Sphingolipid Metabolism: A New Therapeutic Opportunity for Brain Degenerative Disorders

Pardo, Alba Di; Maglione, Vittorio

doi:10.3389/fnins.2018.00249

Cited by 64 publications

(44 citation statements)

References 105 publications

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“…Neuroactive ligand-receptor interactions might play a critical role in the pathogenesis of pituitary gonadotroph adenomas [58]. The modulation of the sphingolipid metabolism and the related signaling pathways might represent a potential therapeutic approach for devastating conditions [59]. In addition, for many years, methylation was believed to play a crucial role in repressing gene expression; therefore, we further analyzed the DEG methylation in LIHC.…”

Section: Discussionmentioning

confidence: 99%

Identification of Diagnostic Biomarkers and Subtypes of Liver Hepatocellular Carcinoma by Multi-Omics Data Analysis

Ouyang

Fan

Ling

et al. 2020

Genes

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As liver hepatocellular carcinoma (LIHC) has high morbidity and mortality rates, improving the clinical diagnosis and treatment of LIHC is an important issue. The advent of the era of precision medicine provides us with new opportunities to cure cancers, including the accumulation of multi-omics data of cancers. Here, we proposed an integration method that involved the Fisher ratio, Spearman correlation coefficient, classified information index, and an ensemble of decision trees (DTs) for biomarker identification based on an unbalanced dataset of LIHC. Then, we obtained 34 differentially expressed genes (DEGs). The ability of the 34 DEGs to discriminate tumor samples from normal samples was evaluated by classification, and a high area under the curve (AUC) was achieved in our studied dataset and in two external validation datasets (AUC = 0.997, 0.973, and 0.949, respectively). Additionally, we also found three subtypes of LIHC, and revealed different biological mechanisms behind the three subtypes. Mutation enrichment analysis showed that subtype 3 had many enriched mutations, including tumor protein p53 (TP53) mutations. Overall, our study suggested that the 34 DEGs could serve as diagnostic biomarkers, and the three subtypes could help with precise treatment for LIHC.

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Section: Discussionmentioning

confidence: 99%

Identification of Diagnostic Biomarkers and Subtypes of Liver Hepatocellular Carcinoma by Multi-Omics Data Analysis

Ouyang

Fan

Ling

et al. 2020

Genes

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“…Ceramide is synthesized de novo in the endoplasmic reticulum or through breakdown of sphingomyelin in Golgi, plasma membrane, or mitochondrial membrane [ 39 ]. Defects in ceramide signaling pathways often result in augmenting programmed cell death in multiple cell types, including neurons [ 40 ]. Previous studies show that ceramide levels are increased in CLN3-deficient cells and brain of CLN3 patients [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Exogenous Flupirtine as Potential Treatment for CLN3 Disease

Maalouf

Makoukji

Saab

et al. 2020

Cells

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CLN3 disease is a fatal neurodegenerative disorder affecting children. Hallmarks include brain atrophy, accelerated neuronal apoptosis, and ceramide elevation. Treatment regimens are supportive, highlighting the importance of novel, disease-modifying drugs. Flupirtine and its new allyl carbamate derivative (compound 6) confer neuroprotective effects in CLN3-deficient cells. This study lays the groundwork for investigating beneficial effects in Cln3Δex7/8 mice. WT/Cln3Δex7/8 mice received flupirtine/compound 6/vehicle for 14 weeks. Short-term effect of flupirtine or compound 6 was tested using a battery of behavioral testing. For flupirtine, gene expression profiles, astrogliosis, and neuronal cell counts were determined. Flupirtine improved neurobehavioral parameters in open field, pole climbing, and Morris water maze tests in Cln3Δex7/8 mice. Several anti-apoptotic markers and ceramide synthesis/degradation enzymes expression was dysregulated in Cln3Δex7/8 mice. Flupirtine reduced astrogliosis in hippocampus and motor cortex of male and female Cln3Δex7/8 mice. Flupirtine increased neuronal cell counts in male mice. The newly synthesized compound 6 showed promising results in open field and pole climbing. In conclusion, flupirtine improved behavioral, neuropathological and biochemical parameters in Cln3Δex7/8 mice, paving the way for potential therapies for CLN3 disease.

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“…Administration of an S1PR selective agonist reduces spatial memory impairments and attenuates the Aβ1-induced neuronal loss in a rat model of Alzheimer's disease (45). S1P receptors stimulate the production of neurotrophin, activate neuronal pro-survival pathways, and delay disease progression in mouse models of Huntington disease (46). Hence, the manipulation of sphingolipid metabolism may represent a great way to develop more effective and targeted therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

Spatio-Temporal Correlates of Gene Expression and Cortical Morphology across Life Course and Aging

Qiu

Zhang

Kennedy

et al. 2020

Preprint

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Evidence from independent neuroimaging and genetic studies supports the concept that brain aging mirrors development. However, it is unclear whether mechanisms linking brain development and aging provide new insights to delay aging and potentially reverse it. This study determined biological mechanisms and phenotypic traits underpinning brain alterations across the life course and in aging by examining spatio-temporal correlations between gene expression and cortical volumes (n=3391) derived from the life course dataset (3-82 years) and the aging dataset (55-82 years). We revealed that a large proportion of genes whose expression was associated with cortical volume across the life course were in astrocytes. These genes, which showed up-regulation during development and down-regulation during aging, contributed to fundamental homeostatic functions of astrocytes crucial, in turn, for neuronal functions. Included among these genes were those encoding components of cAMP and Ras signal pathways, as well as retrograde endocannabinoid signaling. Genes associated with cortical volumes in the aging dataset were also enriched for the sphingolipid signaling pathway, renin-angiotensin system (RAS), proteasome, and TGF-beta signaling pathway, which is linked to the senescence-associated secretory phenotype. Neuroticism, drinking, and smoking were the common phenotypic traits in the life course and aging, while memory was the unique phenotype associated with aging. These findings provide biological mechanisms and phenotypic traits mirroring development and aging as well as unique to aging.

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Sphingolipid Metabolism: A New Therapeutic Opportunity for Brain Degenerative Disorders

Cited by 64 publications

References 105 publications

Identification of Diagnostic Biomarkers and Subtypes of Liver Hepatocellular Carcinoma by Multi-Omics Data Analysis

Identification of Diagnostic Biomarkers and Subtypes of Liver Hepatocellular Carcinoma by Multi-Omics Data Analysis

Exogenous Flupirtine as Potential Treatment for CLN3 Disease

Spatio-Temporal Correlates of Gene Expression and Cortical Morphology across Life Course and Aging

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