Biomarkers of Alzheimer's Disease Associated with Programmed Cell Death Reveal Four Repurposed Drugs.

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. Programmed cell death (PCD) is mainly characterized by unique morphological features and energy-dependent biochemical processes. The predominant pathway leading to cell death in AD has not been thoroughly analyzed, although there is evidence of neuron loss in AD and numerous pathways of PCD have been associated with this process. A better understanding of the systems biology underlying the relationship between AD and PCD could lead to the development of new therapeutic approaches. To this end, publicly available transcriptome data were examined using bioinformatic methods such as differential gene expression and weighted gene coexpression network analysis (WGCNA) to find PCD-related AD biomarkers. The diagnostic significance of these biomarkers was evaluated using a logistic regression-based predictive model. Using these biomarkers, a multifactorial regulatory network was developed. Last, a drug repositioning study was conducted to propose new drugs for the treatment of AD targeting PCD. The development of 3PM (predictive, preventive, and personalized) drugs for the treatment of AD would be enabled by additional research on the effects of these drugs on this disease.

Computational drug repurposing for primary hyperparathyroidism.

In hyperparathyroidism (hyperPTH), excessive amounts of PTH are secreted, interfering with calcium regulation in the body. Several drugs can control the disease's side effects, but none of them is an alternative treatment to surgery. Therefore, new drug candidates are necessary. In this study, three computationally repositioned drugs, DG 041, IMD 0354, and cucurbitacin I, are evaluated in an in vitro model of hyperPTH. First, we integrated publicly available transcriptomics datasets to propose drug candidates. Using 3D spheroids derived from a single primary hyperPTH patient, we assessed their in vitro efficacy. None of the proposed drugs affected the viability of healthy cell control (HEK293) or overactive parathyroid cells at the level of toxicity. This behavior was attributed to the non-cancerous nature of the parathyroid cells, establishing the hyperPTH disease model. Cucurbitacin I and IMD 0354 exhibited a slight inverse relationship between increased drug concentrations and cell viability, whereas DG 041 increased viability. Based on these results, further studies are needed on the mechanism of action of the repurposed drugs, including determining the effects of these drugs on cellular PTH synthesis and secretion and on the metabolic pathways that regulate PTH secretion.

BMP4, SGSH, and SLC11A2 are Predicted to Be Biomarkers of Aging Associated with Programmed Cell Death.

Most neurodegenerative diseases are exacerbated by aging, with symptoms often worsening over time. Programmed cell death (PCD) is a controlled cell suicide mechanism that is essential for the stability, growth, and homeostasis of organisms. Understanding the effects of aging at the level of systems biology could lead to new therapeutic approaches for a broad spectrum of neurodegenerative diseases. In the absence of comprehensive functional studies on the relationship between PCD and aging of the prefrontal cortex, this study provides prefrontal brain biomarkers of aging associated with PCD that could open the way for improved therapeutic techniques for age-related neurodegenerative diseases. To this end, publicly available transcriptome data were subjected to bioinformatic analyses such as differential gene expression, functional enrichment, and the weighted gene coexpression network analysis (WGCNA). The diagnostic utility of the biomarkers was tested using a logistic regression-based prediction model. Three genes, namely BMP4, SGSH, and SLC11A2, were found to be aging biomarkers associated with PCD. Finally, a multifactorial regulatory network with interacting proteins, transcription factors (TFs), competing endogenous RNAs (ceRNAs), and microRNAs (miRNAs) was constructed around these biomarkers. The elements of this multifactorial regulatory network were mainly enriched in BMP signaling. Further exploration of these three biomarkers and their regulatory elements would enable the development of 3PM (predictive, preventive, and personalized) medicine for the treatment of age-related neurodegenerative diseases.

Three candidate anticancer drugs were repositioned by integrative analysis of the transcriptomes of species with different regenerative abilities after injury.

Regeneration is a homeostatic process that involves the restoration of cells and body parts. Most of the molecular mechanisms and signalling pathways involved in wound healing, such as proliferation, have also been associated with cancer cell growth, suggesting that cancer is an over/unhealed wound. In this study, we examined differentially expressed genes in spinal cord samples from regenerative organisms (axolotl and zebrafish) and nonregenerative organisms (mouse and rat) compared to intact control spinal cord samples using publicly available transcriptomics data and bioinformatics analyses. Based on these gene signatures, we investigated 3 small compounds, namely cucurbitacin I, BMS-754807, and PHA-793887 as potential candidates for the treatment of cancer. The predicted target genes of the repositioned compounds were mainly enriched with the greatest number of genes in cancer pathways. The molecular docking results on the binding affinity between the repositioned compounds and their target genes are also reported. The repositioned 3 small compounds showed anticancer effect both in 2D and 3D cell cultures using the prostate cancer cell line as a model. We propose cucurbitacin I, BMS-754807, and PHA-793887 as potential anticancer drug candidates. Future studies on the mechanisms associated with the revealed gene signatures and anticancer effects of these three small compunds would allow scientists to develop therapeutic approaches to combat cancer. This research contributes to the evaluation of mechanisms and gene signatures that either limit or cause cancer, and to the development of new cancer therapies by establishing a link between regeneration and carcinogenesis.

Integrative Analysis of Motor Neuron and Microglial Transcriptomes from SOD1G93A Mice Models Uncover Potential Drug Treatments for ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neurons that mainly affects the motor cortex, brainstem, and spinal cord. Under disease conditions, microglia could possess two distinct profiles, M1 (toxic) and M2 (protective), with the M2 profile observed at disease onset. SOD1 (superoxide dismutase 1) gene mutations account for up to 20% of familial ALS cases. Comparative gene expression differences in M2-protective (early) stage SOD1G93A microglia and age-matched SOD1G93A motor neurons are poorly understood. We evaluated the differential gene expression profiles in SOD1G93A microglia and SOD1G93A motor neurons utilizing publicly available transcriptomics data and bioinformatics analyses, constructed biomolecular networks around them, and identified gene clusters as potential drug targets. Following a drug repositioning strategy, 5 small compounds (belinostat, auranofin, BRD-K78930611, AZD-8055, and COT-10b) were repositioned as potential ALS therapeutic candidates that mimic the protective state of microglia and reverse the toxic state of motor neurons. We anticipate that this study will provide new insights into the ALS pathophysiology linking the M2 state of microglia and drug repositioning.

Mutant SOD1 protein increases Nav1.3 channel excitability.

Amyotrophic lateral sclerosis (ALS) is a lethal paralytic disease caused by the degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Mutations in the gene encoding copper/zinc superoxide dismutase (SOD1) are present in ~20% of familial ALS and ~2% of all ALS cases. The most common SOD1 gene mutation in North America is a missense mutation substituting valine for alanine (A4V). In this study, we analyze sodium channel currents in oocytes expressing either wild-type or mutant (A4V) SOD1 protein. We demonstrate that the A4V mutation confers a propensity to hyperexcitability on a voltage-dependent sodium channel (Nav1.3) mediated by heightened total Na(+) conductance and a hyperpolarizing shift in the voltage dependence of Nav1.3 activation. To estimate the impact of these channel effects on excitability in an intact neuron, we simulated these changes in the program NEURON; this shows that the changes induced by mutant SOD1 increase the spontaneous firing frequency of the simulated neuron. These findings are consistent with the view that excessive excitability of neurons is one component in the pathogenesis of this disease.