with systemic lupus erythematosus (SLE. Here, we review recent genetic evidence suggesting an association between neurodegenerative disorders and persistent immune activation; clinical and experimental evidence indicating previously unidentified immune-mediated pathways of neurodegeneration; and novel immunomodulatory targets and their potential relevance for neurodegenerative disorders.

  13. The role of iron in neurodegeneration - Mössbauer spectroscopy, electron microscopy, enzyme-linked immunosorbent assay and neuroimaging studies

    The possible role of iron in neurodegeneration was studied by various techniques: electron microscopy, enzyme-linked immunosorbent assay, Mössbauer spectroscopy, atomic absorption, ultrasonography and magnetic resonance imaging. The measurements were made on human tissues extracted from liver and from brain structures involved in diseases of the human brain: substantia nigra (Parkinson’s, PD), hippocampal cortex (Alzheimer’s, AD) and globus pallidus (progressive supranuclear palsy, PSP). The sizes of the iron cores of ferritin, the main iron storage compound in tissues, were found to be smaller in brain than in liver. Brain ferritin has a higher proportion of H to L chains compared to liver. A significant decrease of the concentration of L chains in PD compared to control was found. No increase in the concentration of iron in PD versus control was detected; however, there was an increase of labile iron, which constitutes only 2‰ of brain iron. In AD an increase in the concentration of ferritin was noticed, without a significant increase in iron concentration. In PSP an increase of total iron was observed. Our findings suggest that the mechanisms leading to the death of nerve cells in these three diseases may be different, although all may be related to iron mediated oxidative stress. (paper)

  14. Development of passive CLARITY and immunofluorescent labelling of multiple proteins in human cerebellum: understanding mechanisms of neurodegeneration in mitochondrial disease

    Phillips, Jonathan; Laude, Alex; Lightowlers, Robert; Morris, Chris M.; Turnbull, Doug M.; Lax, Nichola Z.

    2016-01-01

    CLARITY enables immunofluorescent labelling and imaging of large volumes of tissue to provide a better insight into the three dimensional relationship between cellular morphology and spatial interactions between different cell types. In the current study, we optimise passive CLARITY and immunofluorescent labelling of neurons and mitochondrial proteins in mouse and human brain tissues to gain further insights into mechanisms of neurodegeneration occurring in mitochondrial disease. This is the first study to utilise human cerebellum fixed in paraformaldehyde and cryoprotected in conjunction with formalin-fixed tissues opening up further avenues for use of archived tissue. We optimised hydrogel-embedding and passive clearance of lipids from both mouse (n = 5) and human (n = 9) cerebellum as well as developing an immunofluorescent protocol that consistently labels different neuronal domains as well as blood vessels. In addition to visualising large structures, we were able to visualise mitochondrial proteins in passively cleared tissues to reveal respiratory chain deficiency associated with mitochondrial disease. We also demonstrate multiple use of tissues by stripping antibodies and re-probing the cerebellum. This technique allows interrogation of large volumes intact brain samples for better understanding of the complex pathological changes taking place in mitochondrial disease. PMID:27181107

  15. SOD1 and DJ-1 Converge at Nrf2 Pathway: A Clue for Antioxidant Therapeutic Potential in Neurodegeneration

    Pamela Milani

    2013-01-01

    Full Text Available Neurodegenerative diseases share diverse pathological features and among these oxidative stress (OS plays a leading role. Impaired activity and reduced expression of antioxidant proteins have been reported as common events in several aging-associated disorders. In this review paper, we first provide an overview of the involvement of reactive oxygen species- (ROS- induced oxidative damage in Parkinson's disease (PD and amyotrophic lateral sclerosis (ALS. Subsequently, we focus on DJ-1 and SOD1 proteins, which are involved in PD and ALS and also exert a prominent role in the interaction between redox homeostasis and neurodegeneration. Interestingly, recent studies demonstrated that DJ-1 and SOD1 are both tightly connected with Nrf2 protein, a transcriptional factor and master regulator of the expression of many antioxidant/detoxification genes. Nrf2 is emerging as a key neuroprotective protein in neurodegenerative diseases, since it helps neuronal cells to cope with toxic insults and OS. We herein summarize the recent literature providing a detailed picture of the promising therapeutic efficacy of Nrf2 natural and synthetic inducers as disease-modifying molecules for the treatment of neurodegenerative diseases.

  16. Cognitive performance and cerebrospinal fluid biomarkers of neurodegeneration: a study of patients with bipolar disorder and healthy controls.

    Rolstad, Sindre; Jakobsson, Joel; Sellgren, Carl; Ekman, Carl-Johan; Blennow, Kaj; Zetterberg, Henrik; Pålsson, Erik; Landén, Mikael

    2015-01-01

    The purpose of the present study was to investigate if cerebrospinal fluid (CSF) biomarkers of neurodegeneration are associated with cognition in bipolar disorder and healthy controls, respectively. CSF concentrations of total and phosphorylated tau, amyloid beta (Aβ)1-42, ratios of Aβ42/40 and Aβ42/38, soluble amyloid precursor protein α and β, and neurofilament light chain protein were analyzed in relation to neuropsychological performance in 82 euthymic bipolar disorder patients and 71 healthy controls. Linear regression models were applied to account for performance in five cognitive domains using the CSF biomarkers. In patients, the CSF biomarkers explained a significant proportion of the variance (15-36%, p=.002 - bipolar subtype I or II. However, the CSF biomarkers specifically mirroring Alzheimer-type brain changes, i.e., P-tau and Aβ1-42, did not contribute significantly. In healthy controls, CSF biomarkers did not explain the variance in cognitive performance. Selected CSF biomarkers of neurodegenerative processes accounted for cognitive performance in persons with bipolar disorder, but not for healthy controls. Specifically, the ratios of Aβ42/40 and Aβ42/38 were consistently associated with altered cognitive performance. PMID:25954806

  17. Alleviation of neuronal energy deficiency by mTOR inhibition as a treatment for mitochondria-related neurodegeneration

    Zheng, Xinde; Boyer, Leah; Jin, Mingji; Kim, Yongsung; Fan, Weiwei; Bardy, Cedric; Berggren, Travis; Evans, Ronald M; Gage, Fred H; Hunter, Tony

    2016-01-01

    mTOR inhibition is beneficial in neurodegenerative disease models and its effects are often attributable to the modulation of autophagy and anti-apoptosis. Here, we report a neglected but important bioenergetic effect of mTOR inhibition in neurons. mTOR inhibition by rapamycin significantly preserves neuronal ATP levels, particularly when oxidative phosphorylation is impaired, such as in neurons treated with mitochondrial inhibitors, or in neurons derived from maternally inherited Leigh syndrome (MILS) patient iPS cells with ATP synthase deficiency. Rapamycin treatment significantly improves the resistance of MILS neurons to glutamate toxicity. Surprisingly, in mitochondrially defective neurons, but not neuroprogenitor cells, ribosomal S6 and S6 kinase phosphorylation increased over time, despite activation of AMPK, which is often linked to mTOR inhibition. A rapamycin-induced decrease in protein synthesis, a major energy-consuming process, may account for its ATP-saving effect. We propose that a mild reduction in protein synthesis may have the potential to treat mitochondria-related neurodegeneration. DOI: http://dx.doi.org/10.7554/eLife.13378.001 PMID:27008180

  18. Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold.

    Boettger, Thomas; Rust, Marco B; Maier, Hannes; Seidenbecher, Thomas; Schweizer, Michaela; Keating, Damien J; Faulhaber, Jörg; Ehmke, Heimo; Pfeffer, Carsten; Scheel, Olaf; Lemcke, Beate; Horst, Jürgen; Leuwer, Rudolf; Pape, Hans-Christian; Völkl, Harald; Hübner, Christian A; Jentsch, Thomas J

    2003-10-15

    K-Cl co-transporters are encoded by four homologous genes and may have roles in transepithelial transport and in the regulation of cell volume and cytoplasmic chloride. KCC3, an isoform mutated in the human Anderman syndrome, is expressed in brain, epithelia and other tissues. To investigate the physiological functions of KCC3, we disrupted its gene in mice. This severely impaired cell volume regulation as assessed in renal tubules and neurons, and moderately raised intraneuronal Cl(-) concentration. Kcc3(-/-) mice showed severe motor abnormalities correlating with a progressive neurodegeneration in the peripheral and CNS. Although no spontaneous seizures were observed, Kcc3(-/-) mice displayed reduced seizure threshold and spike-wave complexes on electrocorticograms. These resembled EEG abnormalities in patients with Anderman syndrome. Kcc3(-/-) mice also displayed arterial hypertension and a slowly progressive deafness. KCC3 was expressed in many, but not all cells of the inner ear K(+) recycling pathway. These cells slowly degenerated, as did sensory hair cells. The present mouse model has revealed important cellular and systemic functions of KCC3 and is highly relevant for Anderman syndrome. PMID:14532115

  19. Changes in oxidative stress parameters and neurodegeneration markers in the brain of the senescence-accelerated mice SAMP-8.

    Sureda, Francesc X; Gutierrez-Cuesta, Javier; Romeu, Marta; Mulero, Miquel; Canudas, Anna Maria; Camins, Antoni; Mallol, Jordi; Pallàs, Mercè

    2006-04-01

    The senescence-accelerated strains of mice (SAMP) are well-characterized animal models of senescence. Senescence may be related to enhanced production or defective control of reactive oxygen species, which lead to neuronal damage. Therefore, the activity of various oxidative-stress related enzymes was determined in the cortex of 5 months-old senescence-accelerated mice prone-8 (SAMP-8) of both sexes and compared with senescence-accelerated mice-resistant-1 (SAMR-1). Glutathione reductase and peroxidase activities in SAMP-8 male mice were lower than in male SAMR-1, and a decreased catalase activity was found in both male and female SAMP-8 mice, which correlates with the lower catalase expression found by Western blotting. Nissl staining showed marked loss of neuronal cells in the cerebral cortex of five month-old SAMP-8 mice. SAMP-8 mice also had marked astrogliosis and microgliosis. We also found an increase in caspase-3 and calpain activity in the cortex. In addition, we observed morphological changes in the immunostaining of tau protein in SAMP-8, indicative of a loss of their structural function. Altogether, these results show that, at as early as 5 months of age, SAMP-8 mice have cytological and molecular alterations indicative of neurodegeneration in the cerebral cortex and suggestive of altered control of the production of oxidative species and hyper-activation of calcium-dependent enzymes. PMID:16542809

  20. Chitosan-shelled oxygen-loaded nanodroplets abrogate hypoxia dysregulation of human keratinocyte gelatinases and inhibitors: New insights for chronic wound healing

    Khadjavi, Amina [Dipartimento di Neuroscienze, Università di Torino, Torino (Italy); Magnetto, Chiara [Istituto Nazionale di Ricerca Metrologica (INRIM), Torino (Italy); Panariti, Alice [Dipartimento di Scienze della Salute, Università di Milano Bicocca, Monza (Italy); Argenziano, Monica [Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Torino (Italy); Gulino, Giulia Rossana [Dipartimento di Oncologia, Università di Torino, Torino (Italy); Rivolta, Ilaria [Dipartimento di Scienze della Salute, Università di Milano Bicocca, Monza (Italy); Cavalli, Roberta [Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Torino (Italy); Giribaldi, Giuliana [Dipartimento di Oncologia, Università di Torino, Torino (Italy); Guiot, Caterina [Dipartimento di Neuroscienze, Università di Torino, Torino (Italy); Prato, Mauro, E-mail: mauro.prato@unito.it [Dipartimento di Neuroscienze, Università di Torino, Torino (Italy); Dipartimento di Scienze della Sanità Pubblica e Pediatriche, Università di Torino, Torino (Italy)

    2015-08-01

    Background: : In chronic wounds, efficient epithelial tissue repair is hampered by hypoxia, and balances between the molecules involved in matrix turn-over such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are seriously impaired. Intriguingly, new oxygenating nanocarriers such as 2H,3H-decafluoropentane-based oxygen-loaded nanodroplets (OLNs) might effectively target chronic wounds. Objective: : To investigate hypoxia and chitosan-shelled OLN effects on MMP/TIMP production by human keratinocytes. Methods: : HaCaT cells were treated for 24 h with 10% v/v OLNs both in normoxia or hypoxia. Cytotoxicity and cell viability were measured through biochemical assays; cellular uptake by confocal microscopy; and MMP and TIMP production by enzyme-linked immunosorbent assay or gelatin zymography. Results: : Normoxic HaCaT cells constitutively released MMP-2, MMP-9, TIMP-1 and TIMP-2. Hypoxia strongly impaired MMP/TIMP balances by reducing MMP-2, MMP-9, and TIMP-2, without affecting TIMP-1 release. After cellular uptake by keratinocytes, nontoxic OLNs abrogated all hypoxia effects on MMP/TIMP secretion, restoring physiological balances. OLN abilities were specifically dependent on time-sustained oxygen diffusion from OLN core. Conclusion: : Chitosan-shelled OLNs effectively counteract hypoxia-dependent dysregulation of MMP/TIMP balances in human keratinocytes. Therefore, topical administration of exogenous oxygen, properly encapsulated in nanodroplet formulations, might be a promising adjuvant approach to promote healing processes in hypoxic wounds. - Highlights: • Hypoxia impairs MMP9/TIMP1 and MMP2/TIMP2 balances in HaCaT human keratinocytes. • Chitosan-shelled oxygen-loaded nanodroplets (OLNs) are internalised by HaCaT cells. • OLNs are not toxic to HaCaT cells. • OLNs effectively counteract hypoxia effects on MMP/TIMP balances in HaCaT cells. • OLNs appear as promising and cost-effective therapeutic tools for hypoxic

  1. Galectin-9 Signaling through TIM-3 Is Involved in Neutrophil-Mediated Gram-Negative Bacterial Killing: An Effect Abrogated within the Cystic Fibrosis Lung

    Vega-Carrascal, Isabel; Bergin, David A.; McElvaney, Oliver J.; McCarthy, Cormac; Banville, Nessa; Pohl, Kerstin; Hirashima, Mitsuomi; Kuchroo, Vijay K.; Reeves, Emer P.; McElvaney, Noel G.

    2016-01-01

    The T cell Ig and mucin domain–containing molecule (TIM) family of receptors have emerged as potential therapeutic targets to correct abnormal immune function in chronic inflammatory conditions. TIM-3 serves as a functional receptor in structural cells of the airways and via the ligand galectin-9 (Gal-9) can modulate the inflammatory response. The aim of this study was to investigate TIM-3 expression and function in neutrophils, focusing on its potential role in cystic fibrosis (CF) lung disease. Results revealed that TIM-3 mRNA and protein expression values of circulating neutrophils were equal between healthy controls (n = 20) and people with CF (n = 26). TIM-3 was detected on resting neutrophil membranes by FACS analysis, and expression levels significantly increased post IL-8 or TNF-α exposure (p < 0.05). Our data suggest a novel role for TIM-3/Gal-9 signaling involving modulation of cytosolic calcium levels. Via TIM-3 interaction, Gal-9 induced neutrophil degranulation and primed the cell for enhanced NADPH oxidase activity. Killing of Pseudomonas aeruginosa was significantly increased upon bacterial opsonization with Gal-9 (p < 0.05), an effect abrogated by blockade of TIM-3 receptors. This mechanism appeared to be Gram-negative bacteria specific and mediated via Gal-9/ LPS binding. Additionally, we have demonstrated that neutrophil TIM-3/Gal-9 signaling is perturbed in the CF airways due to proteolytic degradation of the receptor. In conclusion, results suggest a novel neutrophil defect potentially contributing to the defective bacterial clearance observed in the CF airways and suggest that manipulation of the TIM-3 signaling pathway may be of therapeutic value in CF, preferably in conjunction with antiprotease treatment. PMID:24477913

  2. TGF-β1 induced epithelial to mesenchymal transition (EMT in human bronchial epithelial cells is enhanced by IL-1β but not abrogated by corticosteroids

    Zuraw Bruce L

    2009-10-01

    Full Text Available Abstract Background Chronic persistent asthma is characterized by ongoing airway inflammation and airway remodeling. The processes leading to airway remodeling are poorly understood, and there is increasing evidence that even aggressive anti-inflammatory therapy does not completely prevent this process. We sought to investigate whether TGFβ1 stimulates bronchial epithelial cells to undergo transition to a mesenchymal phenotype, and whether this transition can be abrogated by corticosteroid treatment or enhanced by the pro-inflammatory cytokine IL-1β. Methods BEAS-2B and primary normal human bronchial epithelial cells were stimulated with TGFβ1 and expression of epithelial and mesenchymal markers assessed by quantitative real-time PCR, immunoblotting, immunofluorescence microscopy and zymography. In some cases the epithelial cells were also incubated with corticosteroids or IL-1β. Results were analyzed using non-parametric statistical tests. Results Treatment of BEAS-2B or primary human bronchial epithelial cells with TGFβ1 significantly reduced the expression level of the epithelial adherence junction protein E-cadherin. TGFβ1 then markedly induced mesenchymal marker proteins such as collagen I, tenascin C, fibronectin and α-smooth muscle actin mRNA in a dose dependant manner. The process of mesenchymal transition was accompanied by a morphological change towards a more spindle shaped fibroblast cell type with a more motile and invasive phenotype. Corticosteroid pre-treatment did not significantly alter the TGFβ1 induced transition but IL-1β enhanced the transition. Conclusion Our results indicate, that TGFβ1 can induce mesenchymal transition in the bronchial epithelial cell line and primary cells. Since asthma has been strongly associated with increased expression of TGFβ1 in the airway, epithelial to mesenchymal transition may contribute to the contractile and fibrotic remodeling process that accompanies chronic asthma.

  3. Korean Red Ginseng Extract Enhances the Anticancer Effects of Imatinib Mesylate Through Abrogation p38 and STAT5 Activation in KBM-5 Cells.

    Jung, Sang Yoon; Kim, Chulwon; Kim, Wan-Seok; Lee, Seok-Geun; Lee, Jun-Hee; Shim, Bum Sang; Kim, Sung-Hoon; Ahn, Kyoo Seok; Ahn, Kwang Seok

    2015-07-01

    Although imatinib mesylate (IM) in the treatment of chronic myelogenous leukemia (CML) remains the best example of successful targeted therapy, majority of patients with CML suffer its toxicity profile and develop chemoresistance to existing therapeutic agents. Thus, there is a need to develop novel alternative therapies for the treatment of CML. Here, we investigated whether Korean red ginseng extract (KRGE) could suppress the proliferation and induce chemosensitization in human CML cells. Also, we used a human phospho-antibody array containing 46 antibodies against signaling molecules to examine a subset of phosphorylation events after treatment. Korean red ginseng extract broadly suppressed the proliferation of five different cell lines, but KRGE was found to be the most potent inducer of apoptosis against KBM-5 cells. It also abrogated the expression of Bcl-2 (B-cell lymphoma 2), Bcl-xL (B-cell lymphoma-extra large), survivin, inhibitors of apoptosis protein 1/2, COX-2 (Cyclooxygenase-2), cyclin D1, matrix metalloproteinase-9, and VEGF (Vascular endothelial growth factor), as well as upregulated the expression of pro-apoptotic gene products. Interestingly, KRGE also enhanced the cytotoxic and apoptotic effect of IM in KBM-5 cells. The combination treatment of KRGE and IM caused pronounced suppression of p38 and signal transducer and activator of transcription 5 phosphorylation and induced phosphorylation of p53 compared with the individual treatment. Our results demonstrate that KRGE can enhance the anticancer activity of IM and may have a substantial potential in the treatment of CML. PMID:25857479

  4. Abrogation of ospAB constitutively activates the Rrp2-RpoN-RpoS pathway (sigmaN-sigmaS cascade) in Borrelia burgdorferi.

    He, Ming; Oman, Tara; Xu, Haijun; Blevins, Jon; Norgard, Michael V; Yang, X Frank

    2008-12-01

    Molecular mechanisms underlying the reciprocal regulation of the two major surface lipoproteins and virulence factors of Borrelia burgdorferi, OspA and OspC, are not fully understood. Herein, we report that inactivation of the ospAB operon resulted in overproduction of OspC and many other lipoproteins via the constitutive activation of the Rrp2-RpoN-RpoS pathway. Complementing the ospAB mutant with a wild-type copy of ospA, but not an ospA variant that lacks the lipoprotein signal sequence, restored normal regulation of the Rrp2-RpoN-RpoS pathway; these results indicate that the phenotype was not caused by spurious mutations. Interestingly, while most of the ospAB mutant clones displayed a constitutive ospC expression phenotype, some ospAB mutant clones showed little or no ospC expression. Further analyses revealed that this OspC-negative phenotype was independent of abrogation of ospAB. While activation of the Rrp2-RpoN-RpoS pathway was recently shown to downregulate ospA, our findings suggest that reduction of OspA can also activate this pathway. We postulate that the activation of the Rrp2-RpoN-RpoS pathway and downregulation of OspA form a positive feedback loop that allows spirochaetes to produce and maintain a constant high level of OspC and other lipoproteins during tick feeding, a strategy that is critical for spirochaetal transmission and mammalian infection. PMID:19019147

  5. Betaine supplementation mitigates cisplatin-induced nephrotoxicity by abrogation of oxidative/nitrosative stress and suppression of inflammation and apoptosis in rats.

    Hagar, Hanan; Medany, Azza El; Salam, Reem; Medany, Gamila El; Nayal, Omina A

    2015-02-01

    Cisplatin is one of the most potent chemotherapeutic antitumor drugs used in the treatment of a wide range of solid tumors. Its primary dose-limiting side effect is nephrotoxicity. This study aims to investigate the effect of betaine supplementation on cisplatin-induced nephrotoxicity. A single intraperitoneal injection of cisplatin (5mg/kg) deteriorated the kidney functions as reflected by elevated blood urea nitrogen and serum creatinine levels. Oxidative/nitrosative stress was evident in cisplatin group by increased renal thiobarbituric acid-reactive substances (TBARS), an indicator of lipid peroxidation, reduced renal total antioxidant status and increased renal nitrite concentration. Cisplatin resulted in a decline in the concentrations of reduced glutathione, glutathione peroxidase, catalase, and superoxide dismutase in renal tissues. Renal tumor necrosis factor-α (TNF-α) was also elevated. Expressions of nuclear factor-kappa B (NF-κB) and caspase-3 were up-regulated in renal tissues as indicated by immunohistochemical analysis. Histopathological changes were observed in cisplatin group. Betaine supplementation (250 mg/kg/day) orally via gavage for 21 days prior to cisplatin injection was able to protect against deterioration in kidney function, abrogate the decline in antioxidants enzymes and suppressed the increase in TBARS, nitrite and TNF-α concentrations. Moreover, betaine inhibited NF-κB and caspase-3 activation and improved the histological changes induced by cisplatin. Thus, the present study demonstrated the renoprotective nature of betaine by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant competence in kidney tissues of cisplatin treated rats. Betaine could be a beneficial dietary supplement to attenuate cisplatin nephrotoxicity. PMID:25488130

  6. Interference of daratumumab in monitoring multiple myeloma patients using serum immunofixation electrophoresis can be abrogated using the daratumumab IFE reflex assay (DIRA).

    van de Donk, Niels W C J; Otten, Henny G; El Haddad, Omar; Axel, Amy; Sasser, A Kate; Croockewit, Sandra; Jacobs, Joannes F M

    2016-06-01

    Daratumumab is a fully human anti-CD38 IgG1-κ monoclonal antibody (mAb) currently being evaluated in several Phase 2 and 3 clinical studies for the treatment of multiple myeloma (MM). In this clinical case study we demonstrate that daratumumab can be detected as an individual monoclonal band in serum immunofixation electrophoresis (IFE). M-protein follow-up by IFE is part of the International Myeloma Working Group (IMWG) criteria to assess treatment response. Therefore, it is crucial that the daratumumab band is not confused with the endogenous M-protein of the patient during IFE interpretation. Moreover, a significant number of IgG-κ M-proteins co-migrate with daratumumab. Co-migration introduces a bias in the M-protein quantification since pharmacokinetic studies show that daratumumab peak plasma concentrations reach up to 1 g/L. More importantly, co-migration can mask clearance of the M-protein by IFE which is necessary for classification of complete response by IMWG criteria (negative serum IFE). For optimal M-protein monitoring the laboratory specialist needs to be informed when patients receive daratumumab, and it is essential that the laboratory specialist is aware that a slow migrating band in the γ-region in those patients may be derived from the daratumumab. A daratumumab specific IFE reflex assay (DIRA) has been developed and can be utilized to abrogate interference. The here described mAb interference is not limited to daratumumab, and as therapeutic antibodies gain approval and enter into common clinical practice, laboratory specialists will need additional processes to characterize IFE interference and distinguish endogenous M-protein from therapeutic antibodies. PMID:26812873

  7. A Combination Supplement of Fructo- and Xylo-Oligosaccharides Significantly Abrogates Oxidative Impairments and Neurotoxicity in Maternal/Fetal Milieu Following Gestational Exposure to Acrylamide in Rat.

    Krishna, Gokul; Divyashri, Gangaraju; Prapulla, S G; Muralidhara

    2015-09-01

    Prebiotic oligosaccharides are demonstrated to confer a wide spectrum of physiological benefits during pregnancy. In view of this, focused attempts are being directed towards understanding their role as modulators of brain chemistry and behavior. Epidemiological studies have identified that exposure to neurotoxins during prenatal/early life can profoundly impact neurodevelopment/function. In this context, we have tested the hypothesis that a combination of prebiotic supplements during gestation has the propensity to attenuate acrylamide (ACR) induced oxidative impairments, mitochondrial dysfunction and neurotoxicity in maternal and fetal brain of rats. To achieve this, pregnant dams given oral supplements of a combination of fructo- and xylooligosaccharides (FOS + XOS, 3 g/kg/day) during gestation days (GD 0-19) were exposed to ACR (200 ppm in drinking water, GD 6-19). The behavioral analysis revealed that ACR dams fed prebiotics displayed higher exploratory behavior in the open field test. The prenatal evaluation showed that ACR-induced decrements of placental/fetal weights were markedly restored with prebiotic feeding. Prebiotics significantly offset markers of oxidative stress, restored enzymic antioxidants, cholinergic and mitochondrial function in the maternal and fetal brain. Concomitantly, prebiotics restored ACR-induced depletion in the levels of dopamine and γ-aminobutyric acid in the maternal cortex that positively correlated with cecal bacterial numbers. Collectively, these data suggest that prenatal prebiotic oligosaccharide supplements protect developing brain against oxidative stress-mediated neurotoxicity. While the underlying mechanism/s by which prebiotics abrogate the impact of neurotoxicants in the developing brain merits further studies, we speculate that it may be mediated predominantly through attenuation of oxidative stress and proliferation of enteric microbiota. PMID:26248513

  8. Chitosan-shelled oxygen-loaded nanodroplets abrogate hypoxia dysregulation of human keratinocyte gelatinases and inhibitors: New insights for chronic wound healing

    Background: : In chronic wounds, efficient epithelial tissue repair is hampered by hypoxia, and balances between the molecules involved in matrix turn-over such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are seriously impaired. Intriguingly, new oxygenating nanocarriers such as 2H,3H-decafluoropentane-based oxygen-loaded nanodroplets (OLNs) might effectively target chronic wounds. Objective: : To investigate hypoxia and chitosan-shelled OLN effects on MMP/TIMP production by human keratinocytes. Methods: : HaCaT cells were treated for 24 h with 10% v/v OLNs both in normoxia or hypoxia. Cytotoxicity and cell viability were measured through biochemical assays; cellular uptake by confocal microscopy; and MMP and TIMP production by enzyme-linked immunosorbent assay or gelatin zymography. Results: : Normoxic HaCaT cells constitutively released MMP-2, MMP-9, TIMP-1 and TIMP-2. Hypoxia strongly impaired MMP/TIMP balances by reducing MMP-2, MMP-9, and TIMP-2, without affecting TIMP-1 release. After cellular uptake by keratinocytes, nontoxic OLNs abrogated all hypoxia effects on MMP/TIMP secretion, restoring physiological balances. OLN abilities were specifically dependent on time-sustained oxygen diffusion from OLN core. Conclusion: : Chitosan-shelled OLNs effectively counteract hypoxia-dependent dysregulation of MMP/TIMP balances in human keratinocytes. Therefore, topical administration of exogenous oxygen, properly encapsulated in nanodroplet formulations, might be a promising adjuvant approach to promote healing processes in hypoxic wounds. - Highlights: • Hypoxia impairs MMP9/TIMP1 and MMP2/TIMP2 balances in HaCaT human keratinocytes. • Chitosan-shelled oxygen-loaded nanodroplets (OLNs) are internalised by HaCaT cells. • OLNs are not toxic to HaCaT cells. • OLNs effectively counteract hypoxia effects on MMP/TIMP balances in HaCaT cells. • OLNs appear as promising and cost-effective therapeutic tools for hypoxic

  9. Immunoregulatory functions for murine intraepithelial lymphocytes: gamma/delta T cell receptor-positive (TCR+) T cells abrogate oral tolerance, while alpha/beta TCR+ T cells provide B cell help

    1992-01-01

    Past work has shown that a subset of effector T cells with unique characteristics could abrogate hapten- or antigen-induced tolerance, and the reconstitution of this immune response has been termed contrasuppression. We have studied contrasuppression in a model of oral tolerance (OT) in which adoptively transferred antigen-specific T contrasuppressor (Tcs) cells reverse OT and result in antibody responses to the eliciting antigen. In the present study, we show that murine intraepithelial lymp...

  10. TGF-β1 induced epithelial to mesenchymal transition (EMT) in human bronchial epithelial cells is enhanced by IL-1β but not abrogated by corticosteroids

    Zuraw Bruce L; Doerner Astrid M

    2009-01-01

    Abstract Background Chronic persistent asthma is characterized by ongoing airway inflammation and airway remodeling. The processes leading to airway remodeling are poorly understood, and there is increasing evidence that even aggressive anti-inflammatory therapy does not completely prevent this process. We sought to investigate whether TGFβ1 stimulates bronchial epithelial cells to undergo transition to a mesenchymal phenotype, and whether this transition can be abrogated by corticosteroid tr...

  11. Histone deacetylases suppress CGG repeat-induced neurodegeneration via transcriptional silencing in models of fragile X tremor ataxia syndrome.

    Peter K Todd

    Full Text Available Fragile X Tremor Ataxia Syndrome (FXTAS is a common inherited neurodegenerative disorder caused by expansion of a CGG trinucleotide repeat in the 5'UTR of the fragile X syndrome (FXS gene, FMR1. The expanded CGG repeat is thought to induce toxicity as RNA, and in FXTAS patients mRNA levels for FMR1 are markedly increased. Despite the critical role of FMR1 mRNA in disease pathogenesis, the basis for the increase in FMR1 mRNA expression is unknown. Here we show that overexpressing any of three histone deacetylases (HDACs 3, 6, or 11 suppresses CGG repeat-induced neurodegeneration in a Drosophila model of FXTAS. This suppression results from selective transcriptional repression of the CGG repeat-containing transgene. These findings led us to evaluate the acetylation state of histones at the human FMR1 locus. In patient-derived lymphoblasts and fibroblasts, we determined by chromatin immunoprecipitation that there is increased acetylation of histones at the FMR1 locus in pre-mutation carriers compared to control or FXS derived cell lines. These epigenetic changes correlate with elevated FMR1 mRNA expression in pre-mutation cell lines. Consistent with this finding, histone acetyltransferase (HAT inhibitors repress FMR1 mRNA expression to control levels in pre-mutation carrier cell lines and extend lifespan in CGG repeat-expressing Drosophila. These findings support a disease model whereby the CGG repeat expansion in FXTAS promotes chromatin remodeling in cis, which in turn increases expression of the toxic FMR1 mRNA. Moreover, these results provide proof of principle that HAT inhibitors or HDAC activators might be used to selectively repress transcription at the FMR1 locus.

  12. Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management.

    Kidd, Parris M

    2005-12-01

    Degenerative brain disorders (neurodegeneration) can be frustrating for both conventional and alternative practitioners. A more comprehensive, integrative approach is urgently needed. One emerging focus for intervention is brain energetics. Specifically, mitochondrial insufficiency contributes to the etiopathology of many such disorders. Electron leakages inherent to mitochondrial energetics generate reactive oxygen free radical species that may place the ultimate limit on lifespan. Exogenous toxins, such as mercury and other environmental contaminants, exacerbate mitochondrial electron leakage, hastening their demise and that of their host cells. Studies of the brain in Alzheimer's and other dementias, Down syndrome, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, aging, and constitutive disorders demonstrate impairments of the mitochondrial citric acid cycle and oxidative phosphorylation (OXPHOS) enzymes. Imaging or metabolic assays frequently reveal energetic insufficiency and depleted energy reserve in brain tissue in situ. Orthomolecular nutrients involved in mitochondrial metabolism provide clinical benefit. Among these are the essential minerals and the B vitamin group; vitamins E and K; and the antioxidant and energetic cofactors alpha-lipoic acid (ALA), ubiquinone (coenzyme Q10; CoQ10), and nicotinamide adenine dinucleotide, reduced (NADH). Recent advances in the area of stem cells and growth factors encourage optimism regarding brain regeneration. The trophic nutrients acetyl L-carnitine (ALCAR), glycerophosphocholine (GPC), and phosphatidylserine (PS) provide mitochondrial support and conserve growth factor receptors; all three improved cognition in double-blind trials. The omega-3 fatty acid docosahexaenoic acid (DHA) is enzymatically combined with GPC and PS to form membrane phospholipids for nerve cell expansion. Practical recommendations are presented for integrating these

  13. Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration

    Maria Emilia Figueiredo-Pereira

    2015-01-01

    Full Text Available The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia and prion diseases. Cyclooxygenases (COX -1 and COX-2, which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli. In this review, we highlight the mechanisms by which J2 prostaglandins (1 exert their actions, (2 potentially contribute to the transition from acute to chronic inflammation and to the spreading of neuropathology, (3 disturb the ubiquitin-proteasome pathway and mitochondrial function, and (4 contribute to neurodegenerative disorders such as Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis, as well as stroke, traumatic brain injury, and demyelination in Krabbe disease. We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation. In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects.

  14. NEW ROLES FOR FC RECEPTORS IN NEURODEGENERATION-THE IMPACT ON IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE

    JamesP.Fuller

    2014-08-01

    Full Text Available There are an estimated 18 million Alzheimer’s disease (AD sufferers worldwide and with no disease modifying treatment currently available, development of new therapies represents an enormous unmet clinical need. AD is characterised by episodic memory loss followed by severe cognitive decline and is associated with many neuropathological changes. AD is characterised by deposits of amyloid beta (Aβ, neurofibrillary tangles, and neuroinflammation. Active immunisation or passive immunisation against Aβ leads to the clearance of deposits in transgenic mice expressing human Aβ. This clearance is associated with reversal of associated cognitive deficits, but these results have failed to translate to humans, with both active and passive immunotherapy failing to improve memory loss. One explanation for these observations is that certain anti-Aβ antibodies mediate damage to the cerebral vasculature limiting the top dose and potentially reducing efficacy. Fc gamma receptors (Fcγ are a family of immunoglobulin like receptors which bind to the Fc portion of IgG, and mediate the response of effector cells to immune complexes. Data from both mouse and human studies suggest that cross-linking Fc receptors by therapeutic antibodies and the subsequent pro-inflammatory response mediates the vascular side effects seen following immunotherapy. Increasing evidence is emerging that Fc receptor expression on CNS resident cells, including microglia and neurons, is increased during aging and functionally involved in the pathogenesis of age-related neurodegenerative diseases. We propose that increased expression and ligation of Fc receptors in the CNS, either by endogenous IgG or therapeutic antibodies, has the potential to induce vascular damage and exacerbate neurodegeneration. To produce safe and effective immunotherapies for AD and other neurodegenerative diseases it will be vital to understand the role of Fc receptors in the healthy and diseased brain.

  15. Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease

    Ghosh, Anamitra; Langley, Monica R; Harischandra, Dilshan; Neal, Matthew L; Jin, Huajun; Anantharam, Vellareddy; Joseph, Joy; Brenza, Timothy; Narasimhan, Balaji; Kanthasamy, Arthi; Kalyanaraman, Balaraman; Kanthasamy, Anumantha G.

    2016-01-01

    Mitochondrial dysfunction, oxidative stress and neuroinflammation have been implicated as key mediators contributing to the progressive degeneration of dopaminergic neurons in Parkinson’s disease (PD). Currently, we lack a pharmacological agent that can intervene in all key pathological mechanisms, which would offer better neuroprotective efficacy than a compound that targets a single degenerative mechanism. Herein, we investigated whether mito-apocynin (Mito-Apo), a newly-synthesized and orally available derivative of apocynin that targets mitochondria, protects against oxidative damage, glial-mediated inflammation and nigrostriatal neurodegeneration in cellular and animal models of PD. Mito-Apo treatment in primary mesencephalic cultures significantly attenuated the 1-methyl-4-phenylpyridinium (MPP+)-induced loss of tyrosine hydroxylase (TH)-positive neuronal cells and neurites. Mito-Apo also diminished MPP+-induced increases in glial cell activation and inducible nitric oxide synthase (iNOS) expression. Additionally, Mito-Apo decreased nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE) levels in primary mesencephalic cultures. Importantly, we assessed the neuroprotective property of Mito-Apo in the MPTP mouse model of PD, wherein it restored the behavioral performance of MPTP-treated mice. Immunohistological analysis of nigral dopaminergic neurons and monoamine measurement further confirmed the neuroprotective effect of Mito-Apo against MPTP-induced nigrostriatal dopaminergic neuronal loss. Mito-Apo showed excellent brain bioavailability and also markedly attenuated MPTP-induced oxidative markers in the substantia nigra (SN). Furthermore, oral administration of Mito-Apo significantly suppressed MPTP-induced glial cell activation, upregulation of proinflammatory cytokines, iNOS and gp91phox in IBA1-positive cells of SN. Collectively, these results demonstrate that the novel mitochondria-targeted compound Mito-Apo exhibits profound neuroprotective effects in

  16. Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration.

    Figueiredo-Pereira, Maria E; Rockwell, Patricia; Schmidt-Glenewinkel, Thomas; Serrano, Peter

    2014-01-01

    The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation) may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia, and prion diseases. Cyclooxygenases (COX-1 and COX-2), which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli. In this review, we highlight the mechanisms by which J2 prostaglandins (1) exert their actions, (2) potentially contribute to the transition from acute to chronic inflammation and to the spreading of neuropathology, (3) disturb the ubiquitin-proteasome pathway and mitochondrial function, and (4) contribute to neurodegenerative disorders such as Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis, as well as stroke, traumatic brain injury (TBI), and demyelination in Krabbe disease. We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation. In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects. PMID:25628533

  17. K(Ca)2 and k(ca)3 channels in learning and memory processes, and neurodegeneration.

    Kuiper, Els F E; Nelemans, Ad; Luiten, Paul; Nijholt, Ingrid; Dolga, Amalia; Eisel, Uli

    2012-01-01

    Calcium-activated potassium (K(Ca)) channels are present throughout the central nervous system as well as many peripheral tissues. Activation of K(Ca) channels contribute to maintenance of the neuronal membrane potential and was shown to underlie the afterhyperpolarization (AHP) that regulates action potential firing and limits the firing frequency of repetitive action potentials. Different subtypes of K(Ca) channels were anticipated on the basis of their physiological and pharmacological profiles, and cloning revealed two well defined but phylogenetic distantly related groups of channels. The group subject of this review includes both the small conductance K(Ca)2 channels (K(Ca)2.1, K(Ca)2.2, and K(Ca)2.3) and the intermediate-conductance (K(Ca)3.1) channel. These channels are activated by submicromolar intracellular Ca(2+) concentrations and are voltage independent. Of all K(Ca) channels only the K(Ca)2 channels can be potently but differentially blocked by the bee-venom apamin. In the past few years modulation of K(Ca) channel activation revealed new roles for K(Ca)2 channels in controlling dendritic excitability, synaptic functioning, and synaptic plasticity. Furthermore, K(Ca)2 channels appeared to be involved in neurodegeneration, and learning and memory processes. In this review, we focus on the role of K(Ca)2 and K(Ca)3 channels in these latter mechanisms with emphasis on learning and memory, Alzheimer's disease and on the interplay between neuroinflammation and different neurotransmitters/neuromodulators, their signaling components and K(Ca) channel activation. PMID:22701424

  18. NS1-binding protein abrogates the elevation of cell viability by the influenza A virus NS1 protein in association with CRKL

    Highlights: •NS1 induced excessive phosphorylation of ERK and elevated cell viability. •NS1-BP expression and CRKL knockdown abolished survival effect of NS1. •NS1-BP and NS1 formed the complex through the interaction with CRKL-SH3(N). -- Abstract: The influenza A virus non-structural protein 1 (NS1) is a multifunctional virulence factor consisting of an RNA binding domain and several Src-homology (SH) 2 and SH3 binding motifs, which promotes virus replication in the host cell and helps to evade antiviral immunity. NS1 modulates general host cell physiology in association with various cellular molecules including NS1-binding protein (NS1-BP) and signaling adapter protein CRK-like (CRKL), while the physiological role of NS1-BP during influenza A virus infection especially in association with NS1 remains unclear. In this study, we analyzed the intracellular association of NS1-BP, NS1 and CRKL to elucidate the physiological roles of these molecules in the host cell. In HEK293T cells, enforced expression of NS1 of A/Beijing (H1N1) and A/Indonesia (H5N1) significantly induced excessive phosphorylation of ERK and elevated cell viability, while the over-expression of NS1-BP and the abrogation of CRKL using siRNA abolished such survival effect of NS1. The pull-down assay using GST-fusion CRKL revealed the formation of intracellular complexes of NS1-BP, NS1 and CRKL. In addition, we identified that the N-terminus SH3 domain of CRKL was essential for binding to NS1-BP using GST-fusion CRKL-truncate mutants. This is the first report to elucidate the novel function of NS1-BP collaborating with viral protein NS1 in modulation of host cell physiology. In addition, an alternative role of adaptor protein CRKL in association with NS1 and NS1-BP during influenza A virus infection is demonstrated

  19. NS1-binding protein abrogates the elevation of cell viability by the influenza A virus NS1 protein in association with CRKL

    Miyazaki, Masaya [Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638 (Japan); Nishihara, Hiroshi, E-mail: hnishihara@med.hokudai.ac.jp [Department of Translational Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638 (Japan); Hasegawa, Hideki [Department of Pathology, National Institute of Infectious Diseases, Sinjuku-ku, Tokyo (Japan); Tashiro, Masato [Influenza Virus Research Center, National Institute of Infectious Diseases, Sinjuku-ku, Tokyo (Japan); Wang, Lei [Department of Translational Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638 (Japan); Kimura, Taichi; Tanino, Mishie; Tsuda, Masumi [Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638 (Japan); Tanaka, Shinya [Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638 (Japan); Department of Translational Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638 (Japan)

    2013-11-29

    Highlights: •NS1 induced excessive phosphorylation of ERK and elevated cell viability. •NS1-BP expression and CRKL knockdown abolished survival effect of NS1. •NS1-BP and NS1 formed the complex through the interaction with CRKL-SH3(N). -- Abstract: The influenza A virus non-structural protein 1 (NS1) is a multifunctional virulence factor consisting of an RNA binding domain and several Src-homology (SH) 2 and SH3 binding motifs, which promotes virus replication in the host cell and helps to evade antiviral immunity. NS1 modulates general host cell physiology in association with various cellular molecules including NS1-binding protein (NS1-BP) and signaling adapter protein CRK-like (CRKL), while the physiological role of NS1-BP during influenza A virus infection especially in association with NS1 remains unclear. In this study, we analyzed the intracellular association of NS1-BP, NS1 and CRKL to elucidate the physiological roles of these molecules in the host cell. In HEK293T cells, enforced expression of NS1 of A/Beijing (H1N1) and A/Indonesia (H5N1) significantly induced excessive phosphorylation of ERK and elevated cell viability, while the over-expression of NS1-BP and the abrogation of CRKL using siRNA abolished such survival effect of NS1. The pull-down assay using GST-fusion CRKL revealed the formation of intracellular complexes of NS1-BP, NS1 and CRKL. In addition, we identified that the N-terminus SH3 domain of CRKL was essential for binding to NS1-BP using GST-fusion CRKL-truncate mutants. This is the first report to elucidate the novel function of NS1-BP collaborating with viral protein NS1 in modulation of host cell physiology. In addition, an alternative role of adaptor protein CRKL in association with NS1 and NS1-BP during influenza A virus infection is demonstrated.

  20. Resveratrol abrogates the Temozolomide-induced G2 arrest leading to mitotic catastrophe and reinforces the Temozolomide-induced senescence in glioma cells

    Temozolomide (TMZ) is the most widely used drug to treat glioblastoma (GBM), which is the most common and aggressive primary tumor of the Central Nervous System and one of the hardest challenges in oncotherapy. TMZ is an alkylating agent that induces autophagy, apoptosis and senescence in GBM cells. However, therapy with TMZ increases survival after diagnosis only from 12 to 14.4 months, making the development of combined therapies to treat GBM fundamental. One candidate for GBM therapy is Resveratrol (Rsv), which has additive toxicity with TMZ in several glioma cells in vitro and in vivo. However, the mechanism of Rsv and TMZ additive toxicity, which is the aim of the present work, is not clear, especially concerning cell cycle dynamics and long term effects. Glioma cell lines were treated with Rsv and TMZ, alone or in combinations, and the induction and the role of autophagy, apoptosis, cell cycle dynamics, protein expression and phosphorylation status were measured. We further evaluated the long term senescence induction and clonogenic capacity. As expected, temozolomide caused a G2 cell cycle arrest and extensive DNA damage response. Rsv did not reduced this response, even increasing pATM, pChk2 and gammaH2Ax levels, but abrogated the temozolomide-induced G2 arrest, increasing levels of cyclin B and pRb(S807/811) and reducing levels of pWee1(S642) and pCdk1(Y15). This suggests a cellular state of forced passage through G2 checkpoint despite large DNA damage, a scenario that may produce mitotic catastrophe. Indeed, the proportion of cells with high nuclear irregularity increased from 6 to 26% in 48 h after cotreatment. At a long term, a reduction in clonogenic capacity was observed, accompanied by a large induction of senescence. The presence of Rsv forces cells treated with TMZ through mitosis leading to mitotic catastrophe and senescence, reducing the clonogenic capacity of glioma cells and increasing the chronic effects of temozolomide

  1. Total Lignans of Schisandra chinensis Ameliorates Aβ1-42-Induced Neurodegeneration with Cognitive Impairment in Mice and Primary Mouse Neuronal Cells.

    Zhao, Xu; Liu, Chunmei; Xu, Mengjie; Li, Xiaolong; Bi, Kaishun; Jia, Ying

    2016-01-01

    Lignan compounds extracted from Schisandra chinensis (Turcz.) Baill. have been reported to possess various biological activities, and have potential in the treatment of Alzheimer's disease. This study was designed to investigate the effects of total lignans of Schisandra chinensis (TLS) on cognitive function and neurodegeneration in the model of AD induced by Aβ1-42 in vivo and in vitro. It was found that intragastric infusion with TLS (50 and 200 mg/kg) to Aβ1-42-induced mice significantly increased the number of avoidances in the shuttle-box test and swimming time in the target quadrant in the Morris water maze test. TLS at dose of 200 mg/kg significantly restored the activities of total antioxidant capacity (T-AOC), as well as the level of malondialdehyde (MDA) both in the hippocampus and cerebral cortex in mice. Results of histopathological examination indicated that TLS noticeably ameliorated the neurodegeneration in the hippocampus in mice. On the other hand, TLS (100 μM) could protect the Aβ1-42-induced primary mouse neuronal cells by blocking the decrease of mitochondrial membrane potential (MMP), change the expressions of Bcl-2 (important regulator in the mitochondria apoptosis pathway). Moreover, TLS also decreased the activity of β-secretase 1 (BACE1), crucial protease contributes to the hydrolysis of amyloid precursor protein (APP), and inhibited the expression of JKN/p38, which involved in the MAPKs signaling pathways in both mice and primary mouse neuronal cells. In summary, TLS might protect against cognitive deficits and neurodegeneration by releasing the damage of oxidative stress, inhibiting the expression of BACE1 and the MAPKs inflammatory signaling pathways. PMID:27035824

  2. Total Lignans of Schisandra chinensis Ameliorates Aβ1-42-Induced Neurodegeneration with Cognitive Impairment in Mice and Primary Mouse Neuronal Cells.

    Xu Zhao

    Full Text Available Lignan compounds extracted from Schisandra chinensis (Turcz. Baill. have been reported to possess various biological activities, and have potential in the treatment of Alzheimer's disease. This study was designed to investigate the effects of total lignans of Schisandra chinensis (TLS on cognitive function and neurodegeneration in the model of AD induced by Aβ1-42 in vivo and in vitro. It was found that intragastric infusion with TLS (50 and 200 mg/kg to Aβ1-42-induced mice significantly increased the number of avoidances in the shuttle-box test and swimming time in the target quadrant in the Morris water maze test. TLS at dose of 200 mg/kg significantly restored the activities of total antioxidant capacity (T-AOC, as well as the level of malondialdehyde (MDA both in the hippocampus and cerebral cortex in mice. Results of histopathological examination indicated that TLS noticeably ameliorated the neurodegeneration in the hippocampus in mice. On the other hand, TLS (100 μM could protect the Aβ1-42-induced primary mouse neuronal cells by blocking the decrease of mitochondrial membrane potential (MMP, change the expressions of Bcl-2 (important regulator in the mitochondria apoptosis pathway. Moreover, TLS also decreased the activity of β-secretase 1 (BACE1, crucial protease contributes to the hydrolysis of amyloid precursor protein (APP, and inhibited the expression of JKN/p38, which involved in the MAPKs signaling pathways in both mice and primary mouse neuronal cells. In summary, TLS might protect against cognitive deficits and neurodegeneration by releasing the damage of oxidative stress, inhibiting the expression of BACE1 and the MAPKs inflammatory signaling pathways.

  3. Induction of Neuron-Specific Degradation of Coenzyme A Models Pantothenate Kinase-Associated Neurodegeneration by Reducing Motor Coordination in Mice.

    Stephanie A Shumar

    Full Text Available Pantothenate kinase-associated neurodegeneration, PKAN, is an inherited disorder characterized by progressive impairment in motor coordination and caused by mutations in PANK2, a human gene that encodes one of four pantothenate kinase (PanK isoforms. PanK initiates the synthesis of coenzyme A (CoA, an essential cofactor that plays a key role in energy metabolism and lipid synthesis. Most of the mutations in PANK2 reduce or abolish the activity of the enzyme. This evidence has led to the hypothesis that lower CoA might be the underlying cause of the neurodegeneration in PKAN patients; however, no mouse model of the disease is currently available to investigate the connection between neuronal CoA levels and neurodegeneration. Indeed, genetic and/or dietary manipulations aimed at reducing whole-body CoA synthesis have not produced a desirable PKAN model, and this has greatly hindered the discovery of a treatment for the disease.Cellular CoA levels are tightly regulated by a balance between synthesis and degradation. CoA degradation is catalyzed by two peroxisomal nudix hydrolases, Nudt7 and Nudt19. In this study we sought to reduce neuronal CoA in mice through the alternative approach of increasing Nudt7-mediated CoA degradation. This was achieved by combining the use of an adeno-associated virus-based expression system with the synapsin (Syn promoter. We show that mice with neuronal overexpression of a cytosolic version of Nudt7 (scAAV9-Syn-Nudt7cyt exhibit a significant decrease in brain CoA levels in conjunction with a reduction in motor coordination. These results strongly support the existence of a link between CoA levels and neuronal function and show that scAAV9-Syn-Nudt7cyt mice can be used to model PKAN.

  4. Hypertension exacerbates predisposition to neurodegeneration and memory impairment in the presence of a neuroinflammatory stimulus: Protection by angiotensin converting enzyme inhibition.

    Goel, Ruby; Bhat, Shahnawaz Ali; Rajasekar, N; Hanif, Kashif; Nath, Chandishwar; Shukla, Rakesh

    2015-06-01

    Hypertension is a risk factor for cognitive impairment. Furthermore, neuroinflammation and neurodegeneration are intricately associated with memory impairment. Therefore, the present study aimed to explore the involvement of hypertension and angiotensin system in neurodegeneration and memory dysfunction in the presence of neuroinflammatory stimulus. Memory impairment was induced by chronic neuroinflammation that was developed by repeated intracerebroventricular (ICV) injections of lipopolysaccharide (LPS) on the 1st, 4th, 7th, and 10th day. Memory functions were evaluated by the Morris water maze (MWM) test on days 13-15, followed by biochemical and molecular studies in the cortex and hippocampus regions of rat brain. LPS at the dose of 25μg ICV caused memory impairment in spontaneously hypertensive rats (SHRs) but not in normotensive Wistar rats (NWRs). Memory deficit was obtained with 50μg of LPS (ICV) in NWRs. Control SHRs already exhibited increased angiotensin converting enzyme (ACE) activity and expression, neuroinflammation (increased TNF-α, GFAP, COX-2 and NF-kB), oxidative stress (increased iNOS, ROS and nitrite levels), TLR-4 expression and TUNEL positive cells as compared to control NWRs. Further, LPS (25μg ICV) exaggerated inflammatory response, oxidative stress and apoptosis in SHRs but similar effects were witnessed at 50μg of LPS (ICV) in NWRs. Oral administration of perindopril (ACE inhibitor), at non-antihypertensive dose (0.1mg/kg), for 15days attenuated LPS induced deleterious changes in both NWRs and SHRs. Our data suggest that susceptibility of the brain for neurodegeneration and memory impairment induced by neuroinflammation is enhanced in hypertension, and that can be protected by ACE inhibition. PMID:25869103

  5. Could carnosine suppress zinc-mediated proteasome inhibition and neurodegeneration? Therapeutic potential of a non-toxic but non-patentable dipeptide.

    Hipkiss, Alan R

    2005-01-01

    Ageing and neurodegenerative conditions are often associated with proteasome dysfunction, possibly mediated by zinc and/or copper ions. Studies have shown that (i) the olfactory lobe is normally enriched in carnosine and zinc, (ii) carnosine can suppress copper and zinc toxicity in olfactory neurones, (iii) olfactory dysfunction is often associated with neurodegenerative conditions and (iv) elevated levels of zinc are found in brains of Alzheimer's patients. It is suggested that nasal administration of carnosine should be explored as a possible way of suppressing zinc/copper-mediated proteasome inhibition and consequent neurodegeneration. PMID:16034682

  6. TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson’s disease

    Rayaprolu, Sruti; Mullen, Bianca; Baker, Matt; Lynch, Timothy; Finger, Elizabeth; Seeley, William W.; Hatanpaa, Kimmo J.; Lomen-Hoerth, Catherine; Kertesz, Andrew; Bigio, Eileen H; Lippa, Carol; Josephs, Keith A.; Knopman, David S.; White, Charles L.; Caselli, Richard

    2013-01-01

    Background A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer...

  7. Ethanol Induced Acetylation of Histone at G9a Exon1 and G9a-Mediated Histone H3 Dimethylation leads to Neurodegeneration in Neonatal Mice

    Subbanna, Shivakumar; Nagre, Nagaraja N.; Shivakumar, Madhu; Umapathy, Nagavedi S.; Psychoyos, Delphine; Basavarajappa, Balapal S

    2013-01-01

    The transient exposure of immature rodents to ethanol during postnatal day 7 (P7), comparable to a time point within the third trimester of human pregnancy, induces neurodegeneration. However, the molecular mechanisms underlying the deleterious effects of ethanol on the developing brain are poorly understood. In our previous study, we showed that a high dose administration of ethanol at P7 enhances G9a and leads to caspase-3-mediated degradation of dimethylated H3 on lysine 9 (H3K9me2). In th...

  8. Pantothenate kinase 2 mutation with classic pantothenate-kinase-associated neurodegeneration without 'eye-of-the-tiger' sign on MRI in a pair of siblings

    It has been postulated that all patients with pantothenate kinase 2 (PANK2) mutations causing pantothenate-kinase-associated neurodegeneration (PKAN) are associated with the 'eye-of-the-tiger' sign on MRI. We report a pair of siblings who presented with dystonia and who have been found to be homozygous for 104C>A, S35X mutation, confirming the diagnosis of PKAN. They do not have the typical iron deposition in the globi pallida or substantia nigra on MR imaging. (orig.)

  9. 17β-trenbolone, an anabolic–androgenic steroid as well as an environmental hormone, contributes to neurodegeneration

    Both genetic and environmental factors contribute to neurodegenerative disorders. In a large number of neurodegenerative diseases (for example, Alzheimer's disease (AD)), patients do not carry the mutant genes. Other risk factors, for example the environmental factors, should be evaluated. 17β-trenbolone is a kind of environmental hormone as well as an anabolic–androgenic steroid. 17β-trenbolone is used as a growth promoter for livestock in the USA. Also, a large portion of recreational exercisers inject 17β-trenbolone in large doses and for very long time to increase muscle and strength. 17β-trenbolone is stable in the environment after being excreted. In the present study, 17β-trenbolone was administered to adult and pregnant rats and the primary hippocampal neurons. 17β-trenbolone's distribution and its effects on serum hormone levels and Aβ42 accumulation in vivo and its effects on AD related parameters in vitro were assessed. 17β-trenbolone accumulated in adult rat brain, especially in the hippocampus, and in the fetus brain. It altered Aβ42 accumulation. 17β-trenbolone induced apoptosis of primary hippocampal neurons in vitro and resisted neuroprotective function of testosterone. Presenilin-1 protein expression was down-regulated while β-amyloid peptide 42 (Aβ42) production and caspase-3 activities were increased. Both androgen and estrogen receptors mediated the processes. 17β-trenbolone played critical roles in neurodegeneration. Exercisers who inject large doses of trenbolone and common people who are exposed to 17β-trenbolone by various ways are all influenced chronically and continually. Identification of such environmental risk factors will help us take early prevention measure to slow down the onset of neurodegenerative disorders. - Highlights: • The widely used anabolic–androgenic steroid 17β-trenbolone has neurotoxicity. • 17β-trenbolone crosses the blood brain barrier and placental barrier. • Rat has high level of

  10. 17β-trenbolone, an anabolic–androgenic steroid as well as an environmental hormone, contributes to neurodegeneration

    Ma, Fucui, E-mail: mafucui@hotmail.com [Wenzhou Institute of Biomaterials and Engineering, No. 16 Xinshan Road, Hi-tech Industry Park, Wenzhou (China); Key Laboratory of Animal Resistance, College of Life Science, Shandong Normal University, 88 East Wenhua Road, Jinan 250014 (China); Liu, Daicheng, E-mail: liudch@sdnu.edu.cn [Key Laboratory of Animal Resistance, College of Life Science, Shandong Normal University, 88 East Wenhua Road, Jinan 250014 (China)

    2015-01-01

    Both genetic and environmental factors contribute to neurodegenerative disorders. In a large number of neurodegenerative diseases (for example, Alzheimer's disease (AD)), patients do not carry the mutant genes. Other risk factors, for example the environmental factors, should be evaluated. 17β-trenbolone is a kind of environmental hormone as well as an anabolic–androgenic steroid. 17β-trenbolone is used as a growth promoter for livestock in the USA. Also, a large portion of recreational exercisers inject 17β-trenbolone in large doses and for very long time to increase muscle and strength. 17β-trenbolone is stable in the environment after being excreted. In the present study, 17β-trenbolone was administered to adult and pregnant rats and the primary hippocampal neurons. 17β-trenbolone's distribution and its effects on serum hormone levels and Aβ42 accumulation in vivo and its effects on AD related parameters in vitro were assessed. 17β-trenbolone accumulated in adult rat brain, especially in the hippocampus, and in the fetus brain. It altered Aβ42 accumulation. 17β-trenbolone induced apoptosis of primary hippocampal neurons in vitro and resisted neuroprotective function of testosterone. Presenilin-1 protein expression was down-regulated while β-amyloid peptide 42 (Aβ42) production and caspase-3 activities were increased. Both androgen and estrogen receptors mediated the processes. 17β-trenbolone played critical roles in neurodegeneration. Exercisers who inject large doses of trenbolone and common people who are exposed to 17β-trenbolone by various ways are all influenced chronically and continually. Identification of such environmental risk factors will help us take early prevention measure to slow down the onset of neurodegenerative disorders. - Highlights: • The widely used anabolic–androgenic steroid 17β-trenbolone has neurotoxicity. • 17β-trenbolone crosses the blood brain barrier and placental barrier. • Rat has high level of

  11. Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease.

    Gordon, Richard; Singh, Neeraj; Lawana, Vivek; Ghosh, Anamitra; Harischandra, Dilshan S; Jin, Huajun; Hogan, Colleen; Sarkar, Souvarish; Rokad, Dharmin; Panicker, Nikhil; Anantharam, Vellareddy; Kanthasamy, Anumantha G; Kanthasamy, Arthi

    2016-09-01

    at Ser536. Furthermore, both genetic ablation and siRNA-mediated knockdown of PKCδ attenuated NFκB activation, suggesting that PKCδ regulates NFκB activation subsequent to microglial exposure to inflammatory stimuli. To further investigate the pivotal role of PKCδ in microglial activation in vivo, we utilized pre-clinical models of PD. We found that PKCδ deficiency attenuated the proinflammatory response in the mouse substantia nigra, reduced locomotor deficits and recovered mice from sickness behavior in an LPS-induced neuroinflammation model of PD. Likewise, we found that PKCδ knockout mice treated with MPTP displayed a dampened microglial inflammatory response. Moreover, PKCδ knockout mice exhibited reduced susceptibility to the neurotoxin-induced dopaminergic neurodegeneration and associated motor impairments. Taken together, our studies propose a pivotal role for PKCδ in PD pathology, whereby sustained PKCδ activation drives sustained microglial inflammatory responses and concomitant dopaminergic neurotoxicity consequently leading to neurobehavioral deficits. We conclude that inhibiting PKCδ activation may represent a novel therapeutic strategy in PD treatment. PMID:27151770

  12. [A woman with beta-propeller protein-associated neurodegeneration identified by the WDR45 mutation presenting as Rett-like syndrome in childhood].

    Morisada, Naoya; Tsuneishi, Syuichi; Taguchi, Kazuhiro; Yagi, Ryuzaburo; Nishiyama, Masahiro; Toyoshima, Daisaku; Nakagawa, Taku; Takeshima, Yasuhiro; Takada, Satoshi; Iijima, Kazumoto

    2016-05-01

    Beta-propeller protein-associated neurodegeneration (BPAN) is one of the neurodegenerative disorders characterized by iron deposition in the brain and is the only known disease in humans to be caused by an aberration in autophagocytosis. Here, we present the case of a 42-year-old woman with BPAN identified by the WDR45 mutation. From early childhood, she was recognized as having global developmental delay, and she frequently sucked her hand, which was considered to be a stereotypical movement. She had a febrile convulsion at 6 months of age but there was no history of epilepsy. The delay in language development was more severe than the delay in motor development; she was able to dress herself, walk unaided, and follow simple instructions until adolescence. After the age of 20, her movement ability rapidly declined. By the time she was 42 years old, she was bedridden and unable to communicate. Brain magnetic resonance imaging (MRI) at 21 years revealed no abnormality except non-specific cerebral atrophy. However, MRI at 39 years revealed abnormalities in the globus pallidus and substantia nigra, with neurodegeneration and iron accumulation in the brain. Genetic analysis for WDR45 revealed that she had a splice site mutation (NM_007075.3: c.830 + 2 T > C) which was previously reported, and a diagnosis of BPAN was confirmed. For specific therapies to be developed for BPAN in the future, it is necessary to establish early diagnosis, including genetic analysis. PMID:27349085

  13. Value of determining the cerebrospinal fluid protein markers of amyloidosis and neurodegeneration in the diagnosis of vascular and neurodegenerative cognitive impairments

    Vladimir Yuryevich Lobzin

    2013-01-01

    Full Text Available The article presents data on different forms of moderate cognitive impairments (MCI and the specific features of their transformation to dementia. Cerebrospinal fluid (CSF was investigated in 60 patients with the amnestic and neurodynamic types of MCI, in 15 patients with vascular dementia (VD, 50 patients with Alzheimer’s disease (AD, and 23 patients with mixed vascular and neurodegenerative dementia (MVND. The specific features of β-amyloid and τ-protein concentrations were established in the preclinical stages of dementia, which reflects the main components of the pathogenesis of neurodegeneration. In the amnestic form of MCI and AD, there was drastically decreased Aβ-42 and increased τ-protein levels in SCF. As cognitive impairments progressed, there was a rise in the concentration of τ-protein; its level correlated with the severity of dementia. In MND, the level of Aβ-42 was significantly reduced while the concentration of τ-protein was much increased; moreover, to a greater extent than in AD and VD. Cerebrovascular damage and neurodegeneration were related to each other and mutually worsened clinical and pathogenic effects.

  14. Neuroglia in neurodegeneration

    Heneka, M. T.; Rodríguez Arellano, Jose Julio; Verkhratsky, Alexei

    2010-01-01

    Roč. 63, 1-2 (2010), s. 189-211. ISSN 0165-0173 R&D Projects: GA ČR GA309/09/1696; GA ČR GA305/08/1384 Institutional research plan: CEZ:AV0Z50390703 Keywords : Glia * Astrocyte * Microglia Subject RIV: FH - Neurology Impact factor: 8.842, year: 2010

  15. The evolution of neurodegeneration

    Cookson, Mark R.

    2012-01-01

    There are a number of neurodegenerative diseases that principally affect humans as they age, characterized by the loss of specific groups of neurons in different brain regions. Although these are in general sporadic disorders, it is know clear that many of these diseases have a substantial genetic component. As genes are the raw material with which evolution works, we might benefit from understanding these genes in an evolutionary framework. Here, I will discuss how we can understand whether ...

  16. Phagocytic Clearance in Neurodegeneration

    Sokolowski, Jennifer D.; Mandell, James W.

    2011-01-01

    The cellular and molecular mechanisms of phagocytic clearance of apoptotic cells and debris have been intensely studied in invertebrate model organisms and in the mammalian immune system. This evolutionarily conserved process serves multiple purposes. Uncleared debris from dying cells or aggregated proteins can be toxic and may trigger exaggerated inflammatory responses. Even though apoptotic cell death and debris accumulation are key features of neurodegenerative diseases, relatively little ...

  17. Neurodegeneration and Identity.

    Strohminger, Nina; Nichols, Shaun

    2015-09-01

    There is a widespread notion, both within the sciences and among the general public, that mental deterioration can rob individuals of their identity. Yet there have been no systematic investigations of what types of cognitive damage lead people to appear to no longer be themselves. We measured perceived identity change in patients with three kinds of neurodegenerative disease: frontotemporal dementia, Alzheimer's disease, and amyotrophic lateral sclerosis. Structural equation models revealed that injury to the moral faculty plays the primary role in identity discontinuity. Other cognitive deficits, including amnesia, have no measurable impact on identity persistence. Accordingly, frontotemporal dementia has the greatest effect on perceived identity, and amyotrophic lateral sclerosis has the least. We further demonstrated that perceived identity change fully mediates the impact of neurodegenerative disease on relationship deterioration between patient and caregiver. Our results mark a departure from theories that ground personal identity in memory, distinctiveness, dispositional emotion, or global mental function. PMID:26270072

  18. Sphingolipids in Neurodegeneration

    Haughey, Norman J.

    2010-01-01

    Although the brain contains a high content of sphingolipids, we know relatively little about the roles that sphingolipids play in regulating neural functions. Once regarded only for their structural roles in maintaining the integrity of cellular and sub-cellular compartments, it is now apparent that many sphingolipid species are biologically active and play important roles in regulating signaling events. Recent technological and scientific advances are rapidly increasing our knowledge of the ...

  19. Mitochondria in Neurodegeneration

    Lezi, E; Swerdlow, Russell H.

    2012-01-01

    Many neurodegenerative diseases demonstrate abnormal mitochondrial morphology and biochemical dysfunction. Alterations are often systemic rather than brain-limited. Mitochondrial dysfunction may arise as a consequence of abnormal mitochondrial DNA, mutated nuclear proteins that interact directly or indirectly with mitochondria, or through unknown causes. In most cases it is unclear where mitochondria sit in relation to the overall disease cascades that ultimately causes neuronal dysfunction a...

  20. PET scanning in neurodegeneration

    Structural and functional images of the brain play an important role as useful adjuncts to the clinical symptoms in the diagnosis and management of neurologic and psychiatric diseases. There are various functional imaging modalities to identify functionally impaired, but morphologically preserved tissue and to distinguish it from irreversibly damaged tissue of the Central Nervous System. Functional imaging in general and Nuclear medicine in particular has a key role in diagnosing a variety of neurological disorders at an early stage. The key objective is to identify patterns of physiological abnormality which are predictive of pathology, which can then lead to earlier intervention in the patient's management. Brain SPECT, with perfusion agents or with neuroreceptor imaging radiopharmaceuticals, has become an important clinical tool in current practice. 99mTc-HMPAO SPECT is most useful in distinguishing Alzheimer's disease from vascular dementia and frontotemporal dementia. 201TI- SPECT is an effective study in the diagnosis of CNS tumours. Altered dopaminergic transporter function in patients with Parkinson's disease is diagnosed using 123Iioflupane SPECT studies. This imaging modality has been used in diagnosis, prognosis assessment, and evaluation of response to therapy and detection of benign or malignant viable tissue

  1. In vitro Repair of Oxidative DNA Damage by Human Nucleotide Excision Repair System: Possible Explanation for Neurodegeneration in Xeroderma Pigmentosum Patients

    Reardon, Joyce T.; Bessho, Tadayoshi; Kung, Hsiang Chuan; Bolton, Philip H.; Sancar, Aziz

    1997-08-01

    Xeroderma pigmentosum (XP) patients fail to remove pyrimidine dimers caused by sunlight and, as a consequence, develop multiple cancers in areas exposed to light. The second most common sign, present in 20-30% of XP patients, is a set of neurological abnormalities caused by neuronal death in the central and peripheral nervous systems. Neural tissue is shielded from sunlight-induced DNA damage, so the cause of neurodegeneration in XP patients remains unexplained. In this study, we show that two major oxidative DNA lesions, 8-oxoguanine and thymine glycol, are excised from DNA in vitro by the same enzyme system responsible for removing pyrimidine dimers and other bulky DNA adducts. Our results suggest that XP neurological disease may be caused by defective repair of lesions that are produced in nerve cells by reactive oxygen species generated as by-products of an active oxidative metabolism.

  2. Neurodegeneration in an Animal Model of Chronic Amyloid-beta Oligomer Infusion Is Counteracted by Antibody Treatment Infused with Osmotic Pumps.

    Sajadi, Ahmadali; Provost, Chloé; Pham, Brendon; Brouillette, Jonathan

    2016-01-01

    Decline in hippocampal-dependent explicit memory (memory for facts and events) is one of the earliest clinical symptom of Alzheimer's disease (AD). It is well established that synapse loss and ensuing neurodegeneration are the best predictors for memory impairments in AD. Latest studies have emphasized the neurotoxic role of soluble amyloid-beta oligomers (Aβo) that begin to accumulate in the human brain approximately 10 to 15 yr before the clinical symptoms become apparent. Many reports indicate that soluble Aβo correlate with memory deficits in AD models and humans. The Aβo-induced neurodegeneration observed in neuronal and brain slice cultures has been more challenging to reproduce in many animal models. The model of repeated Aβo infusions shown here overcome this issue and allow addressing two key domains for developing new disease modifying therapies: identify biological markers to diagnose early AD, and determine the molecular mechanisms underpinning Aβo-induced memory deficits at the onset of AD. Since soluble Aβo aggregate relatively fast into insoluble Aβ fibrils that correlate poorly with the clinical state of patients, soluble Aβo are prepared freshly and injected once per day during six days to produce marked cell death in the hippocampus. We used cannula specially design for simultaneous infusions of Aβo and continuous infusion of Aβo antibody (6E10) in the hippocampus using osmotic pumps. This innovative in vivo method can now be used in preclinical studies to validate the efficiency of new AD therapies that might prevent the deposition and neurotoxicity of Aβo in pre-dementia patients. PMID:27585306

  3. Synaptic deficits are rescued in the p25/Cdk5 model of neurodegeneration by the reduction of β-secretase (BACE1)

    Giusti-Rodríguez, Paola; Gao, Jun; Gräff, Johannes; Rei, Damien; Soda, Takahiro; Tsai, Li-Huei

    2011-01-01

    Alzheimer’s disease (AD) is the most common cause of dementia, and is characterized by memory loss and cognitive decline, as well as amyloid β (Aβ) accumulation, and progressive neurodegeneration. Cdk5 is a proline-directed serine/threonine kinase whose activation by the p25 protein has been implicated in a number of neurodegenerative disorders. The CK-p25 inducible mouse model exhibits progressive neuronal death, elevated Aβ, reduced synaptic plasticity, and impaired learning following p25 overexpression in forebrain neurons. Levels of Aβ, as well as the amyloid precursor protein (APP) processing enzyme, β-secretase (BACE1), are also increased in CK-p25 mice. It is unknown what role increased Aβ plays in the cognitive and neurodegenerative phenotype of the CK-p25 mouse. In the current work, we restored Aβ levels in the CK-p25 mouse to those of wildtype mice via the partial genetic deletion of BACE1, allowing us to examine the Aβ-independent phenotype of this mouse model. We show that, in the CK-p25 mouse, normalization of Aβ levels led to a rescue of synaptic and cognitive deficits. Conversely, neuronal loss was not ameliorated. Our findings indicate that increases in p25/Cdk5 activity may mediate cognitive and synaptic impairment via an Aβ-dependent pathway in the CK-p25 mouse. These findings explore the impact of targeting Aβ production in a mouse model of neurodegeneration and cognitive impairment, and how this may translate into therapeutic approaches for sporadic AD. PMID:22049418

  4. Bill project aiming at prohibiting the exploration and exploitation of unconventional hydrocarbons, and at abrogating exclusive search permits for liquid or gaseous hydrocarbon mines, and aiming at ensuring transparency in the issue of search permits and concessions

    As offshore drillings and the search for unconventional gas has faced a strong opposition by part of the French population, this bill project (presented mainly by the Socialist group) aims at prohibiting these practices in France, and notably at abrogating some exclusive search permits which have been recently awarded. The authors outline the main motivations of this bill project: these exploitation and mining techniques are very expensive; they have several negative impacts with respect to environment protection commitments like the Grenelle de l'Environnement and the Grenelle de la Mer; these techniques have also an impact on water resources, and generate pollution which impacts water quality as well as ecosystems and biodiversity; some chemical products used by these techniques are carcinogenic (as it already appeared in the USA and in Canada); and finally, the exploitation of unconventional hydrocarbons has a bad carbon assessment. This presentation if followed by the bill project text

  5. Activation of microglial NADPH oxidase is synergistic with glial iNOS expression in inducing neuronal death: a dual-key mechanism of inflammatory neurodegeneration

    Brown Guy C

    2005-09-01

    Full Text Available Abstract Background Inflammation-activated glia are seen in many CNS pathologies and may kill neurons through the release of cytotoxic mediators, such as nitric oxide from inducible NO synthase (iNOS, and possibly superoxide from NADPH oxidase (NOX. We set out to determine the relative role of these species in inducing neuronal death, and to test the dual-key hypothesis that the production of both species simultaneously is required for significant neuronal death. Methods Primary co-cultures of cerebellar granule neurons and glia from rats were used to investigate the effect of NO (from iNOS, following lipopolysaccharide (LPS and/or cytokine addition or superoxide/hydrogen peroxide (from NOX, following phorbol 12-myristate 13-acetate (PMA, ATP analogue (BzATP, interleukin-1β (IL-1β or arachidonic acid (AA addition on neuronal survival. Results Induction of glial iNOS caused little neuronal death. Similarly, activation of NOX alone resulted in little or no neuronal death. However, if NOX was activated (by PMA or BzATP in the presence of iNOS (induced by LPS and interferon-γ then substantial delayed neuronal death occurred over 48 hours, which was prevented by inhibitors of iNOS (1400W, NOX (apocynin or a peroxynitrite decomposer (FeTPPS. Neurons and glia were also found to stain positive for nitrotyrosine (a putative marker of peroxynitrite only when both iNOS and NOX were simultaneously active. If NOX was activated by weak stimulators (IL-1β, AA or the fibrillogenic prion peptide PrP106-126 in the presence of iNOS, it caused microglial proliferation and delayed neurodegeneration over 6 days, which was prevented by iNOS or NOX inhibitors, a peroxynitrite decomposer or a NMDA-receptor antagonist (MK-801. Conclusion These results suggest a dual-key mechanism, whereby glial iNOS or microglial NOX activation alone is relatively benign, but if activated simultaneously are synergistic in killing neurons, through generating peroxynitrite. This

  6. Elevation of neuron specific enolase and brain iron deposition on susceptibility-weighted imaging as diagnostic clues for beta-propeller protein-associated neurodegeneration in early childhood: Additional case report and review of the literature.

    Takano, Kyoko; Shiba, Naoko; Wakui, Keiko; Yamaguchi, Tomomi; Aida, Noriko; Inaba, Yuji; Fukushima, Yoshimitsu; Kosho, Tomoki

    2016-02-01

    Beta-propeller protein-associated neurodegeneration (BPAN), also known as static encephalopathy of childhood with neurodegeneration in adulthood (SENDA), is a subtype of neurodegeneration with brain iron accumulation (NBIA). BPAN is caused by mutations in an X-linked gene WDR45 that is involved in autophagy. BPAN is characterized by developmental delay or intellectual disability until adolescence or early adulthood, followed by severe dystonia, parkinsonism, and progressive dementia. Brain magnetic resonance imaging (MRI) shows iron deposition in the bilateral globus pallidus (GP) and substantia nigra (SN). Clinical manifestations and laboratory findings in early childhood are limited. We report a 3-year-old girl with BPAN who presented with severe developmental delay and characteristic facial features. In addition to chronic elevation of serum aspartate transaminase, lactate dehydrogenase, creatine kinase, and soluble interleukin-2 receptor, she had persistent elevation of neuron specific enolase (NSE) in serum and cerebrospinal fluid. MRI using susceptibility-weighted imaging (SWI) demonstrated iron accumulation in the GP and SN bilaterally. Targeted next-generation sequencing identified a de novo splice-site mutation, c.831-1G>C in WDR45, which resulted in aberrant splicing evidenced by reverse transcriptase-PCR. Persistent elevation of NSE and iron deposition on SWI may provide clues for diagnosis of BPAN in early childhood. PMID:26481852

  7. Peloruside A: a lead non-taxoid-site microtubule-stabilizing agent with potential activity against cancer, neurodegeneration, and autoimmune disease.

    Kanakkanthara, Arun; Northcote, Peter T; Miller, John H

    2016-04-01

    Covering: 2000 up to 2016Peloruside A, a macrocyclic secondary metabolite from a New Zealand marine sponge, Mycale hentscheli, has shown potent antiproliferative activity in cultured cancer cells as well as inhibitory effects on tumor growth in mouse models. The compound also has promising effects against cell models of neurodegenerative and autoimmune diseases. In mechanistic studies, peloruside A shares with paclitaxel (Taxol®) the ability to stabilize microtubules by binding to β-tubulin. Peloruside A, however, occupies a unique external site on β-tubulin that does not overlap the classical taxoid site that is located on the inside of the microtubule. As such, peloruside A has been of central importance in defining a new microtubule-stabilizer binding site localized on the exterior surface of the microtubule that has led to increased interest in the design of an upscaled total synthesis of the natural product and its analogues. Here, we review advances in the biochemical and biological validation of peloruside A as an attractive therapeutic candidate for the treatment of cancer, neurodegeneration, and autoimmune disease. PMID:26867978

  8. ESCRT-0 dysfunction compromises autophagic degradation of protein aggregates and facilitates ER stress-mediated neurodegeneration via apoptotic and necroptotic pathways

    Oshima, Ryuji; Hasegawa, Takafumi; Tamai, Keiichi; Sugeno, Naoto; Yoshida, Shun; Kobayashi, Junpei; Kikuchi, Akio; Baba, Toru; Futatsugi, Akira; Sato, Ikuro; Satoh, Kennichi; Takeda, Atsushi; Aoki, Masashi; Tanaka, Nobuyuki

    2016-01-01

    Endosomal sorting required for transport (ESCRT) complexes orchestrate endo-lysosomal sorting of ubiquitinated proteins, multivesicular body formation and autophagic degradation. Defects in the ESCRT pathway have been implicated in many neurodegenerative diseases, but the underlying molecular mechanisms that link them to neurodegeneration remain unknown. In this study, we showed that forebrain-specific ablation of ESCRT-0/Hrs induced marked hippocampal neuronal cell loss accompanied by the accumulation of ubiquitinated proteins, including α-synuclein, TDP-43 and huntingtin as well as the autophagic substrate SQSTM1/p62. Consistent with this, silencing of Hrs in cultured cells not only led to α-synuclein and TDP-43 accumulation in addition to impaired autophagic flux but also suppressed cell viability through the induction of ER stress followed by the activation of JNK and RIPK1, a key regulator of necroptosis. Moreover, necrostatin-1, a specific inhibitor of RIPK1, and pan-caspase inhibitors partially reduced the neurotoxicity in the Hrs-silenced cells. Altogether, these findings suggest that the disruption of ESCRT-0/Hrs in the nervous system compromises autophagic/lysosomal degradation of neurodegenerative disease-related proteins, which thereby triggers ER stress-mediated apoptotic and necroptotic cell death. PMID:27112194

  9. Linking aβ42-induced hyperexcitability to neurodegeneration, learning and motor deficits, and a shorter lifespan in an Alzheimer's model.

    Yong Ping

    2015-03-01

    Full Text Available Alzheimer's disease (AD is the most prevalent form of dementia in the elderly. β-amyloid (Aβ accumulation in the brain is thought to be a primary event leading to eventual cognitive and motor dysfunction in AD. Aβ has been shown to promote neuronal hyperactivity, which is consistent with enhanced seizure activity in mouse models and AD patients. Little, however, is known about whether, and how, increased excitability contributes to downstream pathologies of AD. Here, we show that overexpression of human Aβ42 in a Drosophila model indeed induces increased neuronal activity. We found that the underlying mechanism involves the selective degradation of the A-type K+ channel, Kv4. An age-dependent loss of Kv4 leads to an increased probability of AP firing. Interestingly, we find that loss of Kv4 alone results in learning and locomotion defects, as well as a shortened lifespan. To test whether the Aβ42-induced increase in neuronal excitability contributes to, or exacerbates, downstream pathologies, we transgenically over-expressed Kv4 to near wild-type levels in Aβ42-expressing animals. We show that restoration of Kv4 attenuated age-dependent learning and locomotor deficits, slowed the onset of neurodegeneration, and partially rescued premature death seen in Aβ42-expressing animals. We conclude that Aβ42-induced hyperactivity plays a critical role in the age-dependent cognitive and motor decline of this Aβ42-Drosophila model, and possibly in AD.

  10. Oral treatment with the herbal formula B401 protects against aging-dependent neurodegeneration by attenuating oxidative stress and apoptosis in the brain of R6/2 mice

    Wang SE

    2015-11-01

    Full Text Available Sheue-Er Wang,1,2 Ching-Lung Lin,1 Chih-Hsiang Hsu,1 Shuenn-Jyi Sheu,3 Chung-Hsin Wu1 1Department of Life Science, National Taiwan Normal University, Taipei, 2Department of Pathological Inspection, Saint Paul’s Hospital, Taoyuan, 3Brion Research Institute of Taiwan, Taipei, Taiwan Background: Neurodegeneration is characterized by progressive neurological deficits due to selective neuronal loss in the nervous system. Huntington’s disease (HD is an incurable neurodegenerative disorder. Neurodegeneration in HD patients shows aging-dependent pattern. Our previous study has suggested that a herbal formula B401 may have neuroprotective effects in the brains of R6/2 mice. Objective: To clarify possible mechanisms for neurodegeneration, which improves the understanding the aging process. This study focuses on clarifying neurodegenerative mechanisms and searching potential therapeutic targets in HD patients. Methods: The oxidative stress and apoptosis were compared in the brain tissue between R6/2 HD mice with and without oral B401 treatment. Expressions of proteins for oxidative stress and apoptosis in the brain tissue of R6/2 HD mice were examined by using immunostaining and Western blotting techniques. Results: R6/2 HD mice with oral B401 treatment significantly reduced reactive oxygen species levels in the blood, but markedly increased expressions of superoxide dismutase 2 in the brain tissue. Furthermore, R6/2 HD mice with oral B401 treatment significantly increased expressions of B-cell lymphoma 2 (Bcl-2, but significantly reduced expressions of Bcl-2-associated X protein (Bax, calpain, and caspase-3 in the brain tissue. Conclusion: Our findings provide evidence that the herbal formula B401 can remedy for aging-dependent neurodegeneration of R6/2 mice via suppressing oxidative stress and apoptosis in the brain. We suggest that the herbal formula B401 can be developed as a potential health supplement for ameliorating aging

  11. Protective Role of Tinospora cordifolia against Lead-induced Hepatotoxicity

    Sharma, V.; Pandey, D.

    2010-01-01

    The importance of Tinospora cordifolia stem and leaves extract was investigated for its possible hepatoprotective effect in Swiss albino male mice against lead nitrate induced toxicity. Oral administration of plant extracts prevented the occurrence of lead nitrate induced liver damage. The decreased level of tissue enzymes, i.e., superoxide dismutase (SOD), catalase (CAT) and increased level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and a...

  12. Lead induced intergranular fracture in aluminum alloy AA6262

    De Hosson, JTM

    2003-01-01

    The influence of lead on the fracture behavior of aluminum alloy AA6262 is investigated. Under certain conditions, the mode of fracture changes from transgranular microvoid coalescence to an intergranular mechanism. Three different intergranular fracture mechanisms are observed: liquid metal embritt

  13. Lead induced behavioral dysfunction: an animal model of hyperactivity

    Silbergeld, E.K.; Goldberg, A.M.

    1974-01-01

    Although clinically lead poisoning is thought to cause several serious behavioral problems, a causal relationship between lead ingestion and behavioral dysfunction has not been shown. An animal model of lead poisoning was developed in which suckling mice were exposed to lead acetate from birth indirectly through their mothers and then directly after weaning. For the first 60 days, no deaths of offspring occurred due to lead but their growth and development were significantly retarded. Epidemiological evidence exists for the coincidence of lead exposure and hyperactivity syndromes in children. Activity of offspring was measured between 40 and 60 days of age. Treated mice were more than three times as active as agematched controls. Treated and control animals were given drugs used in the treatment and diagnosis of minimal brain dysfunction hyperactivity in children: d- and l-amphetamine, methylphenidate, phenobarbital, and chloral hydrate. Lead-treated hyperactive mice responded paradoxically to all drugs except chloral hydrate: that is, d- and l-amphetamine and methylphenidate suppressed hyperactivity, while phenobarbital increased their levels of motor activity. Chloral hydrate was an effective sedative. Implications of these findings are discussed for the study of the central effects of lead poisoning and for the relationship between lead poisoning and minimal brain dysfunction hyperactivity.

  14. Genetic Association and Gene-gene interaction of HAS2, HABP1 and HYAL3 Implicate Hyaluronan Metabolic Genes in Glaucomatous Neurodegeneration

    Kaustuv Basu

    2012-01-01

    Full Text Available Hyaluronan (HA plays a significant role in maintaining aqueous humor outflow in trabecular meshwork, the primary ocular tissue involved in glaucoma. We examined potential association of the single nucleotide polymorphisms (SNPs of the HA synthesizing gene – hyaluronan synthase 2 (HAS2, hyaluronan binding protein 1 (HABP1 and HA catabolic gene hyaluronidase 3 (HYAL3 in the primary open angle glaucoma (POAG patients in the Indian population. Thirteen tagged SNPs (6 for HAS2, 3 for HABP1 and 4 for HYAL3 were genotyped in 116 high tension (HTG, 321 non-high tension glaucoma (NHTG samples and 96 unrelated, age-matched, glaucoma-negative, control samples. Allelic and genotypic association were analyzed by PLINK v1.04; haplotypes were identified using PHASE v2.1 and gene-gene interaction was analyzed using multifactor dimensionality reduction (MDR v2.0. An allelic association (rs6651224; p = 0.03; OR: 0.49; 95% CI: 0.25–0.94 was observed at the second intron (C>G of HAS2 both for NHTG and HTG. rs1057308 revealed a genotypic association (p = 0.03 at the 5’ UTR of HAS2 with only HTG. TCT haplotype (rs1805429 – rs2472614 – rs8072363 in HABP1 and TTAG and TTGA (rs2285044 – rs3774753 – rs1310073 – rs1076872 in HYAL3 were found to be significantly high (p < 0.05 both for HTG and NHTG compared to controls. Gene-gene interaction revealed HABP1 predominantly interacts with HAS2 in HTG while it associates with both HYAL3 and HAS2 in NHTG. This is the first genetic evidence, albeit from a smaller study, that the natural polymorphisms in the genes involved in hyaluronan metabolism are potentially involved in glaucomatous neurodegeneration.

  15. Neurotrophic effects of a cyanine dye via the PI3K-Akt pathway: attenuation of motor discoordination and neurodegeneration in an ataxic animal model.

    Hitomi Ohta

    Full Text Available BACKGROUND: Neurotrophic factors may be future therapeutic agents for neurodegenerative disease. In the screening of biologically active molecules for neurotrophic potency, we found that a photosensitizing cyanine dye, NK-4, had remarkable neurotrophic activities and was a potent radical scavenger. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we evaluated the effect of NK-4 on the protection of neurons against oxidative damage and investigated the associated intracellular signaling pathways. Subsequently, we evaluated the effect of NK-4 in an animal model of neurodegeneration. In vitro, NK-4 showed dose-dependent protection of PC12 cells from toxicity induced by oxidative stress caused by hydrogen peroxide (H(2O(2 or 6-hydroxydopamine (6-OHDA. Comparison of extracellular signal-regulated kinase signaling pathways between treatment with NK-4 and nerve growth factor (NGF using K252a, an inhibitor of the NGF receptor TrkA, revealed that NK-4 activity occurs independently of NGF receptors. LY294002, a phosphatidylinositol 3-kinase (PI3K inhibitor, blocked the protective effect of NK-4, and NK-4 caused activation of Akt/protein kinase B, a downstream effector of PI3K. These results suggest that the neuroprotective effects of NK-4 are mediated by the PI3K-Akt signaling pathway. NK-4 treatment also attenuated stress-induced activation of SAPK/JNK, which suggests that NK-4 activates a survival signaling pathway and inhibits stress-activated apoptotic pathways independently of the TrkA receptor in neuronal cells. In vivo, administration of NK-4 improved motor coordination in genetic ataxic hamsters, as assessed by rota-rod testing. Histological analysis showed that cerebellar atrophy was significantly attenuated by NK-4 treatment. Notably, the Purkinje cell count in the treated group was threefold higher than that in the vehicle group. CONCLUSIONS/SIGNIFICANCE: These results suggest that NK-4 is a potential agent for therapy for neurodegenerative

  16. TNIK inhibition abrogates colorectal cancer stemness

    Masuda, Mari; Uno, Yuko; Ohbayashi, Naomi; Ohata, Hirokazu; Mimata, Ayako; Kukimoto-Niino, Mutsuko; Moriyama, Hideki; Kashimoto, Shigeki; Inoue, Tomoko; Goto, Naoko; Okamoto, Koji; Shirouzu, Mikako; Sawa, Masaaki; Yamada, Tesshi

    2016-01-01

    Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik−/−/Apcmin/+ mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apcmin/+ mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach. PMID:27562646

  17. Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration

    Burk, Raymond F.; Hill, Kristina E.; Motley, Amy K.; Winfrey, Virginia P.; Kurokawa, Suguru; Mitchell, Stuart L.; Zhang, Wanqi

    2014-01-01

    Selenoprotein P (Sepp1) and its receptor, apolipoprotein E receptor 2 (apoER2), account for brain retaining selenium better than other tissues. The primary sources of Sepp1 in plasma and brain are hepatocytes and astrocytes, respectively. ApoER2 is expressed in varying amounts by tissues; within the brain it is expressed primarily by neurons. Knockout of Sepp1 or apoER2 lowers brain selenium from ∼120 to ∼50 ng/g and leads to severe neurodegeneration and death in mild selenium deficiency. Interactions of Sepp1 and apoER2 that protect against this injury have not been characterized. We studied Sepp1, apoER2, and brain selenium in knockout mice. Immunocytochemistry showed that apoER2 mediates Sepp1 uptake at the blood-brain barrier. When Sepp1−/− or apoER2−/− mice developed severe neurodegeneration caused by mild selenium deficiency, brain selenium was ∼35 ng/g. In extreme selenium deficiency, however, brain selenium of ∼12 ng/g was tolerated when both Sepp1 and apoER2 were intact in the brain. These findings indicate that tandem Sepp1-apoER2 interactions supply selenium for maintenance of brain neurons. One interaction is at the blood-brain barrier, and the other is within the brain. We postulate that Sepp1 inside the blood-brain barrier is taken up by neurons via apoER2, concentrating brain selenium in them.—Burk, R. F., Hill, K. E., Motley, A. K., Winfrey, V. P., Kurokawa, S., Mitchell, S. L., Zhang, W. Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration. PMID:24760755

  18. Inhibition of calcineurin abrogates while inhibition of mTOR promotes regulatory T cell expansion and graft-versus-host disease protection by IL-2 in allogeneic bone marrow transplantation.

    Atsushi Satake

    Full Text Available Regulatory T cells (Tregs attenuate excessive immune responses, making their expansion beneficial in immune-mediated diseases including allogeneic bone marrow transplantation (BMT-associated graft-versus-host disease (GVHD. We have recently reported that Treg expansion does not require phospholipase Cγ activation when IL-2 is provided. As such, the combination of IL-2 and a calcineurin inhibitor (Cyclosporine A; CsA expands Tregs while inhibiting Tconv proliferation and protects against a mouse model of multiple sclerosis. However, CsA inhibits Treg proliferation in the presence of a TCR stimulus, suggesting that CsA may negatively impact Treg proliferation when they receive strong allogeneic MHC-mediated TCR signals. In this study, we show that CsA inhibits Treg proliferation and inducible Treg generation in allogeneic but not in syngeneic BMT when IL-2 is provided. In contrast to CsA, the mTOR inhibitor (Rapamycin almost completely suppressed IL-2-mediated Treg proliferation. However, CsA and Rapamycin inhibited Treg proliferation to a similar extent when TCR stimulation was provided. Furthermore, Rapamycin promoted Treg expansion and inducible Treg generation in allogeneic BMT recipients treated with IL-2. Consistent with these observations, CsA abrogated while Rapamycin promoted the protective effect of IL-2 on allogeneic BMT-induced GVHD. These results suggest that while CsA permits IL-2-induced Treg proliferation in the syngeneic setting (absence of strong TCR signals, CsA in combination with IL-2 may be detrimental for Treg proliferation in an allogeneic setting. Thus, in allogeneic settings, an mTOR inhibitor such as Rapamycin is a better choice for adjunct therapy with IL-2 in expansion of Tregs and protection against allogeneic BMT-induced GVHD.

  19. Neurogenesis, Neurodegeneration, Interneuron Vulnerability, and Amyloid-β in the Olfactory Bulb of APP/PS1 Mouse Model of Alzheimer's Disease

    De la Rosa-Prieto, Carlos; Saiz-Sanchez, Daniel; Ubeda-Banon, Isabel; Flores-Cuadrado, Alicia; Martinez-Marcos, Alino

    2016-01-01

    Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, mostly idiopathic and with palliative treatment. Neuropathologically, it is characterized by intracellular neurofibrillary tangles of tau protein and extracellular plaques of amyloid β peptides. The relationship between AD and neurogenesis is unknown, but two facts are particularly relevant. First, early aggregation sites of both proteinopathies include the hippocampal formation and the olfactory bulb (OB), which have been correlated to memory and olfactory deficits, respectively. These areas are well-recognized integration zones of newly-born neurons in the adult brain. Second, molecules, such as amyloid precursor protein (APP) and presenilin-1 are common to both AD etiology and neurogenic development. Adult neurogenesis in AD models has been studied in the hippocampus, but only occasionally addressed in the OB and results are contradictory. To gain insight on the relationship between adult neurogenesis and AD, this work analyzes neurogenesis, neurodegeneration, interneuron vulnerability, and amyloid-β involvement in the OB of an AD model. Control and double-transgenic mice carrying the APP and the presenilin-1 genes, which give rise amyloid β plaques have been used. BrdU-treated animals have been studied at 16, 30, 43, and 56 weeks of age. New-born cell survival (BrdU), neuronal loss (using neuronal markers NeuN and PGP9.5), differential interneuron (calbindin-, parvalbumin-, calretinin- and somatostatin-expressing populations) vulnerability, and involvement by amyloid β have been analyzed. Neurogenesis increases with aging in the granule cell layer of control animals from 16 to 43 weeks. No neuronal loss has been observed after quantifying NeuN or PGP9.5. Regarding interneuron population vulnerability: calbindin-expressing neurons remains unchanged; parvalbumin-expressing neurons trend to increase with aging in transgenic animals; calretinin-expressing neurons increase with aging in

  20. Neurodegeneration and mirror image agnosia

    Sadanandavalli Retnaswami Chandra

    2014-01-01

    Full Text Available Background: Normal Percept with abnormal meaning (Agnosias has been described from nineteenth century onwards. Later literature became abundant with information on the spectrum of Prosopagnosias. However, selective difficulty in identifying reflected self images with relatively better cognitive functions leads to problems in differentiating it from non-organic psychosis. Aim: In the present study, we investigated patients with dementia who showed difficulty in identifying reflected self images while they were being tested for problems in gnosis with reference to identification of reflected objects, animals, relatives, and themselves and correlate with neuropsychological and radiological parameters. Patients and Methods: Five such patients were identified and tested with a 45 cm × 45 cm mirror kept at 30-cm distance straight ahead of them. Results: Mirror image agnosia is seen in patients with moderate stage posterior dementias who showed neuropsychological and radiological evidence of right parietal dysfunction. Conclusion: Interpretation of reflected self images perception in real time probably involves distinct data-linking circuits in the right parietal lobe, which may get disrupted early in the course of the disease.

  1. Progressive Neurodegeneration in Aspartylglycosaminuria Mice

    Gonzalez-Gomez, Ignacio; Mononen, Ilkka; Heisterkamp, Nora; Groffen, John; Kaartinen, Vesa

    1998-01-01

    Aspartylglycosaminuria (AGU) is one of the most common lysosomal storage disorders in humans. A mouse model for AGU has been recently generated through targeted disruption of the glycosylasparaginase gene, and at a young age the glycosyl asparaginase-deficient mice demonstrated many pathological changes found in human AGU patients (Kaartinen V, Mononen I, Voncken J-W, Gonzalez-Gomez I, Heisterkamp N, Groffen J: A mouse model for aspartylglycosaminuria. Nat Med 1996, 2:1375–1378). Our current ...

  2. Nutrition, brain aging, and neurodegeneration

    The onset of age-related neurodegenerative diseases superimposed on a declining nervous system could enhance the motor and cognitive behavioral deficits that normally occur in senescence. It is likely that, in cases of severe deficits in memory or motor function, hospitalization and/or custodial car...

  3. Bu-Shen-Ning-Xin decoction: inhibition of osteoclastogenesis by abrogation of the RANKL-induced NFATc1 and NF-κB signaling pathways via selective estrogen receptor α

    Wang L

    2015-07-01

    in osteoclast precursor cells; the inhibitory effect was abolished by methyl-piperidino-pyrazole but not the estrogen receptor β antagonist or androgen receptor antagonist.Conclusion: These results collectively suggest that administration of BSNXD presents inhibitory effects on osteoclast differentiation by abrogating the RANKL-induced nuclear factor of activated T-cells, cytoplasmic 1 and NF-κB signaling pathways downstream of estrogen receptor α, thereby contributing to the inhibitory effect on bone resorption.Keywords: herbal formula, osteoclastogenesis, estrogen receptor α, NF-κB, NFATc1

  4. Tau蛋白过度磷酸化机制及其在阿尔茨海默病神经元变性中的作用%Molecular Mechanisms Underlie Alzheimer-like Tau Hyperphosphorylation and Neurodegeneration

    王建枝; 田青

    2012-01-01

    Tau蛋白是神经元中含量最高的微管相关蛋白,其经典生物学功能是促进微管组装和维持微管的稳定性.在阿尔茨海默病(Alzheimer's disease,AD)患者,异常过度磷酸化的Tau蛋白以配对螺旋丝结构形成神经原纤维缠结并在神经元内聚积.大量研究提示,Tau蛋白异常在AD患者神经变性和学习记忆障碍的发生发展中起重要作用.本课题组对Tau蛋白异常磷酸化的机制及其对细胞的影响进行了系列研究,发现Tau蛋白表达和磷酸化具有调节细胞生存命运的新功能,并由此对AD神经细胞变性的本质提出了新见解.本文主要综述作者实验室有关Tau蛋白的部分研究结果.%Tau is the most abundant microtubule associated protein. The normal function of Tau is to promote microtubule assembly and stabilize microtubules. In Alzheimer's disease, Tau is abnormally hyperphosphorylated and the hyperphosphorylated Tau accumulates, in the form of paired helical filaments (PHF), in the neuron to form neurofibrillary tangles. Numerous studies indicate that the abnormal Tau modifications play a crucial role in AD neurodegeneration and the cognitive deficits. We have studied systemically the mechanisms underlie Tau hyperphosphorylation and the effects of Tau phosphorylation on cell viability. We found unexpectedly that expression of the hyperphosphorylated Tau, at certain point, renders the cells more resistant to the exogenously induced cell apoptosis, whereas dephosphorylation of Tau promotes cell apoptosis. We also found that persistent Tau hyperphosphorylation and the cellular accumulation damage the neural functions and thus decrease the viability. Based on these findings, we propose that Tau hyperphosphorylation may play a dual role in leading the neurons to abort from an acute apoptosis and at the same time triggering a chronic neurodegeneration, which may explain why the degenerated neurons observed in the postmortem Alzheimer's brain are enriched

  5. The endocrine dyscrasia that accompanies menopause and andropause induces aberrant cell cycle signaling that triggers re-entry of post-mitotic neurons into the cell cycle, neurodysfunction, neurodegeneration and cognitive disease.

    Atwood, Craig S; Bowen, Richard L

    2015-11-01

    This article is part of a Special Issue "SBN 2014". Sex hormones are physiological factors that promote neurogenesis during embryonic and fetal development. During childhood and adulthood these hormones support the maintenance of brain structure and function via neurogenesis and the formation of dendritic spines, axons and synapses required for the capture, processing and retrieval of information (memories). Not surprisingly, changes in these reproductive hormones that occur with menopause and during andropause are strongly correlated with neurodegeneration and cognitive decline. In this connection, much evidence now indicates that Alzheimer's disease (AD) involves aberrant re-entry of post-mitotic neurons into the cell cycle. Cell cycle abnormalities appear very early in the disease, prior to the appearance of plaques and tangles, and explain the biochemical, neuropathological and cognitive changes observed with disease progression. Intriguingly, a recent animal study has demonstrated that induction of adult neurogenesis results in the loss of previously encoded memories while decreasing neurogenesis after memory formation during infancy mitigated forgetting. Here we review the biochemical, epidemiological and clinical evidence that alterations in sex hormone signaling associated with menopause and andropause drive the aberrant re-entry of post-mitotic neurons into an abortive cell cycle that leads to neurite retraction, neuron dysfunction and neuron death. When the reproductive axis is in balance, gonadotropins such as luteinizing hormone (LH), and its fetal homolog, human chorionic gonadotropin (hCG), promote pluripotent human and totipotent murine embryonic stem cell and neuron proliferation. However, strong evidence supports menopausal/andropausal elevations in the LH:sex steroid ratio as driving aberrant mitotic events. These include the upregulation of tumor necrosis factor; amyloid-β precursor protein processing towards the production of mitogenic Aβ; and

  6. Olfactory dysfunction and cognitive impairment in age-related neurodegeneration: prevalence related to patient selection, diagnostic criteria and therapeutic treatment of aged clients receiving clinical neurology and community-based care.

    Babizhayev, Mark A; Deyev, Anatoliy I; Yegorov, Yegor E

    2011-11-01

    A decrease in olfactory function with age has been attributed to a variety of factors including normal anatomical and physiological changes in aging, surgery, trauma, environmental factors, medications and disease. Olfactory impairment has also been associated with neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease. Deficits in these chemical senses cannot only reduce the pleasure and comfort from food, but represent risk factors for nutritional and immune deficiencies as well as adherence to specific dietary regimens. Therapy is limited, but one should be aware of the existing medical and surgical treatment modalities. Reactive oxygen and nitrogen species, copper and zinc ions, glycating agents and reactive aldehydes, protein cross-linking and proteolytic dysfunction may all contribute to neurodegeneration, olfactory dysfunction, AD. Carnosine (beta-alanyl- L-histidine) is a naturally-occurring, pluripotent, homeostatic transglycating agent. The olfactory lobe is normally enriched in carnosine and zinc. Loss of olfactory function and oxidative damage to olfactory tissue are early symptoms of AD. Protein and lipid oxidation and glycation are integral components of the AD pathophysiology. Carnosine can suppress amyloidbeta peptide toxicity, inhibit production of oxygen free-radicals, scavenge hydroxyl radicals and reactive aldehydes, and suppresses protein glycation. The observations suggest that patented non-hydrolyzed carnosine lubricant drug delivery or perfume toilet water formulations combined with related moiety amino acid structures, such as beta-alanine, should be explored for therapeutic potential towards olfactory dysfunction, AD and other neurodegenerative disorders. "The olfactory system, anatomically, is right in the middle of the part of the brain that's very important for memory. There are strong neural connections between the two." ~ Donald Wilson. PMID:22082323

  7. Traumatic brain injury, neuroimaging, and neurodegeneration

    Erin D. Bigler

    2013-08-01

    Full Text Available Depending on severity, traumatic brain injury (TBI induces immediate neuropathological effects that in the mildest form may be transient but as severity increases results in neural damage and degeneration. The first phase of neural degeneration is explainable by the primary acute and secondary neuropathological effects initiated by the injury; however, neuroimaging studies demonstrate a prolonged period of pathological changes that progressively occur even during the chronic phase. This review examines how neuroimaging may be used in TBI to understand (1 the dynamic changes that occur in brain development relevant to understanding the effects of TBI and how these relate to developmental stage when the brain is injured, (2 how TBI interferes with age-typical brain development and the effects of aging thereafter, and (3 how TBI results in greater frontotemporolimbic damage, results in cerebral atrophy, and is more disruptive to white matter neural connectivity. Neuroimaging quantification in TBI demonstrates degenerative effects from brain injury over time. An adverse synergistic influence of TBI with aging may predispose the brain injured individual for the development of neuropsychiatric and neurodegenerative disorders long after surviving the brain injury.

  8. PATHOBIOLOGY OF NEURODEGENERATION: THE ROLE FOR ASTROGLIA

    VERKHRATSKY, ALEXEI; Zorec, Robert; Rodriguez, Jose J.; Parpura, Vladimir

    2016-01-01

    The common denominator of neurodegenerative diseases, which mainly affect humans, is the progressive death of neural cells resulting in neurological and cognitive deficits. Astroglial cells are the central elements of the homoeostasis, defence and regeneration of the central nervous system, and their malfunction or reactivity contribute to the pathophysiology of neurodegenerative diseases. Pathological remodelling of astroglia in neurodegenerative context is multifaceted. Both astroglial atro...

  9. LRRK2 Pathways Leading to Neurodegeneration.

    Cookson, Mark R

    2015-07-01

    Mutations in LRRK2 are associated with inherited Parkinson's disease (PD) in a large number of families, and the genetic locus containing the LRRK2 gene contains a risk factor for sporadic PD. The LRRK2 protein contains several domains that suggest a role in cellular signaling, including a kinase domain. It is also clear that LRRK2 interacts, either physically or genetically, with several other important proteins implicated in PD, suggesting that LRRK2 may be a central player in the pathways that underlie parkinsonism. As such, LRRK2 has been proposed to be a plausible target for therapeutic intervention, with kinase inhibition being pursued most actively. However, there are still several fundamental aspects of LRRK2 biology and function that remain unresolved at this time. This review will focus on the key questions of normal function of LRRK2 and how this might be related to the pathophysiology of PD. PMID:26008812

  10. Milk metabolites and neurodegeneration: Is there crosstalk?

    Thakur, Keshav; Anand, Akshay

    2015-01-01

    Milk has been considered as a natural source of nutrition for decades. Milk is known to be nutrient-rich which aids the growth and development of the human body. Milk contains both macro- and micronutrients. Breast milk is widely regarded as the optimal source of neonatal nutrition due to its composition of carbohydrates, proteins, minerals and antibodies. However, despite the wide use of milk products, investigations into the role of milk in degenerative diseases have been limited. This revi...

  11. Milk metabolites and neurodegeneration: Is there crosstalk?

    Thakur, Keshav; Anand, Akshay

    2015-10-01

    Milk has been considered as a natural source of nutrition for decades. Milk is known to be nutrient-rich which aids the growth and development of the human body. Milk contains both macro- and micronutrients. Breast milk is widely regarded as the optimal source of neonatal nutrition due to its composition of carbohydrates, proteins, minerals and antibodies. However, despite the wide use of milk products, investigations into the role of milk in degenerative diseases have been limited. This review will examine the relationship between the β-casein gene found in bovine milk and disease states by using age-related macular degeneration as an example. PMID:26526864

  12. Neurodegeneration-associated instability of ribosomal DNA

    Hallgren, Justin; Pietrzak, Maciej; Rempala, Grzegorz; Nelson, Peter T.; Hetman, Michal

    2014-01-01

    Homologous recombination (HR)-mediated instability of the repetitively organized ribosomal DNA (rDNA) has been proposed as a mediator of cell senescence in yeast triggering the DNA damage response. High individual variability in the content of human rDNA suggests that this genomic region remained relatively unstable throughout evolution. Therefore, quantitative real time PCR was used to determine the genomic content of rDNA in post mortem samples of parietal cortex from 14 young- and 9 elderl...

  13. Molecular mechanisms of HIV-1 associated neurodegeneration

    Hakan Ozdener

    2005-06-01

    Since identification of the human immunodeficiency virus-1 (HIV-1), numerous studies suggest a link between neurological impairments, in particular dementia, with acquired immunodeficiency syndrome (AIDS) with alarming occurrence worldwide. Approximately, 60% of HIV-infected people show some form of neurological impairment, and neuropathological changes are found in 90% of autopsied cases. Approximately 30% of untreated HIV-infected persons may develop dementia. The mechanisms behind these pathological changes are still not understood. Mounting data obtained by in vivo and in vitro experiments suggest that neuronal apoptosis is a major feature of HIV associated dementia (HAD), which can occur in the absence of direct infection of neurons. The major pathway of neuronal apoptosis occurs indirectly through release of neurotoxins by activated cells in the central nervous system (CNS) involving the induction of excitotoxicity and oxidative stress. In addition a direct mechanism induced by viral proteins in the pathogenesis of HAD may also play a role. This review focuses on the molecular mechanisms of HIV-associated dementia and possible therapeutic strategies.

  14. Parkinson's disease managing reversible neurodegeneration [Corrigendum

    Hinz M

    2016-06-01

    Full Text Available Hinz M, Stein A, Cole T, McDougall B, Westaway M. Neuropsychiatric Disease and Treatment. 2016;12:763–775.On page 774, Disclosure section, “MH discloses his relationship with DBS Laboratory services and NeuroResearch Clinics, Inc. The other authors report no conflicts of interest in this work” should have been “MH discloses his relationship with DBS Laboratory services and NeuroResearch Clinics, Inc. CHK Nutrition is a subsidiary of West Duluth Distribution Co. The CEO of this company is Amy M. Gunther-Hinz and the Registered Agent is Thais M Hinz. These persons are the daughter and the wife of Dr Marty Hinz. Thais Hinz is also a shareholder of West Duluth Distribution Co. The other authors report no conflicts of interest in this work”. Read the original article

  15. Enzymology of Pyrimidine Metabolism and Neurodegeneration.

    Vincenzetti, Silvia; Polzonetti, Valeria; Micozzi, Daniela; Pucciarelli, Stefania

    2016-01-01

    It is well known that disorders of pyrimidine pathways may lead to neurological, hematological, immunological diseases, renal impairments, and association with malignancies. Nucleotide homeostasis depends on the three stages of pyrimidine metabolism: de novo synthesis, catabolism and recycling of these metabolites. Cytidine and uridine, in addition to be used as substrates for pyrimidine nucleotide salvaging, also act as the precursors of cytidine triphosphate used in the biosynthetic pathway of both brain's phosphatidylcholine and phosphatidylethanolamine via the Kennedy cycle. The synthesis in the brain of phosphatidylcholine and other membrane phosphatides can utilize, in addition to glucose, three compounds present in the blood stream: choline, uridine, and a polyunsaturated fatty acids like docosahexaenoic acid. Some authors, using rat models, found that oral administration of two phospholipid precursors such as uridine and omega-3 fatty acids, along with choline from the diet, can increase the amount of synaptic membrane generated by surviving striatal neurons in rats with induced Parkinson's disease. Other authors found that in hypertensive rat fed with uridine and choline, cognitive deficit resulted improved. Uridine has also been recently considered as a neuroactive molecule, because of its involvement in important neurological functions by improving memory, sleep disorders, anti-epileptic effects, as well as neuronal plasticity. Cytidine and uridine are uptaken by the brain via specific receptors and successively salvaged to the corresponding nucleotides. The present review is devoted to the enzymology of pyrimidine pathways whose importance has attracted the attention of several researchers investigating on the mechanisms underlying the physiopathology of brain. PMID:27063261

  16. Regulated protein aggregation: stress granules and neurodegeneration

    Wolozin Benjamin

    2012-01-01

    Abstract The protein aggregation that occurs in neurodegenerative diseases is classically thought to occur as an undesirable, nonfunctional byproduct of protein misfolding. This model contrasts with the biology of RNA binding proteins, many of which are linked to neurodegenerative diseases. RNA binding proteins use protein aggregation as part of a normal regulated, physiological mechanism controlling protein synthesis. The process of regulated protein aggregation is most evident in formation ...

  17. Vector transmission of leishmania abrogates vaccine-induced protective immunity.

    Nathan C Peters

    2009-06-01

    Full Text Available Numerous experimental vaccines have been developed to protect against the cutaneous and visceral forms of leishmaniasis caused by infection with the obligate intracellular protozoan Leishmania, but a human vaccine still does not exist. Remarkably, the efficacy of anti-Leishmania vaccines has never been fully evaluated under experimental conditions following natural vector transmission by infected sand fly bite. The only immunization strategy known to protect humans against natural exposure is "leishmanization," in which viable L. major parasites are intentionally inoculated into a selected site in the skin. We employed mice with healed L. major infections to mimic leishmanization, and found tissue-seeking, cytokine-producing CD4+ T cells specific for Leishmania at the site of challenge by infected sand fly bite within 24 hours, and these mice were highly resistant to sand fly transmitted infection. In contrast, mice vaccinated with a killed vaccine comprised of autoclaved L. major antigen (ALM+CpG oligodeoxynucleotides that protected against needle inoculation of parasites, showed delayed expression of protective immunity and failed to protect against infected sand fly challenge. Two-photon intra-vital microscopy and flow cytometric analysis revealed that sand fly, but not needle challenge, resulted in the maintenance of a localized neutrophilic response at the inoculation site, and removal of neutrophils following vector transmission led to increased parasite-specific immune responses and promoted the efficacy of the killed vaccine. These observations identify the critical immunological factors influencing vaccine efficacy following natural transmission of Leishmania.

  18. Regulatory Allospecific T Cell Clones Abrogate Chronic Allograft Rejection

    Waaga-Gasser, Ana Maria; Grimm, Martin R.; Lutz, Jens; Lange, Volkmar; Lenhard, Susanne M.; Aviles, Beatriz; Kist-van Holthe, Joana E; Lebedeva, Tatiana; Samsonov, Dimitry; Meyer, Detlef; Hancock, Wayne W.; Heemann, Uwe; Gasser, Martin; Chandraker, Anil

    2009-01-01

    True alloantigen-specific tolerance is the ultimate goal of solid organ transplantation, eliminating the need for long-term immunosuppression. Recent evidence suggests that Th1-derived cytokines are associated with rejection and Th2-derived cytokines with long-term allograft survival, but the roles of these subsets in rejection and tolerance are incompletely understood. Here, we analyzed the functional and regulatory capacities of T cell clones derived from tolerant and rejecting rats (Wistar...

  19. Tumor Regulatory T Cells Potently Abrogate Antitumor Immunity1

    Liu, Zuqiang; Kim, Jin H.; Falo, Louis D.; You, Zhaoyang

    2009-01-01

    Treg from mice bearing a breast tumor were elevated (tumor Treg). In vitro, whereas tumor Treg ability to inhibit tumor-primed CD4+ T cell activity is comparable to Treg from naïve mice (naïve Treg), only tumor Treg suppress naïve CD8+ T cell activation and DC function. Neither tumor Treg nor naïve Treg can suppress antitumor immunity at the effector phase of the immune response induced by adoptively-transferred tumor-primed CD4+ T cells. This is consistent with the observation that, in this ...

  20. Forced swimming stress does not affect monoamine levels and neurodegeneration in rats%强迫性游泳压力对大鼠单胺水平和神经退行性变化没有影响

    Ghulam Abbas; Sabira Naqvi; Shahab Mehmood; Nurul Kabir; Ahsana Dar

    2011-01-01

    Objective The current study was aimed to investigate the correlations between immobility time in the forced swimming test (FST,a behavioral indicator of stress level) and hippocampal monoamine levels (markers of depression),Methods Male Sprague-Dawley rats were subjected to acute,sub-chronic (7 d) or chronic (14 d) FSTs and immobility time was recorded.Levels of noradrenalin,serotonin and dopamine in the hippocampus,and adrenalin level in the plasma were quantified by high-performance liquid chromatography with electrochemical detection.Brain sections from rats after chronic forced swimming or rotenone treatment (3 mg/kg subcutaneously for 4 d) were stained with fluoro jade C.Results The rats subjected to swimming stress (acute,sub-chronic and chronic) showed long immobility times[(214±5),(220±4) and (231±7) s,respectively],indicating that the animals were under stress.However,the rats did not exhibit significant declines in hippocampal monoamine levels,and the plasma adrenalin level was not significantly increased compared to that in unstressed rats.The rats that underwent chronic swimming stress did not manifest fluoro-jade C staining in brain sections,while degenerating neurons were evident after rotenone treatment.Conclusion The immobility time in the FST does not correlate with markers of depression (monoamine levels) and internal stress (adrenalin levels and neurodegeneration),hence this parameter may not be a true indicator of stress level.%目的 本文旨在研究强迫性游泳试验中的不动时间(压力的行为性指示)与海马中单胺水平(抑郁指标)、血浆中肾上腺素水平(循环系统中的压力指标)以及神经退行性变化(fluoro jade C染色法检测)的关系.方法 给予雄性Sprague-Dawley大鼠急性、亚慢性(7天)或慢性(14天)强迫游泳的压力,并在强迫游泳试验中记录大鼠的不动时间.试验结束后,用高效液相色谱电化学检测法测定大鼠海马中去甲肾上腺素、5-羟色胺

  1. Protective Effect of Vitamin E Against Lead-induced Memory and Learning Impairment in Male Rats

    Salehi

    2015-02-01

    Full Text Available Background Lead (Pb2+ is a neurotoxin substance that has been known for its adverse effects on central nervous system and memory. Previous studies reported the potential effect of vitamin E as a memory enhancer. Objectives The purpose of the present study was to assess the protective effects of vitamin E against Pb-induced amnesia. Materials and Methods Forty-eight male Wistar rats (200-250 g were divided equally into the saline, Pb, Pb + vitamin E, and vitamin E alone groups. To induce Pb toxicity, rats received water that contained 0.2% Pb instead of regular water for 1 month. Rats pretreated, treated or post treated with vitamin E (150 mg/kg for 2 months. Passive avoidance learning was assessed using Shuttle-Box after two months. Retention was tested 24 and 48 hours after training. Results The results showed that Pb caused impairment in acquisition and retrieval processes in passive avoidance learning. Vitamin E reversed learning and memory deficits in pre, post or co- exposure with Pb (P < 0.001. Conclusions According to the results of this study, administration of vitamin E to rats counteracts the negative effects of Pb on learning and memory. To more precisely extrapolate these findings to humans, future clinical studies are warranted.

  2. Thymoquinone supplementation ameliorates lead-induced testis function impairment in adult rats.

    Mabrouk, Aymen; Ben Cheikh, Hassen

    2016-06-01

    This study was realized to investigate the possible beneficial effect of thymoquinone (TQ), the major active component of volatile oil of Nigella sativa seeds, against lead (Pb)-induced inhibition of rat testicular functions. Adult rats were randomized into four groups: a control group receiving no treatment; a Pb group exposed to 2000 parts per million (ppm) of Pb acetate in drinking water; a Pb-TQ group co-treated with Pb (as in Pb group) plus TQ (5 mg/kg body weight (b.w.)/day, per orally (p.o.)); and a TQ group receiving TQ (5 mg/kg b.w./day, p.o.). All treatments were for 5 weeks. No significant differences were observed for the body weight gain or for relative testes weight among the four groups of animals. Testicular Pb content significantly increased in metal-intoxicated rats compared with that in control rats. TQ supplementation had no effect on this testicular Pb accumulation. Interestingly, when coadministrated with Pb, TQ significantly improved the low plasma testosterone level and the decreased epididymal sperm count caused by Pb. In conclusion, the results suggest, for the first time, that TQ protects against Pb-induced impairment of testicular steroidogenic and spermatogenic functions. This study will open new perspectives for the clinical use of TQ in Pb intoxication. PMID:25216800

  3. Caloric Restriction Prevents Lead-Induced Oxidative Stress and Inflammation in Rat Liver

    Mustafa Mohammadi; Rana Ghaznavi; Rana Keyhanmanesh; Hamid Reza Sadeghipour; Roya Naderi; Hossein Mohammadi

    2014-01-01

    The aim of the present study is to investigate the effects of caloric restriction on liver of lead-administered rat. Male Sprague-Dawley rats were randomly divided into two groups: Ad libitum fed group (AL, free access to normal rat chow) and caloric restriction group (CR, fed 65% of AL animals' food intake). After 6 weeks, half of the animals of each group were injected lead acetate and the other half were injected saline. Liver tissue samples were collected at the end of the experiments. Gl...

  4. Effect of magnesium on lead induced stress corrosion cracking of UNS N08800

    This research is devoted to the effect of different water chemistries on the passivity and stress corrosion cracking (SCC) of the steam generator tubing alloy. The stability of passive films on UNS N08800 was investigated using cyclic polarization curves, Mott-Schottky measurements, SIMS and XPS. The SCC susceptibility was evaluated with constant extension rate tensile (CERT) tests in simulated neutral crevice chemistries at 300oC. It was found that the SCC susceptibility could be well correlated to the passivity degradation caused by harmful species such as lead. An interaction between lead and magnesium could happen at elevated temperature. (author)

  5. Amelioration of lead induced hepatotoxicity by Allium sativum extracts in Swiss albino mice

    Sharma, Arti; Sharma, Veena; Kansal, Leena

    2010-01-01

    Lead is a blue-gray and highly toxic divalent metal that occurs naturally in the earth’s crust and is spread throughout the environment by various human activities. The efficacy of garlic (Allium sativum) to reduce hepatotoxicity induced by lead nitrate was evaluated experimentally in male mice. Oral treatment with lead nitrate at a dose of 50 mg/kg body weight daily for 40 days (1/45 of LD50) induced a significant increase in the levels of hepatic aspartate aminotransferase, alanine am...

  6. Exposure to lead induces hypoxia-like responses in bullfrog larvae (Rana catesbeiana)

    Rice, T.M.; Blackstone, B.J.; Nixdorf, W.L.; Taylor, D.H.

    1999-10-01

    Amphibians collected around mining sites, areas with extensive automobile traffic, and shooting ranges have been documented to contain high levels of lead. Lead-exposed amphibians might respond as if in hypoxic conditions because exposure is known to decrease hemoglobin levels, damage erythrocytes, and alter respiratory surfaces. Therefore, the authors exposed bullfrog larvae to either 0 or 780 {micro}g/L Pb and either 3.50 or 7.85 mg/L oxygen for 7 d and monitored activity, trips to the surface, and buccal ventilation rates. Activity was significantly decreased in larvae exposed to low oxygen, Pb, or both compared to activity of larvae in high oxygen with no Pb. Larvae exposed to both Pb and low oxygen displayed higher buccal ventilation rates than larvae exposed to either treatment separately. Lead-exposed larvae surfaced significantly more often than unexposed larvae even under high-oxygen conditions. Lead-exposed larvae decreased in mass during the exposure period, whereas unexposed larvae increased in mass. Lead exposure could decrease survival of larvae in the field not only because of physiological problems due to decreased oxygen uptake but also because of greater predation pressure due to increased presence at the surface and reduced growth rates.

  7. Protective effect of Wormwood extract on lead induced neurotoxicity and cognitive disorder

    Kharoubi O

    2010-01-01

    Full Text Available Lead is a ubiquitous and a potent neurotoxicant causes several neurophysiological and behavioural alterations. Considering the vulnerability of the developing brain to Pb neurotoxicity, this study was carried out to investigate the effects of Pb exposure on brain regions acetylcholinesterase (AchE and monoamino oxidase (MAO enzymes activities and on behavioural changes. Wister rat were exposed to 750 ppm of lead acetate in the drinking water for 11-weeks after weaning, and treated by Artemisia Absinthium L. (wormwood extract (200 mg.kg-1 body weight for 4 weeks. The activities of AchE and MAO were determined in the hypothalamus, hippocampus, cortex and striatum of male rat; and general/ Locomotors activity was evaluated in the open-field test. Results indicated a significant decrease in AchE activity in intoxicated group (Pb compared to untreated group (as contral (hypothalamus: -12%, hippocampus: -57%, cerebral cortex: -18% and striatum: -43% and in MAO activity (hypothalamus: -29%, hippocampus: -41%, cerebral cortex: -28% and striatum: -51% respectively, with decrease crossing test score and increase sniffing test score. After, wormwood extract administration, the activity of AchE and MAO were significantly increased in all brain region compared to Pb group, but were significantly lower than control. The locomotors activity was reduced compared to Pb group. These data suggest that administration of wormwood extract for 4 weeks protect against the lead acetate-induced change in behavioural and neurobiochemical parameters changes.

  8. Pacing Lead-Induced Granuloma in the Atrium: A Foreign Body Reaction to Polyurethane

    Shinagawa Yoko

    2013-01-01

    Full Text Available We described a case of an 82-year-old male who presented with a granuloma entrapping the polyurethane-coated pacing lead at the site of contact on the atrium. He had been paced for 8 years without symptoms or signs suggestive of an allergic reaction to the pacemaker system and died from thrombosis of the superior mesenteric artery and heart failure. A histological examination of the nodule showed an incidental granuloma with multinucleated giant cells. No granuloma was found in the heart or the lung.

  9. Co-treatment of chlorpyrifos and lead induce serum lipid disorders in rats: Alleviation by taurine.

    Akande, Motunrayo G; Aliu, Yusuf O; Ambali, Suleiman F; Ayo, Joseph O

    2016-07-01

    The aim of this study was to investigate the effects of taurine (TA) on serum lipid profiles following chronic coadministration of chlorpyrifos (CP) and lead acetate (Pb) in male Wistar rats. Fifty rats randomly distributed into five groups served as subjects. Distilled water (DW) was given to DW group, while soya oil (SO; 1 mL kg(-1)) was given to SO group. The TA group was treated with TA (50 mg kg(-1)). The CP + Pb group was administered sequentially with CP (4.25 mg kg(-1); 1/20th median lethal dose (LD50)) and Pb at 233.25 mg kg(-1) (1/20th LD50), while the TA + CP + Pb group received TA (50 mg kg(-1)), CP (4.25 mg kg(-1)), and Pb (233.25 mg kg(-1)) sequentially. The treatments were administered once daily by oral gavage for 16 weeks. The rats were euthanised, and the blood samples were collected at the termination of the study. Sera obtained from the blood samples were analyzed for total cholesterol, high-density lipoprotein cholesterol, triglycerides, and malondialdehyde, and also the activities of serum antioxidant enzymes including superoxide dismutase, catalase and glutathione peroxidase were analyzed. The low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and atherogenic index were calculated. The results showed that CP and Pb induced alterations in the serum lipid profiles and evoked oxidative stress. TA alleviated the disruptions in the serum lipid profiles of the rats partially by mitigating oxidative stress. It was concluded that TA may be used for prophylaxis against serum lipid disorders in animals that were constantly co-exposed to CP and Pb in the environment. PMID:25537622

  10. Perinatal exposure to lead induces morphological, ultrastructural and molecular alterations in the hippocampus

    Highlights: ► Pre- and neonatal Pb exposure decreased the number of hippocampal neurons. ► Lead caused ultrastructural alterations in CA1 region of hippocampus. ► Hippocampus is highly vulnerable to low level perinatal Pb exposure. ► Lead decreased BDNF level in the developing brain. ► Decreased Bax/Bcl2 ratio may protect hippocampus against Pb-induced apoptosis. -- Abstract: The aim of this paper is to examine if pre- and neonatal exposure to lead (Pb) may intensify or inhibit apoptosis or necroptosis in the developing rat brain. Pregnant experimental females received 0.1% lead acetate (PbAc) in drinking water from the first day of gestation until weaning of the offspring; the control group received distilled water. During the feeding of pups, mothers from the experimental group were still receiving PbAc. Pups were weaned at postnatal day 21 and the young rats of both groups then received only distilled water until postnatal day 28. This treatment protocol resulted in a concentration of Pb in rat offspring whole blood (Pb-B) below the threshold of 10 μg/dL, considered safe for humans.We studied Casp-3 activity and expression, AIF nuclear translocation, DNA fragmentation, as well as Bax, Bcl-2 mRNA and protein expression as well as BDNF concentration in selected structures of the rat brain: forebrain cortex (FC), cerebellum (C) and hippocampus (H). The microscopic examinations showed alterations in hippocampal neurons.Our data shows that pre- and neonatal exposure of rats to Pb, leading to Pb-B below 10 μg/dL, can decrease the number of hippocampus neurons, occurring concomitantly with ultrastructural alterations in this region. We observed no morphological or molecular features of severe apoptosis or necrosis (no active Casp-3 and AIF translocation to nucleus) in young brains, despite the reduced levels of BDNF. The potential protective factor against apoptosis was probably the decreased Bax/Bcl-2 ratio, which requires further investigation. Our findings contribute to further understanding of the mechanisms underlying Pb neurotoxicity and cognition impairment in a Pb-exposed developing brain.

  11. Mitigating effects of Jambul against lead induced toxicity in epididymis and vas deferens of mice

    Abbas, Tahir; Ahmad, Khawaja Raees; Ullah, Asmat; Iqbal, Samreen; Raees, Kausar

    2015-01-01

    Background: Precious fruits like jambul are neglected and wasted while environmental pollutants like lead intake remain overlooked. Objective: The aim of this study was to investigate the effects of the Jambul pulp extract on lead detrimental effects in pseudostratified epithelium and the stereocilia of mice epididymis and vas deferens. Materials and Methods: Thirty young males mice (Mus musculus) were distributed randomly in 3 groups (n= 10) called control, Pb (Lead) and Pb-J (Lead-Jambul). The Pb and Pb-J were provided 50ppm Pb in drinking water ad libitum for 15 days and Pb free water for the next 5 days. The Pb-J group received 0.2ml jambul pulp extract on 12 hourly bases. Control group was not given any treatment. Organs (epididymis and vas deference) were recovered on 21st day after euthanasia. The organs were finally processed for histological and micrometric studies. Results: Marked histologic and micrometric changes in both organs were noted in Pb group. These include significant (P ≤ 0.05) decrease in cross sectional area of caput and cauda epididymis folding tubing along with evident alterations of their endothelial thickness. Prominent signs of apoptosis (vacuolations) in the corpus pseudostratified endothelium and the destruction of stereocilia of the epididymis and vas deferens in Pb compared to control group were observed. Evident signs of recovery, in both organs, such as proliferation and rearrangements in pseudostratified endothelium and the stereocilia along with convincing recovery in micrometric parameters were observed in Pb-J group. Conclusion: The results indicate that epididymis and vas deferens are highly sensitive to Pb exposure while Jambul pulp extract has shown rich mitigating potentials against such histopathologies. PMID:26730248

  12. Lead phytotoxicity in soils and nutrient solutions is related to lead induced phosphorus deficiency.

    Cheyns, Karlien; Peeters, Sofie; Delcourt, Dorien; Smolders, Erik

    2012-05-01

    This study was set up to relate lead (Pb) bioavailability with its toxicity to plants in soils. Tomato and barley seedlings were grown in six different PbCl(2) spiked soils (pH: 4.7-7.4; eCEC: 4.2-41.7 cmol(c)/kg). Soils were leached and pH corrected after spiking to exclude confounding factors. Plant growth was halved at 1600-6500 mg Pb/kg soil for tomato and at 1900-8300 mg Pb/kg soil for barley. These soil Pb threshold were unrelated to soil pH, organic carbon, texture or eCEC and neither soil solution Pb nor Pb(2+) ion activity adequately explained Pb toxicity among soils. Shoot phosphorus (P) concentrations significantly decreased with increasing soil Pb concentrations. Tomato grown in hydroponics at either varying P supply or at increasing Pb (equal initial P) illustrated that shoot P explained growth response in both scenarios. The results suggest that Pb toxicity is partially related to Pb induced P deficiency, likely due to lead phosphate precipitation. PMID:22377902

  13. Protective effect of thymoquinone against lead-induced hepatic toxicity in rats.

    Mabrouk, Aymen; Bel Hadj Salah, Imen; Chaieb, Wafa; Ben Cheikh, Hassen

    2016-06-01

    Lead (Pb) intoxication is a worldwide health problem which frequently affects the liver. This study was carried out to investigate the potential protective effect of thymoquinone (TQ), the major active ingredient of volatile oil of Nigella sativa seeds, against Pb-induced liver damage. Adult male rats were randomized into four groups: Control group received no treatment, Pb group was exposed to 2000 ppm Pb acetate in drinking water, Pb-TQ group was cotreated with Pb plus TQ (5 mg/kg/day, per orally), and TQ group receiving only TQ. All treatments were applied for 5 weeks. Results indicated that Pb exposure increased hepatic Pb content, damaged hepatic histological structure (necrotic foci, hepatic strands disorganization, hypertrophied hepatocytes, cytoplasmic vacuolization, cytoplasmic loss, chromatin condensation, mononuclear cell infiltration, congestion, centrilobular swelling), and changed liver function investigated by plasma biochemical parameters (AST, ALT, ALP, γ-GT, LDH). Pb treatment also decreased total antioxidant status level and increased lipid peroxidation in the liver. Supplementation with TQ remarkably improved the Pb-induced adverse effects without significantly reducing the metal accumulation in the liver. In conclusion, our results indicate, for the first time, a protective effect of TQ against Pb-induced hepatotoxicity and suggest that this component might be clinically useful in Pb intoxication. PMID:26971798

  14. Comparison between electrophysiologic and morphologic changes in lead induced peripheral neuropathy in rats.

    Hwang, Y. M.; Sunwoo, I. N.; Chung, I. H.; Jung, B

    1989-01-01

    Compound nerve action potential (CNAP) of the mixed peripheral nerve is composed of A alpha beta, A delta, and C potentials. All components of CNAPs in the sciatic nerve were recorded by stimulating the tibial nerve of both control and lead-poisoned rats. Marked decrease of nerve conduction velocity and prolonged duration were found in A alpha beta and A delta fibers especially in large myelinated A alpha beta fibers. The amplitude decreased in A alpha beta potential, but the area did not cha...

  15. Hydrogen sulfide ameliorates lead-induced morphological, photosynthetic, oxidative damages and biochemical changes in cotton.

    Bharwana, Saima Aslam; Ali, Shafaqat; Farooq, Muhammad Ahsan; Ali, Basharat; Iqbal, Naeem; Abbas, Farhat; Ahmad, Muhammad Sajid Aqeel

    2014-01-01

    Poisonous lead (Pb), among heavy metals, is a potential pollutant that readily accumulates in soils and thus adversely affects physiological processes in plants. We have evaluated how exogenous H2S affects cotton plant physiological attributes and Pb uptake under Pb stress thereby understanding the role of H2S in physiological processes in plants. Two concentrations (0 and 200 μM) of H2S donor sodium hydrosulfide (NaHS) were experimented on cotton plants under Pb stress (0, 50, and 100 μM). Results have shown that Pb stress decreased plant growth, chlorophyll contents, SPAD value, photosynthesis, antioxidant activity. On the other hand, Pb stress increased the level of malondialdehyde (MDA), electrolyte leakage (EL), and production of H2O2 and uptake of Pb contents in all three parts of plant, viz. root, stem, and leaf. Application of H2S slightly increased plant growth, chlorophyll contents, SPAD value, photosynthesis, and antioxidant activity as compared to control. Hydrogen sulfide supply alleviated the toxic effects of lead on plant growth, chlorophyll contents, SPAD value, photosynthesis, and antioxidant activity in cotton plants. Hydrogen sulfide also reduced MDA, EL, and production of H2O2 and endogenous Pb levels in the three mentioned plant parts. On the basis of our results, we conclude that H2S has promotive effects which could improve plant survival under Pb stress. PMID:23852465

  16. Amelioration of lead induced changes in ovary of mice, by garlic extract

    Objective: To observe the effects of lead acetate and protective role of garlic extract on the histomorphology of the ovary in an animal model. Methods: The experimental trial was conducted at the Department of Anatomy, Army Medical College Rawalpindi, in association with the National Institute of Health (NIH), Islamabad, from April to June 2013. It comprised 30 adult non-pregnant female mice (BALBc strain) weighing 25-27gms. They were divided into three equal groups of 10 mice each. Group A, taken as control, was given normal diet. Group B was given lead acetate at a dose of 30mg/kg/day. Group C was given lead acetate 30mg/kg/day and garlic extract 500mg/kg/day through oral gavage tube for two months. Animals were dissected a day after the last dose. Size, shape, colour and consistency of the ovary was observed. The right ovary was processed, embedded and stained for histological study. Primary follicles were counted and noted. SPSS 18 was used for statistical analysis. Results: The primary follicular count decreased significantly in Group B while it relatively increased in Group C. Morphology of the ovary was affected after exposure to lead acetate in Group B, while in Group C results were the same as in the Group A controls regarding gross architecture of the ovary. Conclusion: Lead alters the normal histology and affects the physiology of the ovary. It interferes with the development of growing follicles in the ovary. Lead, being a reproductive toxicant, can be a cause of infertility in exposed females. (author)

  17. Garlic ameliorates histological changes in the uterine epithelium of lead induced mice

    To evaluate the protective role of garlic extract on the histology of the uterine epithelium exposed to lead acetate in an animal model. Study Design: Laboratory based randomized control trial. Place and Duration of Study: Department of Anatomy, Army Medical College in collaboration with National Institute of health from April to June 2013. Material and Methods: Thirty female BALBc mice were selected. Ten animals were placed in each group. Group A being the control was given normal diet. Group B was given lead acetate at a dose of 30 mg/kg/day. Group C was given lead acetate 30 mg/kg/day and garlic extract 500 mg/kg/day through oral gavage tube for 60 days. Animals were sacrificed and dissected at the end of 60 days. Right uterine horn was processed, embedded and stained for histological study. Height of epithelium was measured. It was taken from apical to basal end of the cells. Results: There was increase in height of the lining epithelium of uterus in group B, mean value 19.70 ± 4.81 meu m when compared to Group A, with mean value 13.25 ± 2.37 meu m. The height of the epithelium was relatively reduced in group C, with mean value 14.50 ± 2.30 meu m when compared with group B. In group C results were same as Group A. The p values were 0.001 when group A was compared to group B, 0.688 when group A was compared to group C and 0.005 when group B was compared to group C. Conclusion: The height of epithelium was markedly increased in lead acetate treated group which returned to normal when co treated with garlic extract. Hence garlic ameliorated the changes induced by lead. (author)

  18. Iron supplement prevents lead-induced disruption of the blood-brain barrier during rat development

    Children are known to be venerable to lead (Pb) toxicity. The blood-brain barrier (BBB) in immature brain is particularly vulnerable to Pb insults. This study was designed to test the hypothesis that Pb exposure damaged the integrity of the BBB in young animals and iron (Fe) supplement may prevent against Pb-induced BBB disruption. Male weanling Sprague-Dawley rats were divided into four groups. Three groups of rats were exposed to Pb in drinking water containing 342 μg Pb/mL as Pb acetate, among which two groups were concurrently administered by oral gavage once every other day with 7 mg Fe/kg and 14 mg Fe/kg as FeSO4 solution as the low and high Fe treatment group, respectively, for 6 weeks. The control group received sodium acetate in drinking water. Pb exposure significantly increased Pb concentrations in blood by 6.6-folds (p < 0.05) and brain tissues by 1.5-2.0-folds (p < 0.05) as compared to controls. Under the electron microscope, Pb exposure in young animals caused an extensive extravascular staining of lanthanum nitrate in brain parenchyma, suggesting a leakage of cerebral vasculature. Western blot showed that Pb treatment led to 29-68% reduction (p < 0.05) in the expression of occludin as compared to the controls. Fe supplement among Pb-exposed rats maintained the normal ultra-structure of the BBB and restored the expression of occludin to normal levels. Moreover, the low dose Fe supplement significantly reduced Pb levels in blood and brain tissues. These data suggest that Pb exposure disrupts the structure of the BBB in young animals. The increased BBB permeability may facilitate the accumulation of Pb. Fe supplement appears to protect the integrity of the BBB against Pb insults, a beneficial effect that may have significant clinical implications

  19. Amelioration of Lead-induced Toxicity in Blood, Liver and Kidney Tissues of Male Wistar Rats by Fermented Ofada Rice

    Eferhire Aganbi

    2015-09-01

    Full Text Available The protective effects of ‘ofada’ rice koji (ORK, fermented ofada rice and ascorbic acid (AA against lead (Pb-induced toxicity in the blood, liver and kidney tissues of male Wistar rats was investigated. The animals were divided into four treatment groups (A – D, n = 5. Groups B, C and D were intoxified by intra-peritoneal injection of 75 mg lead acetate/kg body weight. Groups C and D only had their feed mixed with ORK and AA, respectively. The results showed no significant difference in % packed cell volume (PCV and Pb concentrations. Feeding with ORK and AA significantly decreased alanine aminotransferase activities (36.50 ± 3.54 and 34.02 ± 0.05 UL-1 respectively compared to Pb-only treated group (85.50 ± 3.25 UL-1. The ferric reducing antioxidant power (FRAP for organs increased significantly following intake of feeds mixed with ORK and AA; increases in FRAP was higher for ORK-treated group possibly due to increased total flavonoids concentration following fermentation. Furthermore, Pb-induced high plasma creatinine levels decreased upon treatment with feeds mixed with ORK and ascorbic acid. These findings strongly indicated that feed supplementation with ORK by 45% may be more effective at ameliorating the effects of Pb-induced toxicity in tissues compared to supplementation with AA by 2%.

  20. Therapeutic Effects of Allium sativum on Lead-induced Biochemical changes in Soft tissues of Swiss Albino Mice

    Arti Sharma; Veena Sharma; Leena Kansal

    2009-01-01

    Allium sativum (Meaning pungent) belongs to the Alliaceae family and genus Allium, is generally known in the developing world for its characteristic flavor, a medicinal plant and a source of vegetable oil. Besides, the plant is reported to have various biological activities including hypocholesterolemic, antiatherosclerotic, anticoagulant, antibacterial, antifungal, anti-diabetic, anti-tumor agent; used for treating various disease such as inflammation, cardiovascular and liver diseases. The ...

  1. Alleviation of lead-induced physiological, metabolic, and ultramorphological changes in leaves of upland cotton through glutathione.

    Khan, Mumtaz; Daud, M K; Basharat, Ali; Khan, Muhammad Jamil; Azizullah, Azizullah; Muhammad, Niaz; Muhammad, Noor; Ur Rehman, Zia; Zhu, Shui Jin

    2016-05-01

    Plants face changes in leaves under lead (Pb) toxicity. Reduced glutathione (GSH) has several functions in plant metabolism, but its role in alleviating Pb toxicity in cotton leaves is still unknown. In the present study, cotton seedlings (28 days old) were exposed to 500 μM Pb and 50 μM GSH, both alone and in combination, for a period of 10 days, in the Hoagland solution under controlled growth conditions. Results revealed Pb-induced changes in cotton's leaf morphology, photosynthesis, and oxidative metabolism. However, exogenous application of GSH restored leaf growth. GSH triggered build up of chlorophyll a, chlorophyll b, and carotenoid contents and boosted fluorescence ratios (F v/F m and F v/F 0). Moreover, GSH reduced the malondialdehyde (MDA), hydrogen peroxide (H2O2), and Pb contents in cotton leaves. Results further revealed that total soluble protein contents were decreased under Pb toxicity; however, exogenously applied GSH improved these contents in cotton leaves. Activities of antioxidant enzymes (catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), glutathione reductase (GR), and ascorbate peroxidase (APX)) were also increased by GSH application under Pb toxicity. Microscopic analysis showed that excess Pb shattered thylakoid membranes in chloroplasts. However, GSH stabilized ultrastructure of Pb-stressed cotton leaves. These findings suggested that exogenously applied GSH lessened the adverse effects of Pb and improved cotton's tolerance to oxidative stress. PMID:26782322

  2. Studies of a nuclear matrix protein restricted to normal brain cells and lead-induced intranuclear inclusion bodies of kidney

    Shelton, K.; Egle, P.; Redford, K.; Bigbee, J.

    1986-05-01

    A nuclear matrix protein, p32/6.3, with an unusual tissue distribution, has been identified. Protein from 21 tissues was surveyed by immunoprobing Western blots. In normal adult rats p32/6.3 is found only in grey matter from the cerebrum and the cerebellum, occurring in both neurons and astrocytes. Other brain cell types have not been examined. The protein appears to be developmentally regulated. It is detectable in the brain within a few days after birth and reaches adult levels within one to two weeks. Brain p32/6.3 has been found in all animals tested including rat, mouse, dog, cow, pig, chicken and human. This conservation indicates a fundamental role for p32/6.3 in the nucleus of brain cells. Possible functions for p32/6.3 may be indicated by a second novel occurrence. Chronic lead poisoning characteristically induces intranuclear inclusion bodies in the cells lining kidney proximal tubules. p32/6.3 is a major constituent of these inclusion bodies. They are also rich in lead and other metals including calcium, iron, zinc, copper and cadmium. These diverse observations suggest that p32/6.3 may have a role in metal homeostasis in the brain of normal animals.

  3. Lead-induced genotoxicity to Vicia faba L. roots in relation with metal cell uptake and initial speciation.

    Shahid, M; Pinelli, E; Pourrut, B; Silvestre, J; Dumat, C

    2011-01-01

    Formation of organometallic complexes in soil solution strongly influence metals phytoavailability. However, only few studies deal with the influence of metal speciation both on plant uptake and genotoxicity. In the present study, Vicia faba seedlings were exposed for 6h in controlled hydroponic conditions to 5 μM of lead nitrate alone and chelated to varying degrees by different organic ligands. Ethylenediaminetetraacetic acid and citric acid were, respectively, chosen as models of humic substances and low weight organic acids present in natural soil solutions. Visual Minteq software was used to estimate free lead cations concentration and ultimately to design the experimental layout. For all experimental conditions, both micronucleus test and measure of lead uptake by plants were finally performed. Chelation of Pb by EDTA, a strong chelator, dose-dependently increased the uptake in V. faba roots while its genotoxicity was significantly reduced, suggesting a protective role of EDTA. A weak correlation was observed between total lead concentration absorbed by roots and genotoxicity (r(2)=0.65). In contrast, a strong relationship (r(2)=0.93) exists between Pb(2+) concentration in exposure media and genotoxicity in the experiment performed with EDTA. Citric acid induced labile organometallic complexes did not demonstrate any significant changes in lead genotoxicity or uptake. These results demonstrate that metal speciation knowledge could improve the interpretation of V. faba genotoxicity test performed to test soil quality. PMID:20851467

  4. Nitric oxide in neurodegeneration: potential benefits of non-steroidal anti-inflammatories%一氧化氮在神经退行性疾病中的作用:非类固醇性抗炎药的治疗前景

    GayleHelane Doherty

    2011-01-01

    一氧化氮(nitric oxide,NO)是一类胞内信使.研究表明,神经退行性病人脑组织中催化合成NO的酶的表达水平显著提高,提示NO与神经退行性疾病密切相关.此外,在这些组织中还检测到硝化的蛋白,提示NO在这些组织中具有生物活性.在神经免疫应答中,神经元和胶质细胞(包括小胶质细胞和星形胶质细胞)内都发生了NO水平的改变.很多神经退行性疾病都伴随有神经炎症,抑制神经炎症的信号通路能延迟这些疾病的发展.因此,NO及其释放通路已逐渐成为神经退行性疾病研究领域的热点,对它们的理解能帮助我们找到合适的方案来预防、减缓或者治愈这些疾病.%The cellular messenger nitric oxide(NO)has been linked to neurodegenerative disorders due to the increased expression of the enzymes that catalyze its synthesis in postmortem tissues derived from sufferers of these diseases.Nitrated proteins have also been detected in these samples,revealing that NO is biologically active in regions damaged during neurodegeneration.Modulation of NO levels has been reported not only in the neurons of the central nervous system,but also in the glial cells(microglia and astroglia)activated during the neuroinflammatory response.Neuroinflammation has been found in some neurodegenerative conditions,and inhibition of these neuroinflammatory signals has been shown to delay the progress of such disorders.Thus NO and the pathways triggering its release are emerging as an important research focus in the search for strategies to prevent,halt or cure neurodegenerative diseases.

  5. Environment, epigenetics and neurodegeneration: Focus on nutrition in Alzheimer's disease.

    Nicolia, Vincenzina; Lucarelli, Marco; Fuso, Andrea

    2015-08-01

    Many different environmental factors (nutrients, pollutants, chemicals, physical activity, lifestyle, physical and mental stress) can modulate epigenetic markers in the developing and adult organism. Epigenetics, in turn, can cause and is associated with several neurodegenerative and aging-dependent human diseases. Alzheimer's disease certainly represents one of the most relevant neurodegenerative disorders due to its incidence and its huge socio-economic impact. Therefore, it is easy to understand why recent literature focuses on the epigenetic modifications associated with Alzheimer's disease and other neurodegenerative disorders. One of the most intriguing and, at the same time, worrying evidence is that even "mild" environmental factors (such as behavioral or physical stress) as well as the under-threshold exposure to pollutants and chemicals, can be effective. Finally, even mild nutrients disequilibria can result in long-lasting and functional alterations of many epigenetic markers, although they don't have an immediate acute effect. Therefore, we will probably have to re-define the current risk threshold for many factors, molecules and stresses. Among the many different environmental factors affecting the epigenome, nutrition represents one of the most investigated fields; the reasons are probably that each person interacts with nutrients and that, in turn, nutrients can modulate at molecular level the epigenetic biochemical pathways. The role that nutrition can exert in modulating epigenetic modifications in Alzheimer's disease will be discussed with particular emphasis on the role of B vitamins and DNA methylation. PMID:25456841

  6. Nutrition and neurodegeneration: epidemiological evidence and challenges for future research.

    Gillette-Guyonnet, Sophie; Secher, Marion; Vellas, Bruno

    2013-03-01

    The prevention of dementias, such as Alzheimer's disease (AD), is a growing public health concern, due to a lack of effective curative treatment options and a rising global prevalence. Various potential risk or preventive factors have been suggested by epidemiological research, including modifiable lifestyle factors such as diet. Current epidemiological data are in favour of a protective role of certain micronutrients (B vitamins related to homocysteine metabolism, the anti-oxidant vitamins C and E, flavonoids, polyunsatured omega-3 fatty acids, vitamin D) and macronutrients (fish) in the prevention of cognitive decline and dementia/AD. Some factors have been targeted by interventions tested in randomized controlled trials (RCTs), but many of the results are conflicting with observational evidence. Epidemiological analysis of the relations between nutrient consumption and cognitive decline is complex and it is highly unlikely that a single component plays a major role. In addition, since multiple factors across the life course influence brain function in late life, multidomain interventions might be more promising in the prevention of cognitive decline and dementia/AD. Designing such trials remains very challenging for researchers. The main objective of this paper is to review the epidemiologic data linking potential protective factors to cognitive decline or dementia/AD, focusing particularly on the roles of adiposity, caloric restriction, micro (group B vitamins related to homocysteine metabolism, the anti-oxidant vitamins C and E, flavonoids, polyunsatured omega-3 fatty acids, vitamin D) and macronutrients (fish). Limitations of the current data, divergence with results of interventional prevention studies and challenges for future research are discussed. PMID:23384081

  7. Cerebrolysin protects against rotenone-induced oxidative stress and neurodegeneration

    Abdel-Salam, Omar

    2014-01-01

    Omar ME Abdel-Salam,1 Nadia A Mohammed,2 Eman R Youness,2 Yasser A Khadrawy,3 Enayat A Omara,4 Amany A Sleem51Department of Toxicology and Narcotics, 2Department of Medical Biochemistry, 3Department of Physiology, 4Department of Pathology, 5Department of Pharmacology, National Research Centre, Dokki, Cairo, EgyptAbstract: We investigated the effect of cerebrolysin, a peptide mixture used for promoting memory and recovery from cerebral stroke, on the development of oxidative stress and nigrost...

  8. Cerebrolysin protects against rotenone-induced oxidative stress and neurodegeneration

    Abdel-Salam OME

    2014-05-01

    Full Text Available Omar ME Abdel-Salam,1 Nadia A Mohammed,2 Eman R Youness,2 Yasser A Khadrawy,3 Enayat A Omara,4 Amany A Sleem51Department of Toxicology and Narcotics, 2Department of Medical Biochemistry, 3Department of Physiology, 4Department of Pathology, 5Department of Pharmacology, National Research Centre, Dokki, Cairo, EgyptAbstract: We investigated the effect of cerebrolysin, a peptide mixture used for promoting memory and recovery from cerebral stroke, on the development of oxidative stress and nigrostriatal cell injury induced by rotenone administration in rats. Rotenone 1.5 mg/kg was given subcutaneously three times weekly either alone or in combination with cerebrolysin at 21.5, 43, or 86 mg/kg. Rats were euthanized 14 days after starting the rotenone injection. Lipid peroxidation (malondialdehyde, reduced glutathione (GSH, nitric oxide (nitrite concentrations, paraoxonase 1 (PON1, and acetylcholinesterase (AChE activities – as well as the monocyte chemoattractant protein-1 (MCP-1 and the antiapoptotic protein Bcl-2 – were measured in the brain. Histopathology, tyrosine hydroxylase, inducible nitric oxide synthase (iNOS, tumor necrosis factor-α (TNF-α, and cleaved caspase-3 immunohistochemistry were also performed. Rotenone caused a significantly elevated oxidative stress and proinflammatory response in the different brain regions. Malondialdehyde and nitric oxide concentrations were significantly increased, while GSH markedly decreased in the cerebral cortex, striatum, hippocampus, and in the rest of the brain. PON1 and AChE activities significantly decreased with respect to the control levels after rotenone application. Striatal Bcl-2 was significantly decreased while MCP-1 increased following rotenone injection. Rotenone caused prominent iNOS, TNF-α, and caspase-3 immunostaining in the striatum and resulted in markedly decreased tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum. Cerebrolysin coadministered with rotenone decreased lipid peroxidation, increased GSH, and inhibited the elevation of nitric oxide induced by rotenone. Cerebrolysin also decreased the rotenone-induced decline in the PON1 and AChE activities and the rotenone-mediated changes in the striatal Bcl-2 and MCP-1 levels. The drug reduced iNOs, TNF-α, and caspase 3 expressions and increased the tyrosine hydroxylase immunoreactivity in the striatum. Cerebrolysin markedly prevented the development of neuronal damage in the cortex and striatum. These data suggest that cerebrolysin may have potential therapeutic effect in Parkinson’s disease.Keywords: brain oxidative stress, neuroinflammation, apoptosis, nigrostriatal damage

  9. UBQLN2 mutation causing heterogeneous X-linked dominant neurodegeneration.

    Fahed, Akl C; McDonough, Barbara; Gouvion, Cynthia M; Newell, Kathy L; Dure, Leon S; Bebin, Martina; Bick, Alexander G; Seidman, Jonathan G; Harter, Donald H; Seidman, Christine E

    2014-05-01

    We report a 5-generation family with phenotypically diverse neurodegenerative disease including relentlessly progressive choreoathetoid movements, dysarthria, dysphagia, spastic paralysis, and behavioral dementia in descendants of a 67-year-old woman with amyotrophic lateral sclerosis. Disease onset varied with gender, occurring in male children and adult women. Exome sequence analyses revealed a novel mutation (c.1490C>T, p.P497L) in the ubiquilin-2 gene (UBQLN2) with X-linked inheritance in all studied affected individuals. As ubiquilin-2-positive inclusions were identified in brain, we suggest that mutant peptide predisposes to protein misfolding and accumulation. Our findings expand the spectrum of neurodegenerative phenotypes caused by UBQLN2 mutations. PMID:24771548

  10. UBQLN2 Mutation Causing Heterogeneous X-linked Dominant Neurodegeneration

    Fahed, Akl C.; McDonough, Barbara; Gouvion, Cynthia M; Newell, Kathy L; Dure, Leon S.; Bebin, Martina; Bick, Alexander G.; Seidman, J G; Harter, Donald H.; Seidman, Christine E.

    2014-01-01

    We report a five-generation family with phenotypically diverse neurodegenerative disease including relentlessly progressive choreoathetoid movements, dysarthria, dysphagia, spastic paralysis, and behavioral dementia in descendants of a 67-year-old woman with amyotrophic lateral sclerosis. Disease onset varied with gender, occurring in male children and adult women. Exome sequence analyses revealed a novel mutation (c.1490C>T, p.P497L) in the ubiquilin-2 gene (UBQLN2) with X-linked inheritance...

  11. Nutrition and neurodegeneration: epidemiological evidence and challenges for future research

    Gillette‐Guyonnet, Sophie; Secher, Marion; Vellas, Bruno

    2013-01-01

    The prevention of dementias, such as Alzheimer's disease (AD), is a growing public health concern, due to a lack of effective curative treatment options and a rising global prevalence. Various potential risk or preventive factors have been suggested by epidemiological research, including modifiable lifestyle factors such as diet. Current epidemiological data are in favour of a protective role of certain micronutrients (B vitamins related to homocysteine metabolism, the anti‐oxidant vitamins C...

  12. Deficient vesicular storage: A common theme in catecholaminergic neurodegeneration.

    Goldstein, David S; Holmes, Courtney; Sullivan, Patti; Mash, Deborah C; Sidransky, Ellen; Stefani, Alessandro; Kopin, Irwin J; Sharabi, Yehonatan

    2015-09-01

    Several neurodegenerative diseases involve loss of catecholamine neurons--Parkinson's disease (PD) is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are lost has been mysterious. Accumulating evidence supports the concept of "autotoxicity"--inherent cytotoxicity caused by catecholamine metabolites. Since vesicular sequestration limits the buildup of toxic products of enzymatic and spontaneous oxidation of catecholamines, a vesicular storage defect could play a pathogenic role in the death of catecholaminergic neurons in a variety of neurodegenerative diseases. In putamen, deficient vesicular storage is revealed in vivo by accelerated loss of (18)F-DOPA-derived radioactivity and post-mortem by decreased tissue dopamine (DA):DOPA ratios; in myocardium in vivo by accelerated loss of (18)F-dopamine-derived radioactivity and post-mortem by increased 3,4-dihydroxyphenylglycol:norepinephrine (DHPG:NE) ratios; and in sympathetic noradrenergic nerves overall in vivo by increased plasma F-dihydroxyphenylacetic acid (F-DOPAC):DHPG ratios. We retrospectively analyzed data from 20 conditions with decreased or intact catecholaminergic innervation, involving different etiologies, pathogenetic mechanisms, and lesion locations. All conditions involving parkinsonism had accelerated loss of putamen (18)F-DOPA-derived radioactivity; in those with post-mortem data there were also decreased putamen DA:DOPA ratios. All conditions involving cardiac sympathetic denervation had accelerated loss of myocardial (18)F-dopamine-derived radioactivity; in those with post-mortem data there were increased myocardial DHPG:NE ratios. All conditions involving localized loss of catecholaminergic innervation had evidence of decreased vesicular storage specifically in the denervated regions. Thus, across neurodegenerative diseases, loss of catecholaminergic neurons seems to be associated with decreased vesicular storage in the residual neurons. PMID:26255205

  13. Drosophila melanogaster in the Study of Human Neurodegeneration

    Hirth, Frank

    2010-01-01

    Human neurodegenerative diseases are devastating illnesses that predominantly affect elderly people. The majority of the diseases are associated with pathogenic oligomers from misfolded proteins, eventually causing the formation of aggregates and the progressive loss of neurons in the brain and nervous system. Several of these proteinopathies are sporadic and the cause of pathogenesis remains elusive. Heritable forms are associated with genetic defects, suggesting that the affected protein is...

  14. The Role Stress Granules and RNA Binding Proteins in Neurodegeneration

    Vanderweyde, Tara; Youmans, Katie; Liu-Yesucevitz, Liqun; Wolozin, Benjamin

    2013-01-01

    The eukaryotic stress response involves translational suppression of non-housekeeping proteins and the sequestration of unnecessary mRNA transcripts into stress granules (SGs). This process is dependent on mRNA binding proteins (RBPs) that interact with capped mRNA transcripts through RNA recognition motifs, and exhibit reversible aggregation through hydrophobic poly-glycine domains, some of which are homologous to yeast prion proteins. The activity and aggregation of RBPs appears to be impor...

  15. Antisense Oligonucleotides: Treating Neurodegeneration at the Level of RNA

    DeVos, Sarah L.; Miller, Timothy M.

    2013-01-01

    Adequate therapies are lacking for Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and other neurodegenerative diseases. The ability to use antisense oligonucleotides (ASOs) to target disease-associated genes by means of RNA may offer a potent approach for the treatment of these, and other, neurodegenerative disorders. In modifying the basic backbone chemistry, chemical groups, and target sequence, ASOs can act through numerous mechanisms to decr...

  16. p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration.

    Turnquist, C; Horikawa, I; Foran, E; Major, E O; Vojtesek, B; Lane, D P; Lu, X; Harris, B T; Harris, C C

    2016-09-01

    Bidirectional interactions between astrocytes and neurons have physiological roles in the central nervous system and an altered state or dysfunction of such interactions may be associated with neurodegenerative diseases, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Astrocytes exert structural, metabolic and functional effects on neurons, which can be either neurotoxic or neuroprotective. Their neurotoxic effect is mediated via the senescence-associated secretory phenotype (SASP) involving pro-inflammatory cytokines (e.g., IL-6), while their neuroprotective effect is attributed to neurotrophic growth factors (e.g., NGF). We here demonstrate that the p53 isoforms Δ133p53 and p53β are expressed in astrocytes and regulate their toxic and protective effects on neurons. Primary human astrocytes undergoing cellular senescence upon serial passaging in vitro showed diminished expression of Δ133p53 and increased p53β, which were attributed to the autophagic degradation and the SRSF3-mediated alternative RNA splicing, respectively. Early-passage astrocytes with Δ133p53 knockdown or p53β overexpression were induced to show SASP and to exert neurotoxicity in co-culture with neurons. Restored expression of Δ133p53 in near-senescent, otherwise neurotoxic astrocytes conferred them with neuroprotective activity through repression of SASP and induction of neurotrophic growth factors. Brain tissues from AD and ALS patients possessed increased numbers of senescent astrocytes and, like senescent astrocytes in vitro, showed decreased Δ133p53 and increased p53β expression, supporting that our in vitro findings recapitulate in vivo pathology of these neurodegenerative diseases. Our finding that Δ133p53 enhances the neuroprotective function of aged and senescent astrocytes suggests that the p53 isoforms and their regulatory mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases. PMID:27104929

  17. Endocannabinoid System: Emerging Role from Neurodevelopment to Neurodegeneration

    Basavarajappa, Balapal S.; Nixon, Ralph A.; Arancio, Ottavio

    2009-01-01

    The endocannabinoid system, including endogenous ligands ('endocannabinoids' ECs), their receptors, synthesizing and degrading enzymes, as well as transporter molecules, has been detected from the earliest stages of embryonic development and throughout pre- and postnatal development. ECs are bioactive lipids, which comprise amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG) are the best studied EC...

  18. Application of medical cannabis in patients with the neurodegeneration disorders

    Lidia Kotuła; Paulina Sobstyl; Jan Sobstyl; Paulina Chwil; Karol Terlecki; Jolanta Karwat; Paulina Gil-Kulik; Alicja Niedojadło; Janusz Kocki

    2014-01-01

    Medical cannabis is the dried flowers of the female Cannabis sativa L. plant. Cannabis contains a number of active elements, including dronabinol (THC) and cannabidiol (CBD). Dronabinol is usually the main ingredient. The body’s own cannabinoid system has been identified. The discovery of this system, which comprises endocannabinoids and receptors, confirmed that cannabis has a positive effect on certain illnesses and conditions. Two types of cannabinoid receptors have been identified: CB1 an...

  19. Calcium and cell death signaling in neurodegeneration and aging

    Soraya Smaili

    2009-09-01

    Full Text Available Transient increase in cytosolic (Cac2+ and mitochondrial Ca2+ (Ca m2+ are essential elements in the control of many physiological processes. However, sustained increases in Ca c2+ and Ca m2+ may contribute to oxidative stress and cell death. Several events are related to the increase in Ca m2+, including regulation and activation of a number of Ca2+ dependent enzymes, such as phospholipases, proteases and nucleases. Mitochondria and endoplasmic reticulum (ER play pivotal roles in the maintenance of intracellular Ca2+ homeostasis and regulation of cell death. Several lines of evidence have shown that, in the presence of some apoptotic stimuli, the activation of mitochondrial processes maylead to the release of cytochrome c followed by the activation of caspases, nuclear fragmentation and apoptotic cell death. The aim of this review was to show how changes in calcium signaling can be related to the apoptotic cell death induction. Calcium homeostasis was also shown to be an important mechanism involved in neurodegenerative and aging processes.Aumentos transientes no cálcio citosólico (Ca c2+ e mitocondrial (Ca m2+ são elementos essenciais no controle de muitos processos fisiológicos. No entanto, aumentos sustentados do Ca c2+ e do Ca m2+ podem contribuir para o estresse oxidativo ea morte celular. Muitos eventos estão relacionados ao aumentono Ca c2+, incluindo a regulação e ativação de várias enzimas dependentes de Ca2+ como as fosfolipases, proteases e nucleases. A mitocôndria e o retículo endoplasmático têm um papel central na manutenção da homeostase intracellular de Ca c2+ e na regulação da morte celular. Várias evidências mostraram que, na presença de certos estímulos apoptóticos, a ativação dos processos mitocondriais pode promover a liberação de citocromo c, seguida da ativação de caspases, fragmentação nuclear e morte celular por apoptose. O objetivo desta revisão é mostrar como aumentos na sinalização de Ca2+ podem estar relacionados aos eventos de indução da morte celular apoptótica. Além disso, evidenciar como a homeostase de Ca2+ pode ser importante e está envolvida nos mecanismos presentes nos processos de neurodegeneração e envelhecimento.

  20. Linking pathways in the developing and aging brain with neurodegeneration

    G.G. Kovacs; H. Adle-Biassett; I. Milenkovic; S. Cipriani; J. van Scheppingen; E. Aronica

    2014-01-01

    The molecular and cellular mechanisms, which coordinate the critical stages of brain development to reach a normal structural organization with appropriate networks, are progressively being elucidated. Experimental and clinical studies provide evidence of the occurrence of developmental alterations

  1. Role of melatonin in Alzheimer-like neurodegeneration

    Jian-zhi WANG; Ze-fen WANG

    2006-01-01

    Alzheimer disease (AD), an age-related neurodegenerative disorder with progressive loss of memory and deterioration of comprehensive cognition, is characterized by extracellular senile plaques of aggregated β-amyloid (Aβ), and intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein. Recent studies showed that melatonin, an indoleamine secreted by the pineal gland, may play an important role in aging and AD as an antioxidant and neuroprotector.Melatonin decreases during aging and patients with AD have a more profound reduction in this hormone. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning, and slows down the progression of cognitive impairment in Alzheimer's patients. Melatonin efficiently protects neuronal cells from Aβ-mediated toxicity via antioxidant and anti-amyloid properties: it not only inhibits Aβ generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Aβ. Our recent studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation. Although the exact mechanism is still not fully understood,a direct regulatory influence of melatonin on the activities of protein kinases and protein phosphatases is proposed. Additionally, melatonin also plays a role in protecting cholinergic neurons and in anti-inflammation. Here, the neuroprotective effects of melatonin and the underlying mechanisms by which it exerts its effects are reviewed. The capacity of melatonin to prevent or ameliorate tau and Aβ pathology further enhances its potential in the prevention or treatment of AD.

  2. Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease

    Turmaine, Mark; Raza, Aysha; Mahal, Amarbirpal; Mangiarini, Laura; Bates, Gillian P.; Davies, Stephen W.

    2000-01-01

    Huntington's disease (HD) is a fatal inherited neurodegenerative disorder characterized by personality changes, motor impairment, and subcortical dementia. HD is one of a number of diseases caused by expression of an expanded polyglutamine repeat. We have developed several lines of mice that are transgenic for exon 1 of the HD gene containing an expanded CAG sequence. These mice exhibit a defined neurological phenotype along with neuronal changes that are pathognomonic for the disease. We hav...

  3. Progress in prevention of toxico-nutritional neurodegenerations

    Lambein, Fernand; Diasolua Ngudi, Delphin; Kuo, Yu-Haey

    2010-01-01

    Grass pea (Lathyrus sativus) is a survival food during drought in Ethiopia and the Indian Subcontinent, producing the cheapest dietary protein and saving thousands of lives. It also is a mixed blessing as the cause of the crippling neurolathyrism after prolonged over-consumption. Cassava (Manihot esculenta) is a protein-poor root crop that is the staple food for over half a billion people in Africa, South America and Southeast Asia, and the cheapest source of dietary carbohydrates. Over-consu...

  4. Ku70 alleviates neurodegeneration in Drosophila models of Huntington's disease.

    Takuya Tamura

    Full Text Available DNA damage accumulates in genome DNA during the long life of neurons, thus DNA damage repair is indispensable to keep normal functions of neurons. We previously reported that Ku70, a critical molecule for DNA double strand break (DSB repair, is involved in the pathology of Huntington's disease (HD. Mutant huntingtin (Htt impaired Ku70 function via direct interaction, and Ku70 supplementation recovered phenotypes of a mouse HD model. In this study, we generate multiple Drosophila HD models that express mutant huntingtin (Htt in eye or motor neuron by different drivers and show various phenotypes. In such fly models, Ku70 co-expression recovers lifespan, locomotive activity and eye degeneration. In contrast, Ku70 reduction by heterozygous null mutation or siRNA-mediated knock down accelerates lifespan shortening and locomotion disability. These results collectively support that Ku70 is a critical mediator of the HD pathology and a candidate therapeutic target in HD.

  5. Brain mapping as a tool to study neurodegeneration

    Apostolova, Liana G.; Thompson, Paul M.

    2007-01-01

    Alzheimer’s disease (AD) is the most common neurodegenerative disorder for those 65 years or older, currently affects 4.5 million Americans, and is predicted to rise to 13.2 million by the year 2050 in the U.S. alone. Neuroimaging and brain mapping techniques provide extraordinary power to understand AD, providing spatially detailed information on the extent and trajectory of the disease as it spreads in the living brain. Computational anatomy techniques, applied to large databases of brain M...

  6. Morphometric analysis of Huntington's disease neurodegeneration in Drosophila

    Song, W.; Smith Dell; Syed, A.; Lukacsovich, T; Barbaro, BA; Purcell, J.; Bornemann, DJ; J. Burke; Marsh, JL

    2013-01-01

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. The HD gene encodes the huntingtin protein (HTT) that contains polyglutamine tracts of variable length. Expansions of the CAG repeat near the amino terminus to encode 40 or more glutamines (polyQ) lead to disease. At least eight other expanded polyQ diseases have been described [1]. HD can be faithfully modeled in Drosophila with the key features of the disease such as late onset, slowly progressing degeneration, f...

  7. Ferro e neurodegeneração = Iron and neurodegeneration

    Fernandez, Liana L.

    2007-01-01

    Conclusões: a revisão da literatura sugere que o estresse oxidativo, associado ao desequilíbrio na homeostase do ferro, seja uma via importante em relação à patogênese da neurodegeneração. Esses dados requerem novas investigações para esclarecer se este desequilíbrio é causa ou conseqüência do processo neurodegenerativo

  8. Anandamide, but not 2-arachidonoylglycerol, accumulates during in vivo neurodegeneration

    Hansen, H.H.; Lastres-Becker, I.; Berrendero, F.; Manzanares, J.; Javier Fernández-Ruiz, J.; Schmid, P.C.; Schmid, H.H.O.; Bittigau, P.; Ikonomidou, C.; Hansen, Harald S.

    2001-01-01

    . However, it is not known how glutamatergic insults affect in vivo endocannabinoid homeostasis, i.e. N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), as well as other constituents of their lipid families, N-acylethanolamines (NAEs) and 2-monoacylglycerols (2-MAGs), respectively...... intracerebral NMDA injection, while less severe insults triggered by mild concussive head trauma or NMDA receptor blockade produced a less pronounced NAE accumulation. By contrast, levels of 2-AG and other 2-MAGs were virtually unaffected by the insults employed, rendering it likely that key enzymes in...

  9. AlzPharm: integration of neurodegeneration data using RDF

    Miller Perry

    2007-05-01

    Full Text Available Abstract Background Neuroscientists often need to access a wide range of data sets distributed over the Internet. These data sets, however, are typically neither integrated nor interoperable, resulting in a barrier to answering complex neuroscience research questions. Domain ontologies can enable the querying heterogeneous data sets, but they are not sufficient for neuroscience since the data of interest commonly span multiple research domains. To this end, e-Neuroscience seeks to provide an integrated platform for neuroscientists to discover new knowledge through seamless integration of the very diverse types of neuroscience data. Here we present a Semantic Web approach to building this e-Neuroscience framework by using the Resource Description Framework (RDF and its vocabulary description language, RDF Schema (RDFS, as a standard data model to facilitate both representation and integration of the data. Results We have constructed a pilot ontology for BrainPharm (a subset of SenseLab using RDFS and then converted a subset of the BrainPharm data into RDF according to the ontological structure. We have also integrated the converted BrainPharm data with existing RDF hypothesis and publication data from a pilot version of SWAN (Semantic Web Applications in Neuromedicine. Our implementation uses the RDF Data Model in Oracle Database 10g release 2 for data integration, query, and inference, while our Web interface allows users to query the data and retrieve the results in a convenient fashion. Conclusion Accessing and integrating biomedical data which cuts across multiple disciplines will be increasingly indispensable and beneficial to neuroscience researchers. The Semantic Web approach we undertook has demonstrated a promising way to semantically integrate data sets created independently. It also shows how advanced queries and inferences can be performed over the integrated data, which are hard to achieve using traditional data integration approaches. Our pilot results suggest that our Semantic Web approach is suitable for realizing e-Neuroscience and generic enough to be applied in other biomedical fields.

  10. Chronic Stress and Glucocorticoids: From Neuronal Plasticity to Neurodegeneration

    Sheela Vyas

    2016-01-01

    Full Text Available Stress and stress hormones, glucocorticoids (GCs, exert widespread actions in central nervous system, ranging from the regulation of gene transcription, cellular signaling, modulation of synaptic structure, and transmission and glial function to behavior. Their actions are mediated by glucocorticoid and mineralocorticoid receptors which are nuclear receptors/transcription factors. While GCs primarily act to maintain homeostasis by inducing physiological and behavioral adaptation, prolonged exposure to stress and elevated GC levels may result in neuro- and psychopathology. There is now ample evidence for cause-effect relationships between prolonged stress, elevated GC levels, and cognitive and mood disorders while the evidence for a link between chronic stress/GC and neurodegenerative disorders such as Alzheimer’s (AD and Parkinson’s (PD diseases is growing. This brief review considers some of the cellular mechanisms through which stress and GC may contribute to the pathogenesis of AD and PD.

  11. Therapeutic strategies in an animal model of neurodegeneration

    Borre, Y.E.

    2013-01-01

    Neurodegenerative diseases have complex and multifactorial etiologies, creating an enormous burden on society without an effective treatment. This thesis utilized olfactory bulbectomized rats to investigate therapeutic approaches to neurodegenerative disorders. Removal of the olfactory bulbs, leads

  12. Role of autophagy in neurodegeneration and new for its study

    García Ledo, Lucía

    2015-01-01

    La autofagia es un mecanismo celular de degradación y reciclaje ligado a lisosomas. Es una respuesta a estrés, principalmente a la falta de nutrientes pero también a hipoxia, estrés oxidativo. Sus funciones principales incluyen proporcionar energía y aminoácidos y contribuir al mantenimiento de la proteostasis celular. Se conocen tres tipos de autofagia: macroautofagia, autofagia mediada por chaperonas (CMA) y microautofagia. Las dos primeras son las más descritas. Macroautofagia se caracteri...

  13. Integrative neurobiology of metabolic diseases, neuroinflammation, and neurodegeneration

    Gertjan eVan Dijk

    2015-05-01

    Full Text Available Alzheimer’s disease (AD is a complex, multifactorial disease with a number of leading mechanisms, including neuroinflammation, processing of amyloid precursor protein (APP to amyloid β peptide, tau protein hyperphosphorylation, relocalization and deposition. These mechanisms are propagated by obesity, the metabolic syndrome and type-2 diabetes mellitus. Stress, sedentariness, dietary overconsumption of saturated fat and refined sugars, and circadian derangements/disturbed sleep contribute to obesity and related metabolic diseases, but also accelerate age-related damage and senescence that all feed the risk of developing AD too. The complex and interacting mechanisms are not yet completely understood and will require further analysis. Instead of investigating AD as a mono- or oligocausal disease we should address the disease by understanding the multiple underlying mechanisms and how these interact. Future research therefore might concentrate on integrating these by systems biology approaches, but also to regard them from an evolutionary medicine point of view. The current review addresses several of these interacting mechanisms in animal models and compares them with clinical data giving an overview about our current knowledge and puts them into an integrated framework.

  14. Ataxin-2 repeat-length variation and neurodegeneration

    Ross, Owen A.; Rutherford, Nicola J.; Baker, Matt; Soto-Ortolaza, Alexandra I.; Carrasquillo, Minerva M.; DeJesus-Hernandez, Mariely; Adamson, Jennifer; Li, Ma; Volkening, Kathryn; Finger, Elizabeth; Seeley, William W.; Hatanpaa, Kimmo J.; Lomen-Hoerth, Catherine; Kertesz, Andrew; Bigio, Eileen H

    2011-01-01

    Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In...

  15. Ataxin-2 repeat-length variation and neurodegeneration

    Ross, Owen A.; Rutherford, Nicola J.; Baker, Matt; Soto-Ortolaza, Alexandra I.; Carrasquillo, Minerva M.; DeJesus-Hernandez, Mariely; Adamson, Jennifer; Li, Ma; Volkening, Kathryn; Finger, Elizabeth; Seeley, William W.; Hatanpaa, Kimmo J.; Lomen-Hoerth, Catherine; Kertesz, Andrew; Bigio, Eileen H.; Lippa, Carol; Woodruff, Bryan K.; Knopman, David S.; White, Charles L.; Van Gerpen, Jay A.; Meschia, James F.; Mackenzie, Ian R.; Boylan, Kevin; Boeve, Bradley F.; Miller, Bruce L.; Strong, Michael J.; Uitti, Ryan J.; Younkin, Steven G.; Graff-Radford, Neill R.; Petersen, Ronald C.; Wszolek, Zbigniew K.; Dickson, Dennis W.; Rademakers, Rosa

    2011-01-01

    Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR = 5.57; P= 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR = 5.83; P= 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31–33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy. PMID:21610160

  16. #606721 PARTIAL LIPODYSTROPHY, CONGENITAL CATARACTS, AND NEURODEGENERATION [OMIM

    Full Text Available FIELD NO 606721 FIELD TI #606721 PARTIAL LIPODYSTROPHY, CONGENITAL CATARACTS, AND NEURODEGENERAT ... , glucose, and cholesterol levels were normal. The lean ... body phenotype and metabolic defects observed in t ... E.; Lisanti, M. P.: Caveolin-1-deficient mice are lean , resistant to diet-induced obesity, and show hyper ...

  17. Genetics Home Reference: fatty acid hydroxylase-associated neurodegeneration

    ... fatty acid 2-hydroxylase adds a single oxygen atom to a hydrogen atom at a particular point on a fatty acid ... C, Alshehhi AA, Proukakis C, Sibtain NA, Maier H, Sharifi R, Patton MA, Bashir W, Koul R, ...

  18. Development of gene and stem cell therapy for ocular neurodegeneration

    Zhang, Jing-Xue; Wang, Ning-Li; Lu, Qing-Jun

    2015-01-01

    Retinal degenerative diseases pose a serious threat to eye health, but there is currently no effective treatment available. Recent years have witnessed rapid development of several cutting-edge technologies, such as gene therapy, stem cell therapy, and tissue engineering. Due to the special features of ocular structure, some of these technologies have been translated into ophthalmological clinic practice with fruitful achievements, setting a good example for other fields. This paper reviews t...

  19. Ion Channels and Zinc: Mechanisms of Neurotoxicity and Neurodegeneration

    Deborah R. Morris

    2012-01-01

    Full Text Available Ionotropic glutamate receptors, such as NMDA, AMPA and kainate receptors, are ligand-gated ion channels that mediate much of the excitatory neurotransmission in the brain. Not only do these receptors bind glutamate, but they are also regulated by and facilitate the postsynaptic uptake of the trace metal zinc. This paper discusses the role of the excitotoxic influx and accumulation of zinc, the mechanisms responsible for its cytotoxicity, and a number of disorders of the central nervous system that have been linked to these neuronal ion channels and zinc toxicity including ischemic brain injury, traumatic brain injury, and epilepsy.

  20. The Role of Cyclo(His-Pro) in Neurodegeneration

    Grottelli, Silvia; Ferrari, Ilaria; Pietrini, Grazia; Peirce, Matthew J.; Minelli, Alba; Bellezza, Ilaria

    2016-01-01

    Neurodegenerative diseases may have distinct genetic etiologies and pathological manifestations, yet share common cellular mechanisms underpinning neuronal damage and dysfunction. These cellular mechanisms include excitotoxicity, calcium dysregulation, oxidative damage, ER stress and neuroinflammation. Recent data have identified a dual role in these events for glial cells, such as microglia and astrocytes, which are able both to induce and to protect against damage induced by diverse stresses. Cyclo(His-Pro), a cyclic dipeptide derived from the hydrolytic removal of the amino-terminal pyroglutamic acid residue of the hypothalamic thyrotropin-releasing hormone, may be important in regulating the nature of the glial cell contribution. Cyclo(His-Pro) is ubiquitous in the central nervous system and is a key substrate of organic cation transporters, which are strongly linked to neuroprotection. The cyclic dipeptide can also cross the brain-blood-barrier and, once in the brain, can affect diverse inflammatory and stress responses by modifying the Nrf2-NF-κB signaling axis. For these reasons, cyclo(His-Pro) has striking potential for therapeutic application by both parenteral and oral administration routes and may represent an important new tool in counteracting neuroinflammation-based degenerative pathologies. In this review, we discuss the chemistry and biology of cyclo(His-Pro), how it may interact with the biological mechanisms driving neurodegenerative disease, such as amyotrophic lateral sclerosis, and thereby act to preserve or restore neuronal function. PMID:27529240

  1. Pin1 and neurodegeneration: a new player for prion disorders?

    Elisa Isopi

    2015-07-01

    Full Text Available Pin1 is a peptidyl-prolyl isomerase that catalyzes the cis/trans conversion of phosphorylated proteins at serine or threonine residues which precede a proline. The peptidyl-prolyl isomerization induces a conformational change of the proteins involved in cell signaling process. Pin1 dysregulation has been associated with some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease. Proline-directed phosphorylation is a common regulator of these pathologies and a recent work showed that it is also involved in prion disorders. In fact, prion protein phosphorylation at the Ser-43-Pro motif induces prion protein conversion into a disease-associated form. Furthermore, phosphorylation at Ser-43-Pro has been observed to increase in the cerebral spinal fluid of sporadic Creutzfeldt-Jakob Disease patients. These findings provide new insights into the pathogenesis of prion disorders, suggesting Pin1 as a potential new player in the disease. In this paper, we review the mechanisms underlying Pin1 involvement in the aforementioned neurodegenerative pathologies focusing on the potential role of Pin1 in prion disorders.

  2. Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis.

    Witte, Maarten E; Mahad, Don J; Lassmann, Hans; van Horssen, Jack

    2014-03-01

    Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Current treatments are very effective in reducing the neuroinflammatory attack, but fail to significantly halt disease progression and associated loss of neuronal tissue. In recent years, it has become increasingly clear that dysfunctional mitochondria are important contributors to damage and loss of both axons and neurons. Observations in animal and histopathological studies suggest that infiltrating leukocytes and activated microglia play a central role in neuronal mitochondrial dysfunction. This review provides a comprehensive overview on the current knowledge regarding mitochondrial dysfunction in MS. Importantly, more insight into the cause and consequences of impaired mitochondrial function provide a basis for mitochondrial-targeted medicine to combat progressive MS. PMID:24369898

  3. Mitochondria-associated membranes as hubs for neurodegeneration

    Krols, Michiel; Van Isterdael, Gert; Asselbergh, Bob; Kremer, Anna; Lippens, Saskia; Timmerman, Vincent; Janssens, Sophie

    2016-01-01

    There is a growing appreciation that membrane-bound organelles in eukaryotic cells communicate directly with one another through direct membrane contact sites. Mitochondria-associated membranes are specialized subdomains of the endoplasmic reticulum that function as membrane contact sites between the endoplasmic reticulum and mitochondria. These sites have emerged as major players in lipid metabolism and calcium signaling. More recently also autophagy and mitochondrial dynamics have been foun...

  4. Mitochondrial metals as a potential therapeutic target in neurodegeneration

    Grubman, A; White, A R; Liddell, J.R.

    2014-01-01

    Transition metals are critical for enzyme function and protein folding, but in excess can mediate neurotoxic oxidative processes. As mitochondria are particularly vulnerable to oxidative damage due to radicals generated during ATP production, mitochondrial biometal homeostasis must therefore be tightly controlled to safely harness the redox potential of metal enzyme cofactors. Dysregulation of metal functions is evident in numerous neurological disorders including Alzheimer's disease, stroke,...

  5. In vitro dopaminergic neurotoxicity of pesticides; a link with neurodegeneration?

    Heusinkveld, H.J.

    2014-01-01

    Ever since people culture crops for food- and feed production, they use chemical compounds to destroy and repel plagues threatening production. Based on their primary target these compounds are classified as e.g. insecticides, herbicides or fungicides. In epidemiological studies, pesticide exposure

  6. In vitro dopaminergic neurotoxicity of pesticides : a link with neurodegeneration?

    Heusinkveld, Harm J.; van den Berg, Martin; Westerink, Remco H S

    2014-01-01

    Around the globe, chemical compounds are used to treat or repel pests and plagues that pose a threat to food and feed production. From epidemiological studies, it is known that there is a link between exposure to certain chemical classes of these so-called pesticides and the prevalence of neurodegen

  7. Lipid disequilibrium in biological membranes, a possible pathway to neurodegeneration.

    Witt, Stephan N

    2014-12-01

    We recently reported that knocking down the enzyme phosphatidylserine decarboxylase, which synthesizes the phospholipid phosphatidylethanolamine (PE) in mitochondria, perturbs the homeostasis of the human Parkinson disease (PD) protein α-synuclein (expressed in yeast or worms). In yeast, low PE in the psd1Δ deletion mutant induces α-synuclein to enter cytoplasmic foci, the level of this protein increases 3-fold compared to wild-type cells, and the mutant cells are severely sick. The metabolite ethanolamine protects both yeast and worms from the deleterious synergistic effects of low mitochondrial PE and α-synuclein. Here we highlight a Drosophila mutant called easily shocked-thought to be a model of epilepsy-that cannot use ethanolamine to synthesize PE. We also highlight recently identified mutated genes associated with defective lipid metabolism in PD and epilepsy patients. We propose that disruptions in lipid homeostasis (synthesis and degradation) may be responsible for some cases of PD and epilepsy. PMID:26480301

  8. Parkinson's Disease and Neurodegeneration: GABA-Collapse Hypothesis

    Błaszczyk, Janusz W.

    2016-01-01

    Neurodegenerative diseases constitute a heterogeneous group of age-related disorders that are characterized by a slow but irreversible deterioration of brain functions. Evidence accumulated over more than two decades has implicated calcium-related homeostatic mechanisms, giving rise to the Ca2+ hypothesis of brain aging and, ultimately, cell death. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter within the central (CNS), peripheral and enteric nervous systems. It appears to be involved in a wide variety of physiological functions within and outside the nervous system, that are maintained through a complex interaction between GABA and calcium-dependent neurotransmission and cellular metabolic functions. Within CNS the Ca2+/GABA mechanism stabilizes neuronal activity both at cellular and systemic levels. Decline in the Ca2+/GABA control initiates several cascading processes leading to both weakened protective barriers (in particular the blood-brain barrier) and accumulations of intracellular deposits of calcium and Lewy bodies. Linking such a vital mechanism of synaptic transmission with metabolism (both at cellular and tissue level) by means of a common reciprocal Ca2+/GABA inhibition results in a fragile balance, which is prone to destabilization and auto-destruction. The GABA decline etiology proposed here appears to apply to all human neurodegenerative processes initiated by abnormal intracellular calcium levels. Therefore, the original description of Parkinson's disease (PD) as due to the selective damage of dopaminergic neurons in the mesencephalon should be updated into the concept of a severe multisystemic neurodegenerative disorder of the nervous system, whose clinical symptoms reflect the localization and progression of the most advanced GABA pathology. A future and more complete therapeutic approach to PD should be aimed first at slowing (or stopping) the progression of Ca2+/GABA functional decline. PMID:27375426

  9. Development of gene and stem cell therapy for ocular neurodegeneration

    Jing-Xue; Zhang; Ning-Li; Wang; Qing-Jun; Lu

    2015-01-01

    Retinal degenerative diseases pose a serious threat to eye health, but there is currently no effective treatment available. Recent years have witnessed rapid development of several cutting-edge technologies, such as gene therapy, stem cell therapy, and tissue engineering. Due to the special features of ocular structure, some of these technologies have been translated into ophthalmological clinic practice with fruitful achievements, setting a good example for other fields. This paper reviews the development of the gene and stem cell therapies in ophthalmology.

  10. Inhibition of the mitochondrial respiratory chain function abrogates quartz induced DNA damage in lung epithelial cells

    Respirable quartz dust has been classified as a human carcinogen by the International Agency for Research on Cancer. The aim of our study was to investigate the mechanisms of DNA damage by DQ12 quartz in RLE-6TN rat lung epithelial type II cells (RLE). Transmission electron microscopy and flow-cytometry analysis showed a rapid particle uptake (30 min to 4 h) of quartz by the RLE cells, but particles were not found within the cell nuclei. This suggests that DNA strand breakage and induction of 8-hydroxydeoxyguanosine - as also observed in these cells during these treatment intervals - did not result from direct physical interactions between particles and DNA, or from short-lived particle surface-derived reactive oxygen species. DNA damage by quartz was significantly reduced in the presence of the mitochondrial inhibitors rotenone and antimycin-A. In the absence of quartz, these inhibitors did not affect DNA damage, but they reduced cellular oxygen consumption. No signs of apoptosis were observed by quartz. Flow-cytometry analysis indicated that the reduced DNA damage by rotenone was not due to a possible mitochondria-mediated reduction of particle uptake by the RLE cells. Further proof of concept for the role of mitochondria was shown by the failure of quartz to elicit DNA damage in mitochondria-depleted 143B (rho-0) osteosarcoma cells, at concentrations where it elicited DNA damage in the parental 143B cell line. In conclusion, our data show that respirable quartz particles can elicit oxidative DNA damage in vitro without entering the nuclei of type II cells, which are considered to be important target cells in quartz carcinogenesis. Furthermore, our observations indicate that such indirect DNA damage involves the mitochondrial electron transport chain function, by an as-yet-to-be elucidated mechanism

  11. Plant proteolytic enzyme papain abrogates angiogenic activation of human umbilical vein endothelial cells (HUVEC) in vitro

    Mohr, Thomas; Desser, Lucia

    2013-01-01

    Background Vascular endothelial growth factor (VEGF) is a key regulator of physiologic and pathogenic angiogenesis in diseases such as cancer and diabetic retinopathy. It is known that cysteine proteases from plants, like bromelain and papain are capable to suppress inflammatory activation. Recent studies have demonstrated that they may interfere with angiogenesis related pathways as well. The aim of this study was to investigate the anti-angiogenic effects of papain on human umbilical vein e...

  12. Interferon-α abrogates tolerance induction by human tolerogenic dendritic cells.

    Nicole Bacher

    Full Text Available BACKGROUND: Administration of interferon-α (IFN-α represents an approved adjuvant therapy as reported for malignancies like melanoma and several viral infections. In malignant diseases, tolerance processes are critically involved in tumor progression. In this study, the effect of IFN-α on tolerance induction by human tolerogenic dendritic cells (DC was analyzed. We focussed on tolerogenic IL-10-modulated DC (IL-10 DC that are known to induce anergic regulatory T cells (iTregs. METHODOLOGY/PRINCIPAL FINDINGS: IFN-α promoted an enhanced maturation of IL-10 DC as demonstrated by upregulation of the differentiation marker CD83 as well as costimulatory molecules. IFN-α treatment resulted in an increased capacity of DC to stimulate T cell activation compared to control tolerogenic DC. We observed a strengthened T cell proliferation and increased IFN-γ production of CD4(+ and CD8(+ T cells stimulated by IFN-α-DC, demonstrating a restoration of the immunogenic capacity of tolerogenic DC in the presence of IFN-α. Notably, restimulation experiments revealed that IFN-α treatment of tolerogenic DC abolished the induction of T cell anergy and suppressor function of iTregs. In contrast, IFN-α neither affected the priming of iTregs nor converted iTregs into effector T cells. CONCLUSIONS/SIGNIFICANCE: IFN-α inhibits the induction of T cell tolerance by reversing the tolerogenic function of human DC.

  13. Phosphorylation of human hnRNP protein A1 abrogates in vitro strand annealing activity.

    Cobianchi, F; Calvio, C; Stoppini, M; Buvoli, M; Riva, S

    1993-01-01

    In HeLa cells metabolically labeled in vivo with [32P] orthophosphate in the presence of okadaic acid the concentration of phosphorylated A1 protein was increased significantly as compared to controls. Purified recombinant hnRNP protein A1 served as an excellent substrate in vitro for the catalytic subunit of cAMP-dependent protein kinase (PKA) and for casein kinase II (CKII). Thin layer electrophoresis of A1 acid hydrolysates showed the protein to be phosphorylated exclusively on serine resi...

  14. Modafinil abrogates methamphetamine-induced neuroinflammation and apoptotic effects in the mouse striatum.

    Mariana Raineri

    Full Text Available Methamphetamine is a drug of abuse that can cause neurotoxic damage in humans and animals. Modafinil, a wake-promoting compound approved for the treatment of sleeping disorders, is being prescribed off label for the treatment of methamphetamine dependence. The aim of the present study was to investigate if modafinil could counteract methamphetamine-induced neuroinflammatory processes, which occur in conjunction with degeneration of dopaminergic terminals in the mouse striatum. We evaluated the effect of a toxic methamphetamine binge in female C57BL/6 mice (4 × 5 mg/kg, i.p., 2 h apart and modafinil co-administration (2 × 90 mg/kg, i.p., 1 h before the first and fourth methamphetamine injections on glial cells (microglia and astroglia. We also evaluated the striatal expression of the pro-apoptotic BAX and anti-apoptotic Bcl-2 proteins, which are known to mediate methamphetamine-induced apoptotic effects. Modafinil by itself did not cause reactive gliosis and counteracted methamphetamine-induced microglial and astroglial activation. Modafinil also counteracted the decrease in tyrosine hydroxylase and dopamine transporter levels and prevented methamphetamine-induced increases in the pro-apoptotic BAX and decreases in the anti-apoptotic Bcl-2 protein expression. Our results indicate that modafinil can interfere with methamphetamine actions and provide protection against dopamine toxicity, cell death, and neuroinflammation in the mouse striatum.

  15. Quercetin abrogates IL-6/STAT3 signaling and inhibits glioblastoma cell line growth and migration

    Michaud-Levesque, Jonathan; Bousquet-Gagnon, Nathalie; Beliveau, Richard, E-mail: oncomol@nobel.si.uqam.ca

    2012-05-01

    Evidence has suggested that STAT3 functions as an oncogene in gliomagenesis. As a consequence, changes in the inflammatory microenvironment are thought to promote tumor development. Regardless of its origin, cancer-related inflammation has many tumor-promoting effects, such as the promotion of cell cycle progression, cell proliferation, cell migration and cell survival. Given that IL-6, a major cancer-related inflammatory cytokine, regulates STAT3 activation and is upregulated in glioblastoma, we sought to investigate the inhibitory effects of the chemopreventive flavonoid quercetin on glioblastoma cell proliferation and migration triggered by IL-6, and to determine the underlying mechanisms of action. In this study, we show that quercetin is a potent inhibitor of the IL-6-induced STAT3 signaling pathway in T98G and U87 glioblastoma cells. Exposure to quercetin resulted in the reduction of GP130, JAK1 and STAT3 activation by IL-6, as well as a marked decrease of the proliferative and migratory properties of glioblastoma cells induced by IL-6. Interestingly, quercetin also modulated the expression of two target genes regulated by STAT3, i.e. cyclin D1 and matrix metalloproteinase-2 (MMP-2). Moreover, quercetin reduced the recruitment of STAT3 at the cyclin D1 promoter and inhibited Rb phosphorylation in the presence of IL-6. Overall, these results provide new insight into the role of quercetin as a blocker of the STAT3 activation pathway stimulated by IL-6, with a potential role in the prevention and treatment of glioblastoma.

  16. P17.17INHIBITION OF DNA DAMAGE RESPONSE ABROGATES GLIOBLASTOMA CANCER STEM CELL RADIORESISTANCE

    Carruthers, R.; Ahmed, S.; Chalmers, A. J.

    2014-01-01

    GBM recurrence following radiotherapy is due to a subset of tumour propagating cells with stem like characteristics (cancer stem cells, CSC). CSCs have the ability to recapitulate the tumour of origin whereas the majority of tumour cells (tumour bulk) do not. CSCs in GBM have been reported to exhibit an upregulated DNA damage response (DDR) and a radioresistant phenotype. However, literature and opinion regarding GBM CSC radiosensitivity is conflicting. The prospect of influencing GBM CSC rad...

  17. Quercetin abrogates IL-6/STAT3 signaling and inhibits glioblastoma cell line growth and migration

    Evidence has suggested that STAT3 functions as an oncogene in gliomagenesis. As a consequence, changes in the inflammatory microenvironment are thought to promote tumor development. Regardless of its origin, cancer-related inflammation has many tumor-promoting effects, such as the promotion of cell cycle progression, cell proliferation, cell migration and cell survival. Given that IL-6, a major cancer-related inflammatory cytokine, regulates STAT3 activation and is upregulated in glioblastoma, we sought to investigate the inhibitory effects of the chemopreventive flavonoid quercetin on glioblastoma cell proliferation and migration triggered by IL-6, and to determine the underlying mechanisms of action. In this study, we show that quercetin is a potent inhibitor of the IL-6-induced STAT3 signaling pathway in T98G and U87 glioblastoma cells. Exposure to quercetin resulted in the reduction of GP130, JAK1 and STAT3 activation by IL-6, as well as a marked decrease of the proliferative and migratory properties of glioblastoma cells induced by IL-6. Interestingly, quercetin also modulated the expression of two target genes regulated by STAT3, i.e. cyclin D1 and matrix metalloproteinase-2 (MMP-2). Moreover, quercetin reduced the recruitment of STAT3 at the cyclin D1 promoter and inhibited Rb phosphorylation in the presence of IL-6. Overall, these results provide new insight into the role of quercetin as a blocker of the STAT3 activation pathway stimulated by IL-6, with a potential role in the prevention and treatment of glioblastoma.

  18. The National Defence Council : the lack of the elements of crime does not abrogate moral responsibility

    2008-01-01

    Presidendi kokkukutsutud riigikaitse nõukogu asus üksmeelsele seisukohale, et aastatel 2004ئ2006 toimunud sõjaväeluure ohvitseride ebaseaduslik jälitustegevus ja meelsusvalve on demokraatlikus ühiskonnas lubamatu ja ohtlik

  19. Abrogation of TNF-mediated cytotoxicity by space flight involves protein kinase C

    Woods, K. M.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    Experiments conducted on STS-50 indicated that space flight significantly inhibited tumor necrosis factor (TNF)-mediated killing of LM929 cells compared to ground controls. In ground-based studies, activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate (PMA) also inhibited TNF-mediated killing of LM929 cells. Therefore, we used PKC inhibitors to determine if the inhibitory effects of spaceflight on TNF-mediated cytotoxicity involved the activation of PKC. In experiments conducted onboard space shuttle mission STS-54, we saw that in the presence of the protein kinase C inhibitors H7 and H8, TNF-mediated cytotoxicity was restored to levels of those observed in the ground controls. Subsequent experiments done during the STS-57 mission tested the dose response of two protein kinase inhibitors, H7 and HA1004. We again saw that killing was restored in a dose-dependent manner, with inhibitor concentrations known to inhibit PKC being most effective. These data suggest that space flight ameliorates the action of TNF by affecting PKC in target cells.

  20. A Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis.

    Bold, Guido; Schnell, Christian; Furet, Pascal; McSheehy, Paul; Brüggen, Josef; Mestan, Jürgen; Manley, Paul W; Drückes, Peter; Burglin, Marion; Dürler, Ursula; Loretan, Jacqueline; Reuter, Robert; Wartmann, Markus; Theuer, Andreas; Bauer-Probst, Beatrice; Martiny-Baron, Georg; Allegrini, Peter; Goepfert, Arnaud; Wood, Jeanette; Littlewood-Evans, Amanda

    2016-01-14

    This paper describes the identification of 6-(pyrimidin-4-yloxy)-naphthalene-1-carboxamides as a new class of potent and selective human vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitors. In biochemical and cellular assays, the compounds exhibit single-digit nanomolar potency toward VEGFR2. Compounds of this series show good exposure in rodents when dosed orally. They potently inhibit VEGF-driven angiogenesis in a chamber model and rodent tumor models at daily doses of less than 3 mg/kg by targeting the tumor vasculature as demonstrated by ELISA for TIE-2 in lysates or by immunohistochemical analysis. This novel series of compounds shows a potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role. PMID:26629594

  1. Red ginseng abrogates oxidative stress via mitochondria protection mediated by LKB1-AMPK pathway

    Dong, Guang-Zhi; Jang, Eun Jeong; Kang, Seung Ho; Cho, Il Je; Park, Sun-Dong; Kim, Sang Chan; Kim, Young Woo

    2013-01-01

    Background Korean ginseng (Panax ginseng C.A. Meyer) has been used as a botanical medicine throughout the history of Asian traditional Oriental medicine. Formulated red ginseng (one form of Korean ginseng) has been shown to have antioxidant and chemopreventive effects. Methods This study investigated the cytoprotective effects and mechanism of action of Korean red ginseng extract (RGE) against severe ROS production and mitochondrial impairment in a cytotoxic cell model induced by AA + iron. R...

  2. Oral tolerance to cancer can be abrogated by T regulatory cell inhibition.

    Whelan, Maria C; Casey, Garrett; Larkin, John O; Guinn, Barbara-ann; O'Sullivan, Gerald C; Tangney, Mark

    2014-01-01

    Oral administration of tumour cells induces an immune hypo-responsiveness known as oral tolerance. We have previously shown that oral tolerance to a cancer is tumour antigen specific, non-cross-reactive and confers a tumour growth advantage. We investigated the utilisation of regulatory T cell (Treg) depletion on oral tolerance to a cancer and its ability to control tumour growth. Balb/C mice were gavage fed homogenised tumour tissue--JBS fibrosarcoma (to induce oral tolerance to a cancer), or PBS as control. Growth of subcutaneous JBS tumours were measured; splenic tissue excised and flow cytometry used to quantify and compare systemic Tregs and T effector (Teff) cell populations. Prior to and/or following tumour feeding, mice were intraperitoneally administered anti-CD25, to inactivate systemic Tregs, or given isotype antibody as a control. Mice which were orally tolerised prior to subcutaneous tumour induction, displayed significantly higher systemic Treg levels (14% vs 6%) and faster tumour growth rates than controls (p<0.05). Complete regression of tumours were only seen after Treg inactivation and occurred in all groups--this was not inhibited by tumour feeding. The cure rates for Treg inactivation were 60% during tolerisation, 75% during tumour growth and 100% during inactivation for both tolerisation and tumour growth. Depletion of Tregs gave rise to an increased number of Teff cells. Treg depletion post-tolerisation and post-tumour induction led to the complete regression of all tumours on tumour bearing mice. Oral administration of tumour tissue, confers a tumour growth advantage and is accompanied by an increase in systemic Treg levels. The administration of anti-CD25 Ab decreased Treg numbers and caused an increase in Teffs. Most notably Treg cell inhibition overcame established oral tolerance with consequent tumor regression, especially relevant to foregut cancers where oral tolerance is likely to be induced by the shedding of tumour tissue into the gut. PMID:24832130

  3. Heat Inactivation of Garlic (Allium sativum) Extract Abrogates Growth Inhibition of HeLa Cells.

    Chintapalli, Renuka; Murray, Matthew J J; Murray, James T

    2016-07-01

    The potential anticancer properties of garlic (Allium sativum) may depend on the method of preparation and its storage. Storage of garlic has not been thoroughly investigated to determine whether anticancer properties are retained. Garlic was prepared and processed to mimic normal options for storage and preparation for consumption. Cytotoxicity was determined by crystal violet assay and mechanisms of cytotoxicity were established by microscopy, SDS-PAGE, and Western immunoblotting. Significant (P garlic. Depending on the method of storage, garlic extract induced either type I or type II programmed cell death, detectable by caspase 9 cleavage, or Poly (adenosine diphosphate-ribose) polymerase (PARP) cleavage and LC3-II accumulation, respectively. The conflicting literature on the anticancer properties of garlic may be explained by differences in processing and storage. This study has highlighted that the potency of the antiproliferative properties of cooked garlic, compared to the uncooked form, is diminished in HeLa cells. PMID:27176674

  4. Abrogated inflammatory response promotes neurogenesis in a murine model of Japanese encephalitis.

    Sulagna Das

    Full Text Available BACKGROUND: Japanese encephalitis virus (JEV induces neuroinflammation with typical features of viral encephalitis, including inflammatory cell infiltration, activation of microglia, and neuronal degeneration. The detrimental effects of inflammation on neurogenesis have been reported in various models of acute and chronic inflammation. We investigated whether JEV-induced inflammation has similar adverse effects on neurogenesis and whether those effects can be reversed using an anti-inflammatory compound minocycline. METHODOLOGY/PRINCIPAL FINDINGS: Here, using in vitro studies and mouse models, we observed that an acute inflammatory milieu is created in the subventricular neurogenic niche following Japanese encephalitis (JE and a resultant impairment in neurogenesis occurs, which can be reversed with minocycline treatment. Immunohistological studies showed that proliferating cells were replenished and the population of migrating neuroblasts was restored in the niche following minocycline treatment. In vitro, we checked for the efficacy of minocycline as an anti-inflammatory compound and cytokine bead array showed that production of cyto/chemokines decreased in JEV-activated BV2 cells. Furthermore, mouse neurospheres grown in the conditioned media from JEV-activated microglia exhibit arrest in both proliferation and differentiation of the spheres compared to conditioned media from control microglia. These effects were completely reversed when conditioned media from JEV-activated and minocycline treated microglia was used. CONCLUSION/SIGNIFICANCE: This study provides conclusive evidence that JEV-activated microglia and the resultant inflammatory molecules are anti-proliferative and anti-neurogenic for NSPCs growth and development, and therefore contribute to the viral neuropathogenesis. The role of minocycline in restoring neurogenesis may implicate enhanced neuronal repair and attenuation of the neuropsychiatric sequelae in JE survivors.

  5. Potential Roles of Stevia rebaudiana Bertoni in Abrogating Insulin Resistance and Diabetes: A Review

    Nabilatul Hani Mohd-Radzman

    2013-01-01

    Full Text Available Insulin resistance is a key factor in metabolic disorders like hyperglycemia and hyperinsulinemia, which are promoted by obesity and may later lead to Type II diabetes mellitus. In recent years, researchers have identified links between insulin resistance and many noncommunicable illnesses other than diabetes. Hence, studying insulin resistance is of particular importance in unravelling the pathways employed by such diseases. In this review, mechanisms involving free fatty acids, adipocytokines such as TNFα and PPARγ and serine kinases like JNK and IKKβ, asserted to be responsible in the development of insulin resistance, will be discussed. Suggested mechanisms for actions in normal and disrupted states were also visualised in several manually constructed diagrams to capture an overall view of the insulin-signalling pathway and its related components. The underlying constituents of medicinal significance found in the Stevia rebaudiana Bertoni plant (among other plants that potentiate antihyperglycemic activities were explored in further depth. Understanding these factors and their mechanisms may be essential for comprehending the progression of insulin resistance towards the development of diabetes mellitus.

  6. Potential Roles of Stevia rebaudiana Bertoni in Abrogating Insulin Resistance and Diabetes: A Review

    Nabilatul Hani Mohd-Radzman; Ismail, W. I. W.; Zainah Adam; Siti Safura Jaapar; Aishah Adam

    2013-01-01

    Insulin resistance is a key factor in metabolic disorders like hyperglycemia and hyperinsulinemia, which are promoted by obesity and may later lead to Type II diabetes mellitus. In recent years, researchers have identified links between insulin resistance and many noncommunicable illnesses other than diabetes. Hence, studying insulin resistance is of particular importance in unravelling the pathways employed by such diseases. In this review, mechanisms involving free fatty acids, adipocytokin...

  7. Structural centrosome aberrations favor proliferation by abrogating microtubule-dependent tissue integrity of breast epithelial mammospheres.

    Schnerch, D; Nigg, E A

    2016-05-01

    Structural centrosome aberrations are frequently observed in early stage carcinomas, but their role in malignant transformation is poorly understood. Here, we examined the impact of overexpression of Ninein-like protein (Nlp) on the architecture of polarized epithelia in three-dimensional mammospheres. When Nlp was overexpressed to levels resembling those seen in human tumors, it formed striking centrosome-related bodies (CRBs), which sequestered Ninein and affected the kinetics of microtubule (MT) nucleation and release. In turn, the profound reorganization of the MT cytoskeleton resulted in mislocalization of several adhesion and junction proteins as well as the tumor suppressor Scribble, resulting in the disruption of epithelial polarity, cell-cell interactions and mammosphere architecture. Remarkably, cells harboring Nlp-CRBs displayed an enhanced proliferative response to epidermal growth factor. These results demonstrate that structural centrosome aberrations cause not only the disruption of epithelial polarity but also favor overproliferation, two phenotypes typically associated with human carcinomas. PMID:26364601

  8. MMP-9 cleaves SP-D and abrogates its innate immune functions in vitro.

    Preston E Bratcher

    Full Text Available Possession of a properly functioning innate immune system in the lung is vital to prevent infections due to the ongoing exposure of the lung to pathogens. While mechanisms of pulmonary innate immunity have been well studied, our knowledge of how these systems are altered in disease states, leading to increased susceptibility to infections, is limited. One innate immune protein in the lung, the pulmonary collectin SP-D, has been shown to be important in innate immune defense, as well as clearance of allergens and apoptotic cells. MMP-9 is a protease with a wide variety of substrates, and has been found to be dysregulated in a myriad of lung diseases ranging from asthma to cystic fibrosis; in many of these conditions, there are decreased levels of SP-D. Our results indicate that MMP-9 is able to cleave SP-D in vitro and this cleavage leads to loss of its innate immune functions, including its abilities to aggregate bacteria and increase phagocytosis by mouse alveolar macrophages. However, MMP-9-cleaved SP-D was still detected in a solid-phase E. coli LPS-binding assay, while NE-cleaved SP-D was not. In addition, MMP-9 seems to cleave SP-D much more efficiently than NE at physiological levels of calcium. Previous studies have shown that in several diseases, including cystic fibrosis and asthma, patients have increased expression of MMP-9 in the lungs as well as decreased levels of intact SP-D. As patients suffering from many of the diseases in which MMP-9 is over-expressed can be more susceptible to pulmonary infections, it is possible that MMP-9 cleavage of SP-D may contribute to this phenotype.

  9. Blocking CHK1 Expression Induces Apoptosis and Abrogates the G2 Checkpoint Mechanism

    Yan Luo

    2001-01-01

    Full Text Available Checkpoint kinase 1 (Chki is a checkpoint gene that is activated after DNA damage. It phosphorylates and inactivates the Cdc2 activating phosphatase Cdc25C. This in turn inactivates Cdc2, which leads to G2/M arrest. We report that blocking Chki expression by antisense or ribozymes in mammalian cells induces apoptosis and interferes with the G2/M arrest induced by adriamycin. The Chki inhibitor UCN-01 also blocks the G2 arrest after DNA damage and renders cells more susceptible to adriamycin. These results indicate that Chki is an essential gene for the checkpoint mechanism during normal cell proliferation as well as in the DNA damage response.

  10. Abrogation of junctional adhesion molecule-A expression induces cell apoptosis and reduces breast cancer progression.

    Masato Murakami

    Full Text Available Intercellular junctions promote homotypic cell to cell adhesion and transfer intracellular signals which control cell growth and apoptosis. Junctional adhesion molecule-A (JAM-A is a transmembrane immunoglobulin located at tight junctions of normal epithelial cells of mammary ducts and glands. In the present paper we show that JAM-A acts as a survival factor for mammary carcinoma cells. JAM-A null mice expressing Polyoma Middle T under MMTV promoter develop significantly smaller mammary tumors than JAM-A positive mice. Angiogenesis and inflammatory or immune infiltrate were not statistically modified in absence of JAM-A but tumor cell apoptosis was significantly increased. Tumor cells isolated from JAM-A null mice or 4T1 cells incubated with JAM-A blocking antibodies showed reduced growth and increased apoptosis which paralleled altered junctional architecture and adhesive function. In a breast cancer clinical data set, tissue microarray data show that JAM-A expression correlates with poor prognosis. Gene expression analysis of mouse tumor samples showed a correlation between genes enriched in human G3 tumors and genes over expressed in JAM-A +/+ mammary tumors. Conversely, genes enriched in G1 human tumors correlate with genes overexpressed in JAM-A-/- tumors. We conclude that down regulation of JAM-A reduces tumor aggressive behavior by increasing cell susceptibility to apoptosis. JAM-A may be considered a negative prognostic factor and a potential therapeutic target.

  11. Mesenchymal stem cells abrogate experimental asthma by altering dendritic cell function.

    Zeng, Shao-Lin; Wang, Li-Hui; Li, Ping; Wang, Wei; Yang, Jiong

    2015-08-01

    Mesenchymal stem cells (MSCs) have been investigated in the treatment of numerous autoimmune diseases. However, the immune properties of MSCs on the development of asthma have remained to be fully elucidated. Airway dendritic cells (DCs) have an important role in the pathogenesis of allergic asthma, and disrupting their function may be a novel therapeutic approach. The present study used a mouse model of asthma to demonstrate that transplantation of MSCs suppressed features of asthma by targeting the function of lung myeloid DCs. MSCs suppressed the maturation and migration of lung DCs to the mediastinal lymph nodes, and thereby reducing the allergen-specific T helper type 2 (Th2) response in the nodes. In addition, MSC-treated DCs were less potent in activating naive and effector Th2 cells and the capacity of producing chemokine (C-C motif) ligand 17 (CCL17) and CCL22, which are chemokines attracting Th2 cells, to the airways was reduced. These results supported that MSCs may be used as a potential treatment for asthma. PMID:25936350

  12. COSMOS-rice technology abrogates the biotoxic effects of municipal solid waste incinerator residues.

    Guarienti, Michela; Cardozo, Sdenka Moscoso; Borgese, Laura; Lira, Gloria Rodrigo; Depero, Laura E; Bontempi, Elza; Presta, Marco

    2016-07-01

    Fly ashes generated by municipal solid waste incinerator (MSWI) are classified as hazardous waste and usually landfilled. For the sustainable reuse of these materials is necessary to reduce the resulting impact on human health and environment. The COSMOS-rice technology has been recently proposed for the treatment of fly ashes mixed with rice husk ash, to obtain a low-cost composite material with significant performances. Here, aquatic biotoxicity assays, including daphnidae and zebrafish embryo-based tests, were used to assess the biosafety efficacy of this technology. Exposure to lixiviated MSWI fly ash caused dose-dependent biotoxic effects on daphnidae and zebrafish embryos with alterations of embryonic development, teratogenous defects and apoptotic events. On the contrary, no biotoxic effects were observed in daphnidae and zebrafish embryos exposed to lixiviated COSMOS-rice material. Accordingly, whole-mount in situ hybridization analysis of the expression of various tissue-specific genes in zebrafish embryos provided genetic evidence about the ability of COSMOS-rice stabilization process to minimize the biotoxic effects of MSWI fly ash. These results demonstrate at the biological level that the newly developed COSMOS-rice technology is an efficient and cost-effective method to process MSWI fly ash, producing a biologically safe and reusable material. PMID:27149148

  13. Neonatal androgenization exacerbates alcohol-induced liver injury in adult rats, an effect abrogated by estrogen.

    Whitney M Ellefson

    Full Text Available Alcoholic liver disease (ALD affects millions of people worldwide and is a major cause of morbidity and mortality. However, fewer than 10% of heavy drinkers progress to later stages of injury, suggesting other factors in ALD development, including environmental exposures and genetics. Females display greater susceptibility to the early damaging effects of ethanol. Estrogen (E2 and ethanol metabolizing enzymes (cytochrome P450, CYP450 are implicated in sex differences of ALD. Sex steroid hormones are developmentally regulated by the hypothalamic-pituitary-gonadal (HPG axis, which controls sex-specific cycling of gonadal steroid production and expression of hepatic enzymes. The aim of this study was to determine if early postnatal inhibition of adult cyclic E2 alters ethanol metabolizing enzyme expression contributing to the development of ALD in adulthood. An androgenized rat model was used to inhibit cyclic E2 production. Control females (Ctrl, androgenized females (Andro and Andro females with E2 implants were administered either an ethanol or isocalorically-matched control Lieber-DeCarli diet for four weeks and liver injury and CYP450 expression assessed. Androgenization exacerbated the deleterious effects of ethanol demonstrated by increased steatosis, lipid peroxidation, profibrotic gene expression and decreased antioxidant defenses compared to Ctrl. Additionally, CYP2E1 expression was down-regulated in Andro animals on both diets. No change was observed in CYP1A2 protein expression. Further, continuous exogenous administration of E2 to Andro in adulthood attenuated these effects, suggesting that E2 has protective effects in the androgenized animal. Therefore, early postnatal inhibition of cyclic E2 modulates development and progression of ALD in adulthood.

  14. Abrogating endocrine resistance by targeting ER alpha and PI3K in breast cancer

    ToddWMiller

    2012-10-01

    Full Text Available Antiestrogen therapies targeting estrogen receptor alpha (ER signaling are a mainstay for patients with ER+ breast cancer. While many cancers exhibit resistance to antiestrogen therapies, a large body of clinical and experimental evidence indicates that hyperactivation of the phosphatidylinositol 3-kinase (PI3K pathway promotes antiestrogen resistance. In addition, continued ligand-independent ER signaling in the setting of estrogen deprivation may contribute to resistance to endocrine therapy. PI3K activates several proteins which promote cell cycle progression and survival. In ER+ breast cancer cells, PI3K promotes ligand-dependent and -independent ER transcriptional activity. Models of antiestrogen-resistant breast cancer often remain sensitive to estrogen stimulation and PI3K inhibition, suggesting that clinical trials with combinations of drugs targeting both the PI3K and ER pathways are warranted. Herein, we review recent findings on the roles of PI3K and ER in antiestrogen resistance, and clinical trials testing drug combinations which target both pathways. We also discuss the need for clinical investigation of ER downregulators in combination with PI3K inhibitors.

  15. Influence Of Whey Protein For Abrogating Liver Injury In Female Rats

    The objective of this study was to determine the possible benefits of whey protein concentrate (44% protein, 5% fat and 4.6% ash in dry weight) against liver injury induced by CCl4 . It was carried out by evaluating the effect of the daily feeding of female rats on diet containing 15% whey protein instead of soybean protein for four weeks on some biochemical and histological changes in liver of female rats.The data showed that injection with CCl4 (1 ml /kg body weight 3 times / week) caused significant decrease in body weight with disturbances in liver functions as significant increase in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transferase and bilirubin and significant decrease in serum albumin, FT3 and an increase in AFP levels. A marked significant decrease in glutathione content and significant increase in lipid peroxidation was also observed in hepatic tissues. The histological examination revealed that CCl4 treatment showed marked degenerative changes in liver hepatocytes and sinusoids.The results also showed that feeding on diet containing whey protein for two or four weeks during CCl4 treatment minimized the disturbance of the liver functions and liver histology.

  16. Naringin abrogated radiation induced oxidative stress through modulation of redox regulated cellular signaling system

    Ionizing radiation is widely used as major diagnostic and therapeutic applications. However, the deleterious effects of ionizing radiation are due to generation of reactive oxygen species. The amounts of ionizing radiation that can be given to treat malignant tumours are often limited by toxicity in the surrounding normal tissues and organs. The aim of this study was to investigate the role of Naringin (NG), a natural flavonoid, present in many plant parts against radiation induced oxidative stress with an evidence based exploration of the mechanism involved. Isolated murine splenocyte were irradiated with γ radiation (6 Gy) along with/without different concentrations of NG (50 and 100 μM). Biochemical, immunoblot, flow cytometry and immunofluorescence study was subject to be performed to observe its molecular mechanisms of action. Pretreatment with NG significantly prevented the radiation induced intracellular ROS generation, therefore prevented cellular TBARS formation and development of cellular nitrite. NG showed the significant reduction in nuclear DNA damage with respect to irradiated splenocyte through inhibition of DNA-PKcs and p-γH2AX. It recovered radiation induced reduced cell viability through modulation of redox regulated cell signaling system. It resulted in significant inhibition of radiation induced G1/S phase cell cycle arrest mediated by modulation of p53 dependent p21/WAF1 expression followed by Cyclin E and CDK2 expression. NG was involved in blocking radiation induced p38 function; reversed radiation mediated differential stress response through inhibition of NF-κB pathway. It prevented p-IKKα/β, p-IκBα, p-p65, COX2 expression. It also reversed the radiation induced p38/NF-κB guided inflammatory development. Thus it down regulated radiation induced CRP, MCP-1, and iNOS2 gene expression. This novel role of naringin provides a basis for therapeutic applications in future against radiation induced molecular and cellular functional impairment. (author)

  17. Therapeutic targeting of Krüppel-like factor 4 abrogates microglial activation

    Kaushik Deepak

    2012-03-01

    Full Text Available Abstract Background Neuroinflammation occurs as a result of microglial activation in response to invading micro-organisms or other inflammatory stimuli within the central nervous system. According to our earlier findings, Krüppel-like factor 4 (Klf4, a zinc finger transcription factor, is involved in microglial activation and subsequent release of proinflammatory cytokines, tumor necrosis factor alpha, macrophage chemoattractant protein-1 and interleukin-6 as well as proinflammatory enzymes, inducible nitric oxide synthase and cyclooxygenase-2 in lipopolysaccharide-treated microglial cells. Our current study focuses on finding the molecular mechanism of the anti-inflammatory activities of honokiol in lipopolysaccharide-treated microglia with emphasis on the regulation of Klf4. Methods For in vitro studies, mouse microglial BV-2 cell lines as well as primary microglia were treated with 500 ng/mL lipopolysaccharide as well as 1 μM and 10 μM of honokiol. We cloned full-length Klf4 cDNA in pcDNA3.1 expression vector and transfected BV-2 cells with this construct using lipofectamine for overexpression studies. For in vivo studies, brain tissues were isolated from BALB/c mice treated with 5 mg/kg body weight of lipopolysaccharide either with or without 2.5 or 5 mg/kg body weight of honokiol. Expression of Klf4, cyclooxygenase-2, inducible nitric oxide synthase and phospho-nuclear factor-kappa B was measured using immunoblotting. We also measured the levels of cytokines, reactive oxygen species and nitric oxide in different conditions. Results Our findings suggest that honokiol can substantially downregulate the production of proinflammatory cytokines and inflammatory enzymes in lipopolysaccharide-stimulated microglia. In addition, honokiol downregulates lipopolysaccharide-induced upregulation of both Klf4 and phospho-nuclear factor-kappa B in these cells. We also found that overexpression of Klf4 in BV-2 cells suppresses the anti-inflammatory action of honokiol. Conclusions Honokiol potentially reduces inflammation in activated microglia in a Klf4-dependent manner.

  18. Secoisolariciresinol Diglucoside Abrogates Oxidative Stress-Induced Damage in Cardiac Iron Overload Condition

    Stephanie Puukila; Sean Bryan; Anna Laakso; Jessica Abdel-Malak; Carli Gurney; Adrian Agostino; Adriane Belló-Klein; Kailash Prasad; Neelam Khaper

    2015-01-01

    Cardiac iron overload is directly associated with cardiac dysfunction and can ultimately lead to heart failure. This study examined the effect of secoisolariciresinol diglucoside (SDG), a component of flaxseed, on iron overload induced cardiac damage by evaluating oxidative stress, inflammation and apoptosis in H9c2 cardiomyocytes. Cells were incubated with 50 μ5M iron for 24 hours and/or a 24 hour pre-treatment of 500 μ M SDG. Cardiac iron overload resulted in increased oxidative stress and ...

  19. Chrysin abrogates early hepatocarcinogenesis and induces apoptosis in N-nitrosodiethylamine-induced preneoplastic nodules in rats

    Flavonoids possess strong anti-oxidant and cancer chemopreventive activities. Chrysin (5,7-dihydroxyflavone) occurs naturally in many plants, honey, and propolis. In vitro, chrysin acts as a general anti-oxidant, causes cell cycle arrest and promotes cell death. However, the mechanism by which chrysin inhibits cancer cell growth and the subcellular pathways activated remains poorly understood. Effect of dietary supplementation with chrysin on proliferation and apoptosis during diethylnitrosamine (DEN)-induced early hepatocarcinogenesis was investigated in male Wistar rats. To induce hepatocarcinogenesis, rats were given DEN injections (i.p., 200 mg/kg) three times at a 15 day interval. An oral dose of chrysin (250 mg/kg bodyweight) was given three times weekly for 3 weeks, commencing 1 week after the last dose of DEN. Changes in the mRNA expression of COX-2, NFkB p65, p53, Bcl-xL and β-arrestin-2 were assessed by quantitative real-time PCR. Changes in the protein levels were measured by western blotting. Chrysin administration significantly (P < 0.001) reduced the number and size of nodules formed. Also, a significant (P < 0.01) reduction in serum activities of AST, ALT, ALP, LDH and γGT was noticed. Expression of COX-2 and NFkB p65 was significantly reduced whereas that of p53, Bax and caspase 3 increased at the mRNA and protein levels. Likewise, a decrease in levels of β-arrestin and the anti-apoptotic marker Bcl-xL was also noted. These findings suggest that chrysin exerts global hepato-protective effect and its chemopreventive activity is associated with p53-mediated apoptosis during early hepatocarcinogenesis.

  20. Herpesvirus Telomerase RNA (vTR) with a Mutated Template Sequence Abrogates Herpesvirus-Induced Lymphomagenesis

    Kaufer, Benedikt B; Sina Arndt; Sascha Trapp; Nikolaus Osterrieder; Jarosinski, Keith W.

    2011-01-01

    Telomerase reverse transcriptase (TERT) and telomerase RNA (TR) represent the enzymatically active components of telomerase. In the complex, TR provides the template for the addition of telomeric repeats to telomeres, a protective structure at the end of linear chromosomes. Human TR with a mutation in the template region has been previously shown to inhibit proliferation of cancer cells in vitro. In this report, we examined the effects of a mutation in the template of a virus encoded TR (vTR)...

  1. Molecular Insights into Microbial β-Glucuronidase Inhibition to Abrogate CPT-11 Toxicity

    Roberts, Adam B.; Wallace, Bret D.; Venkatesh, Madhu Kumar; Mani, Sridhar; Redinbo, Matthew R.

    2013-01-01

    Bacterial β-glucuronidases expressed by the symbiotic intestinal microbiota appear to play important roles in drug-induced epithelial cell toxicity in the gastrointestinal (GI) tract. For the anticancer drug CPT-11 (irinotecan) and the nonsteroidal anti-inflammatory drug diclofenac, it has been shown that removal of the glucuronide moieties from drug metabolites by bacterial β-glucuronidases in the GI lumen can significantly damage the intestinal epithelium. Furthermore, selective disruption ...

  2. Monoclonal Antibody Therapy does not Abrogate Rejection Risk in Renal Transplant Recipients

    Sanjeev Goswami

    2013-01-01

    Monoclonal antibodies are being increasingly used as therapeutic agents in medicine. Rituximab (anti-CD20) and Daclizumab (anti-IL2Rα) are two such monoclonal antibodies used to prevent organ rejection, but are not fail-safe. We have analyzed the pre and post-transplant antibody profile in serum of renal transplant recipients receiving Rituximab and /or Daclizumab. Study Group: Kidney recipients with acute rejection and having PRA > 10% pre-transplant were selected for the study (n=11). Those...

  3. Abrogation of genetically controlled resistance of mice to Treponema pallidum by irradiation

    On intradermal infection, transient primary lesions, characteristic of those seen in naturally acquired human syphilis, can be produced regularly in some strains of mice but not others, indicating a genetic basis for host susceptibility. However strains of mice which normally fail to develop lesions, do so after exposure to ionising radiation. Here the importance of an intact immune system in the outcome of local infection is illustrated by the use of radiation-induced immunosuppression. The mice were exposed to lethal doses of total body irradiation from a 137Ce source (137 rad per min), 850-1,050 rad depending on mouse strain. (UK)

  4. Constitutive activation of BMP signalling abrogates experimental metastasis of OVCA429 cells via reduced cell adhesion

    Shepherd Trevor G

    2010-02-01

    Full Text Available Abstract Background Activation of bone morphogenetic protein (BMP4 signalling in human ovarian cancer cells induces a number of phenotypic changes in vitro, including altered cell morphology, adhesion, motility and invasion, relative to normal human ovarian surface epithelial cells. From these in vitro analyses, we had hypothesized that active BMP signalling promotes the metastatic potential of ovarian cancer. Methods To test this directly, we engineered OVCA429 human ovarian cancer cells possessing doxycycline-inducible expression of a constitutively-active mutant BMP receptor, ALK3QD, and administered these cells to immunocompromised mice. Further characterization was performed in vitro to address the role of activated BMP signalling on the EOC phenotype, with particular emphasis on epithelial-mesenchymal transition (EMT and cell adhesion. Results Unexpectedly, doxycycline-induced ALK3QD expression in OVCA429 cells reduced tumour implantation on peritoneal surfaces and ascites formation when xenografted into immunocompromised mice by intraperitoneal injection. To determine the potential mechanisms controlling this in vivo observation, we followed with several cell culture experiments. Doxycycline-induced ALK3QD expression enhanced the refractile, spindle-shaped morphology of cultured OVCA429 cells eliciting an EMT-like response. Using in vitro wound healing assays, we observed that ALK3QD-expressing cells migrated with long, cytoplasmic projections extending into the wound space. The phenotypic alterations of ALK3QD-expressing cells correlated with changes in specific gene expression patterns of EMT, including increased Snail and Slug and reduced E-cadherin mRNA expression. In addition, ALK3QD signalling reduced β1- and β3-integrin expression, critical molecules involved in ovarian cancer cell adhesion. The combination of reduced E-cadherin and β-integrin expression correlates directly with the reduced EOC cell cohesion in spheroids and reduced cell adhesion to the extracellular matrix substrates fibronectin and vitronectin that was observed. Conclusions We propose that the key steps of ovarian cancer metastasis, specifically cell cohesion of multicellular aggregates in ascites and cell adhesion for reattachment to secondary sites, may be inhibited by overactive BMP signalling, thereby decreasing the ultimate malignant potential of ovarian cancer in this model system.

  5. GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells

    Pai, Sung-Yun; Truitt, Morgan L.; Ho, I-Cheng

    2004-01-01

    T helper type 2 (Th2) cells secrete IL-4, IL-5, IL-10, and IL-13 and mediate allergic and asthmatic disease. GATA-3 is a Th2-specific transcription factor that appears in overexpression studies and transgenic systems to function as a Th2 lineage determinant. Because GATA-3 is also crucial for development of the T lineage and throughout thymic development, direct demonstration that GATA-3 is required for Th2 development by targeted deletion has been lacking. Using a conditional knockout approa...

  6. Prion pathogenesis is faithfully reproduced in cerebellar organotypic slice cultures.

    Jeppe Falsig

    Full Text Available Prions cause neurodegeneration in vivo, yet prion-infected cultured cells do not show cytotoxicity. This has hampered mechanistic studies of prion-induced neurodegeneration. Here we report that prion-infected cultured organotypic cerebellar slices (COCS experienced progressive spongiform neurodegeneration closely reproducing prion disease, with three different prion strains giving rise to three distinct patterns of prion protein deposition. Neurodegeneration did not occur when PrP was genetically removed from neurons, and a comprehensive pharmacological screen indicated that neurodegeneration was abrogated by compounds known to antagonize prion replication. Prion infection of COCS and mice led to enhanced fodrin cleavage, suggesting the involvement of calpains or caspases in pathogenesis. Accordingly, neurotoxicity and fodrin cleavage were prevented by calpain inhibitors but not by caspase inhibitors, whereas prion replication proceeded unimpeded. Hence calpain inhibition can uncouple prion replication from its neurotoxic sequelae. These data validate COCS as a powerful model system that faithfully reproduces most morphological hallmarks of prion infections. The exquisite accessibility of COCS to pharmacological manipulations was instrumental in recognizing the role of calpains in neurotoxicity, and significantly extends the collection of tools necessary for rigorously dissecting prion pathogenesis.

  7. Ubiquitous hazardous metal lead induces TNF-α in human phagocytic THP-1 cells: Primary role of ERK 1/2

    Induction of tumor necrosis factor-α (TNF-α) in response to lead (Pb) exposure has been implicated in its immunotoxicity. However, the molecular mechanism by which Pb upregulates the level of TNF-α is wagely known. An attempt was therefore made to elucidate the mechanistic aspect of TNF-α induction, mainly focusing transcriptional and post transcriptional regulation via mitogen activated protein kinases (MAPKs) activation. We observed that exposure of Pb to human monocytic THP-1 cells resulted in significant enhanced production of TNF-α m-RNA and protein secretion. Moreover, the stability of TNF-α m-RNA was also increased as indicated by its half life. Notably, activation of ERK 1/2, p38 and JNK in Pb exposed THP-1 was also evident. Specific inhibitor of ERK1/2, PD 98059 caused significant inhibition in production and stability of TNF-α m-RNA. However, SB 203580 partially inhibited production and stability of TNF-α m-RNA. Interestingly, a combined exposure of these two inhibitors completely blocked modulation of TNF-α m-RNA. Data tends to suggest that expression and stability of TNF-α induction due to Pb exposure is mainly regulated through ERK. Briefly, these observations are useful in understanding some mechanistic aspects of proinflammatory and immunotoxicity of Pb, a globally acknowledged key environmental contaminant.

  8. Levothyroxine rescues the lead-induced hypothyroidism and impairment of long-term potentiation in hippocampal CA1 region of the developmental rats

    Lead (Pb) exposure during development has been associated with impaired long-term potentiation (LTP). Hypothyroidism happening upon subjects with occupational exposure to Pb is suggestive of an adverse effect of Pb on thyroid homeostasis, leading to the hypothesis that Pb exposure may alter thyroid hormone homeostasis. Hippocampus is one of the targets of Pb exposure, and is sensitive to and dependent on thyroid hormones, leading us to explore whether levothyroxine (L-T4) administration could alter the thyroid disequilibrium and impairment of LTP in rat hippocampus caused by Pb exposure. Our results show that Pb exposure caused a decrease in triiodothyronine (T3) and tetraiodothyronine (T4) levels accompanied by a dramatic decrease of TSH and application of L-T4 restored these changes to about control levels. Hippocampal and blood Pb concentration were significantly reduced following L-T4 treatment. L-T4 treatment rescued the impairment of LTP induced by the Pb exposure. These results suggest that Pb exposure may lead to thyroid dysfunction and induce hypothyroidism and provide a direct electrophysiological proof that L-T4 relieves chronic Pb exposure-induced impairment of synaptic plasticity. - Highlights: → Lead may interfere with thyroid hormone homeostasis and induce hypothyroidism. → Levothyroxine decreases the hippocampal and blood Pb concentration. → Levothyroxine amends the T3, T4 and TSH levels in blood. → Levothyroxine rescues the impaired LTP in CA1.

  9. Combined exposure to nano-silica and lead induced potentiation of oxidative stress and DNA damage in human lung epithelial cells.

    Lu, Chun-Feng; Yuan, Xiao-Yan; Li, Li-Zhong; Zhou, Wei; Zhao, Jun; Wang, Yi-Mei; Peng, Shuang-Qing

    2015-12-01

    Growing evidence has confirmed that exposure to ambient particulate matters (PM) is associated with increased morbidity and mortality of cardiovascular and pulmonary diseases. Ambient PM is a complex mixture of particles and air pollutants. Harmful effects of PM are specifically associated with ultrafine particles (UFPs) that can adsorb high concentrations of toxic air pollutants and are easily inhaled into the lungs. However, combined effects of UFPs and air pollutants on human health remain unclear. In the present study, we elucidated the combined toxicity of silica nanoparticles (nano-SiO2), a typical UFP, and lead acetate (Pb), a typical air pollutant. Lung adenocarcinoma A549 cells were exposed to nano-SiO2 and Pb alone or their combination, and their combined toxicity was investigated by focusing on cellular oxidative stress and DNA damage. Factorial analyses were performed to determine the potential interactions between nano-SiO2 and Pb. Our results showed that exposure of A549 cells to a modest cytotoxic concentration of Pb alone induced oxidative stress, as evidenced by elevated reactive oxygen species generation and lipid peroxidation, and reduced glutathione content and superoxide dismutase and glutathione peroxidase activities. In addition, exposure of A549 cells to Pb alone induced DNA damage, as evaluated by alkaline comet assay. Exposure of A549 cells to non-cytotoxic concentration of nano-SiO2 did not induce cellular oxidative stress and DNA damage. However, exposure to the combination of nano-SiO2 and Pb potentiated oxidative stress and DNA damage in A549 cells. Factorial analyses indicated that the potentiation of combined toxicity of nano-SiO2 and Pb was induced by additive or synergistic interactions. PMID:26432026

  10. The Antagonistic Effect of Selenium on Lead-Induced Inflammatory Factors and Heat Shock Proteins mRNA Expression in Chicken Livers.

    Wang, Hao; Li, Shu; Teng, Xiaohua

    2016-06-01

    The aim of this study was to investigate the effect of lead (Pb) poisoning on nitric oxide (NO) content, inducible nitric oxide synthase (iNOS) activity, the messenger RNA (mRNA) levels of inflammatory factors (nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), prostaglandin E synthases (PTGEs), and iNOS), heat shock proteins (HSPs) (HSP27, HSP40, HSP60, HSP70, and HSP90), and the antagonistic effect of selenium (Se) on Pb in chicken livers. One hundred eighty 7-day-old male chickens were randomly divided into four groups and were fed commercial diet and drinking water, Na2SeO3-added commercial diet and drinking water, commercial diet and (CH3OO)2Pb-added drinking water, and Na2SeO3-added commercial diet and (CH3OO)2Pb-added drinking water, respectively, for 30, 60, and 90 days. Then, NO content, iNOS activity, and the mRNA levels of NF-κB, TNF-α, COX-2, PTGEs, iNOS, HSP27, HSP40, HSP60, HSP70, and HSP90 were examined in chicken livers. The results showed that Pb poisoning induced NO content, iNOS activity, and mRNA expression of inflammation factors and HSPs in chicken livers. In addition, Se alleviated Pb-induced increase of inflammation factor and HSP expression in chicken livers. PMID:26470710

  11. Inhibition of ROS elevation and damage to mitochondrial function prevents lead-induced neurotoxic effects on structures and functions of AFD neurons in Caenorhabditis elegans

    Qiuli Wu; Peidang Liu; Yinxia Li; Min Du; Xiaojuan Xing; Dayong Wang

    2012-01-01

    Here we investigated the possible roles of oxidative stress in the formation of decreased thermotaxis to cultivation temperature in lead (Pb)-exposed nematodes Caenorhabditis elagans.Exposure to Pb at the examined concentrations decreased thermotaxis behaviors,and induced severe deficits in the structural properties of AFD sensory neurons.Meanwhile,Pb exposure caused the induction of severe oxidative damage,reactive oxygen species (ROS) production,and mitochondrial dysfunction in young adults.Moreover,pre-treatment with the antioxidants dimethyl sulfoxide (DMSO),ascorbate and N-acetyl-L-cysteine (NAC),used to inhibit both the ROS elevation and the mitochondrial dysfunction caused by Pb exposure,at the L2-1arval stage prevented the induction of oxidative damage and the formation of severe deficits in thermotaxis and structural properties of AFD sensory neurons in Pb-exposed young adults.Therefore,the formation of oxidative stress caused by Pb exposure may be due to both the induction of ROS elevation and damage to mitochondrial function,and oxidative stress may play a key role in inducing the neurotoxic effects on the structures and function of AFT sensory neurons in Pb-exposed nematodes.

  12. The Antagonistic Effect of Selenium on Lead-Induced Inflammatory Factors and Heat Shock Protein mRNA Level in Chicken Cartilage Tissue.

    Zheng, Shufang; Song, Huanyu; Gao, Han; Liu, Chunpeng; Zhang, Ziwei; Fu, Jing

    2016-09-01

    Selenium (Se) is recognized as a necessary trace mineral in animal diets, including those of birds. Lead (Pb) is a toxic heavy metal and can damage organs in humans and animals. Complex antagonistic interactions between Se and heavy metals have been reported in previous studies. However, little is known regarding the effects of Se on Pb-induced toxicity and the expression of inflammatory factors and heat shock proteins (HSPs) in the cartilage of chickens. In this present study, we fed chickens either with Se or Pb or both Se and Pb supplement and later analyzed the mRNA expressions of inflammatory factors (inducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2)) and HSPs (Hsp27, Hsp40, Hsp60, Hsp70, and Hsp90). The results showed that Se and Pb influenced the expression of inflammatory factors and HSP genes in the chicken cartilage tissues. Additionally, we also found that antagonistic interaction existed between Se and Pb supplementation. Our findings suggested that Se could exert a antagonistic effect on Pb in chicken cartilage tissues. PMID:26831653

  13. Lead induces similar gene expression changes in brains of gestationally exposed adult mice and in neurons differentiated from mouse embryonic stem cells.

    Francisco Javier Sánchez-Martín

    Full Text Available Exposure to environmental toxicants during embryonic life causes changes in the expression of developmental genes that may last for a lifetime and adversely affect the exposed individual. Developmental exposure to lead (Pb, an ubiquitous environmental contaminant, causes deficits in cognitive functions and IQ, behavioral effects, and attention deficit hyperactivity disorder (ADHD. Long-term effects observed after early life exposure to Pb include reduction of gray matter, alteration of myelin structure, and increment of criminal behavior in adults. Despite growing research interest, the molecular mechanisms responsible for the effects of lead in the central nervous system are still largely unknown. To study the molecular changes due to Pb exposure during neurodevelopment, we exposed mice to Pb in utero and examined the expression of neural markers, neurotrophins, transcription factors and glutamate-related genes in hippocampus, cortex, and thalamus at postnatal day 60. We found that hippocampus was the area where gene expression changes due to Pb exposure were more pronounced. To recapitulate gestational Pb exposure in vitro, we differentiated mouse embryonic stem cells (ESC into neurons and treated ESC-derived neurons with Pb for the length of the differentiation process. These neurons expressed the characteristic neuronal markers Tubb3, Syp, Gap43, Hud, Ngn1, Vglut1 (a marker of glutamatergic neurons, and all the glutamate receptor subunits, but not the glial marker Gafp. Importantly, several of the changes observed in Pb-exposed mouse brains in vivo were also observed in Pb-treated ESC-derived neurons, including those affecting expression of Ngn1, Bdnf exon IV, Grin1, Grin2D, Grik5, Gria4, and Grm6. We conclude that our ESC-derived model of toxicant exposure during neural differentiation promises to be a useful model to analyze mechanisms of neurotoxicity induced by Pb and other environmental agents.

  14. Elucidation of lead-induced oxidative stress in Talinum triangulare roots by analysis of antioxidant responses and DNA damage at cellular level.

    Kumar, Abhay; Prasad, M N V; Mohan Murali Achary, V; Panda, Brahma B

    2013-07-01

    Hydroponic experiments were performed with Talinum triangulare (Jacq.) Willd. focusing the root cellular biochemistry with special emphasis on DNA damage, structural, and elemental analyses in Pb(NO3)2 exposed with 0, 0.25, 0.5, 0.75, 1.0, and 1.25 mM for 7 days. Lead (Pb) increased reactive oxygen species production, lipid peroxidation, protein oxidation, cell death, and DNA damage and decreased the protein content in a dose-dependent manner. Likewise, a dose-dependent induction of antioxidative enzymes superoxide dismutase and catalase by Pb was evident. Ascorbate peroxidase on the other hand responded biphasically to Pb treatments by showing induction at low (0.25 and 0.50) and repression at high (0.75-1.25 mM) concentrations. The estimation of proline content also indicated a similar biphasic trend. Scanning electron microscope and energy-dispersive X-ray spectroscopy analysis showed that 1.25 mM Pb treatment resulted in ultrastructural modifications in roots and stem tissue that was marked by the change in the elemental profile. The findings pointed to the role of oxidative stress in the underlying Pb phytotoxicity and genotoxicity in T. triangulare. PMID:23263755

  15. Proteomic responses to lead-induced oxidative stress in Talinum triangulare Jacq. (Willd.) roots: identification of key biomarkers related to glutathione metabolisms.

    Kumar, Abhay; Majeti, Narasimha Vara Prasad

    2014-01-01

    In this study, Talinum triangulare Jacq. (Willd.) treated with different lead (Pb) concentrations for 7 days has been investigated to understand the mechanisms of ascorbate-glutathione metabolisms in response to Pb-induced oxidative stress. Proteomic study was performed for control and 1.25 mM Pb-treated plants to examine the root protein dynamics in the presence of Pb. Results of our analysis showed that Pb treatment caused a decrease in non-protein thiols, reduced glutathione (GSH), total ascorbate, total glutathione, GSH/oxidized glutathione (GSSG) ratio, and activities of glutathione reductase and γ-glutamylcysteine synthetase. Conversely, cysteine and GSSG contents and glutathione-S-transferase activity was increased after Pb treatment. Fourier transform infrared spectroscopy confirmed our metabolic and proteomic studies and showed that amino, phenolic, and carboxylic acids as well as alcoholic, amide, and ester-containing biomolecules had key roles in detoxification of Pb/Pb-induced toxic metabolites. Proteomic analysis revealed an increase in relative abundance of 20 major proteins and 3 new proteins (appeared only in 1.25 mM Pb). Abundant proteins during 1.25 mM Pb stress conditions have given a very clear indication about their involvement in root architecture, energy metabolism, reactive oxygen species (ROS) detoxification, cell signaling, primary and secondary metabolisms, and molecular transport systems. Relative accumulation patterns of both common and newly identified proteins are highly correlated with our other morphological, physiological, and biochemical parameters. PMID:24705950

  16. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma

    Rijt, Leonie; Jung, S.; KleinJan, Alex; Vos, Nanda; Willart, M.; Duez, C.; Hoogsteden, Henk; LAMBRECHT, Bart

    2005-01-01

    textabstractAlthough dendritic cells (DCs) play an important role in sensitization to inhaled allergens, their function in ongoing T helper (Th)2 cell-mediated eosinophilic airway inflammation underlying bronchial asthma is currently unknown. Here, we show in an ovalbumin (OVA)-driven murine asthma model that airway DCs acquire a mature phenotype and interact with CD4(+) T cells within sites of peribronchial and perivascular inflammation. To study whether DCs contributed to inflammation, we d...

  17. RhoA Activation Sensitizes Cells to Proteotoxic Stimuli by Abrogating the HSF1-Dependent Heat Shock Response.

    Roelien A M Meijering

    Full Text Available The heat shock response (HSR is an ancient and highly conserved program of stress-induced gene expression, aimed at reestablishing protein homeostasis to preserve cellular fitness. Cells that fail to activate or maintain this protective response are hypersensitive to proteotoxic stress. The HSR is mediated by the heat shock transcription factor 1 (HSF1, which binds to conserved heat shock elements (HSE in the promoter region of heat shock genes, resulting in the expression of heat shock proteins (HSP. Recently, we observed that hyperactivation of RhoA conditions cardiomyocytes for the cardiac arrhythmia atrial fibrillation. Also, the HSR is annihilated in atrial fibrillation, and induction of HSR mitigates sensitization of cells to this disease. Therefore, we hypothesized active RhoA to suppress the HSR resulting in sensitization of cells for proteotoxic stimuli.Stimulation of RhoA activity significantly suppressed the proteotoxic stress-induced HSR in HL-1 atrial cardiomyocytes as determined with a luciferase reporter construct driven by the HSF1 regulated human HSP70 (HSPA1A promoter and HSP protein expression by Western Blot analysis. Inversely, RhoA inhibition boosted the proteotoxic stress-induced HSR. While active RhoA did not preclude HSF1 nuclear accumulation, phosphorylation, acetylation, or sumoylation, it did impair binding of HSF1 to the hsp genes promoter element HSE. Impaired binding results in suppression of HSP expression and sensitized cells to proteotoxic stress.These results reveal that active RhoA negatively regulates the HSR via attenuation of the HSF1-HSE binding and thus may play a role in sensitizing cells to proteotoxic stimuli.

  18. RhoA Activation Sensitizes Cells to Proteotoxic Stimuli by Abrogating the HSF1-Dependent Heat Shock Response

    Meijering, Roelien A. M.; Wiersma, Marit; van Marion, Denise M. S.; Zhang, Deli; Hoogstra-Berends, Femke; Dijkhuis, Anne-Jan; Schmidt, Martina; Wieland, Thomas; Kampinga, Harm H.; Henning, Robert H.; Brundel, Bianca J. J. M.

    2015-01-01

    Background The heat shock response (HSR) is an ancient and highly conserved program of stress-induced gene expression, aimed at reestablishing protein homeostasis to preserve cellular fitness. Cells that fail to activate or maintain this protective response are hypersensitive to proteotoxic stress.

  19. HCMV-infected cells maintain efficient nucleotide excision repair of the viral genome while abrogating repair of the host genome.

    John M O'Dowd

    Full Text Available Many viruses subvert the host cell's ability to mount and complete various DNA damage responses (DDRs after infection. HCMV infection of permissive fibroblasts activates host DDRs at the time of viral deposition and during replication, but the DDRs remain uncompleted without arrest or apoptosis. We believe this was in part due to partitioning of the damage response and double strand break repair components. After extraction of soluble proteins, the localization of these components fell into three groups: specifically associated with the viral replication centers (RCs, diffused throughout the nucleoplasm and excluded from the RCs. Others have shown that cells are incapable of processing exogenously introduced damage after infection. We hypothesized that the inability of the cells to process damage might be due to the differential association of repair components within the RCs and, in turn, potentially preferential repair of the viral genome and compromised repair of the host genome. To test this hypothesis we used multiple strategies to examine repair of UV-induced DNA damage in mock and virus-infected fibroblasts. Comet assays indicated that repair was initiated, but was not completed in infected cells. Quantitative analysis of immunofluorescent localization of cyclobutane pyrimidine dimers (CPDs revealed that after 24 h of repair, CPDs were significantly reduced in viral DNA, but not significantly changed in the infected host DNA. To further quantitate CPD repair, we developed a novel dual-color Southern protocol allowing visualization of host and viral DNA simultaneously. Combining this Southern methodology with a CPD-specific T4 endonuclease V alkaline agarose assay to quantitate repair of adducts, we found efficient repair of CPDs from the viral DNA but not host cellular DNA. Our data confirm that NER functions in HCMV-infected cells and almost exclusively repairs the viral genome to the detriment of the host's genome.

  20. A Pyrococcus homolog of the leucine-responsive regulatory protein, LrpA, inhibits transcription by abrogating RNA polymerase recruitment

    Dahlke, Isabell; Thomm, Michael

    2002-01-01

    The genomes of Archaea harbor homologs of the global bacterial regulator leucine-responsive regulatory protein (Lrp). Archaeal Lrp homologs are helix–turn–helix DNA-binding proteins that specifically repress the transcription of their own genes in vitro. Here, we analyze the interaction of Pyrococcus LrpA with components of the archaeal transcriptional machinery at the lrpA promoter. DNA–protein complexes can be isolated by electrophoretic mobility shift assays that contain both LrpA and the ...