Cellular Redox Homeostasis

Cellular redox homeostasis is an essential and dynamic process that ensures the balance between reducing and oxidizing reactions within cells and regulates a plethora of biological responses and events. The study of these biochemical reactions has proven difficult over time, but recent technical and methodological developments have contributed to the rapid growth of the redox field and to our understanding of its importance in biology. The aim of this short review is to give the reader an overall understanding of redox regulation in the areas of cellular signaling, development, and disease, as well as to introduce some recent discoveries in those fields

Pan-cancer transcriptomic analysis associates long non-coding RNAs with key mutational driver events

Thousands of long non-coding RNAs (lncRNAs) lie interspersed with coding genes across the genome, and a small subset has been implicated as downstream effectors in oncogenic pathways. Here we make use of transcriptome and exome sequencing data from thousands of tumours across 19 cancer types, to identify lncRNAs that are induced or repressed in relation to somatic mutations in key oncogenic driver genes. Our screen confirms known coding and non-coding effectors and also associates many new lncRNAs to relevant pathways. The associations are often highly reproducible across cancer types, and while many lncRNAs are co-expressed with their protein-coding hosts or neighbours, some are intergenic and independent. We highlight lncRNAs with possible functions downstream of the tumour suppressor TP53 and the master antioxidant transcription factor NFE2L2. Our study provides a comprehensive overview of lncRNA transcriptional alterations in relation to key driver mutational events in human cancers

<i>KRAS</i> Mutations Impact Clinical Outcome in Metastatic Non-Small Cell Lung Cancer

There is an urgent need to identify new predictive biomarkers for treatment response to both platinum doublet chemotherapy (PT) and immune checkpoint blockade (ICB). Here, we evaluated whether treatment outcome could be affected by KRAS mutational status in patients with metastatic (Stage IV) non-small cell lung cancer (NSCLC). All consecutive patients molecularly assessed and diagnosed between 2016–2018 with Stage IV NSCLC in the region of West Sweden were included in this multi-center retrospective study. The primary study outcome was overall survival (OS). Out of 580 Stage IV NSCLC patients, 35.5% harbored an activating mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT was a negative factor for OS (p = 0.014). On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.478, 95% CI 1.207–1.709, p n = 195), KRASMUT was a negative factor for survival (p = 0.018), with median OS of 9 months vs. KRASWT at 11 months. On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.564, 95% CI 1.124–2.177, p = 0.008). KRASMUT patients with high PD-L1 expression (PD-L1high) had better OS than PD-L1highKRASWT patients (p = 0.036). In response to first-line ICB, KRASMUT patients had a significantly (p = 0.006) better outcome than KRASWT patients, with a median OS of 23 vs. 6 months. On multivariable Cox analysis, KRASMUT status was an independent prognostic factor for better OS (HR 0.349, 95% CI 0.148–0.822, p = 0.016). kRAS mutations are associated with better response to treatment with immune checkpoint blockade and worse response to platinum doublet chemotherapy as well as shorter general OS in Stage IV NSCLC

An evaluation of P wave dispersion, QT, corrected QT and corrected QT dispersion intervals on the electrocardiograms of malnourished adults

The aim of our study was to investigate P wave dispersion (Pwd), QT, corrected QT (QTc), QT dispersion (QTd) and corrected QT dispersion (QTcd) intervals in subjects with malnutrition diagnosed in the pre-anaesthetic assessment, compared to those without malnutrition

Zinc finger protein 148 Is dispensable for primitive and definitive hematopoiesis in mice

Hematopoiesis is regulated by transcription factors that induce cell fate and differentiation in hematopoietic stem cells into fully differentiated hematopoietic cell types. The transcription factor zinc finger protein 148 (Zfp148) interacts with the hematopoietic transcription factor Gata1 and has been implicated to play an important role in primitive and definitive hematopoiesis in zebra fish and mouse chimeras. We have recently created a gene-trap knockout mouse model deficient for Zfp148, opening up for analyses of hematopoiesis in a conventional loss-of-function model in vivo. Here, we show that Zfp148-deficient neonatal and adult mice have normal or slightly increased levels of hemoglobin, hematocrit, platelets and white blood cells, compared to wild type controls. Hematopoietic lineages in bone marrow, thymus and spleen from Zfp148 (gt/gt) mice were further investigated by flow cytometry. There were no differences in T-cells (CD4 and CD8 single positive cells, CD4 and CD8 double negative/positive cells) in either organ. However, the fraction of CD69- and B220-positive cells among lymphocytes in spleen was slightly lower at postnatal day 14 in Zfp148 (gt/gt) mice compared to wild type mice. Our results demonstrate that Zfp148-deficient mice generate normal mature hematopoietic populations thus challenging earlier studies indicating that Zfp148 plays a critical role during hematopoietic development

Zfp148 deficiency causes lung maturation defects and lethality in newborn mice that are rescued by deletion of p53 or antioxidant treatment.

The transcription factor Zfp148 (Zbp-89, BFCOL, BERF1, htβ) interacts physically with the tumor suppressor p53 and is implicated in cell cycle control, but the physiological role of Zfp148 remains unknown. Here we show that Zfp148 deficiency leads to respiratory distress and lethality in newborn mice. Zfp148 deficiency prevented structural maturation of the prenatal lung without affecting type II cell differentiation or surfactant production. BrdU analyses revealed that Zfp148 deficiency caused proliferation arrest of pulmonary cells at E18.5-19.5. Similarly, Zfp148-deficient fibroblasts exhibited proliferative arrest that was dependent on p53, raising the possibility that cell stress is part of the underlying mechanism. Indeed, Zfp148 deficiency lowered the threshold for activation of p53 under oxidative conditions. Moreover, both in vivo and cellular phenotypes were rescued on Trp53(+/-) or Trp53(-/-) backgrounds and by antioxidant treatment. Thus, Zfp148 prevents respiratory distress and lethality in newborn mice by attenuating oxidative stress-dependent p53-activity during the saccular stage of lung development. Our results establish Zfp148 as a novel player in mammalian lung maturation and demonstrate that Zfp148 is critical for cell cycle progression in vivo

Elevated Nrf-2 responses are insufficient to mitigate protein carbonylation in hepatospecific PTEN deletion mice

<div><p>Objective</p><p>In the liver, a contributing factor in the pathogenesis of non-alcoholic fatty liver disease (NASH) is oxidative stress, which leads to the accumulation of highly reactive electrophilic α/β unsaturated aldehydes. The objective of this study was to determine the impact of NASH on protein carbonylation and antioxidant responses in a murine model.</p><p>Methods</p><p>Liver-specific phosphatase and tensin homolog (PTEN)-deletion mice (PTEN^LKO) or control littermates were fed a standard chow diet for 45–55 weeks followed by analysis for liver injury, oxidative stress and inflammation.</p><p>Results</p><p>Histology and Picrosirius red-staining of collagen deposition within the extracellular matrix revealed extensive steatosis and fibrosis in the PTEN^LKO mice but no steatosis or fibrosis in controls. Increased steatosis and fibrosis corresponded with significant increases in inflammation. PTEN-deficient livers showed significantly increased cell-specific oxidative damage, as detected by 4-hydroxy-2-nonenal (4-HNE) and acrolein staining. Elevated staining correlated with an increase in nuclear DNA repair foci (γH2A.X) and cellular proliferation index (Ki67) within zones 1 and 3, indicating oxidative damage was zonally restricted and was associated with increased DNA damage and cell proliferation. Immunoblots showed that total levels of antioxidant response proteins induced by nuclear factor erythroid-2-like-2 (Nrf2), including GSTμ, GSTπ and CBR1/3, but not HO-1, were elevated in PTEN^LKO as compared to controls, and IHC showed this response also occurred only in zones 1 and 3. Furthermore, an analysis of autophagy markers revealed significant elevation of p62 and LC3II expression. Mass spectrometric (MS) analysis identified significantly more carbonylated proteins in whole cell extracts prepared from PTEN^LKO mice (966) as compared to controls (809). Pathway analyses of identified proteins did not uncover specific pathways that were preferentially carbonylated in PTEN^LKO livers but, did reveal specific strongly increased carbonylation of thioredoxin reductase and of glutathione-<i>S</i>-transferases (GST) M6, O1, and O2.</p><p>Conclusions</p><p>Results show that disruption of PTEN resulted in steatohepatitis, fibrosis and caused hepatic induction of the Nrf2-dependent antioxidant system at least in part due to elevation of p62. This response was both cell-type and zone specific. However, these responses were insufficient to mitigate the accumulation of products of lipid peroxidation.</p></div