The role of mycotoxins in neurodegenerative diseases: current state of the art and future perspectives of research

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Vu Thu Thuy Nguyen ◽  
Svenja König ◽  
Simone Eggert ◽  
Kristina Endres ◽  
Stefan Kins
Keyword(s):  
Neurodegenerative Diseases ◽  
Research Field ◽  
Model Systems ◽  
Fungal Metabolites ◽  
Future Perspectives ◽  
Adverse Health Effects ◽  
Current State

Abstract Mycotoxins are fungal metabolites that can cause various diseases in humans and animals. The adverse health effects of mycotoxins such as liver failure, immune deficiency, and cancer are well-described. However, growing evidence suggests an additional link between these fungal metabolites and neurodegenerative diseases. Despite the wealth of these initial reports, reliable conclusions are still constrained by limited access to human patients and availability of suitable cell or animal model systems. This review summarizes knowledge on mycotoxins associated with neurodegenerative diseases and the assumed underlying pathophysiological mechanisms. The limitations of the common in vivo and in vitro experiments to identify the role of mycotoxins in neurotoxicity and thereby in neurodegenerative diseases are elucidated and possible future perspectives to further evolve this research field are presented.

scholarly journals DNAJB6b is Downregulated in Synucleinopathies

2021 ◽  
pp. 1-13
Author(s):  
Jonas Folke ◽  
Sertan Arkan ◽  
Isak Martinsson ◽  
Susana Aznar ◽  
Gunnar Gouras ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Substantia Nigra Pars Compacta ◽  
Endogenous Protein ◽  
Highly Sensitive ◽  
Brain Material ◽  
Health And Disease ◽  
Isoform B

Background: α-synuclein (α-syn) aggregation contributes to the progression of multiple neurodegenerative diseases. We recently found that the isoform b of the co-chaperone DNAJB6 is a strong suppressor of a-syn aggregation in vivo and in vitro. However, nothing is known about the role of the endogenous isoform b of DNAJB6 (DNAJB6b) in health and disease, due to lack of specific antibodies. Objective: Here we generated a novel anti-DNAJB6b antibody to analyze the localization and expression this isoform in cells, in tissue and in clinical material. Methods: To address this we used immunocytochemistry, immunohistochemistry, as well as a novel quantitative DNAJB6 specific ELISA method. Results: The endogenous protein is mainly expressed in the cytoplasm and in neurites in vitro, where it is found more in dendrites than in axons. We further verified in vivo that DNAJB6b is expressed in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), which is a neuronal subpopulation highly sensitive to α-syn aggregation, that degenerate to a large extend in patients with Parkinson’s disease (PD) and multiple system atrophy (MSA). When we analyzed the expression levels of DNAJB6b in brain material from PD and MSA patients, we found a downregulation of DNAJB6b by use of ELISA based quantification. Interestingly, this was also true when analyzing tissue from patients with progressive supranuclear palsy, a taupathic atypical parkinsonian disorder. However, the total level of DNAJB6 was upregulated in these three diseases, which may indicate an upregulation of the other major isoform of DNAJB6, DNAJB6a. Conclusion: This study shows that DNAJB6b is downregulated in several different neurodegenerative diseases, which makes it an interesting target to further investigate in relation to amyloid protein aggregation and disease progression.

The role of pulmonary intravascular macrophages in porcine reproductive and respiratory syndrome virus infection

2000 ◽  
Vol 1 (2) ◽  
pp. 95-102 ◽  
Author(s):  
Roongroje Thanawongnuwech ◽  
Patrick G. Halbur ◽  
Eileen L. Thacker
Keyword(s):  
Virus Titer ◽  
Respiratory Syndrome Virus ◽  
The Past ◽  
Current State ◽  
Viral Particles ◽  
Increased Susceptibility ◽  
Pulmonary Intravascular Macrophages

AbstractThe objective of this article is to summarize the current state of knowledge of the complex interaction of porcine reproductive and respiratory syndrome virus (PRRSV) and porcine pulmonary intravascular macrophages (PIMs). PIMs play an important role in pulmonary surveillance, and in the past few years we have investigated their role in PRRSV infection. PRRSV antigens and nucleic acids have been demonstrated in PIMs bothin vitroandin vivo. Examination of cultured PIMs infected with PRRSV revealed the accumulation of viral particles in the smooth-walled vesicles. PRRSV-infected PIMsin vitroyielded a virus titer similar to pulmonary alveolar macrophages. PRRSV infection induces either apoptosis or cell lysis of PIMs. Thein vitrobactericidal activity of PRRSV-infected PIMs is significantly decreased. Phagocytic activity of PIMs, as measured by pulmonary copper clearance, is significantly decreased in PRRSV-infected pigs. This evidence supports the hypothesis that PRRSV-induced damage to PIMs results in increased susceptibility to bacteremic diseases. Recent studies with PRRSV andStreptococcus suiscoinfection confirmed that PRRSV predisposes pigs toS. suisinfection and bacteremia. These results could explain the increase in bacterial respiratory diseases and septicemias observed in PRRSV-infected pigs.

Abstract P482: Elucidating And Characterizing The Molecular Mechanistic Role Of Phospholamban L39 Stop In The Pathophysiology Of Cardiomyopathy Using Patient-derived Human Induced Pluripotent Stem Cells And Humanized Knock-in Mouse Model Systems

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Anichavezhi Devendran ◽  
Rasheed Bailey ◽  
Sumanta Kar ◽  
Francesca Stillitano ◽  
Irene Turnbull ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mouse Model ◽  
Mononuclear Cells ◽  
Embryonic Stem ◽  
Model Systems ◽  
Patient Specific ◽  
Induced Pluripotent

Background: Heart failure (HF) is a complex clinical condition associated with substantial morbidity and mortality worldwide. The contractile dysfunction and arrhythmogenesis related to HF has been linked to the remodelling of calcium (Ca ++ ) handling. Phospholamban (PLN) has emerged as a key regulator of intracellular Ca ++ concentration. Of the PLN mutations, L39X is intriguing as it has not been fully characterized. This mutation is believed to be functionally equivalent to PLN null (KO) but contrary to PLN KO mice, L39X carriers develop a lethal cardiomyopathy (CMP). Our study aims at using induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) from homozygous L39X carriers to elucidate the role of L39X in human pathophysiology. Our plan also involves the characterization of humanized L39X knock-in mice (KM), which we hypothesize will develop a CMP from mis-localization of PLN and disruption of Ca ++ signalling. Methodology and Results: Mononuclear cells from Hom L39X carriers were obtained to generate 11 integration-free patient-specific iPSC clones. The iPSC-CMs were derived using established protocols. Compared to the WT iPSC-CMs, the Hom L39X derived-CMs PLN had an abnormal cytoplasmic distribution and formed intracellular aggregates, with the loss of perinuclear localization. There was also a 70% and 50% reduction of mRNA and protein expression of PLN respectively in L39X compared to WT iPSC-CMs. These findings indicated that L39X PLN is both under-expressed and mis-localized within the cell. To validate this observation in-vivo, we genetically modified FVB mice to harbour the human L39X. Following electroporation, positively transfected mouse embryonic stem cells were injected into host blastocysts to make humanized KM that were subsequently used to generate either a protamine-Cre (endogenous PLN driven expression) or a cardiac TNT mouse (i.e., CMP specific). Conclusion: Our data confirm an abnormal intracellular distribution of PLN, with the loss of perinuclear accumulation and mis-localization, suggestive of ineffective targeting to or retention of L39X. The mouse model will be critically important to validate the in-vitro observations and provides an ideal platform for future studies centred on the development of novel therapeutic strategies including virally delivered CRISPR/Cas9 for in-vivo gene editing and testing of biochemical signalling pathways.

scholarly journals The lack of rhodanese RhdA affects the sensitivity of Azotobacter vinelandii to oxidative events

2009 ◽  
Vol 418 (1) ◽  
pp. 135-143 ◽  
Author(s):  
Angelo Cereda ◽  
Aristodemo Carpen ◽  
Gianluca Picariello ◽  
Gabriella Tedeschi ◽  
Silvia Pagani
Keyword(s):  
Oxidative Damage ◽  
Active Site ◽  
Azotobacter Vinelandii ◽  
Redox Balance ◽  
Growth Conditions ◽  
Model Systems ◽  
Phenotypic Characterization

The rhdA gene of Azotobacter vinelandii codes for RhdA, a rhodanese-domain protein with an active-site loop structure which has not currently been found in proteins of the rhodanese-homology superfamily. Considering the lack of information on the functional role of the ubiquitous rhodaneses, in the present study we examined the in vivo functions of RhdA by using an A. vinelandii mutant strain (MV474), in which the rhdA gene was disrupted by deletion. Preliminary phenotypic characterization of the rhdA mutant suggested that RhdA could exert protection over Fe–S enzymes, which are easy targets for oxidative damage. To highlight the role of RhdA in preserving sensitive Fe–S clusters, in the present study we analysed the defects of the rhdA-null strain by exploiting growth conditions which resulted in enhancing the catalytic deficiency of enzymes with vulnerable Fe–S clusters. We found that a lack of RhdA impaired A. vinelandii growth in the presence of gluconate, a carbon source that activates the Entner–Doudoroff pathway in which the first enzyme, 6-phosphogluconate dehydratase, employs a 4Fe–4S cluster as an active-site catalyst. By combining proteomics, enzymatic profiles and model systems to generate oxidative stress, evidence is provided that to rescue the effects of a lack of RhdA, A. vinelandii needed to activate defensive activities against oxidative damage. The possible functionality of RhdA as a redox switch which helps A. vinelandii in maintaining the cellular redox balance was investigated by using an in vitro model system that demonstrated reversible chemical modifications in the highly reactive RhdA Cys230 thiol.

scholarly journals Role of Vitamin E and the Orexin System in Neuroprotection

2021 ◽  
Vol 11 (8) ◽  
pp. 1098
Author(s):  
Maria Ester La Torre ◽  
Ines Villano ◽  
Marcellino Monda ◽  
Antonietta Messina ◽  
Giuseppe Cibelli ◽  
...  
Keyword(s):  
Vitamin E ◽  
Neurodegenerative Diseases ◽  
Antioxidant Properties ◽  
Phenotypic Change ◽  
The Central Nervous System ◽  
Specific Receptors

Microglia are the first line of defense at the level of the central nervous system (CNS). Phenotypic change in microglia can be regulated by various factors, including the orexin system. Neuroinflammation is an inflammatory process mediated by cytokines, by the lack of interaction of specific receptors such as the OX2-OX2R complex, caused by systemic tissue damage or, more often, associated with direct damage to the CNS. Chronic activation of microglia could lead to long-term neurodegenerative diseases. This review aims to explore how tocopherol (vitamin E) and the orexin system may play a role in the prevention and treatment of microglia inflammation and, consequently, in neurodegenerative diseases thanks to its antioxidant properties. The results of animal and in vitro studies provide evidence to support the use of tocopherol for a reduction in microglia inflammation as well as a greater activation of the orexinergic system. Although there is much in vivo and in vitro evidence of vitamin E antioxidant and protective abilities, there are still conflicting results for its use as a treatment for neurodegenerative diseases that speculate that vitamin E, under certain conditions or genetic predispositions, can be pro-oxidant and harmful.

Epigenetics in Neurodegenerative Diseases: The Role of Histone Deacetylases

2019 ◽  
Vol 18 (1) ◽  
pp. 11-18 ◽  
Author(s):  
Sorabh Sharma ◽  
K.C. Sarathlal ◽  
Rajeev Taliyan
Keyword(s):  
Neurodegenerative Diseases ◽  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Beneficial Effects ◽  
In Vivo Animal Models ◽  
Preclinical And Clinical Studies

Background & Objective: Imbalance in histone acetylation levels and consequently the dysfunction in transcription are associated with a wide variety of neurodegenerative diseases. Histone proteins acetylation and deacetylation is carried out by two opposite acting enzymes, histone acetyltransferases and histone deacetylases (HDACs), respectively. In-vitro and in-vivo animal models of neurodegenerative diseases and post mortem brains of patients have been reported overexpressed level of HDACs. In recent past numerous studies have indicated that HDAC inhibitors (HDACIs) might be a promising class of therapeutic agents for treating these devastating diseases. HDACs being a part of repressive complexes, the outcome of their inhibition has been attributed to enhanced gene expression due to heightened histone acetylation. Beneficial effects of HDACIs has been explored both in preclinical and clinical studies of these diseases. Thus, their screening as future therapeutics for neurodegenerative diseases has been widely explored. Conclusion: In this review, we focus on the putative role of HDACs in neurodegeneration and further discuss their potential as a new therapeutic avenue for treating neurodegenerative diseases.

scholarly journals POSCAbilities: The Application of the Prion Organotypic Slice Culture Assay to Neurodegenerative Disease Research

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1079
Author(s):  
Hailey Pineau ◽  
Valerie Sim
Keyword(s):  
Neurodegenerative Diseases ◽  
Prion Diseases ◽  
In Vitro Models ◽  
Slice Culture ◽  
Advantages And Disadvantages ◽  
Organotypic Slice Culture ◽  
Drug Treatments

Prion diseases are fatal, transmissible neurodegenerative disorders whose pathogenesis is driven by the misfolding, self-templating and cell-to-cell spread of the prion protein. Other neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease, share some of these prion-like features, with different aggregation-prone proteins. Consequently, researchers have begun to apply prion-specific techniques, like the prion organotypic slice culture assay (POSCA), to these disorders. In this review we explore the ways in which the prion phenomenon has been used in organotypic cultures to study neurodegenerative diseases from the perspective of protein aggregation and spreading, strain propagation, the role of glia in pathogenesis, and efficacy of drug treatments. We also present an overview of the advantages and disadvantages of this culture system compared to in vivo and in vitro models and provide suggestions for new directions.

scholarly journals The Role of Echinocandins in Candida Biofilm–Related Vascular Catheter Infections: In Vitro and In Vivo Model Systems

2015 ◽  
Vol 61 (suppl_6) ◽  
pp. S618-S621 ◽  
Author(s):  
Mahmoud Ghannoum ◽  
Emmanuel Roilides ◽  
Aspasia Katragkou ◽  
Vidmantas Petraitis ◽  
Thomas J. Walsh
Keyword(s):  
Model Systems ◽  
In Vivo Model ◽  
Catheter Infections ◽  
Candida Biofilm

scholarly journals Deciphering the role of hydrophobic and hydrophilic bile acids in angiogenesis using in vitro and in vivo model systems

MedChemComm ◽  
2017 ◽  
Vol 8 (12) ◽  
pp. 2248-2257 ◽  
Author(s):  
Somanath Kundu ◽  
Sandhya Bansal ◽  
Kalai Mangai Muthukumarasamy ◽  
Chetana Sachidanandan ◽  
Rajender K. Motiani ◽  
...  
Keyword(s):  
Bile Acids ◽  
Chenodeoxycholic Acid ◽  
Model Systems ◽  
In Vivo Model ◽  
Zebrafish Model ◽  
Sar Studies

SAR studies revealed the pro-angiogenic properties of chenodeoxycholic acid in a zebrafish model.

scholarly journals Thrombogenic Risk Induced by Intravascular Mesenchymal Stem Cell Therapy: Current Status and Future Perspectives

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1160 ◽  
Author(s):  
Louise Coppin ◽  
Etienne Sokal ◽  
Xavier Stéphenne
Keyword(s):  
Clinical Trials ◽  
In Vivo Studies ◽  
Current Status ◽  
Future Perspectives ◽  
Complement Pathway ◽  
Mesenchymal Stem Cell Therapy ◽  
Dual Activation

Mesenchymal stem cells (MSCs) are currently studied and used in numerous clinical trials. Nevertheless, some concerns have been raised regarding the safety of these infusions and the thrombogenic risk they induce. MSCs express procoagulant activity (PCA) linked to the expression of tissue factor (TF) that, when in contact with blood, initiates coagulation. Some even describe a dual activation of both the coagulation and the complement pathway, called Instant Blood-Mediated Inflammatory Reaction (IBMIR), explaining the disappointing results and low engraftment rates in clinical trials. However, nowadays, different approaches to modulate the PCA of MSCs and thus control the thrombogenic risk after cell infusion are being studied. This review summarizes both in vitro and in vivo studies on the PCA of MSC of various origins. It further emphasizes the crucial role of TF linked to the PCA of MSCs. Furthermore, optimization of MSC therapy protocols using different methods to control the PCA of MSCs are described.

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