gene mutation in amyotrophic lateral sclerosis: a new case report and systematic review.

Objective: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with upper and lower motor neuron degeneration and necrosis, characterized by progressive muscle weakness, atrophy, and paralysis. The mutation-associated ALS has been classified as ALS6. We reported a case of ALS6 with de novo mutation and investigated retrospectively the characteristics of cases with mutation.

Identification of Piperlongumine as Potent Inhibitor of Necroptosis.

Purpose: Excessive necroptosis contributes to the pathogenesis of several inflammatory and neurodegenerative diseases. Here, using a high-throughput screening approach, we investigated the anti-necroptosis effects of piperlongumine, an alkaloid isolated from the long pepper plant, in vitro and in a mouse model of systemic inflammatory response syndrome (SIRS).

Methods: A natural compound library was screened for anti-necroptosis effects in cellular.

Caffeine Supplementation and FOXM1 Inhibition Enhance the Antitumor Effect of Statins in Neuroblastoma.

Unlabelled: High-risk neuroblastoma exhibits transcriptional activation of the mevalonate pathway that produces cholesterol and nonsterol isoprenoids. A better understanding of how this metabolic reprogramming contributes to neuroblastoma development could help identify potential prevention and treatment strategies. Here, we report that both the cholesterol and nonsterol geranylgeranyl-pyrophosphate branches of the mevalonate pathway are critical to sustain neuroblastoma cell growth.

Repositioning linifanib as a potent anti-necroptosis agent for sepsis.

Sepsis is a systemic inflammatory syndrome (SIRS) caused by acute microbial infection, and it has an extremely high mortality rate. Tumor necrosis factor-α (TNF-α)-induced necroptosis contributes to the pathophysiology of sepsis, so inhibiting necroptosis might be expected to improve clinical outcomes in septic patients. Here we predicted candidate drugs for treating sepsis in silico by combining genes differentially expressed in septic patients and controls combined with interrogation of the Library of Integrated Network-based Cellular Signatures (LINCS) L1000 perturbation database.

Repurposing crizotinib to target RIPK1-dependent cell death.

Receptor-interacting protein kinase 1 (RIPK1) has emerged as a key regulator of cell death and inflammation, which are implicated in the pathogenesis of many inflammatory and degenerative diseases. RIPK1 is therefore a putative therapeutic target in many of these diseases. However, no pharmacological inhibitor of RIPK1-mediated cell death is currently in clinical use.

OPTN variants in ALS cases: a case report of a novel mutation and literature review.

Introduction: Optineurin (OPTN)-associated mutations have been implicated in the development of type 12 amyotrophic lateral sclerosis (ALS12). We reported a case of ALS with a new OPTN variant (p.D527fs) and reviewed relevant literature to better understand the phenotypes and pathophysiological mechanisms of ALS12.

Cofilin 1 promotes the pathogenicity and transmission of pathological α-synuclein in mouse models of Parkinson's disease.

The pathological hallmark of Parkinson's disease (PD) is the presence of Lewy bodies (LBs) with aggregated α-synuclein being the major component. The abnormal α-synuclein aggregates transfer between cells, recruit endogenous α-synuclein into toxic LBs, and finally trigger neuronal injury. However, the molecular mechanisms mediating the aggregation and transmission of pathological α-synuclein remain unknown.

Becker muscular dystrophy: case report, review of the literature, and analysis of differentially expressed hub genes.

Introduction: Becker muscular dystrophy (BMD) is a genetic and progressive neuromuscular disease caused by mutations in the dystrophin gene with no available cure. A case report and comprehensive review of BMD cases aim to provide important clues for early diagnosis and implications for clinical practice. Genes and pathways identified from microarray data of muscle samples from patients with BMD help uncover the potential mechanism and provide novel therapeutic targets for dystrophin-deficient muscular dystrophies.

Therapeutic targeting of both dihydroorotate dehydrogenase and nucleoside transport in MYCN-amplified neuroblastoma.

Metabolic reprogramming is an integral part of the growth-promoting program driven by the MYC family of oncogenes. However, this reprogramming also imposes metabolic dependencies that could be exploited therapeutically. Here we report that the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is an attractive therapeutic target for MYCN-amplified neuroblastoma, a childhood cancer with poor prognosis.

Cofilin 1 promotes the aggregation and cell-to-cell transmission of α-synuclein in Parkinson's disease.

The histopathological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates referred to as Lewy bodies (LBs), in which α-synuclein is the major component. Converging evidence supports the prion-like transmission of α-synuclein aggregates in the onset and progression of PD. Intracellular α-synuclein aggregates into pathological fibrils, which can be transferred from aggregate-producing cells to aggregate-free cells, triggering neuronal injury and the progression of pathology.

Prediction of drug response in multilayer networks based on fusion of multiomics data.

Predicting the response of each individual patient to a drug is a key issue assailing personalized medicine. Our study predicted drug response based on the fusion of multiomics data with low-dimensional feature vector representation on a multilayer network model. We named this new method DREMO (Drug Response prEdiction based on MultiOmics data fusion).

Glycine decarboxylase is a transcriptional target of MYCN required for neuroblastoma cell proliferation and tumorigenicity.

Genomic amplification of the oncogene MYCN is a major driver in the development of high-risk neuroblastoma, a pediatric cancer with poor prognosis. Given the challenge in targeting MYCN directly for therapy, we sought to identify MYCN-dependent metabolic vulnerabilities that can be targeted therapeutically. Here, we report that the gene encoding glycine decarboxylase (GLDC), which catalyzes the first and rate-limiting step in glycine breakdown with the production of the one-carbon unit 5,10-methylene-tetrahydrofolate, is a direct transcriptional target of MYCN.

Metabolic Reprogramming by MYCN Confers Dependence on the Serine-Glycine-One-Carbon Biosynthetic Pathway.

amplification drives the development of neuronal cancers in children and adults. Given the challenge in therapeutically targeting MYCN directly, we searched for MYCN-activated metabolic pathways as potential drug targets. Here we report that neuroblastoma cells with amplification show increased transcriptional activation of the serine-glycine-one-carbon (SGOC) biosynthetic pathway and an increased dependence on this pathway for supplying glucose-derived carbon for serine and glycine synthesis.

Conserved Disease Modules Extracted From Multilayer Heterogeneous Disease and Gene Networks for Understanding Disease Mechanisms and Predicting Disease Treatments.

Disease relationship studies for understanding the pathogenesis of complex diseases, diagnosis, prognosis, and drug development are important. Traditional approaches consider one type of disease data or aggregating multiple types of disease data into a single network, which results in important temporal- or context-related information loss and may distort the actual organization. Therefore, it is necessary to apply multilayer network model to consider multiple types of relationships between diseases and the important interplays between different relationships.

Histone demethylase KDM6B has an anti-tumorigenic function in neuroblastoma by promoting differentiation.

Induction of differentiation is a therapeutic strategy in high-risk neuroblastoma, a childhood cancer of the sympathetic nervous system. Neuroblastoma differentiation requires transcriptional upregulation of neuronal genes. How this process is regulated at epigenetic levels is not well understood.

Clonidine preconditioning improved cerebral ischemia-induced learning and memory deficits in rats via ERK1/2-CREB/ NF-κB-NR2B pathway.

Clonidine, a classical α-2 adrenergic agonists, has been shown to antagonize brain damage caused by hypoxia, cerebral ischemia and excitotoxicity and reduce cerebral infarction volume in recent studies. We herein investigate the regulatory effect and possible underlying mechanism of clonidine on learning and memory in rats with cerebral ischemia. The cerebral ischemia rat model was established by right middle cerebral artery occlusion for 2h and reperfusion for 28 days.

Clonidine preconditioning alleviated focal cerebral ischemic insult in rats via up-regulating p-NMDAR1 and down-regulating NMDAR2A / p-NMDAR2B.

A brain ischemia rat model was established by middle cerebral artery occlusion (MCAO) for 2h and reperfusion for 4h to investigate the underlying mechanism of the neuroprotection action of clonidine, a classical alpha-2 adrenergic agonist, on cerebral ischemia. Clonidine and yohimbine were intraperitoneally given to the rats each day for a week before ischemia. Neurological deficits evaluations were carried out at 6h after operation.

The prognostic value of MGMT promoter status by pyrosequencing assay for glioblastoma patients' survival: a meta-analysis.

Background: The prognostic value of the status of O-methylguanine-DNA methyltransferase (MGMT) promoter methylation measured by pyrosequencing assay (PSQ) among glioblastoma (GBM) patients was examined in meta-analysis.

Methods: Eligible studies that reported the association between the status of MGMT promoter methylation by PSQ and prognostic value of GBM patients from three electronic databases, like PubMed, EMBASE, and Cochrane library were involved in meta-analysis. Using Stata 11.

Transcriptional Profiling Reveals a Common Metabolic Program in High-Risk Human Neuroblastoma and Mouse Neuroblastoma Sphere-Forming Cells.

High-risk neuroblastoma remains one of the deadliest childhood cancers. Identification of metabolic pathways that drive or maintain high-risk neuroblastoma may open new avenues of therapeutic interventions. Here, we report the isolation and propagation of neuroblastoma sphere-forming cells with self-renewal and differentiation potential from tumors of the TH-MYCN mouse, an animal model of high-risk neuroblastoma with MYCN amplification.

KDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism.

The histone lysine demethylase KDM4C is often overexpressed in cancers primarily through gene amplification. The molecular mechanisms of KDM4C action in tumorigenesis are not well defined. Here, we report that KDM4C transcriptionally activates amino acid biosynthesis and transport, leading to a significant increase in intracellular amino acid levels.

Dopamine inhibits excitatory neurotransmission in basolateral amygdala during development via pre-synaptic mechanism.

Objectives: Dopaminergic signaling in the basolateral amygdala (BLA) is important for emotion-related activity. However, little is known about the influence of dopamine (DA) on excitatory synaptic transmission of pyramidal neurons in BLA at early developmental stage. Here in this study, we observed the effect of DA on excitatory neurotransmission in the pyramidal cells of BLA in acute slices.