scholarly journals A Multiparametric Activity Profiling Platform for Neuron Disease Phenotyping and Drug Screening

2021 ◽  
Author(s):  
Bruno Boivin ◽  
Kasper C.D. Roet ◽  
Xuan Huang ◽  
Kyle W. Karhohs ◽  
Mohammad H. Rohban ◽  
...  
Keyword(s):  
Image Processing ◽  
Complex Disease ◽  
Therapeutic Potential ◽  
Cellular Activity ◽  
Pathological Features ◽  
Disease Phenotype ◽  
Activity Profile ◽  
Disease Phenotypes ◽  
Analysis Platform ◽  
Lateral Sclerosis

Patient stem cell-derived models enable imaging of complex disease phenotypes and the development of scalable drug discovery platforms. Current preclinical methods for assessing cellular activity do not, however, capture the full intricacies of disease-induced disturbances, and instead typically focus on a single parameter, which impairs both the understanding of disease and the discovery of effective therapeutics. Here, we describe a cloud-based image processing and analysis platform that captures the intricate activity profile revealed by GCaMP fluorescent recordings of intracellular calcium changes and enables the discovery of molecules that correct 153 parameters that define the amyotrophic lateral sclerosis motor neuron disease phenotype. In a high-throughput screen, we identified compounds that revert the multiparametric disease profile to that found in healthy cells, a novel and robust measure of therapeutic potential quite distinct from unidimensional screening. This platform can guide the development of therapeutics that counteract the multifaceted pathological features of diseased cellular activity.

scholarly journals A Multiparametric Activity Profiling Platform for Neuron Disease Phenotyping and Drug Screening

2021 ◽  
Author(s):  
Bruno Boivin ◽  
Kasper C.D. Roet ◽  
Xuan Huang ◽  
Kyle W. Karhohs ◽  
Mohammad H. Rohban ◽  
...  
Keyword(s):  
Image Processing ◽  
Complex Disease ◽  
Therapeutic Potential ◽  
Cellular Activity ◽  
Pathological Features ◽  
Disease Phenotype ◽  
Activity Profile ◽  
Disease Phenotypes ◽  
Analysis Platform ◽  
Lateral Sclerosis

Patient stem cell-derived models enable imaging of complex disease phenotypes and the development of scalable drug discovery platforms. Current preclinical methods for assessing cellular activity do not, however, capture the full intricacies of disease-induced disturbances, and instead typically focus on a single parameter, which impairs both the understanding of disease and the discovery of effective therapeutics. Here, we describe a cloud-based image processing and analysis platform that captures the intricate activity profile revealed by GCaMP fluorescent recordings of intracellular calcium changes and enables discovery of molecules that correct 153 parameters that define the amyotrophic lateral sclerosis motor neuron disease phenotype. In a high-throughput screen we identified compounds that revert the multiparametric disease profile to that found in healthy cells, a novel and robust measure of therapeutic potential quite distinct from unidimensional screening. This platform can guide the development of therapeutics that counteract the multifaceted pathological features of diseased cellular activity.

Structurally Related Edaravone Analogues: Synthesis, Antiradical, Antioxidant, and Copper-Chelating Properties

2020 ◽  
Vol 18 (10) ◽  
pp. 779-790 ◽  
Author(s):  
Alexandre LeBlanc ◽  
Miroslava Cuperlovic-Culf ◽  
Pier Jr. Morin ◽  
Mohamed Touaibia
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Therapeutic Potential ◽  
Antioxidant Properties ◽  
Radical Scavenging ◽  
Therapeutic Options ◽  
Partial Charge ◽  
Associated Diseases ◽  
Significant Interest ◽  
Lateral Sclerosis

Background:: The current therapeutic options available to patients diagnosed with Amyotrophic Lateral Sclerosis (ALS) are limited and edaravone is a compound that has gained significant interest for its therapeutic potential in this condition. Objectives: : The current work was thus undertaken to synthesize and characterize a series of edaravone analogues. Methods: A total of 17 analogues were synthesized and characterized for their antioxidant properties, radical scavenging potential and copper-chelating capabilities. Results: Radical scavenging and copper-chelating properties were notably observed for edaravone. Analogues bearing hydrogen in position 1 and a phenyl at position 3 and a phenyl in both positions of pyrazol-5 (4H)-one displayed substantial radical scavenging, antioxidants and copper-chelating properties. High accessibility of electronegative groups combined with higher electronegativity and partial charge of the carbonyl moiety in edaravone might explain the observed difference in the activity of edaravone relative to the closely related analogues 6 and 7 bearing hydrogen at position 1 and a phenyl at position 3 (6) and a phenyl in both positions (7). Conclusion: Overall, this study reveals a subset of edaravone analogues with interesting properties. Further investigation of these compounds is foreseen in relevant models of oxidative stress-associated diseases in order to assess their therapeutic potential in such conditions.

The role of microRNAs in gliomas – Therapeutic implications

2020 ◽  
Vol 13 ◽  
Author(s):  
Theodora Katsila ◽  
Dimitrios Kardamakis
Keyword(s):  
Complex Disease ◽  
Malignant Gliomas ◽  
Kappa Statistic ◽  
Individual Variability ◽  
Response To Treatment ◽  
Disease Phenotype ◽  
Therapeutic Implications ◽  
Non Invasive ◽  
Gene Environment ◽  
Sas Macro

Background: Malignant gliomas constitute a complex disease phenotype that demands optimum decisionmaking. Despite being the most common type of primary brain tumors, gliomas are highly heterogeneous when their pathophysiology and response to treatment are considered. Such inter-individual variability also renders differential and early diagnosis extremely difficult. Recent evidence highlight that the gene-environment interplay becomes of fundamental importance in oncogenesis and progression of gliomas. Objective: To unmask key features of the gliomas disease phenotype and map the inter-individual variability of patients, we explore genotype-to-phenotype associations. Emphasis is put on microRNAs as they regulate gene expression, have been implicated in the pathogenesis of gliomas and may serve as theranostics, empowering non-invasive strategies (circulating free or in exosomes). Method: We mined text and omic datasets (as of 2019) and conducted a mixed-method content analysis. A novel framework was developed to meet the aims of our analysis, interrogating data in terms of content and context. We relied on literature data from PubMed/Medline and Scopus, as they are considered the largest abstract and citation databases of peer-reviewed literature. To avoid selection biases, both publicly available and private texts have been assessed. Both percent agreement and Cohen's kappa statistic have been calculated to avoid biases by SAS macro MAGREE with multicategorical ratings. Results: Gliomas serve as a paradigm for multifaceted datasets, despite data sparsity and scarcity. miRNAs and miRNAbased therapeutics are ready for prime time. Exosomal miRNAs empower non-invasive strategies, surpassing circulating free miRNAs, when accuracy and precision are considered. Conclusion: miRNAs holds promise as theranostics.

scholarly journals Management of Cardiorenal Metabolic Syndrome in Diabetes Mellitus: A Phytotherapeutic Perspective

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Min Kyong Song ◽  
Neal M. Davies ◽  
Basil D. Roufogalis ◽  
Tom Hsun-Wei Huang
Keyword(s):  
Complex Disease ◽  
Therapeutic Potential ◽  
Cardiorenal Syndrome ◽  
Current Therapy ◽  
Novel Therapies ◽  
Development Of Resistance ◽  
Feedback Cycle ◽  
Large Numbers ◽  
Traditional Natural ◽  
Natural Medicines

Cardiorenal syndrome (CRS) is a complex disease in which the heart and kidney are simultaneously affected and their deleterious declining functions are reinforced in a feedback cycle, with an accelerated progression. Although the coexistence of kidney and heart failure in the same individual carries an extremely bad prognosis, the exact cause of deterioration and the pathophysiological mechanisms underlying the initiation and maintenance of the interaction are complex, multifactorial in nature, and poorly understood. Current therapy includes diuretics, natriuretic hormones, aquaretics (arginine vasopressin antagonists), vasodilators, and inotropes. However, large numbers of patients still develop intractable disease. Moreover, the development of resistance to many standard therapies, such as diuretics and inotropes, has led to an increasing movement toward utilization and development of novel therapies. Herbal and traditional natural medicines may complement or provide an alternative to prevent or delay the progression of CRS. This review provides an analysis of the possible mechanisms and the therapeutic potential of phytotherapeutic medicines for the amelioration of the progression of CRS.

scholarly journals Amplifying the heat shock response ameliorates pathology in mouse and human models of ALS and FTD.

2021 ◽  
Author(s):  
Mhoriam Ahmed ◽  
Charlotte Spicer ◽  
Jasmine Harley ◽  
Nikolaj Petersen ◽  
Paul Taylor ◽  
...  
Keyword(s):  
Heat Shock ◽  
Motor Neurons ◽  
Heat Shock Response ◽  
Therapeutic Potential ◽  
Experimental Models ◽  
Pathological Changes ◽  
Beneficial Effects ◽  
Disease Spectrum ◽  
Shock Response ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are now widely considered to be part of a disease spectrum with the identification of common pathological features and genetic causes. However, despite these advances, there remains no effective therapy for these conditions. In this study we demonstrate that mice expressing mutant valosin containing protein (VCP) develop an ALS/FTD-like phenotype in the spinal cord and brain, and treatment with arimoclomol, a pharmacological amplifier of the cytoprotective heat shock response ameliorates this phenotype. Moreover, the beneficial effects of arimoclomol are seen in both fibroblasts and iPSC-derived motor neurons from patients. Importantly, we show the pathological changes targeted by arimoclomol in our experimental models are present in post-mortem FTD patient tissue. Together with previous data demonstrating the efficacy of arimoclomol in SOD1-ALS models, our findings suggest that arimoclomol may have therapeutic potential not only in non-SOD1 ALS but also for the treatment of FTD.

scholarly journals Genomic Portrait of a Sporadic Amyotrophic Lateral Sclerosis Case in a Large Spinocerebellar Ataxia Type 1 Family

2020 ◽  
Vol 10 (4) ◽  
pp. 262
Author(s):  
Giovanna Morello ◽  
Giulia Gentile ◽  
Rossella Spataro ◽  
Antonio Gianmaria Spampinato ◽  
Maria Guarnaccia ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Spinocerebellar Ataxia ◽  
Complex Disease ◽  
Spinocerebellar Ataxia Type ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Spinocerebellar Ataxia Type 1 ◽  
Pathogenic Variants ◽  
Lateral Sclerosis

Background: Repeat expansions in the spinocerebellar ataxia type 1 (SCA1) gene ATXN1 increases the risk for amyotrophic lateral sclerosis (ALS), supporting a relationship between these disorders. We recently reported the co-existence, in a large SCA1 family, of a clinically definite ALS individual bearing an intermediate ATXN1 expansion and SCA1 patients with a full expansion, some of which manifested signs of lower motor neuron involvement. Methods: In this study, we employed a systems biology approach that integrated multiple genomic analyses of the ALS patient and some SCA1 family members. Results: Our analysis identified common and distinctive candidate genes/variants and related biological processes that, in addition to or in combination with ATXN1, may contribute to motor neuron degeneration phenotype. Among these, we distinguished ALS-specific likely pathogenic variants in TAF15 and C9ORF72, two ALS-linked genes involved in the regulation of RNA metabolism, similarly to ATXN1, suggesting a selective role for this pathway in ALS pathogenesis. Conclusions: Overall, our work supports the utility to apply personal genomic information for characterizing complex disease phenotypes.

scholarly journals Anthocyanins and Their Metabolites as Therapeutic Agents for Neurodegenerative Disease

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 333 ◽  
Author(s):  
Aimee N. Winter ◽  
Paula C. Bickford
Keyword(s):  
Neurodegenerative Diseases ◽  
Nitrosative Stress ◽  
Therapeutic Potential ◽  
Stress Protein ◽  
Motor Impairments ◽  
Oxidative And Nitrosative Stress ◽  
Beneficial Effects ◽  
Neuronal Populations ◽  
Neurodegenerative Process ◽  
Lateral Sclerosis

Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), are characterized by the death of neurons within specific regions of the brain or spinal cord. While the etiology of many neurodegenerative diseases remains elusive, several factors are thought to contribute to the neurodegenerative process, such as oxidative and nitrosative stress, excitotoxicity, endoplasmic reticulum stress, protein aggregation, and neuroinflammation. These processes culminate in the death of vulnerable neuronal populations, which manifests symptomatically as cognitive and/or motor impairments. Until recently, most treatments for these disorders have targeted single aspects of disease pathology; however, this strategy has proved largely ineffective, and focus has now turned towards therapeutics which target multiple aspects underlying neurodegeneration. Anthocyanins are unique flavonoid compounds that have been shown to modulate several of the factors contributing to neuronal death, and interest in their use as therapeutics for neurodegeneration has grown in recent years. Additionally, due to observations that the bioavailability of anthocyanins is low relative to that of their metabolites, it has been proposed that anthocyanin metabolites may play a significant part in mediating the beneficial effects of an anthocyanin-rich diet. Thus, in this review, we will explore the evidence evaluating the neuroprotective and therapeutic potential of anthocyanins and their common metabolites for treating neurodegenerative diseases.

scholarly journals Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p

2012 ◽  
Vol 123 (3) ◽  
pp. 409-417 ◽  
Author(s):  
Heather Stewart ◽  
Nicola J. Rutherford ◽  
Hannah Briemberg ◽  
Charles Krieger ◽  
Neil Cashman ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Pathological Features ◽  
C9orf72 Gene ◽  
Chromosome 9P ◽  
Lateral Sclerosis ◽  
Clinical And Pathological Features

scholarly journals Visualizing Cell Death in Experimental Focal Cerebral Ischemia: Promises, Problems, and Perspectives

2011 ◽  
Vol 32 (2) ◽  
pp. 213-231 ◽  
Author(s):  
Marietta Zille ◽  
Tracy D Farr ◽  
Ingo Przesdzing ◽  
Jochen Müller ◽  
Clemens Sommer ◽  
...  
Keyword(s):  
Cell Death ◽  
Complex Disease ◽  
Focal Cerebral Ischemia ◽  
Cell Damage ◽  
Brain Cells ◽  
Pathological Features ◽  
Advantages And Disadvantages ◽  
Different Types ◽  
Immunohistochemical Techniques ◽  
Eventual Death

One of the hallmarks of stroke pathophysiology is the widespread death of many different types of brain cells. As our understanding of the complex disease that is stroke has grown, it is now generally accepted that various different mechanisms can result in cell damage and eventual death. A plethora of techniques is available to identify various pathological features of cell death in stroke; each has its own drawbacks and pitfalls, and most are unable to distinguish between different types of cell death, which partially explains the widespread misuse of many terms. The purpose of this review is to summarize the standard histopathological and immunohistochemical techniques used to identify various pathological features of stroke. We then discuss how these methods should be properly interpreted on the basis of what they are showing, as well as advantages and disadvantages that require consideration. As there is much interest in the visualization of stroke using noninvasive imaging strategies, we also specifically discuss how these techniques can be interpreted within the context of cell death.

Sign in / Sign up

Export Citation Format

Share Document