scholarly journals Placental Mitochondrial Abnormalities in Preeclampsia

2021 ◽  
Author(s):  
Philippe Vangrieken ◽  
Salwan Al-Nasiry ◽  
Aalt Bast ◽  
Pieter A. Leermakers ◽  
Christy B. M. Tulen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Biogenesis ◽  
Expression Profiles ◽  
Mitochondrial Fission ◽  
Gene Expression Profiles ◽  
Molecular Pathways ◽  
Mrna Levels ◽  
Mitochondrial Content ◽  
Mitochondrial Abnormalities ◽  
Protein Levels

AbstractPreeclampsia complicates 5–8% of all pregnancies worldwide, and although its pathophysiology remains obscure, placental oxidative stress and mitochondrial abnormalities are considered to play a key role. Mitochondrial abnormalities in preeclamptic placentae have been described, but the extent to which mitochondrial content and the molecular pathways controlling this (mitochondrial biogenesis and mitophagy) are affected in preeclamptic placentae is unknown. Therefore, in preeclamptic (n = 12) and control (n = 11) placentae, we comprehensively assessed multiple indices of placental antioxidant status, mitochondrial content, mitochondrial biogenesis, mitophagy, and mitochondrial fusion and fission. In addition, we also explored gene expression profiles related to inflammation and apoptosis. Preeclamptic placentae were characterized by higher levels of oxidized glutathione, a higher total antioxidant capacity, and higher mRNA levels of the mitochondrial-located antioxidant enzyme manganese-dependent superoxide dismutase 2 compared to controls. Furthermore, mitochondrial content was significantly lower in preeclamptic placentae, which was accompanied by an increased abundance of key constituents of glycolysis. Moreover, mRNA and protein levels of key molecules involved in the regulation of mitochondrial biogenesis were lower in preeclamptic placentae, while the abundance of constituents of the mitophagy, autophagy, and mitochondrial fission machinery was higher compared to controls. In addition, we found evidence for activation of apoptosis and inflammation in preeclamptic placentae. This study is the first to comprehensively demonstrate abnormalities at the level of the mitochondrion and the molecular pathways controlling mitochondrial content/function in preeclamptic placentae. These aberrations may well contribute to the pathophysiology of preeclampsia by upregulating placental inflammation, oxidative stress, and apoptosis.

scholarly journals Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma

2020 ◽  
Vol 318 (3) ◽  
pp. G419-G427 ◽  
Author(s):  
Tatsuhide Nabeshima ◽  
Shin Hamada ◽  
Keiko Taguchi ◽  
Yu Tanaka ◽  
Ryotaro Matsumoto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cancer Progression ◽  
Stress Responses ◽  
Target Genes ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Related Factor ◽  
Loss Of Function ◽  
P53 Expression ◽  
Nrf2 Activation

The activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway contributes to cancer progression in addition to oxidative stress responses. Loss-of-function Keap1 mutations were reported to activate Nrf2, leading to cancer progression. We examined the effects of Keap1 deletion in a cholangiocarcinoma mouse model using a mutant K-ras/ p53 mouse. Introduction of the Keap1 deletion into liver-specific mutant K-ras/ p53 expression resulted in the formation of invasive cholangiocarcinoma. Comprehensive analyses of the gene expression profiles identified broad upregulation of Nrf2-target genes such as Nqo1 and Gstm1 in the Keap1-deleted mutant K-ras/ p53 expressing livers, accompanied by upregulation of cholangiocyte-related genes. Among these genes, the transcriptional factor Sox9 was highly expressed in the dysplastic bile duct. The Keap-Nrf2-Sox9 axis might serve as a novel therapeutic target for cholangiocarcinoma. NEW & NOTEWORTHY The Keap1-Nrf2 system has a wide variety of effects in addition to the oxidative stress response in cancer cells. Addition of the liver-specific Keap1 deletion to mice harboring mutant K-ras and p53 accelerated cholangiocarcinoma formation, together with the hallmarks of Nrf2 activation. This process involved the expansion of Sox9-positive cells, indicating increased differentiation toward the cholangiocyte phenotype.

scholarly journals Reactive Oxygen Species-Mediated Control of Mitochondrial Biogenesis

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Edgar D. Yoboue ◽  
Anne Devin
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Biogenesis ◽  
Redox State ◽  
Mitochondrial Genomes ◽  
Oxygen Species ◽  
Mitochondrial Content ◽  
Cellular Redox ◽  
High Importance ◽  
Complex Process ◽  
Long Time

Mitochondrial biogenesis is a complex process. It necessitates the contribution of both the nuclear and the mitochondrial genomes and therefore crosstalk between the nucleus and mitochondria. It is now well established that cellular mitochondrial content can vary according to a number of stimuli and physiological states in eukaryotes. The knowledge of the actors and signals regulating the mitochondrial biogenesis is thus of high importance. The cellular redox state has been considered for a long time as a key element in the regulation of various processes. In this paper, we report the involvement of the oxidative stress in the regulation of some actors of mitochondrial biogenesis.

scholarly journals The Role of the FOXO1/β2-AR/p-NF-κB p65 Pathway in the Development of Endometrial Stromal Cells in Pregnant Mice under Restraint Stress

2021 ◽  
Vol 22 (3) ◽  
pp. 1478
Author(s):  
Jiayin Lu ◽  
Yaoxing Chen ◽  
Zixu Wang ◽  
Jing Cao ◽  
Yulan Dong
Keyword(s):  
Oxidative Stress ◽  
Stromal Cells ◽  
Restraint Stress ◽  
Target Genes ◽  
Mrna Levels ◽  
Endometrial Stromal Cells ◽  
Protein Levels ◽  
Pregnant Mice

Restraint stress causes various maternal diseases during pregnancy. β2-Adrenergic receptor (β2-AR) and Forkhead transcription factor class O 1 (FOXO1) are critical factors not only in stress, but also in reproduction. However, the role of FOXO1 in restraint stress, causing changes in the β2-AR pathway in pregnant mice, has been unclear. The aim of this research was to investigate the β2-AR pathway of restraint stress and its impact on the oxidative stress of the maternal uterus. In the study, maternal mice were treated with restraint stress by being restrained in a transparent and ventilated device before sacrifice on Pregnancy Day 5 (P5), Pregnancy Day 10 (P10), Pregnancy Day 15 (P15), and Pregnancy Day 20 (P20) as well as on Non-Pregnancy Day 5 (NP5). Restraint stress augmented blood corticosterone (CORT), norepinephrine (NE), and blood glucose levels, while oestradiol (E2) levels decreased. Moreover, restraint stress increased the mRNA levels of the FOXO family, β2-AR, and even the protein levels of FOXO1 and β2-AR in the uterus and ovaries. Furthermore, restraint stress increased uterine oxidative stress level. In vitro, the protein levels of FOXO1 were also obviously increased when β2-AR was activated in endometrial stromal cells (ESCs). In addition, phosphorylated-nuclear factor kappa-B p65 (p-NF-κB p65) and its target genes decreased significantly when FOXO1 was inhibited. Overall, it can be said that the β2-AR/FOXO1/p-NF-κB p65 pathway was activated when pregnant mice were under restraint stress. This study provides a scientific basis for the origin of psychological stress in pregnant women.

scholarly journals Integrative Genomics with Mediation Analysis in a Survival Context

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Szilárd Nemes ◽  
Toshima Z. Parris ◽  
Anna Danielsson ◽  
Zakaria Einbeigi ◽  
Gunnar Steineck ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Genomic Analysis ◽  
Mrna Levels ◽  
Integrative Genomics ◽  
Asymptotic Results ◽  
Data Set ◽  
Cancer Data ◽  
Dna And Rna ◽  
Altered Gene

DNA copy number aberrations (DCNA) and subsequent altered gene expression profiles may have a major impact on tumor initiation, on development, and eventually on recurrence and cancer-specific mortality. However, most methods employed in integrative genomic analysis of the two biological levels, DNA and RNA, do not consider survival time. In the present note, we propose the adoption of a survival analysis-based framework for the integrative analysis of DCNA and mRNA levels to reveal their implication on patient clinical outcome with the prerequisite that the effect of DCNA on survival is mediated by mRNA levels. The specific aim of the paper is to offer a feasible framework to test the DCNA-mRNA-survival pathway. We provide statistical inference algorithms for mediation based on asymptotic results. Furthermore, we illustrate the applicability of the method in an integrative genomic analysis setting by using a breast cancer data set consisting of 141 invasive breast tumors. In addition, we provide implementation in R.

scholarly journals MITOL deletion in the brain impairs mitochondrial structure and ER tethering leading to oxidative stress

2019 ◽  
Vol 2 (4) ◽  
pp. e201900308 ◽  
Author(s):  
Shun Nagashima ◽  
Keisuke Takeda ◽  
Nobuhiko Ohno ◽  
Satoshi Ishido ◽  
Motohide Aoki ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Microglial Activation ◽  
Developmental Disorders ◽  
Inflammatory Diseases ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Three Dimensional ◽  
Abnormal Behavior ◽  
Mitochondrial Abnormalities

Mitochondrial abnormalities are associated with developmental disorders, although a causal relationship remains largely unknown. Here, we report that increased oxidative stress in neurons by deletion of mitochondrial ubiquitin ligase MITOL causes a potential neuroinflammation including aberrant astrogliosis and microglial activation, indicating that mitochondrial abnormalities might confer a risk for inflammatory diseases in brain such as psychiatric disorders. A role of MITOL in both mitochondrial dynamics and ER-mitochondria tethering prompted us to characterize three-dimensional structures of mitochondria in vivo. In MITOL-deficient neurons, we observed a significant reduction in the ER-mitochondria contact sites, which might lead to perturbation of phospholipids transfer, consequently reduce cardiolipin biogenesis. We also found that branched large mitochondria disappeared by deletion of MITOL. These morphological abnormalities of mitochondria resulted in enhanced oxidative stress in brain, which led to astrogliosis and microglial activation partly causing abnormal behavior. In conclusion, the reduced ER-mitochondria tethering and excessive mitochondrial fission may trigger neuroinflammation through oxidative stress.

scholarly journals Analysis of ceRNA networks and identification of potential drug targets for drug-resistant leukemia cell K562/ADR

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11429
Author(s):  
Zhaoping Liu ◽  
Yanyan Wang ◽  
Zhenru Xu ◽  
Shunling Yuan ◽  
Yanglin Ou ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Targets ◽  
Regulatory Networks ◽  
Expression Profiles ◽  
Leukemia Cell ◽  
Gene Expression Profiles ◽  
Leukemia Cells ◽  
Mrna Levels ◽  
Drug Resistant ◽  
Cerna Network

Background Drug resistance is the main obstacle in the treatment of leukemia. As a member of the competitive endogenous RNA (ceRNA) mechanism, underlying roles of lncRNA are rarely reported in drug-resistant leukemia cells. Methods The gene expression profiles of lncRNAs and mRNAs in doxorubicin-resistant K562/ADR and sensitive K562 cells were established by RNA sequencing (RNA-seq). Expression of differentially expressed lncRNAs (DElncRNAs) and DEmRNAs was validated by qRT-PCR. The potential biological functions of DElncRNAs targets were identified by GO and KEGG pathway enrichment analyses, and the lncRNA-miRNA-mRNA ceRNA network was further constructed. K562/ADR cells were transfected with CCDC26 and LINC01515 siRNAs to detect the mRNA levels of GLRX5 and DICER1, respectively. The cell survival rate after transfection was detected by CCK-8 assay. Results The ceRNA network was composed of 409 lncRNA-miRNA pairs and 306 miRNA-mRNA pairs based on 67 DElncRNAs, 58 DEmiRNAs and 192 DEmRNAs. Knockdown of CCDC26 and LINC01515 increased the sensitivity of K562/ADR cells to doxorubicin and significantly reduced the half-maximal inhibitory concentration (IC50) of doxorubicin. Furthermore, knockdown of GLRX5 and DICER1 increased the sensitivity of K562/ADR cells to doxorubicin and significantly reduced the IC50 of doxorubicin. Conclusions The ceRNA regulatory networks may play important roles in drug resistance of leukemia cells. CCDC26/miR-140-5p/GLRX5 and LINC01515/miR-425-5p/DICER1 may be potential targets for drug resistance in K562/ADR cells. This study provides a promising strategy to overcome drug resistance and deepens the understanding of the ceRNA regulatory mechanism related to drug resistance in CML cells.

scholarly journals Induction of Oxidative Stress and Apoptosis in the Injured Brain: Potential Relevance to Brain Regeneration in Zebrafish.

2021 ◽  
Author(s):  
Surendra Kumar Anand ◽  
Manas Ranjan Sahu ◽  
Amal Chandra Mondal
Keyword(s):  
Oxidative Stress ◽  
Mrna Levels ◽  
Adult Zebrafish ◽  
Zebrafish Model ◽  
Stab Injury ◽  
Zebrafish Brain ◽  
Protein Levels ◽  
Injured Brain ◽  
Brain Regeneration ◽  
The Impact

Abstract In the recent years, zebrafish, owing to its tremendous adult neurogenic capacity, has emerged as a useful vertebrate model to study brain regeneration. Recent findings suggest a significant role of the BDNF/TrkB signaling as a mediator of brain regeneration following a stab injury in the adult zebrafish brain. Since BDNF has been implicated in a plethora of physiological processes, we hypothesized that these processes are affected in the injured zebrafish brain. In this small study, we examined the indicators of oxidative stress and of apoptosis using biochemical assays, RT-PCR and IHC to reflect upon the impact of stab injury on oxidative stress levels and apoptosis in the injured adult zebafish brain. Our results indicate induction of oxidative stress in the injured adult zebrafish brain. Also, apoptosis was induced in the injured brain as indicated by increased protein levels of cleaved caspase3 as well as enhanced mRNA levels of both pro-apoptotic and anti-apoptotic genes. This knowledge contributes to the overall understanding of adult neurogenesis in the zebrafish model and raises new questions pertaining to the compensatory physiological mechanisms in response to traumatic brain injury in the adult zebrafish brain.

scholarly journals A Theacrine-Based Supplement Increases Cellular NAD+ Levels and Affects Biomarkers Related to Sirtuin Activity in C2C12 Muscle Cells In Vitro

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3727
Author(s):  
Petey W. Mumford ◽  
Shelby C. Osburn ◽  
Carlton D. Fox ◽  
Joshua S. Godwin ◽  
Michael D. Roberts
Keyword(s):  
Cell Line ◽  
Mitochondrial Biogenesis ◽  
C2c12 Myoblast ◽  
Mrna Levels ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Protein Levels ◽  
Myoblast Cell Line ◽  
Rodent Cell ◽  
Myoblast Cell

There is evidence in rodents to suggest that theacrine-based supplements modulate tissue sirtuin activity as well as other biological processes associated with aging. Herein, we examined if a theacrine-based supplement (termed NAD3) altered sirtuin activity in vitro while also affecting markers of mitochondrial biogenesis. The murine C2C12 myoblast cell line was used for experimentation. Following 7 days of differentiation, myotubes were treated with 0.45 mg/mL of NAD3 (containing ~2 mM theacrine) for 3 and 24 h (n = 6 treatment wells per time point). Relative to control (CTL)-treated cells, NAD3 treatments increased (p < 0.05) Sirt1 mRNA levels at 3 h, as well as global sirtuin activity at 3 and 24 h. Follow-up experiments comparing 24 h NAD3 or CTL treatments indicated that NAD3 increased nicotinamide phosphoribosyltransferase (NAMPT) and SIRT1 protein levels (p < 0.05). Cellular nicotinamide adenine dinucleotide (NAD+) levels were also elevated nearly two-fold after 24 h of NAD3 versus CTL treatments (p < 0.001). Markers of mitochondrial biogenesis were minimally affected. Although these data are limited to select biomarkers in vitro, these preliminary findings suggest that a theacrine-based supplement can modulate select biomarkers related to NAD+ biogenesis and sirtuin activity. However, these changes did not drive increases in mitochondrial biogenesis. While promising, these data are limited to a rodent cell line and human muscle biopsy studies are needed to validate and elucidate the significance of these findings.

scholarly journals Effect of Sulforaphane and 5-Aza-2’-Deoxycytidine on Melanoma Cell Growth

Medicines ◽  
2019 ◽  
Vol 6 (3) ◽  
pp. 71 ◽  
Author(s):  
Tung-chin Chiang ◽  
Brian Koss ◽  
L. Joseph Su ◽  
Charity L. Washam ◽  
Stephanie D. Byrum ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Growth ◽  
Gene Transcription ◽  
Melanoma Cell ◽  
Dna Methyltransferase ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Epigenetic Modifications ◽  
Driving Mechanism ◽  
Epigenetic Drug

Background: UV exposure-induced oxidative stress is implicated as a driving mechanism for melanoma. Increased oxidative stress results in DNA damage and epigenetic dysregulation. Accordingly, we explored whether a low dose of the antioxidant sulforaphane (SFN) in combination with the epigenetic drug 5-aza-2’-deoxycytidine (DAC) could slow melanoma cell growth. SFN is a natural bioactivated product of the cruciferous family, while DAC is a DNA methyltransferase inhibitor. Methods: Melanoma cell growth characteristics, gene transcription profiles, and histone epigenetic modifications were measured after single and combination treatments with SFN and DAC. Results: We detected melanoma cell growth inhibition and specific changes in gene expression profiles upon combinational treatments with SFN and DAC, while no significant alterations in histone epigenetic modifications were observed. Dysregulated gene transcription of a key immunoregulator cytokine—C-C motif ligand 5 (CCL-5)—was validated. Conclusions: These results indicate a potential combinatorial effect of a dietary antioxidant and an FDA-approved epigenetic drug in controlling melanoma cell growth.

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