scholarly journals Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein

2019 ◽  
Vol 12 (572) ◽  
pp. eaau4543 ◽  
Author(s):  
Dilshan S. Harischandra ◽  
Dharmin Rokad ◽  
Matthew L. Neal ◽  
Shivani Ghaisas ◽  
Sireesha Manne ◽  
...  
Keyword(s):  
Potential Role ◽  
Neuronal Model ◽  
Experimental Models ◽  
Bimolecular Fluorescence Complementation ◽  
Wild Type ◽  
Biological Mechanisms ◽  
Extracellular Medium ◽  
Cell To Cell Transfer ◽  
Serum Exosomes

The aggregation of α-synuclein (αSyn) is considered a key pathophysiological feature of certain neurodegenerative disorders, collectively termed synucleinopathies. Given that a prion-like, cell-to-cell transfer of misfolded αSyn has been recognized in the spreading of αSyn pathology in synucleinopathies, we investigated the biological mechanisms underlying the propagation of the disease with respect to environmental neurotoxic stress. Considering the potential role of the divalent metal manganese (Mn2+) in protein aggregation, we characterized its effect on αSyn misfolding and transmission in experimental models of Parkinson’s disease. In cultured dopaminergic neuronal cells stably expressing wild-type human αSyn, misfolded αSyn was secreted through exosomes into the extracellular medium upon Mn2+ exposure. These exosomes were endocytosed through caveolae into primary microglial cells, thereby mounting neuroinflammatory responses. Furthermore, Mn2+-elicited exosomes exerted a neurotoxic effect in a human dopaminergic neuronal model (LUHMES cells). Moreover, bimolecular fluorescence complementation (BiFC) analysis revealed that Mn2+ accelerated the cell-to-cell transmission of αSyn, resulting in dopaminergic neurotoxicity in a mouse model of Mn2+ exposure. Welders exposed to Mn2+ had increased misfolded αSyn content in their serum exosomes. Stereotaxically delivering αSyn-containing exosomes, isolated from Mn2+-treated αSyn-expressing cells, into the striatum initiated Parkinsonian-like pathological features in mice. Together, these results indicate that Mn2+ exposure promotes αSyn secretion in exosomal vesicles, which subsequently evokes proinflammatory and neurodegenerative responses in both cell culture and animal models.

scholarly journals NMR and LC-MS-Based Metabolomics to Study Osmotic Stress in Lignan-Deficient Flax

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 767
Author(s):  
Kamar Hamade ◽  
Ophélie Fliniaux ◽  
Jean-Xavier Fontaine ◽  
Roland Molinié ◽  
Elvis Otogo Nnang ◽  
...  
Keyword(s):  
Stress Response ◽  
Osmotic Stress ◽  
Biosynthetic Pathway ◽  
Potential Role ◽  
Plant Secondary Metabolites ◽  
Wild Type ◽  
Osmotic Stress Response ◽  
Transgenic Flax ◽  
Insight Into

Lignans, phenolic plant secondary metabolites, are derived from the phenylpropanoid biosynthetic pathway. Although, being investigated for their health benefits in terms of antioxidant, antitumor, anti-inflammatory and antiviral properties, the role of these molecules in plants remains incompletely elucidated; a potential role in stress response mechanisms has been, however, proposed. In this study, a non-targeted metabolomic analysis of the roots, stems, and leaves of wild-type and PLR1-RNAi transgenic flax, devoid of (+) secoisolariciresinol diglucoside ((+) SDG)—the main flaxseed lignan, was performed using 1H-NMR and LC-MS, in order to obtain further insight into the involvement of lignan in the response of plant to osmotic stress. Results showed that wild-type and lignan-deficient flax plants have different metabolic responses after being exposed to osmotic stress conditions, but they both showed the capacity to induce an adaptive response to osmotic stress. These findings suggest the indirect involvement of lignans in osmotic stress response.

Abstract 450: The Role of CD38 as a Therapeutic Target for Protection Against Doxorubicin-induced Cardiotoxicity Through Nad+ Boosting

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Thais R Peclat ◽  
Guillermo Agorrody ◽  
Lilian S Gomez ◽  
Eduardo N Chini
Keyword(s):  
Single Dose ◽  
Therapeutic Target ◽  
Potential Role ◽  
Damage Mechanism ◽  
Treated Group ◽  
Wild Type ◽  
Chemotherapeutic Treatment ◽  
Positive Effect ◽  
Dose Injection

Background: Doxorubicin is a chemotherapy medication used to treat several types of cancer. Its major adverse effect is cardiotoxicity, which may limit its use. Doxorubicin-induced cardiotoxicity (DIC), once developed, carries a poor prognosis. Therefore strategies to prevent or treat DIC are of paramount importance but have not yet been fully developed. Being NAD + a critical nucleotide which is involved in oxy-reduction reactions and CD38 the main NAD + -consuming enzyme responsible for NAD levels regulation and homeostasis, we aim to investigate the link of CD38 and NAD + metabolism in DIC and its potential role as a therapeutic target. Methods: We compared Wild-type (WT) control mice with WT mice treated with a single dose injection of 15 mg/kg of doxorubicin who received vehicle or an antibody that blocksCD38 ecto-enzymatic activity. We also compared genetically CD38 catalytic inactive (CI) mice treated or not with the same single dose injection. Results: Doxorubicin caused a decrease in Ejection Fraction (EF) in WT mice. We also observed that CD38 CI mice treated with doxorubicin did not have changes in EF compared to their control. When compared to WT receiving just doxorubicin, WT mice treated also with the antibody had a trend to improve EF. As for exercise performance, our results show a decrease in exercise capacity induced by doxorubicin that was reversed in the antibody group and did not happen in the CD38 CI mice treated with doxorubicin. Doxorubicin caused a decrease in heart rate variability (HRV) which was improved in the antibody treated group. Moreover, our results show a survival rate that is similar to what has been previously shown, with 50% mortality associated with doxorubicin. Blockage of CD38 activity with antibody reduced mortality in this model to approximately 20%. Mechanistically, we did not observe decreases in NAD+ levels induced by Doxorubicin. However, boost of NAD induced by blocking CD38 was related to protection against DIC. Conclusion: Our results indicate that the damage mechanism of DIC may not be related directly with NAD decrease, but NAD boosting induced by CD38 blockage seems to have a positive effect in protection against cardiac dysfunction related to this chemotherapeutic treatment.

scholarly journals Targeting myeloid-cell specific integrin α9β1 inhibits arterial thrombosis in mice

Blood ◽  
2020 ◽  
Vol 135 (11) ◽  
pp. 857-861 ◽  
Author(s):  
Nirav Dhanesha ◽  
Manasa K. Nayak ◽  
Prakash Doddapattar ◽  
Manish Jain ◽  
Gagan D. Flora ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Potential Role ◽  
Myeloid Cell ◽  
Neutrophil Extracellular Traps ◽  
Cathepsin G ◽  
Wild Type ◽  
Extracellular Traps ◽  
Laser Injury ◽  
Activated Platelets

Abstract Evidence suggests that neutrophils contribute to thrombosis via several mechanisms, including neutrophil extracellular traps (NETs) formation. Integrin α9β1 is highly expressed on neutrophils when compared with monocytes. It undergoes affinity upregulation on neutrophil activation, and stabilizes adhesion to the activated endothelium. The role of integrin α9 in arterial thrombosis remains unexplored. We generated novel myeloid cell-specific integrin α9−/− mice (α9fl/flLysMCre+) to study the role of integrin α9 in arterial thrombosis. α9fl/fl littermates were used as controls. We report that α9fl/flLysMCre+ mice were less susceptible to arterial thrombosis in ferric chloride (FeCl3) and laser injury-induced thrombosis models with unaltered hemostasis. Neutrophil elastase-positive cells were significantly reduced in α9fl/flLysMCre+ mice concomitant with reduction in neutrophil count, myeloperoxidase levels, and red blood cells in the FeCl3 injury-induced carotid thrombus. The percentage of cells releasing NETs was significantly reduced in α9fl/flLysMCre+ mouse neutrophils stimulated with thrombin-activated platelets. Furthermore, we found a significant decrease in neutrophil-mediated platelet aggregation and cathepsin-G secretion in α9fl/flLysMCre+ mice. Transfusion of α9fl/fl neutrophils in α9fl/flLysMCre+ mice restored thrombosis similar to α9fl/fl mice. Treatment of wild-type mice with anti-integrin α9 antibody inhibited arterial thrombosis. This study identifies the potential role of integrin α9 in modulating arterial thrombosis.

scholarly journals Cloning of wheat keto-acyl thiolase 2B reveals a role of jasmonic acid in grain weight determination

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yun Chen ◽  
Yan Yan ◽  
Tian-Tian Wu ◽  
Guo-Liang Zhang ◽  
Huanran Yin ◽  
...  
Keyword(s):  
Jasmonic Acid ◽  
Potential Role ◽  
Wheat Yield ◽  
Grain Weight ◽  
Wild Type ◽  
Wheat Improvement ◽  
Stop Mutation ◽  
Enhanced Expression ◽  
Component Traits

AbstractGrain weight (GW) is one of the component traits of wheat yield. Existing reports have shown that multiple phytohormones are involved in the regulation of GW in different crops. However, the potential role of jasmonic acid (JA) remains unclear. Here, we report that triticale grain weight 1 (tgw1) mutant, with marked reductions in both GW and JA content, is caused by a premature stop mutation in keto-acyl thiolase 2B (KAT-2B) involved in β-oxidation during JA synthesis. KAT-2B overexpression increases GW in wild type and boosts yield. Additionally, KAT-2B compliments the grain defect in tgw1 and rescues the lethal phenotype of the Arabidopsis kat2 mutant in a sucrose-free medium. Despite the suppression of JA synthesis in tgw1 mutant, ABA synthesis is upregulated, which is accompanied by enhanced expression of SAG3 and reduction of chlorophyll content in leaves. Together, these results demonstrate a role of the JA synthetic gene KAT-2B in controlling GW and its potential application value for wheat improvement.

scholarly journals Role of Overweight and Obesity in Gastrointestinal Disease

Nutrients ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 111 ◽  
Author(s):  
Sara Emerenziani ◽  
Michele Pier Luca Guarino ◽  
Laura Trillo Asensio ◽  
Annamaria Altomare ◽  
Mentore Ribolsi ◽  
...  
Keyword(s):  
Potential Role ◽  
Gastrointestinal Disease ◽  
Overweight And Obesity ◽  
Biological Mechanisms ◽  
Pathological Conditions ◽  
Severe Impairment ◽  
Prevalence Of Obesity ◽  
Inflammatory Bowel ◽  
Overall Mortality

The prevalence of obesity is increasing worldwide, leading to a severe impairment of overall health. Actually, obesity has been associated with several pathological conditions, causing an excess overall mortality. In particular, overweight and obesity are well known risk factors for a variety of gastrointestinal (GI) disorders i.e., functional GI disorders as well as, inflammatory bowel disease (IBD), pancreatitis, and GI cancer. The aim of the present review is to summarize the potential role of overweight and obesity in GI disease with particular focus on plausible biological mechanisms that could explain the association between obesity and GI disease based on the most recent evidence in the literature.

scholarly journals Braun Lipoprotein (Lpp) Contributes to Virulence of Yersiniae: Potential Role of Lpp in Inducing Bubonic and Pneumonic Plague

2008 ◽  
Vol 76 (4) ◽  
pp. 1390-1409 ◽  
Author(s):  
Jian Sha ◽  
Stacy L. Agar ◽  
Wallace B. Baze ◽  
Juan P. Olano ◽  
Amin A. Fadl ◽  
...  
Keyword(s):  
Acute Inflammation ◽  
Potential Role ◽  
Lethal Dose ◽  
Wild Type ◽  
Pneumonic Plague ◽  
Essentially Normal ◽  
Serovar Typhimurium ◽  
Highly Virulent ◽  
Lethal Doses

ABSTRACT Yersinia pestis evolved from Y. pseudotuberculosis to become the causative agent of bubonic and pneumonic plague. We identified a homolog of the Salmonella enterica serovar Typhimurium lipoprotein (lpp) gene in Yersinia species and prepared lpp gene deletion mutants of Y. pseudotuberculosis YPIII, Y. pestis KIM/D27 (pigmentation locus minus), and Y. pestis CO92 with reduced virulence. Mice injected via the intraperitoneal route with 5 × 107 CFU of the Δlpp KIM/D27 mutant survived a month, even though this would have constituted a lethal dose for the parental KIM/D27 strain. Subsequently, these Δlpp KIM/D27-injected mice were solidly protected against an intranasally administered, highly virulent Y. pestis CO92 strain when it was given as five 50% lethal doses (LD50). In a parallel study with the pneumonic plague mouse model, after 72 h postinfection, the lungs of animals infected with wild-type (WT) Y. pestis CO92 and given a subinhibitory dose of levofloxacin had acute inflammation, edema, and masses of bacteria, while the lung tissue appeared essentially normal in mice inoculated with the Δlpp mutant of CO92 and given the same dose of levofloxacin. Importantly, while WT Y. pestis CO92 could be detected in the bloodstreams and spleens of infected mice at 72 h postinfection, the Δlpp mutant of CO92 could not be detected in those organs. Furthermore, the levels of cytokines/chemokines detected in the sera were significantly lower in animals infected with the Δlpp mutant than in those infected with WT CO92. Additionally, the Δlpp mutant was more rapidly killed by macrophages than was the WT CO92 strain. These data provided evidence that the Δlpp mutants of yersiniae were significantly attenuated and could be useful tools in the development of new vaccines.

Potential role of the NADPH oxidase NOX1 in the pathogenesis of 5-fluorouracil-induced intestinal mucositis in mice

2012 ◽  
Vol 302 (10) ◽  
pp. G1133-G1142 ◽  
Author(s):  
Masashi Yasuda ◽  
Shinichi Kato ◽  
Naoki Yamanaka ◽  
Maho Iimori ◽  
Daichi Utsumi ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Caspase 3 ◽  
Potential Role ◽  
Chemotherapeutic Agent ◽  
Wild Type ◽  
Villus Height ◽  
Tnf Α ◽  
Nadph Oxidase 1 ◽  
Intestinal Mucositis

Although NADPH oxidase 1 (NOX1) has been shown to be highly expressed in the gastrointestinal tract, the physiological and pathophysiological roles of this enzyme are not yet fully understood. In the present study, we investigated the role of NOX1 in the pathogenesis of intestinal mucositis induced by the cancer chemotherapeutic agent 5-fluorouracil (5-FU) in mice. Intestinal mucositis was induced in Nox1 knockout (Nox1KO) and littermate wild-type (WT) mice via single, daily administration of 5-FU for 5 days. In WT mice, 5-FU caused severe intestinal mucositis characterized by a shortening of villus height, a disruption of crypts, a loss of body weight, and diarrhea. In Nox1KO mice, however, the severity of mucositis was significantly reduced, particularly with respect to crypt disruption. The numbers of apoptotic caspase-3- and caspase-8-activated cells in the intestinal crypt increased 24 h after the first 5-FU administration but were overall significantly lower in Nox1KO than in WT mice. Furthermore, the 5-FU-mediated upregulation of TNF-α, IL-1β, and NOX1 and the production of reactive oxygen species were significantly attenuated in Nox1KO mice compared with that in WT mice. These findings suggest that NOX1 plays an important role in the pathogenesis of 5-FU-induced intestinal mucositis. NOX1-derived ROS production following administration of 5-FU may promote the apoptotic response through upregulation of inflammatory cytokines.

scholarly journals Potential role of P-selectin glycoprotein ligand-1 in haematological diseases

2004 ◽  
Vol 23 (3) ◽  
pp. 265-269
Author(s):  
János Kappelmayer
Keyword(s):  
Knockout Mouse ◽  
Potential Role ◽  
Bleeding Tendency ◽  
Alternative Route ◽  
Wild Type ◽  
Normal Peripheral Blood ◽  
Procoagulant Effect ◽  
Haematological Disorders ◽  
Acute Myeloid

PSGL-1 is a major counterreceptor of all three types of selectins that is expressed in several leukocyte subsets. Data presented, here prove that this mucin may be implied in haematological disorders. We established on normal peripheral blood and in samples derived from 20 AML patients that PSGL-1 is differently expressed in various leukocyte subsets. Myeloblasts appearing in acute myeloid leukaemia patients express significantly less PSGL-1 (12 000 ? 5300) than mature neutrophils (p< 0.001). In monocytic leukaemias, however, the amount of PSGL-1 on monocytic precursors is displayed in a fairly broad range which was not significantly different from that of mature monocytes (p=0.084). Monoblasts/promononocytes possess more PSGL-1 than myeloblasts and the expression pattern is completely non-overlapping. This would imply a differential expression of PSGL-1 during myeloid haemopoietic development and suggests, that the quantitation of surface PSGL-1 may help in differentiating myeloblasts from monoblasts by immunophenotyping in different AML subsets. PSGL-1 has also a certain role in the generation of procoagulant microparticles (MP) as in the PSGL-1 knockout mouse the MP number failed to increase with age and the MP contained significantly less tissue factor than wild type mice. Since PSGL-1 P-selectin interaction is crucial in generating a procoagulant effect we tested the hypothesis that the administration of a P-selectin IgG chimera (Psel-Ig) corrects bleeding tendency in a murine haemophilia model and in human haemophilic blood. The addition of Psel-Ig resulted in significant improvement of the bleeding tendency in mice and in the generation of MP in human hemophilic blood. Thus, the Psel-Ig can become an alternative route to control bleeding tendency in coagulopathies.

scholarly journals Comparison of a human neuronal model proteome upon Japanese encephalitis or West Nile Virus infection and potential role of mosquito saliva in neuropathogenesis

PLoS ONE ◽  
2020 ◽  
Vol 15 (5) ◽  
pp. e0232585 ◽  
Author(s):  
Benoit Besson ◽  
Justine Basset ◽  
Sandrine Gatellier ◽  
Hélène Chabrolles ◽  
Thibault Chaze ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Virus Infection ◽  
Japanese Encephalitis ◽  
Potential Role ◽  
West Nile Virus Infection ◽  
Neuronal Model ◽  
West Nile ◽  
Mosquito Saliva

scholarly journals Modulation of Oxidative Stress by Ozone Therapy in the Prevention and Treatment of Chemotherapy-Induced Toxicity: Review and Prospects

Antioxidants ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 588 ◽  
Author(s):  
Bernardino Clavo ◽  
Francisco Rodríguez-Esparragón ◽  
Delvys Rodríguez-Abreu ◽  
Gregorio Martínez-Sánchez ◽  
Pedro Llontop ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Free Radicals ◽  
Potential Role ◽  
Antioxidant Response ◽  
Experimental Models ◽  
Ozone Therapy ◽  
Oxidative Stress Parameters ◽  
Randomized Controlled ◽  
Causes Of Mortality

(1) Background: Cancer is one of the leading causes of mortality worldwide. Radiotherapy and chemotherapy attempt to kill tumor cells by different mechanisms mediated by an intracellular increase of free radicals. However, free radicals can also increase in healthy cells and lead to oxidative stress, resulting in further damage to healthy tissues. Approaches to prevent or treat many of these side effects are limited. Ozone therapy can induce a controlled oxidative stress able to stimulate an adaptive antioxidant response in healthy tissue. This review describes the studies using ozone therapy to prevent and/or treat chemotherapy-induced toxicity, and how its effect is linked to a modification of free radicals and antioxidants. (2) Methods: This review encompasses a total of 13 peer-reviewed original articles (most of them with assessment of oxidative stress parameters) and some related works. It is mainly focused on four drugs: Cisplatin, Methotrexate, Doxorubicin, and Bleomycin. (3) Results: In experimental models and the few existing clinical studies, modulation of free radicals and antioxidants by ozone therapy was associated with decreased chemotherapy-induced toxicity. (4) Conclusions: The potential role of ozone therapy in the management of chemotherapy-induced toxicity merits further research. Randomized controlled trials are ongoing.

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