scholarly journals A Propagated Skeleton Approach to High Throughput Screening of Neurite Outgrowth for In Vitro Parkinson’s Disease Modelling

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 931
Author(s):  
Justus Schikora ◽  
Nina Kiwatrowski ◽  
Nils Förster ◽  
Leonie Selbach ◽  
Friederike Ostendorf ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurite Outgrowth ◽  
High Throughput ◽  
High Throughput Screening ◽  
Image Data ◽  
Large Data ◽  
Therapeutic Effects ◽  
Data Sets

Neuronal models of neurodegenerative diseases such as Parkinson’s Disease (PD) are extensively studied in pathological and therapeutical research with neurite outgrowth being a core feature. Screening of neurite outgrowth enables characterization of various stimuli and therapeutic effects after lesion. In this study, we describe an autonomous computational assay for a high throughput skeletonization approach allowing for quantification of neurite outgrowth in large data sets from fluorescence microscopic imaging. Development and validation of the assay was conducted with differentiated SH-SY5Y cells and primary mesencephalic dopaminergic neurons (MDN) treated with the neurotoxic lesioning compound Rotenone. Results of manual annotation using NeuronJ and automated data were shown to correlate strongly (R2-value 0.9077 for SH-SY5Y cells and R2-value 0.9297 for MDN). Pooled linear regressions of results from SH-SY5Y cell image data could be integrated into an equation formula (y=0.5410·x+1792; y=0.8789·x+0.09191 for normalized results) with y depicting automated and x depicting manual data. This automated neurite length algorithm constitutes a valuable tool for modelling of neurite outgrowth that can be easily applied to evaluate therapeutic compounds with high throughput approaches.

scholarly journals Therapeutic Effects of Multifunctional Tetramethylpyrazine Nitrone on Models of Parkinson’s Disease in Vitro and in Vivo

2014 ◽  
Vol 37 (2) ◽  
pp. 274-285 ◽  
Author(s):  
Baojian Guo ◽  
Daping Xu ◽  
Hongwei Duan ◽  
Jing Du ◽  
Zaijun Zhang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Therapeutic Effects

PTX3 secreted by human adipose-derived stem cells promotes dopaminergic neuron repair in Parkinson's disease via inhibiting apoptosis

2021 ◽  
Author(s):  
Changlin Lian ◽  
Qiongzhen Huang ◽  
Xiangyang Zhong ◽  
Zhenyan He ◽  
Boyang Liu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Brain Slices ◽  
Human Mesenchymal Stem Cells ◽  
Substantia Nigra Pars Compacta ◽  
Therapeutic Effects ◽  
Label Free

Abstract Background Adipose-derived human mesenchymal stem cells (hADSCs) transplantation has recently emerged as a promising method in the treatment of Parkinson's disease (PD), however, the mechanism underlying has not been fully illustrated. Methods In this study, the therapeutic effects of the striatum stereotaxic injected hADSCs in 6-OHDA-induced mouse model were evaluated. Furthermore, an in vitro model of PD was constructed using tissue-organized brain slices. And the therapeutic effect was evaluated by co-culture of hADSCs and 6-OHDA-constructed brain slice. Within the analysis of hADSCs' exocrine proteins through RNA-seq, Human protein cytokine arrays and label-free quantitative proteomics, key extracellular factors were identified in hADSCs secretion environment.The degeneration of DA neurons and apoptosis were measured in PD samples in vivo and vitro models, and the beneficial effects were evaluated through quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot,Fluoro-Jade C, Tunel assay and immunofluorescence analysis. Results In this study, we discovered that hADSCs protected the dopaminergic (DA) neurons in vivo and vitro models.we identified Pentraxin3 (PTX3) as a key extracellular factor in hADSCs secretion environment. Moreover, we found that human recombinant Pentraxin3 (rhPTX3) treatment could rescue the physiological behaviour of the PD mice in-vivo, as well as prevent DA neurons from death and increase the neuronal terminals in the Ventral tegmental area (VTA) + substantia nigra pars compacta (SNc) and striatum (STR) on the PD brain slices in-vitro. Furthermore, within testing on the pro-apoptotic markers of PD mice brain following the treatment of rhPTX3, we found that rhPTX3 can prevent the apoptosis and the degeneration of DA neurons. Conclusions Overall, the current study investigated that PTX3, a hADSCs secreted protein, played a potential role in protecting the DA neurons from apoptosis and degeneration in PD progression as well as improving the motor performances in PD mice to give a possible mechanism of how hADSCs works in the cell replacement therapy in PD. Importantly, our study also provided potential translational implications for the development of PTX3-based therapeutics in PD.

scholarly journals Artificial Neural Network—Based Analysis of High-Throughput Screening Data for Improved Prediction of Active Compounds

2009 ◽  
Vol 14 (10) ◽  
pp. 1236-1244 ◽  
Author(s):  
Swapan Chakrabarti ◽  
Stan R. Svojanovsky ◽  
Romana Slavik ◽  
Gunda I. Georg ◽  
George S. Wilson ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Back Propagation ◽  
Large Data ◽  
Classification Performance ◽  
Data Sets ◽  
Data Set ◽  
Active Compounds ◽  
Physicochemical Features ◽  
Artificial Neural

Artificial neural networks (ANNs) are trained using high-throughput screening (HTS) data to recover active compounds from a large data set. Improved classification performance was obtained on combining predictions made by multiple ANNs. The HTS data, acquired from a methionine aminopeptidases inhibition study, consisted of a library of 43,347 compounds, and the ratio of active to nonactive compounds, R A/N, was 0.0321. Back-propagation ANNs were trained and validated using principal components derived from the physicochemical features of the compounds. On selecting the training parameters carefully, an ANN recovers one-third of all active compounds from the validation set with a 3-fold gain in R A/N value. Further gains in RA/N values were obtained upon combining the predictions made by a number of ANNs. The generalization property of the back-propagation ANNs was used to train those ANNs with the same training samples, after being initialized with different sets of random weights. As a result, only 10% of all available compounds were needed for training and validation, and the rest of the data set was screened with more than a 10-fold gain of the original RA/N value. Thus, ANNs trained with limited HTS data might become useful in recovering active compounds from large data sets.

scholarly journals ROS networks: designs, aging, Parkinson’s disease and precision therapies

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Alexey N. Kolodkin ◽  
Raju Prasad Sharma ◽  
Anna Maria Colangelo ◽  
Andrew Ignatenko ◽  
Francesca Martorana ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Data Sets ◽  
Control Coefficient ◽  
Molecular Processes ◽  
Time Control ◽  
Vitro Data ◽  
In Vitro Data

Abstract How the network around ROS protects against oxidative stress and Parkinson’s disease (PD), and how processes at the minutes timescale cause disease and aging after decades, remains enigmatic. Challenging whether the ROS network is as complex as it seems, we built a fairly comprehensive version thereof which we disentangled into a hierarchy of only five simpler subnetworks each delivering one type of robustness. The comprehensive dynamic model described in vitro data sets from two independent laboratories. Notwithstanding its five-fold robustness, it exhibited a relatively sudden breakdown, after some 80 years of virtually steady performance: it predicted aging. PD-related conditions such as lack of DJ-1 protein or increased α-synuclein accelerated the collapse, while antioxidants or caffeine retarded it. Introducing a new concept (aging-time-control coefficient), we found that as many as 25 out of 57 molecular processes controlled aging. We identified new targets for “life-extending interventions”: mitochondrial synthesis, KEAP1 degradation, and p62 metabolism.

scholarly journals Microfluidic Technologies for High Throughput Screening Through Sorting and On-Chip Culture of C. elegans

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4292 ◽  
Author(s):  
Daniel Midkiff ◽  
Adriana San-Miguel
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Model Organism ◽  
Large Data ◽  
Large Data Sets ◽  
Data Sets ◽  
C Elegans ◽  
Drug Candidates ◽  
On Chip ◽  
And Behavior

The nematode Caenorhabditis elegans is a powerful model organism that has been widely used to study molecular biology, cell development, neurobiology, and aging. Despite their use for the past several decades, the conventional techniques for growth, imaging, and behavioral analysis of C. elegans can be cumbersome, and acquiring large data sets in a high-throughput manner can be challenging. Developments in microfluidic “lab-on-a-chip” technologies have improved studies of C. elegans by increasing experimental control and throughput. Microfluidic features such as on-chip control layers, immobilization channels, and chamber arrays have been incorporated to develop increasingly complex platforms that make experimental techniques more powerful. Genetic and chemical screens are performed on C. elegans to determine gene function and phenotypic outcomes of perturbations, to test the effect that chemicals have on health and behavior, and to find drug candidates. In this review, we will discuss microfluidic technologies that have been used to increase the throughput of genetic and chemical screens in C. elegans. We will discuss screens for neurobiology, aging, development, behavior, and many other biological processes. We will also discuss robotic technologies that assist in microfluidic screens, as well as alternate platforms that perform functions similar to microfluidics.

scholarly journals A Computational Analysis in a Cohort of Parkinson’s Disease Patients and Clock-Modified Colorectal Cancer Cells Reveals Common Expression Alterations in Clock-Regulated Genes

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5978
Author(s):  
Müge Yalçin ◽  
Deeksha Malhan ◽  
Alireza Basti ◽  
Ana Rita Peralta ◽  
Joaquim J. Ferreira ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Time Course ◽  
Clock Genes ◽  
Expression Profiles ◽  
Circadian Disruption ◽  
Data Sets ◽  
The Core

Increasing evidence suggests a role for circadian dysregulation in prompting disease-related phenotypes in mammals. Cancer and neurodegenerative disorders are two aging related diseases reported to be associated with circadian disruption. In this study, we investigated a possible effect of circadian disruption in Parkinson’s disease (PD) and colorectal cancer (CRC). We used high-throughput data sets retrieved from whole blood of idiopathic PD (IPD) patients and time course data sets derived from an in vitro model of CRC including the wildtype and three core-clock knockout (KO) cell lines. Several gene expression alterations in IPD patients resembled the expression profiles in the core-clock KO cells. These include expression changes in DBP, GBA, TEF, SNCA, SERPINA1 and TGFB1. Notably, our results pointed to alterations in the core-clock network in IPD patients when compared to healthy controls and revealed variations in the expression profile of PD-associated genes (e.g., HRAS and GBA) upon disruption of the core-clock genes. Our study characterizes changes at the transcriptomic level following circadian clock disruption on common cellular pathways associated with cancer and neurodegeneration (e.g., immune system, energy metabolism and RNA processing), and it points to a significant influence on the overall survival of colon cancer patients for several genes resulting from our analysis (e.g., TUBB6, PAK6, SLC11A1).

scholarly journals Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

2018 ◽  
Vol 115 (41) ◽  
pp. 10481-10486 ◽  
Author(s):  
Jordi Pujols ◽  
Samuel Peña-Díaz ◽  
Diana F. Lázaro ◽  
Francesca Peccati ◽  
Francisca Pinheiro ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Small Molecule ◽  
Dopaminergic Neurons ◽  
High Throughput Screening ◽  
Protein Misfolding ◽  
Lewy Bodies ◽  
Molar Ratio ◽  
Lewy Neurites

Parkinson’s disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of intracellular protein inclusions, known as Lewy bodies and Lewy neurites, which are mainly composed of α-synuclein. Here, we exploited a high-throughput screening methodology to identify a small molecule (SynuClean-D) able to inhibit α-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wild-type α-synuclein and the familiar A30P and H50Q variants in a substoichiometric molar ratio. This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of α-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature α-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity. The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing α-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by α-synuclein. SynuClean-D–treated worms show decreased α-synuclein aggregation in muscle and a concomitant motility recovery. More importantly, this compound is able to rescue dopaminergic neurons from α-synuclein–induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson’s disease.

scholarly journals Therapeutic Effects of TP5, a Cdk5/p25 Inhibitor, in in vitro and in vivo models of Parkinson’s Disease

2021 ◽  
pp. 100006
Author(s):  
Judith Tran ◽  
Shane Taylor ◽  
Anika Gupta ◽  
Niranjana Amin ◽  
Harish Pant ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Therapeutic Effects ◽  
In Vivo Models
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