scholarly journals Human Trisomic iPSCs from Down Syndrome Fibroblasts Manifest Mitochondrial Alterations Early during Neuronal Differentiation

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 609
Author(s):  
Nunzia Mollo ◽  
Matteo Esposito ◽  
Miriam Aurilia ◽  
Roberta Scognamiglio ◽  
Rossella Accarino ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mitochondrial Dysfunction ◽  
Neuronal Differentiation ◽  
Expression Profiles ◽  
Meta Analysis ◽  
Atp Synthesis ◽  
Differentiation Markers ◽  
Differentiation Potential ◽  
Atp Production ◽  
Mitochondrial Alterations

Background: The presence of mitochondrial alterations in Down syndrome suggests that it might affect neuronal differentiation. We established a model of trisomic iPSCs, differentiating into neural precursor cells (NPCs) to monitor the occurrence of differentiation defects and mitochondrial dysfunction. Methods: Isogenic trisomic and euploid iPSCs were differentiated into NPCs in monolayer cultures using the dual-SMAD inhibition protocol. Expression of pluripotency and neural differentiation genes was assessed by qRT-PCR and immunofluorescence. Meta-analysis of expression data was performed on iPSCs. Mitochondrial Ca2+, reactive oxygen species (ROS) and ATP production were investigated using fluorescent probes. Oxygen consumption rate (OCR) was determined by Seahorse Analyzer. Results: NPCs at day 7 of induction uniformly expressed the differentiation markers PAX6, SOX2 and NESTIN but not the stemness marker OCT4. At day 21, trisomic NPCs expressed higher levels of typical glial differentiation genes. Expression profiles indicated that mitochondrial genes were dysregulated in trisomic iPSCs. Trisomic NPCs showed altered mitochondrial Ca2+, reduced OCR and ATP synthesis, and elevated ROS production. Conclusions: Human trisomic iPSCs can be rapidly and efficiently differentiated into NPC monolayers. The trisomic NPCs obtained exhibit greater glial-like differentiation potential than their euploid counterparts and manifest mitochondrial dysfunction as early as day 7 of neuronal differentiation.

Mitochondrial Dysfunction and Oxidative Stress in Bipolar Disorder

2009 ◽  
Vol 24 (S1) ◽  
pp. 1-1 ◽  
Author(s):  
A. Andreazza
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Bipolar Disorder ◽  
Oxidative Damage ◽  
Mitochondrial Dysfunction ◽  
Frontal Cortex ◽  
Meta Analysis ◽  
Therapeutic Interventions ◽  
Atp Production ◽  
And Oxidative Stress

While we continue to refine our understanding of the pathophysiology of bipolar disorder (BD), several hypotheses have been postulated including a role for monoamines, gamma-amino butyric acid, glutamate, and second messenger signaling pathways. Recently, mitochondrial dysfunction and oxidative stress have been identified by a number of studies, as an important etiological factor in this disorder. Mitochondria play a crucial role in ATP production through oxidative phosphorylation, a process carried out by the electron transport chain (ETC) complexes. During the transfer of electrons along this ETC, the ROS can be generated, especially in complex I and III4. Growing body of evidence suggests the association of mitochondrial dysfunction and BD. Recent DNA microarray analysis in post-mortem frontal cortex and hippocampus revealed that the expression of several mRNAs coding for ETC complexes I-V subunits was decreased in subjects with BD. Supporting the key involvement of oxidative damage in BD, assays conducted with peripheral blood samples have demonstrated that BD is associated with alterations in antioxidant enzymes and increased lipid peroxidation. Recently we found that oxidative damage to lipid is present in the frontal cortex of BD subjects. A meta-analysis suggested that the levels of lipid peroxidation are elevated in BD providing support for oxidative stress hypothesis of BD. Furthermore, BD subjects showed increased DNA damage, as well as, upregulation of apoptotic genes. These data not only suggest that oxidative mechanisms may form unifying common pathogenic pathways in psychiatric disorders, but also introduce new targets for the development of therapeutic interventions.

scholarly journals Transcriptomic metaanalyses of autistic brains reveals shared gene expression and biological pathway abnormalities with cancer

2018 ◽  
Author(s):  
Jaume Forés-Martos ◽  
Ferrán Catalá-López ◽  
Jon Sánchez-Valle ◽  
Kristina Ibáñez ◽  
Héctor Tejero ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Expression Profiles ◽  
Meta Analysis ◽  
Gene Expression Profiles ◽  
Atp Synthesis ◽  
Autism Spectrum ◽  
Functional Enrichment ◽  
Biological Processes ◽  
Cancer Types

AbstractEpidemiological and clinical evidence points to cancer as a comorbidity in people with autism spectrum disorders (ASD). A significant overlap of genes and biological processes between both diseases has also been reported. Here, for the first time, we compared the gene expression profiles of ASD frontal cortex tissues and 22 cancer types obtained by differential expression meta-analysis. Four cancer types (brain, thyroid, kidney, and pancreatic cancers) presented a significant overlap in gene expression deregulations in the same direction as ASD whereas two cancer types (lung and prostate cancers) showed differential expression profiles significantly deregulated in the opposite direction from ASD. Functional enrichment and LINCS L1000 based drug set enrichment analyses revealed the implication of several biological processes and pathways that were affected jointly in both diseases, including impairments of the immune system, and impairments in oxidative phosphorylation and ATP synthesis among others. Our data also suggest that brain and kidney cancer have patterns of transcriptomic dysregulation in the PI3K/AKT/MTOR axis that are similar to those found in ASD. These shared transcriptomic alterations could help explain epidemiological observations suggesting direct and inverse comorbid associations between ASD and particular cancer types.

scholarly journals MITOCHONDRIAL DISEASE THERAPY

2021 ◽  
pp. 24-30
Author(s):  
KANIKA KHAJURIA ◽  
VIJAY KHAJURIA ◽  
VINEETA SAWHNEY
Keyword(s):  
Mitochondrial Dysfunction ◽  
Nuclear Dna ◽  
Mitochondrial Diseases ◽  
Atp Synthesis ◽  
Atp Production ◽  
Complex Disorders ◽  
Disease Therapy ◽  
Biogenesis Of Mitochondria ◽  
Beneficial Outcome

Mitochondria perform number of important functions, including synthesis of adenosine triphosphate (ATP) and generation of reactive oxygen species (ROS). Most of the organs depend on ATP to perform. Therefore, in depleted or dysfunctional mitochondrial states, there is less energy production coupled with the accumulation of oxidants. Oxidative stress is involved in the pathophysiology of various disorders especially involving neurons and the cardiovascular system. Mitochondrial diseases are a clinically heterogeneous group of disorders resulting from either inherited or spontaneous mutations in mitochondrial deoxyribonucleic acid (mtDNA) or nuclear DNA. In primary mitochondrial dysfunction disease, the mutation affects the oxidative phosphorylation (OXPHOS) functioning, while secondary mitochondrial dysfunction does not involve OXPHOS genes. Since mutations of genes are involved, therefore, therefore the mitochondrial dysfunctional states are not easy to treat. However, number of strategies that lead to increase ATP production, counter ROS facilitates improvement. The current strategy is to focus on stimulating the biogenesis of mitochondria, antioxidants, and cofactors to enhance ATP synthesis. The role of non-pharmaceuticals cannot be underestimated either. The exercise, diet, and environment influence have well-established beneficial outcome in these disorders. Gene therapy holds promise in the future management of these complex disorders.

The Oral Intake of Organic Germanium, Ge-132, Elevates α-Tocopherol Levels in the Plas-ma and Modulates Hepatic Gene Expression Profiles to Promote Immune Activation in Mice

2014 ◽  
Vol 84 (3-4) ◽  
pp. 0183-0195 ◽  
Author(s):  
Takashi Nakamura ◽  
Tomoya Takeda ◽  
Yoshihiko Tokuji
Keyword(s):  
Gene Expression ◽  
Immune Activation ◽  
Expression Profiles ◽  
Water Soluble ◽  
Alpha Tocopherol ◽  
Hepatic Gene Expression ◽  
Tocopherol Concentration ◽  
Altered Expression ◽  
Atp Production ◽  
Transfer Protein

The common water-soluble organic germanium compound poly-trans-[(2-carboxyethyl) germasesquioxane] (Ge-132) exhibits activities related to immune responses and antioxidant induction. In this study, we evaluated the antioxidative effect of dietary Ge-132 in the plasma of mice. Male ICR mice (seven mice per group) received an AIN-76 diet with 0.05 % Ge-132; three groups received the Ge-132-containing diet for 0, 1 or 4 days. The plasma alpha-tocopherol (α-tocopherol) concentration increased from 6.85 to 9.60 μg/ml after 4 days of Ge-132 intake (p < 0.05). We evaluated the changes in hepatic gene expression related to antioxidative activity as well as in the entire expression profile after one day of Ge-132 intake, using DNA microarray technology. We identified 1,220 genes with altered expression levels greater than 1.5-fold (increased or decreased) as a result of Ge-132 intake, and α-tocopherol transfer protein (Ttpa) gene expression was increased 1.62-fold. Immune activation was identified as the category with the most changes (containing 60 Gene Ontology (GO) term biological processes (BPs), 41 genes) via functional clustering analysis of altered gene expression. Ge-132 affected genes in clusters related to ATP production (22 GO term BPs, 21 genes), lipid metabolism (4 GO term BPs, 38 genes) and apoptosis (5 GO term BPs). Many GO term BPs containing these categories were significantly affected by the Ge-132 intake. Oral Ge-132 intake may therefore have increased plasma α-tocopherol levels by up-regulating α-tocopherol transfer protein (Ttpa) gene expression.

scholarly journals Lateral rectus muscle differentiation potential in paralytic esotropia patients

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qing Xia ◽  
Xiangtian Ling ◽  
Zhonghao Wang ◽  
Tao Shen ◽  
Minghao Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Rectus Muscle ◽  
Lateral Rectus ◽  
Control Group ◽  
Differentiation Potential ◽  
Partial Restoration ◽  
Reverse Transcription Pcr ◽  
Lateral Rectus Muscle

Abstract Purpose and background Recently, we found that maximal medial rectus recession and lateral rectus resection in patients with complete lateral rectus paralysis resulted in a partial restoration of abduction. In an attempt to understand some of the mechanisms involved with this effect we examined gene expression profiles of lateral recti from these patients, with our focus being directed to genes related to myogenesis. Materials and methods Lateral recti resected from patients with complete lateral rectus paralysis and those from concomitant esotropia (controls) were collected. Differences in gene expression profiles between these two groups were examined using microarray analysis and quantitative Reverse-transcription PCR (qRT-PCR). Results A total of 3056 differentially expressed genes (DEGs) were identified between these two groups. Within the paralytic esotropia group, 2081 genes were up-regulated and 975 down-regulated. The results of RT-PCR revealed that PAX7, MYOG, PITX1, SIX1 and SIX4 showed higher levels of expression, while that of MYOD a lower level of expression within the paralytic esotropia group as compared with that in the control group (p < 0.05). Conclusion The decreased expression of MYOD in the paralytic esotropia group suggested that extraocular muscle satellite cell (EOMSCs) differentiation processes were inhibited. Whereas the high expression levels of PAX7, SIX1/4 and MYOG, suggested that the EOMSCs were showing an effective potential for differentiation. The stimulation resulting from muscle surgery may induce EOMSCs to differentiate and thus restore abduction function.

scholarly journals Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells

APOPTOSIS ◽  
2021 ◽  
Author(s):  
Michela Raimondi ◽  
Fabrizio Fontana ◽  
Monica Marzagalli ◽  
Matteo Audano ◽  
Giangiacomo Beretta ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Atp Synthesis ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Ros Generation ◽  
Therapy Outcomes ◽  
Human Melanoma Cells ◽  
Oxphos Complex

Abstract Melanoma is an aggressive tumor with still poor therapy outcomes. δ-tocotrienol (δ-TT) is a vitamin E derivative displaying potent anti-cancer properties. Previously, we demonstrated that δ-TT triggers apoptosis in human melanoma cells. Here, we investigated whether it might also activate paraptosis, a non-canonical programmed cell death. In accordance with the main paraptotic features, δ-TT was shown to promote cytoplasmic vacuolization, associated with endoplasmic reticulum/mitochondrial dilation and protein synthesis, as well as MAPK activation in A375 and BLM cell lines. Moreover, treated cells exhibited a significant reduced expression of OXPHOS complex I and a marked decrease in oxygen consumption and mitochondrial membrane potential, culminating in decreased ATP synthesis and AMPK phosphorylation. This mitochondrial dysfunction resulted in ROS overproduction, found to be responsible for paraptosis induction. Additionally, δ-TT caused Ca2+ homeostasis disruption, with endoplasmic reticulum-derived ions accumulating in mitochondria and activating the paraptotic signaling. Interestingly, by using both IP3R and VDAC inhibitors, a close cause-effect relationship between mitochondrial Ca2+ overload and ROS generation was evidenced. Collectively, these results provide novel insights into δ-TT anti-melanoma activity, highlighting its ability to induce mitochondrial dysfunction-mediated paraptosis. Graphic Abstract δ-tocotrienol induces paraptotic cell death in human melanoma cells, causing endoplasmic reticulum dilation and mitochondrial swelling. These alterations induce an impairment of mitochondrial function, ROS production and calcium overload.

scholarly journals Epilepsy in Mitochondrial Diseases—Current State of Knowledge on Aetiology and Treatment

Children ◽  
2021 ◽  
Vol 8 (7) ◽  
pp. 532
Author(s):  
Dorota Wesół-Kucharska ◽  
Dariusz Rokicki ◽  
Aleksandra Jezela-Stanek
Keyword(s):  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Clinical Picture ◽  
Poor Prognosis ◽  
Treatment Options ◽  
Mitochondrial Diseases ◽  
Energy Deficit ◽  
Atp Production ◽  
Current State

Mitochondrial diseases are a heterogeneous group of diseases resulting from energy deficit and reduced adenosine triphosphate (ATP) production due to impaired oxidative phosphorylation. The manifestation of mitochondrial disease is usually multi-organ. Epilepsy is one of the most common manifestations of diseases resulting from mitochondrial dysfunction, especially in children. The onset of epilepsy is associated with poor prognosis, while its treatment is very challenging, which further adversely affects the course of these disorders. Fortunately, our knowledge of mitochondrial diseases is still growing, which gives hope for patients to improve their condition in the future. The paper presents the pathophysiology, clinical picture and treatment options for epilepsy in patients with mitochondrial disease.

484 Bioturing browser: interactively explore public single cell sequencing data

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A520-A520
Author(s):  
Son Pham ◽  
Tri Le ◽  
Tan Phan ◽  
Minh Pham ◽  
Huy Nguyen ◽  
...  
Keyword(s):  
Single Cell ◽  
Immune Cell ◽  
Expression Profiles ◽  
Meta Analysis ◽  
Cell Types ◽  
Sequencing Data ◽  
Single Cell Sequencing ◽  
Data Formats ◽  
Cancer Types ◽  
Cell Data

BackgroundSingle-cell sequencing technology has opened an unprecedented ability to interrogate cancer. It reveals significant insights into the intratumoral heterogeneity, metastasis, therapeutic resistance, which facilitates target discovery and validation in cancer treatment. With rapid advancements in throughput and strategies, a particular immuno-oncology study can produce multi-omics profiles for several thousands of individual cells. This overflow of single-cell data poses formidable challenges, including standardizing data formats across studies, performing reanalysis for individual datasets and meta-analysis.MethodsN/AResultsWe present BioTuring Browser, an interactive platform for accessing and reanalyzing published single-cell omics data. The platform is currently hosting a curated database of more than 10 million cells from 247 projects, covering more than 120 immune cell types and subtypes, and 15 different cancer types. All data are processed and annotated with standardized labels of cell types, diseases, therapeutic responses, etc. to be instantly accessed and explored in a uniform visualization and analytics interface. Based on this massive curated database, BioTuring Browser supports searching similar expression profiles, querying a target across datasets and automatic cell type annotation. The platform supports single-cell RNA-seq, CITE-seq and TCR-seq data. BioTuring Browser is now available for download at www.bioturing.com.ConclusionsN/A

scholarly journals Stable DNMT3L overexpression in SH-SY5Y neurons recreates a facet of the genome-wide Down syndrome DNA methylation signature

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Benjamin I. Laufer ◽  
J. Antonio Gomez ◽  
Julia M. Jianu ◽  
Janine M. LaSalle
Keyword(s):  
Dna Methylation ◽  
Down Syndrome ◽  
Neuronal Differentiation ◽  
Molecular Mechanisms ◽  
Cpg Island ◽  
Differential Methylation ◽  
Chromosome 21 ◽  
Pairwise Comparisons ◽  
Genome Wide ◽  
A Genome

Abstract Background Down syndrome (DS) is characterized by a genome-wide profile of differential DNA methylation that is skewed towards hypermethylation in most tissues, including brain, and includes pan-tissue differential methylation. The molecular mechanisms involve the overexpression of genes related to DNA methylation on chromosome 21. Here, we stably overexpressed the chromosome 21 gene DNA methyltransferase 3L (DNMT3L) in the human SH-SY5Y neuroblastoma cell line and assayed DNA methylation at over 26 million CpGs by whole genome bisulfite sequencing (WGBS) at three different developmental phases (undifferentiated, differentiating, and differentiated). Results DNMT3L overexpression resulted in global CpG and CpG island hypermethylation as well as thousands of differentially methylated regions (DMRs). The DNMT3L DMRs were skewed towards hypermethylation and mapped to genes involved in neurodevelopment, cellular signaling, and gene regulation. Consensus DNMT3L DMRs showed that cell lines clustered by genotype and then differentiation phase, demonstrating sets of common genes affected across neuronal differentiation. The hypermethylated DNMT3L DMRs from all pairwise comparisons were enriched for regions of bivalent chromatin marked by H3K4me3 as well as differentially methylated sites from previous DS studies of diverse tissues. In contrast, the hypomethylated DNMT3L DMRs from all pairwise comparisons displayed a tissue-specific profile enriched for regions of heterochromatin marked by H3K9me3 during embryonic development. Conclusions Taken together, these results support a mechanism whereby regions of bivalent chromatin that lose H3K4me3 during neuronal differentiation are targeted by excess DNMT3L and become hypermethylated. Overall, these findings demonstrate that DNMT3L overexpression during neurodevelopment recreates a facet of the genome-wide DS DNA methylation signature by targeting known genes and gene clusters that display pan-tissue differential methylation in DS.

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