scholarly journals NQO1 Binds and Supports SIRT1 Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Peter Tsvetkov ◽  
Julia Adler ◽  
Romano Strobelt ◽  
Yaarit Adamovich ◽  
Gad Asher ◽  
...  
Keyword(s):  
Target Genes ◽  
Protective Role ◽  
Class Iii ◽  
Mitochondrial Stress ◽  
Protein Levels ◽  
Related Enzyme ◽  
Metabolic Sensing ◽  
Regulatory Loop ◽  
Nadh Oxidoreductase

Silent information regulator 2-related enzyme 1 (SIRT1) is an NAD+-dependent class III deacetylase and a key component of the cellular metabolic sensing pathway. The requirement of NAD+ for SIRT1 activity led us to assume that NQO1, an NADH oxidoreductase producing NAD+, regulates SIRT1 activity. We show here that SIRT1 is capable of increasing NQO1 (NAD(P)H Dehydrogenase Quinone 1) transcription and protein levels. NQO1 physically interacts with SIRT1 but not with an enzymatically dead SIRT1 H363Y mutant. The interaction of NQO1 with SIRT1 is markedly increased under mitochondrial inhibition. Interestingly, under this condition the nuclear pool of NQO1 is elevated. Depletion of NQO1 compromises the role of SIRT1 in inducing transcription of several target genes and eliminates the protective role of SIRT1 following mitochondrial inhibition. Our results suggest that SIRT1 and NQO1 form a regulatory loop where SIRT1 regulates NQO1 expression and NQO1 binds and mediates the protective role of SIRT1 during mitochondrial stress. The interplay between an NADH oxidoreductase enzyme and an NAD+ dependent deacetylase may act as a rheostat in sensing mitochondrial stress.

scholarly journals NQO1 binds and supports SIRT1 function

2017 ◽  
Author(s):  
Peter Tsvetkov ◽  
Julia Adler ◽  
Yaarit Adamovich ◽  
Gad Asher ◽  
Nina Reuven ◽  
...  
Keyword(s):  
Target Genes ◽  
Protective Role ◽  
Class Iii ◽  
Mitochondrial Stress ◽  
Protein Levels ◽  
Related Enzyme ◽  
Metabolic Sensing ◽  
Regulatory Loop ◽  
Nadh Oxidoreductase

AbstractSilent information regulator 2-related enzyme 1 (SIRT1) is an NAD+-dependent class III deacetylase and a key component of the cellular metabolic sensing pathway. The requirement of NAD+ for SIRT1 activity led us to assume that NQO1, an NADH oxidoreductase producing NAD+, regulates SIRT1 activity. We show here that SIRT1 is capable of increasing NQO1 (NAD(P)H Dehydrogenase Quinone 1) transcription and protein levels. NQO1 physically interacts with SIRT1 but not with an enzymatically dead SIRT1 H363Y mutant. The interaction of NQO1 with SIRT1 is markedly increased under mitochondrial inhibition. Interestingly, under this condition the nuclear pool of NQO1 is elevated. Depletion of NQO1 compromises the role of SIRT1 in inducing transcription of several target genes and eliminates the protective role of SIRT1 following mitochondrial inhibition. Our results suggest that SIRT1 and NQO1 form a regulatory loop where SIRT1 regulates NQO1 expression and NQO1 binds and mediates the protective role of SIRT1 during mitochondrial stress. The interplay between an NADH oxidoreductase enzyme and an NAD+ dependent deacetylase may act as a rheostat in sensing mitochondrial stress.

scholarly journals Protective role of estrogen against excessive erythrocytosis in Monge’s disease

2021 ◽  
Vol 53 (1) ◽  
pp. 125-135
Author(s):  
Priti Azad ◽  
Francisco C. Villafuerte ◽  
Daniela Bermudez ◽  
Gargi Patel ◽  
Gabriel G. Haddad
Keyword(s):  
High Altitude ◽  
Messenger Rna ◽  
Target Genes ◽  
Protective Role ◽  
Mrna Levels ◽  
Protein Levels ◽  
Hypoxic Conditions ◽  
Andean Population

AbstractMonge’s disease (chronic mountain sickness (CMS)) is a maladaptive condition caused by chronic (years) exposure to high-altitude hypoxia. One of the defining features of CMS is excessive erythrocytosis with extremely high hematocrit levels. In the Andean population, CMS prevalence is vastly different between males and females, being rare in females. Furthermore, there is a sharp increase in CMS incidence in females after menopause. In this study, we assessed the role of sex hormones (testosterone, progesterone, and estrogen) in CMS and non-CMS cells using a well-characterized in vitro erythroid platform. While we found that there was a mild (nonsignificant) increase in RBC production with testosterone, we observed that estrogen, in physiologic concentrations, reduced sharply CD235a+ cells (glycophorin A; a marker of RBC), from 56% in the untreated CMS cells to 10% in the treated CMS cells, in a stage-specific and dose-responsive manner. At the molecular level, we determined that estrogen has a direct effect on GATA1, remarkably decreasing the messenger RNA (mRNA) and protein levels of GATA1 (p < 0.01) and its target genes (Alas2, BclxL, and Epor, p < 0.001). These changes result in a significant increase in apoptosis of erythroid cells. We also demonstrate that estrogen regulates erythropoiesis in CMS patients through estrogen beta signaling and that its inhibition can diminish the effects of estrogen by significantly increasing HIF1, VEGF, and GATA1 mRNA levels. Taken altogether, our results indicate that estrogen has a major impact on the regulation of erythropoiesis, particularly under chronic hypoxic conditions, and has the potential to treat blood diseases, such as high altitude severe erythrocytosis.

scholarly journals Macrophage migration inhibitory factor may play a protective role in osteoarthritis

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Ming Liu ◽  
Zikun Xie ◽  
Guang Sun ◽  
Liujun Chen ◽  
Dake Qi ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Protective Role ◽  
Macrophage Migration ◽  
Chain Reaction ◽  
Protein Levels ◽  
Tnf Α ◽  
Polymerase Chain

Abstract Background Osteoarthritis (OA) is the most prevalent form of arthritis and the major cause of disability and overall diminution of quality of life in the elderly population. Currently there is no cure for OA, partly due to the large gaps in our understanding of its underlying molecular and cellular mechanisms. Macrophage migration inhibitory factor (MIF) is a procytokine that mediates pleiotropic inflammatory effects in inflammatory diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, data on the role of MIF in OA is limited with conflicting results. We undertook this study to investigate the role of MIF in OA by examining MIF genotype, mRNA expression, and protein levels in the Newfoundland Osteoarthritis Study. Methods One hundred nineteen end-stage knee/hip OA patients, 16 RA patients, and 113 healthy controls were included in the study. Two polymorphisms in the MIF gene, rs755622, and -794 CATT5-8, were genotyped using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and PCR followed by automated capillary electrophoresis, respectively. MIF mRNA levels in articular cartilage and subchondral bone were measured by quantitative polymerase chain reaction. Plasma concentrations of MIF, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) were measured by enzyme-linked immunosorbent assay. Results rs755622 and -794 CATT5-8 genotypes were not associated with MIF mRNA or protein levels or OA (all p ≥ 0.19). MIF mRNA level in cartilage was lower in OA patients than in controls (p = 0.028) and RA patients (p = 0.004), while the levels in bone were comparable between OA patients and controls (p = 0.165). MIF protein level in plasma was lower in OA patients than in controls (p = 3.01 × 10−10), while the levels of TNF-α, IL-6 and IL-1β in plasma were all significantly higher in OA patients than in controls (all p ≤ 0.0007). Multivariable logistic regression showed lower MIF and higher IL-1β protein levels in plasma were independently associated with OA (OR per SD increase = 0.10 and 8.08; 95% CI = 0.04–0.19 and 4.42–16.82, respectively), but TNF-α and IL-6 became non-significant. Conclusions Reduced MIF mRNA and protein expression in OA patients suggested MIF might have a protective role in OA and could serve as a biomarker to differentiate OA from other joint disorders.

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 Upregulation of Mitochondrial Redox Sensitive Proteins in LPS-Treated Stefin B-Deficient Macrophages

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1476 ◽  
Author(s):  
Mojca Trstenjak Prebanda ◽  
Janja Završnik ◽  
Boris Turk ◽  
Nataša Kopitar Jerala
Keyword(s):  
Redox Homeostasis ◽  
Redox Status ◽  
Protective Role ◽  
Protein Levels ◽  
Lps Challenge ◽  
Pyrin Domain ◽  
Cysteine Cathepsins ◽  
Peroxiredoxin 3 ◽  
Superoxide Dismutase 2

Stefin B (cystatin B) is an intracellular inhibitor of cysteine cathepsins and mutations in the stefin B gene, resulting in the development of Unverricht–Lundborg disease, which is a form of myoclonic epilepsy. It was suggested that a key mechanism behind stefin B-mediated disease progression was impaired redox homeostasis. Stefin B-deficient mice were found more sensitive to lipopolysaccharide (LPS)-induced sepsis as a consequence of increased expression of caspase-11 and Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing (NLRP nflammasome activation and higher levels of mitochondrial reactive oxygen species (ROS). In the present study, we investigated if LPS-triggered oxidative stress affected the protein levels and redox status of redox sensitive proteins—thioredoxin, peroxiredoxins, and superoxide dismutases in macrophages and spleens of LPS-injected mice. LPS challenge was found to result in a marked elevation in mitochondrial peroxiredoxin 3 (Prx3), sulfiredoxin, and superoxide dismutase 2 (Sod2) in stefin B-deficient macrophages and spleens. We determined that sulfiredoxin is targeted to mitochondria after LPS challenge. In conclusion, the upregulation of mitochondrial redox-sensitive proteins Prx3 and Sod2 in stefin B-deficient cells implies a protective role of stefin B in mitochondrial function.

scholarly journals miR-135b Plays a Neuroprotective Role by Targeting GSK3β in MPP+-Intoxicated SH-SY5Y Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Jianlei Zhang ◽  
Wei Liu ◽  
Yabo Wang ◽  
Shengnan Zhao ◽  
Na Chang
Keyword(s):  
Cell Proliferation ◽  
Glycogen Synthase ◽  
Underlying Mechanism ◽  
Protective Role ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Protective Effects ◽  
Inflammatory Cytokine Production ◽  
Protein Levels

miR-135a-5p was reported to play a crucial role in the protective effects of hydrogen sulfide against Parkinson’s disease (PD) by targeting rho-associated protein kinase 2 (ROCK2). However, the role of another member of miR-135 family (miR-135b) and the underlying mechanism in PD are still unclear. qRT-PCR and western blot showed that miR-135 was downregulated and glycogen synthase kinase 3β (GSK3β) was upregulated at mRNA and protein levels in MPP+-intoxicated SH-SY5Y cells in a dose- and time-dependent manner. MTT, TUNEL, and ELISA assays revealed that miR-135b overexpression significantly promoted cell proliferation and inhibited apoptosis and production of TNF-α and IL-1β in SH-SY5Y cells in the presence of MPP+. Luciferase reporter assay demonstrated that GSK3β was a direct target of miR-135b. Moreover, sodium nitroprusside (SNP), a GSK3β activator, dramatically reversed the effects of miR-135b upregulation on cell proliferation, apoptosis, and inflammatory cytokine production in MPP+-intoxicated SH-SY5Y cells. Taken together, miR-135b exerts a protective role via promotion of proliferation and suppression of apoptosis and neuroinflammation by targeting GSK3β in MPP+-intoxicated SH-SY5Y cells, providing a potential therapeutic target for the treatment of PD.

scholarly journals Suppression of PTEN Expression by NF-κB Prevents Apoptosis

2004 ◽  
Vol 24 (3) ◽  
pp. 1007-1021 ◽  
Author(s):  
Krishna Murthi Vasudevan ◽  
Sushma Gurumurthy ◽  
Vivek M. Rangnekar
Keyword(s):  
Dna Binding ◽  
Target Genes ◽  
Negative Regulator ◽  
Pten Expression ◽  
Pten Gene ◽  
Transcription Activator ◽  
Potent Inducer ◽  
Protein Levels ◽  
Induced Apoptosis ◽  
Regulatory Loop

ABSTRACT NF-κB is a heterodimeric transcription activator consisting of the DNA binding subunit p50 and the transactivation subunit p65/RelA. NF-κB prevents cell death caused by tumor necrosis factor (TNF) and other genotoxic insults by directly inducing antiapoptotic target genes. We report here that the tumor suppressor PTEN, which functions as a negative regulator of phosphatidylinositol (PI)-3 kinase/Akt-mediated cell survival pathway, is down regulated by p65 but not by p50. Moreover, a subset of human lung or thyroid cancer cells expressing high levels of endogenous p65 showed decreased expression of PTEN that could be rescued by specific inhibition of the NF-κB pathway with IκB overexpression as well as with small interfering RNA directed against p65. Importantly, TNF, a potent inducer of NF-κB activity, suppressed PTEN gene expression in IKKβ+/+ cells but not in IKKβ−/− cells, which are deficient in the NF-κB activation pathway. These findings indicated that NF-κB activation was necessary and sufficient for inhibition of PTEN expression. The promoter, RNA, and protein levels of PTEN are down-regulated by NF-κB. The mechanism underlying suppression of PTEN expression by NF-κB was independent of p65 DNA binding or transcription function and involved sequestration of limiting pools of transcriptional coactivators CBP/p300 by p65. Restoration of PTEN expression inhibited NF-κB transcriptional activity and augmented TNF-induced apoptosis, indicating a negative regulatory loop involving PTEN and NF-κB. PTEN is, thus, a novel target whose suppression is critical for antiapoptosis by NF-κB.

scholarly journals The chromatin remodeler ISWI regulates the cellular response to hypoxia: role of FIH

2011 ◽  
Vol 22 (21) ◽  
pp. 4171-4181 ◽  
Author(s):  
Andrew Melvin ◽  
Sharon Mudie ◽  
Sonia Rocha
Keyword(s):  
Rna Polymerase Ii ◽  
Chromatin Remodeling ◽  
Cellular Response ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylases ◽  
Additional Information ◽  
Protein Levels ◽  
Survival Factor

The hypoxia-inducible factor (HIF) is a master regulator of the cellular response to hypoxia. Its levels and activity are controlled by dioxygenases called prolyl-hydroxylases and factor inhibiting HIF (FIH). To activate genes, HIF has to access sequences in DNA that are integrated in chromatin. It is known that the chromatin-remodeling complex switch/sucrose nonfermentable (SWI/SNF) is essential for HIF activity. However, no additional information exists about the role of other chromatin-remodeling enzymes in hypoxia. Here we describe the role of imitation switch (ISWI) in the cellular response to hypoxia. We find that unlike SWI/SNF, ISWI depletion enhances HIF activity without altering its levels. Furthermore, ISWI knockdown only alters a subset of HIF target genes. Mechanistically, we find that ISWI is required for full expression of FIH mRNA and protein levels by changing RNA polymerase II loading to the FIH promoter. Of interest, exogenous FIH can rescue the ISWI-mediated upregulation of CA9 but not BNIP3, suggesting that FIH-independent mechanisms are also involved. Of importance, ISWI depletion alters the cellular response to hypoxia by reducing autophagy and increasing apoptosis. These results demonstrate a novel role for ISWI as a survival factor during the cellular response to hypoxia.

scholarly journals Two functionally redundant FK506-binding proteins regulate multidrug resistance gene expression and govern azole antifungal resistance

2021 ◽  
Author(s):  
Romila Moirangthem ◽  
Kundan Kumar ◽  
Rupinder Kaur
Keyword(s):  
Gene Expression ◽  
Binding Proteins ◽  
Target Genes ◽  
Fungal Infections ◽  
Antifungal Resistance ◽  
Azole Resistance ◽  
Multidrug Resistance Gene ◽  
Protein Levels ◽  
Fk506 Binding Proteins

Increasing resistance to antifungal therapy is an impediment to effective treatment of fungal infections. Candida glabrata is an opportunistic human fungal pathogen which is inherently less susceptible to cost-effective azole antifungals. Gain-of-function mutations in the Zn-finger pleiotropic drug resistance transcriptional activator-encoding gene, CgPDR1, are the most prevalent cause of azole resistance in clinical settings. CgPDR1 is also transcriptionally activated upon azole exposure, however, factors governing CgPDR1 gene expression are not yet fully understood. Here, we have uncovered a novel role for two FK506-binding proteins, CgFpr3 and CgFpr4, in regulation of the CgPDR1 regulon. We show that CgFpr3 and CgFpr4 possess peptidyl-prolyl isomerase domain, and act redundantly to control CgPDR1 expression, as Cgfpr3Δ4Δ mutant displayed elevated expression of CgPDR1 gene, along with overexpression of its target genes, CgCDR1, CgCDR2 and CgSNQ2, that code for ATP-binding cassette multidrug transporters. Further, CgFpr3 and CgFpr4 are required for maintenance of histone H3 and H4 protein levels, and fluconazole exposure leads to elevated H3 and H4 protein levels. Consistent with a role of histone proteins in azole resistance, disruption of genes coding for the histone demethylase CgRph1 and histone H3K36-specific methyltransferase CgSet2 leads to increased and decreased susceptibility to fluconazole, respectively, with Cgrph1Δ mutant displaying significantly lower basal expression of CgPDR1 and CgCDR1 genes. These data underscore a hitherto unknown role of histone methylation in modulating the most common azole antifungal resistance mechanism. Altogether, our findings establish a link between CgFpr-mediated histone homeostasis and CgPDR1 gene expression, and implicate CgFpr in virulence of C. glabrata.

Protective role of interleukin-6 in coagulatory and hemostatic disturbance induced by lipopolysaccharide in mice

2004 ◽  
Vol 91 (06) ◽  
pp. 1194-1201 ◽  
Author(s):  
Ken-ichiro Inoue ◽  
Rie Yanagisawa ◽  
Miho Sakurai ◽  
Akinori Shimada ◽  
Takehito Morita ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Intraperitoneal Administration ◽  
Pulmonary Hemorrhage ◽  
Protective Role ◽  
Protein Levels ◽  
Proinflammatory Mediators ◽  
Lps Challenge ◽  
Inflammatory Protein ◽  
Significant Prolongation

SummaryAlthough the role of interleukin (IL)-6 in inflammatory diseases has been previously examined, its role in hemostasis, fibrinolysis, and coagulation during inflammation remains to be established. The present study elucidated the role of IL-6 in hemostatic and coagulatory changes during severe inflammation induced by intraperitoneal administration of lipopolysaccharide (LPS: 1 mg/kg) using IL-6 null (-/-) mice. After LPS challenge, IL-6 (-/-) mice revealed significant prolongation of prothrombin time and activated partial thromboplastin time and a significant decrease in platelet counts as compared with wild type mice. LPS treatment induced marked pulmonary hemorrhage with neutrophilic inflammation in IL-6 (-/-) mice, in contrast, only mild neutrophilic infiltration in WT mice confirmed by macroscopic and histological findings.The protein levels of proinflammatory mediators, such as IL-1?, macrophage inflammatory protein (MIP)-1a., MIP-2, macrophage chemoattractant protein1, granulocyte/macrophage-colony-stimulating factor, and keratinocyte chemoattractant in the lungs were significantly greater in IL-6 (-/-) mice than in WT mice after LPS challenge. These results directly indicate that IL-6 is protective against coagulatory and hemostatic disturbance and subsequent pulmonary hemorrhage induced by bacterial endotoxin, at least partly, via the modulation of proinflammatory processes.

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