Oxidative Stress Dysregulation Research Articles

Abstract 4449: Hepatic steatosis induced by bioactive lipids

Abstract Introduction: HCC is the most common form of liver cancer and is the sixth most common cancer globally. Despite the clinical advancement of immune checkpoint inhibitors, median survival continues to be less than twenty months and most patients develop resistance making it one of the deadliest malignancies. The rate of liver cancer continues to rise, which is coupled to the high prevalence of steatosis and steatohepatitis that accounts for about 25% in the general population. Pathologically, 80% of liver cancer occurs in patients with an underlying liver disease that displays liver steatosis. Thus, it is paramount to better characterize the transition from steatosis to HCC. Methods: Utilizing a Pten deleted mouse model (PtenloxP/loxP; Alb-Cre+) that recapitulates HCC progression, protein and lipid fractions were isolated to explore differentially expressed proteins and their correlations with bioactive lipid metabolism. Global untargeted differential proteomics was done with fractionation using a qExactive. Lipid fractions were analyzed using a Sciex 6500 for targeted lipidomic analysis. In addition, genetic knockout hepatocyte cell lines of each AKT isoform were used to explore the involvement of the PI3K/AKT signal. Further, a phosphoproteomic enrichment was performed to discover downstream signaling targets. Results: The PTEN regulated PI3K/AKT signal is induced in 54% of all liver cancers and represents the dominant signaling pathway regulating liver cancer progression. Untargeted differential proteomic analysis of Pten deleted mice livers revealed significant dysregulation in oxidative stress and eicosanoid metabolism among the top enriched disease and biological functions when the phenotype progressed from steatosis to HCC. Analysis of publicly available liver cancer patient samples from the NCI Proteomic Data Commons further shows strong correlation between PTEN protein abundance and the expression of enzymes involved in eicosanoid metabolism. Our analysis using a bio-active lipid multi reaction monitoring panel of Pten deleted mouse livers further validates significant decreases in resolving eicosanoid levels along with increases in proinflammatory eicosanoid precursors as steatosis progress to HCC. These data suggest a potential hepatic AKT-dependency in regulating the shift towards proinflammatory eicosanoids. Primary isolated hepatocytes from mouse livers lacking either AKT1 or AKT2 were analyzed to elucidate AKT’s regulatory role in hepatic eicosanoid metabolism. Proteomic and lipidomic analysis of these hepatocytes supported a unique AKT isoform specific role in the regulation of eicosanoids via potential isoform specific signaling interactions with MAPK. Conclusion: Eicosanoid metabolism dysregulation plays a key role in the progression from steatosis to HCC and appears to be regulated in an AKT isoform specific manner via interactions with MAPK signaling. Citation Format: Mario Alba, Ielyzaveta Slarve, Brandon Ebright, Yiren Zhou, Whitaker Cohn, Yunyi Jia, Elizabeth Elton, Jared Khan, Aditi Datta, Lina He, Qi Tang, Pranav Pammidimukkala, Taojian Tu, Phillip Nguyen, Jonathan Katz, Julian Whitelegge, Stan Louie, Bangyan Stiles. Hepatic steatosis induced by bioactive lipids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4449.

Inhibiting the Keap1/Nrf2 Protein-Protein Interaction with Protein-Like Polymers.

Successful and selective inhibition of the cytosolic protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associating protein 1 (Keap1) can enhance the antioxidant response, with the potential for a therapeutic effect in a range of settings including in neurodegenerative disease (ND). Small molecule inhibitors have been developed, yet many have off-target effects, or are otherwise limited by poor cellular permeability. Peptide-based strategies have also been attempted to enhance specificity, yet face challenges due to susceptibility to degradation and lack of cellular penetration. Herein, these barriers are overcome utilizing a polymer-based proteomimetics. The protein-like polymer (PLP) consists of a synthetic, lipophilic polymer backbone displaying water soluble Keap1-binding peptides on each monomer unit forming a brush polymer architecture. The PLPs are capable of engaging Keap1 and displacing the cellular protective transcription factor Nrf2, which then translocates to the nucleus, activating the antioxidant response element (ARE). PLPs exhibit increased Keap1 binding affinity by several orders of magnitude compared to free peptides, maintain serum stability, are cell-penetrant, and selectively activate the ARE pathway in cells, including in primary cortical neuronal cultures. Keap1/Nrf2-inhibitory PLPs have the potential to impact the treatment of disease states associated with dysregulation of oxidative stress, such as NDs.

Neuronal knockdown of Cullin3 as a Drosophila model of autism spectrum disorder

Mutations in Cullin-3 (Cul3), a conserved gene encoding a ubiquitin ligase, are strongly associated with autism spectrum disorder (ASD). Here, we characterize ASD-related pathologies caused by neuron-specific Cul3 knockdown in Drosophila. We confirmed that neuronal Cul3 knockdown causes short sleep, paralleling sleep disturbances in ASD. Because sleep defects and ASD are linked to metabolic dysregulation, we tested the starvation response of neuronal Cul3 knockdown flies; they starved faster and had lower triacylglyceride levels than controls, suggesting defects in metabolic homeostasis. ASD is also characterized by increased biomarkers of oxidative stress; we found that neuronal Cul3 knockdown increased sensitivity to hyperoxia, an exogenous oxidative stress. Additional hallmarks of ASD are deficits in social interactions and learning. Using a courtship suppression assay that measures social interactions and memory of prior courtship, we found that neuronal Cul3 knockdown reduced courtship and learning compared to controls. Finally, we found that neuronal Cul3 depletion alters the anatomy of the mushroom body, a brain region required for memory and sleep. Taken together, the ASD-related phenotypes of neuronal Cul3 knockdown flies establish these flies as a genetic model to study molecular and cellular mechanisms underlying ASD pathology, including metabolic and oxidative stress dysregulation and neurodevelopment.

Hydrogen Sulfide: An Emerging Regulator of Oxidative Stress and Cellular Homeostasis-A Comprehensive One-Year Review.

Hydrogen sulfide (H2S), traditionally recognized as a toxic gas, has emerged as a critical regulator in many biological processes, including oxidative stress and cellular homeostasis. This review presents an exhaustive overview of the current understanding of H2S and its multifaceted role in mammalian cellular functioning and oxidative stress management. We delve into the biological sources and function of H2S, mechanisms underlying oxidative stress and cellular homeostasis, and the intricate relationships between these processes. We explore evidence from recent experimental and clinical studies, unraveling the intricate biochemical and molecular mechanisms dictating H2S's roles in modulating oxidative stress responses and maintaining cellular homeostasis. The clinical implications and therapeutic potential of H2S in conditions characterized by oxidative stress dysregulation and disrupted homeostasis are discussed, highlighting the emerging significance of H2S in health and disease. Finally, this review underscores current challenges, controversies, and future directions in the field, emphasizing the need for further research to harness H2S's potential as a therapeutic agent for diseases associated with oxidative stress and homeostatic imbalance. Through this review, we aim to emphasize H2S's pivotal role in cellular function, encouraging further exploration into this burgeoning area of research.

Comprehensive analysis of hub biomarkers associated with immune and oxidative stress in Hashimoto's thyroiditis

Hashimoto's thyroiditis (HT) is a type of autoimmune disorder with a complex interplay between immune disorder and oxidative stress (OS). This research aimed to discover biomarkers and potential treatment targets associated with immune and OS dysregulation in HT through integrated bioinformatics analysis and clinical validations. Differential gene expression analysis of GSE138198 dataset from the GEO database identified 1490 differentially expressed genes (DEGs) in HT, including 883 upregulated and 607 downregulated genes. Weighted gene co-expression network analysis explored module genes associated with HT. Overlapping the differentially expressed module genes with immune-related and OS-related genes identified eight differentially expressed module genes associated with immune and OS (DEIOGs) in HT. Protein-protein interaction network analysis identified five hub genes (TNFAIP3, FOS, PTK2B, STAT1, and MMP9). We confirmed four hub genes (TNFAIP3, PTK2B, STAT1 and MMP9) in GSE29315 dataset and clinical thyroid samples, which showed high diagnostic accuracy (AUC >0.7) for HT. The expression of these four genes was positively correlated with serum thyroid peroxidase antibody, thyroglobulin antibody levels, and inflammatory infiltration scores in clinical thyroid samples. Immune profiling revealed distinct profiles in HT, such as B cells memory, monocytes and macrophages. Additionally, all hub genes were inversely associated with monocytes. Further, miRNA-mRNA network analysis was conducted, and a regulatory network comprising four hub genes, 238 miRNAs and 32 TFs was established. These findings suggest that immune cells play a crucial role in the development of HT, and the hub genes TNFAIP3, PTK2B, STAT1, and MMP9 may be key players in HT through immune- and OS-related signaling pathways. Our results may provide valuable insights into the pathogenesis and therapeutic monitoring of HT.

Research Progress of Antioxidants in Oxidative Stress Therapy after Spinal Cord Injury.

Spinal cord injury (SCI) is a serious problem in the central nervous system resulting in high disability and mortality with complex pathophysiological mechanisms. Oxidative stress is one of the main secondary reactions of SCI, and its main pathophysiological marker is the production of excess reactive oxygen species. The overproduction of reactive oxygen species and insufficient antioxidant capacity lead to the occurrence of oxidative stress and neuroinflammation, and the dysregulation of oxidative stress and neuroinflammation leads to further aggravation of damage. Oxidative stress can initiate a variety of inflammatory and apoptotic pathways, and targeted antioxidant therapy can greatly reduce oxidative stress and reduce neuroinflammation, which has a certain positive effect on rehabilitation and prognosis in SCI. This article reviewed the research on different types of antioxidants and related treatments in SCI, focusing on the mechanisms of oxidative stress.

Curcumin-loaded graphene oxide quantum dots enhance otoprotective effects via blocking cuproptosis.

Background: Cisplatin (CIS) is widely used to treat various cancers but can cause ototoxicity and sensory hair cell loss in the inner ear. Copper induces an excessive production of reactive oxygen species (ROS) in hair cells, leading to the development of various antioxidants. Methods and results: This study aimed to evaluate the potential antioxidant properties of curcumin (CUR) in the inner ear organ of corti-1 cells (OC1) and animal models (zebrafish and guinea pigs). Graphene oxide quantum dots (GOQDs) enabled CUR to penetrate the round window membrane (RWM) and maintain the concentration in the perilymph after inner ear administration. The results showed that CUR/GOQDs had favorable biocompatibility and strongly affected ROS generation induced by CIS in OC1 cells. DCFHDA Green staining demonstrated that CUR/GOQDs successfully reversed the decrease in mitochondrial membrane potential induced by CIS in vitro and rescued cells from early cuproptosis, which was confirmed by FDX1 staining. Additionally, the experiment found that CUR decreased the expression of cuproptosis proteins (FDX1, LIAS, and LIPT1) and increased the expression of the Bcl-2 protein. Conclusion: The results demonstrate that CUR/GOQDs is a promising therapeutic agent that can prevent CIS-induced ototoxicity by blocking the cuproptosis signal pathway.

Unscrambling the Role of Redox-Active Biometals in Dopaminergic Neuronal Death and Promising Metal Chelation-Based Therapy for Parkinson's Disease.

Biometals are all metal ions that are essential for all living organisms. About 40% of all enzymes with known structures require biometals to function correctly. The main target of damage by biometals is the central nervous system (CNS). Biometal dysregulation (metal deficiency or overload) is related to pathological processes. Chronic occupational and environmental exposure to biometals, including iron and copper, is related to an increased risk of developing Parkinson's disease (PD). Indeed, biometals have been shown to induce a dopaminergic neuronal loss in the substantia nigra. Although the etiology of PD is still unknown, oxidative stress dysregulation, mitochondrial dysfunction, and inhibition of both the ubiquitin-proteasome system (UPS) and autophagy are related to dopaminergic neuronal death. Herein, we addressed the involvement of redox-active biometals, iron, and copper, as oxidative stress and neuronal death inducers, as well as the current metal chelation-based therapy in PD.

Mitochondrial Pathophysiology on Chronic Kidney Disease.

In healthy kidneys, interstitial fibroblasts are responsible for the maintenance of renal architecture. Progressive interstitial fibrosis is thought to be a common pathway for chronic kidney diseases (CKD). Diabetes is one of the boosters of CKD. There is no effective treatment to improve kidney function in CKD patients. The kidney is a highly demanding organ, rich in redox reactions occurring in mitochondria, making it particularly vulnerable to oxidative stress (OS). A dysregulation in OS leads to an impairment of the Electron transport chain (ETC). Gene deficiencies in the ETC are closely related to the development of kidney disease, providing evidence that mitochondria integrity is a key player in the early detection of CKD. The development of novel CKD therapies is needed since current methods of treatment are ineffective. Antioxidant targeted therapies and metabolic approaches revealed promising results to delay the progression of some markers associated with kidney disease. Herein, we discuss the role and possible origin of fibroblasts and the possible potentiators of CKD. We will focus on the important features of mitochondria in renal cell function and discuss their role in kidney disease progression. We also discuss the potential of antioxidants and pharmacologic agents to delay kidney disease progression.

Recent Reports on Redox Stress-Induced Mitochondrial DNA Variations, Neuroglial Interactions, and NMDA Receptor System in Pathophysiology of Schizophrenia.

Schizophrenia (SZ) is a chronic psychiatric disorder affecting several people worldwide. Mitochondrial DNA (mtDNA) variations could invoke changes in the OXPHOS system, calcium buffering, and ROS production, which have significant implications for glial cell survival during SZ. Oxidative stress has been implicated in glial cells-mediated pathogenesis of SZ; the brain comparatively more prone to oxidative damage through NMDAR. A confluence of scientific evidence points to mtDNA alterations, Nrf2 signaling, dynamic alterations in dorsolateral prefrontal cortex (DLPFC), and provocation of oxidative stress that enhance pathophysiology of SZ. Furthermore, the alterations in excitatory signaling related to NMDAR signaling were particularly reported for SZ pathophysiology. Current review reported the recent evidence for the role of mtDNA variations and oxidative stress in relation to pathophysiology of SZ, NMDAR hypofunction, and glutathione deficiency. NMDAR system is influenced by redox dysregulation in oxidative stress, inflammation, and antioxidant mediators. Several studies have demonstrated the relationship of these variables on severity of pathophysiology in SZ. An extensive literature search was conducted using Medline, PubMed, PsycINFO, CINAHL PLUS, BIOSIS Preview, Google scholar, and Cochrane databases. We summarize consistent evidence pointing out a plausible model that may elucidate the crosstalk between mtDNA alterations in glial cells and redox dysregulation during oxidative stress and the perturbation of NMDA neurotransmitter system during current therapeutic modalities for the SZ treatment. This review can be beneficial for the development of promising novel diagnostics, and therapeutic modalities by ascertaining the mtDNA variations, redox state, and efficacy of pharmacological agents to mitigate redox dysregulation and augment NMDAR function to treat cognitive and behavioral symptoms in SZ.

Autonomic Disbalance During Systemic Inflammation is Associated with Oxidative Stress Changes in Sepsis Survivor Rats.

Sepsis affects 31.5 million people worldwide. It is characterized by an intense drop in blood pressure driving to cardiovascular morbidity and mortality. Modern supportive care has increased survival in patients; however, after experiencing sepsis, several complications are observed, which may be potentiated by new inflammatory events. Nevertheless, the interplay between sepsis survivors and a new immune challenge in cardiovascular regulation has not been previously defined. We hypothesized that cecal ligation and puncture (CLP) cause persistent cardiovascular dysfunctions in rats as well as changes in autonomic-induced cardiovascular responses to lipopolysaccharide (LPS). Male Wistar rats had mean arterial pressure (MAP) and heart rate (HR) recorded before and after LPS or saline administration to control or CLP survivor rats. CLP survivor rats had similar baseline MAP and HR when compared to control. LPS caused a drop in MAP accompanied by tachycardia in control, while CLP survivor rats had a noteworthy enhanced MAP and a blunted tachycardia. LPS-induced hemodynamic changes were related to an autonomic disbalance to the heart and resistance vessels that were expressed as an increased low- and high-frequency power of pulse interval in CLP survivors after saline and enhancement in the low-frequency power of systolic arterial pressure in control rats after LPS. LPS-induced plasma interferon γ, but not interleukin-10 surges, was blunted in CLP survivor rats. To further access whether or not LPS-induced autonomic disbalance in CLP survivor rats was associated with oxidative stress dysregulation, superoxide dismutase (SOD) activity and thiobarbituric acid reactive substances (TBARS) plasma levels changes were measured. LPS-induced oxidative stress was higher in CLP survivor rats. These findings indicate that key changes in hemodynamic regulation of CLP survivors rats take place in response to LPS that are associated with oxidative stress changes, i.e., reduced SOD activity and increased TBARS levels.

Mitochondrial Transplantation Modulates Inflammation and Apoptosis, Alleviating Tendinopathy Both In Vivo and In Vitro.

Tendinopathy is a common musculoskeletal condition causing pain and dysfunction. Conventional treatment and surgical procedures for tendinopathy are insufficient; accordingly, recent research has focused on tendon-healing regenerative approaches. Tendon injuries usually occur in the hypoxic critical zone, characterized by increased oxidative stress and mitochondrial dysfunction; thus, exogenous intact mitochondria may be therapeutic. We aimed to assess whether mitochondrial transplantation could induce anti-inflammatory activity and modulate the metabolic state of a tendinopathy model. Exogenous mitochondria were successfully delivered into damaged tenocytes by centrifugation. Levels of Tenomodulin and Collagen I in damaged tenocytes were restored with reductions in nuclear factor-κB and matrix metalloproteinase 1. The dysregulation of oxidative stress and mitochondrial membrane potential was attenuated by mitochondrial transplantation. Activated mitochondrial fission markers, such as fission 1 and dynamin-related protein 1, were dose-dependently downregulated. Apoptosis signaling pathway proteins were restored to the pre-damage levels. Similar changes were observed in a collagenase injection-induced rat model of tendinopathy. Exogenous mitochondria incorporated into the Achilles tendon reduced inflammatory and fission marker levels. Notably, collagen production was restored. Our results demonstrate the therapeutic effects of direct mitochondrial transplantation in tendinopathy. These effects may be explained by alterations in anti-inflammatory and apoptotic processes via changes in mitochondrial dynamics.

Polybrominated diphenyl ethers exert genotoxic effects in pantropic spotted dolphin fibroblast cell lines.

Cetaceans accumulate persistent and toxic substances such as polybrominated diphenyl ethers in their tissue. PBDEs are ubiquitous in marine environments, and their exposure to mammals is linked to numerous health effects such as endocrine disruption, neurotoxicity, carcinogenicity, and fetal toxicity. However, the toxicological effects and mechanism of toxicity in cetaceans remains poorly understood. The effects of BDE-47 (0.1-0.5μgmL-1), BDE-100 (0.1-0.5μgmL-1), and BDE-209 (0.25-1.0μgmL-1) exposure on cell viability, oxidative stress, mitochondrial structure, and apoptosis were evaluated using a recently established pantropical spotted dolphin (Stenella attenuata) skin fibroblast cell line (PSD-LWHT) as an invitro model. However, the production of reactive oxygen species (ROS) increased following exposure to 1.0μgmL-1 PBDE while superoxide anion, hydroxyl radicals, and inducible nitric oxide increased in a dose-dependent manner. At 0.5-1.0μgmL-1, PBDEs significantly reduced the mitochondrial membrane potential. In addition, exposure to BDE-47 and -209 significantly affected mitochondrial structure as well as cell signaling and transduction compared to BDE-100. Although PBDE exposure did not affect cell viability, a significant increase in cell apoptosis markers (Bcl2 and caspase-9) was observed. This study demonstrated that BDE-47, -100, and-209 congeners might cause cytotoxic and genotoxic effects as they play a crucial role in the dysregulation of oxidative stress and alteration of mitochondrial and cell membrane structure and activity in the fibroblast cells. Hence, these results suggest that PBDEs might have adverse health effects on cetaceans inhabiting contaminated marine environments.

Transcriptional profiling reveals altered biological characteristics of chorionic stem cells from women with gestational diabetes

BackgroundGestational diabetes (GDM) is a common complication of pregnancy. The impact of pregnancy complications on placental function suggests that extraembryonic stem cells in the placenta may also be affected during pregnancy. Neonatal tissue-derived stem cells, with the advantages of their differentiation capacity and non-invasive isolation processes, have been proposed as a promising therapeutic avenue for GDM management through potential cell therapy approaches. However, the influence of GDM on autologous stem cells remains unclear. Thus, studies that provide comprehensive understanding of stem cells isolated from women with GDM are essential to guide future clinical applications.MethodsHuman chorionic membrane-derived stem cells (CMSCs) were isolated from placentas of healthy and GDM pregnancies. Transcriptional profiling was performed by DNA microarray, and differentially regulated genes between GDM- and Healthy-CMSCs were used to analyse molecular functions, differentiation, and pathway enrichment. Altered genes and biological functions were validated via real-time PCR and in vitro assays.ResultsGDM-CMSCs displayed, vs. Healthy-CMSCs, 162 upregulated genes associated with increased migration ability, epithelial development, and growth factor-associated signal transduction while the 269 downregulated genes were strongly linked to angiogenesis and cellular metabolic processes. Notably, significantly reduced expression of detoxification enzymes belonging to the aldehyde dehydrogenase gene families (ALDH1A1/1A2, ALDH2, ALDH3) accounted for downregulation across several metabolic pathways. ALDH activity and inhibitor assays indicated that reduced gene expression of ALDHs affected ALDH enzymatic functions and resulted in oxidative stress dysregulation in GDM-CMSCs.ConclusionOur combined transcriptional analysis and in vitro functional characterisation have provided novel insights into fundamental biological differences in GDM- and Healthy-CMSCs. Enhanced mobility of GDM-CMSCs may promote MSC migration toward injured sites; however, impaired cellular metabolic activity may negatively affect any perceived benefit.

Green synthesized MgO nanoparticles infer biocompatibility by reducing in vivo molecular nanotoxicity in embryonic zebrafish through arginine interaction elicited apoptosis

Increasing demand for magnesium oxide (MgO) nanoparticles (NP) due to their extensive use in different physical and biological applications has raised concern on their biocompatibility and toxicity to human health and ecological safety. This has instigated quest for detailed information on their toxicity mechanism, along with ecofriendly synthesis as a potential solution. This study explores the toxicity of MgO NP at the molecular level using embryonic zebrafish (Danio rerio) and depicts the green synthesis of MgO (G-MgO) NP using the extract from a medicinal plant Calotropis gigantea. Synthesized G-MgO NP were characterized using microscopy, spectroscopy, and dynamic light scattering. Stable 55 ± 10 nm sized MgO NP were generated with a zeta potential of 45 ± 15 mV and hydrodynamic size 110 ± 20 nm. UV–Vis spectrum showed a standard peak at 357 nm. Comparative cellular toxicity analysis showed higher biocompatibility of G-MgO NP compared to MgO NP with reference to the morphological changes, notochord development, and heartbeat rate in embryonic zebrafish LC50 of G-MgO NP was 520 μg/mL compared to 410 μg/mL of MgO NP. Molecular toxicity investigation revealed that the toxic effects of MgO NP was mainly due to the influential dysregulation in oxidative stress leading to apoptosis because of the accumulation and internalization of nanoparticles and their interaction with cellular proteins like Sod1 and p53, thereby affecting structural integrity and functionality. The study delineated the nanotoxicity of MgO NP and suggests the adoption and use of new green methodology for future production.

Cytotoxic and genotoxic effects of the flame retardants (PBDE-47, PBDE-99 and PBDE-209) in human bronchial epithelial cells.

Polybrominated diphenyl ethers (PBDEs) are widespread as flame-retardants in different types of consumer products. PBDEs present in the air or dust and their inhalation can damage human health by influencing the respiratory system. We evaluated the effects of environment relevant concentrations (0.01-1μM) of PBDE-47, PBDE-99 and PBDE-209 on the mechanism of oxidative stress, dysregulation of cell proliferation, apoptosis, and DNA damage and repair (in term of H2AX phosphorylation ser139) in an in-vitro/ex-vivo model of bronchial epithelial cells. PBDEs (-47,-99 and-209) at the environment relevant concentrations (0.01 and 1μM) induce oxidative stress (in term of NOX-4 expression as well as ROS and JC-1 production), activate the mechanism of DNA-damage and repair affecting Olive Tail length (comet assay) production and H2AX phosphorylation (ser139) in normal human bronchial epithelial cells. Furthermore PBDEs, although do not affect cell viability, induce cell apoptosis and single cell capacity to grow into a colony (like a cancer phenotype) in bronchial epithelial cells. Finally, PBDE-47 had a greater effect than-99 and-209. PBDE-47, -99 and-209 congeners exert cytotoxic and genotoxic effects, and play a critical role in the dysregulation of oxidative stress, damaging DNA and the related gene expression in bronchial epithelial cells. Our findings might suggest that PBDEs inhalation might have adverse effect on human health regarding pulmonary diseases in the areas of environmental pollution.

Lipopolysaccharide in systemic circulation induces activation of inflammatory response and oxidative stress in cardiorenal syndrome type 1.

Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury. In this study, we evaluate the role of lipopolysaccharide (LPS) and various inflammatory markers in the developing acute kidney injury (AKI) in acute heart failure (AHF) patients. We enrolled 31 AHF patients and 20 CRS type 1 (the cause of AKI was presumed to be related to cardiac dysfunction) and 17 healthy volunteers without AHF, AKI or CKD, as control group (CTR). We assessed levels of LPS, proinflammatory cytokines (TNF-α, IL-6, IL-18), and oxidative stress marker (myeloperoxidase, MPO). We observed a significant increase in LPS, TNF-α, IL-6, IL-18 and MPO levels in CRS type 1 and AHF group compared to CTR. LPS levels resulted significantly higher in CRS type 1 patients compared with AHF (118.2pg/mL, IQR 77.8-217.6 versus 13.5pg/mL, IQR 12.0-17.0, p = 0.008). We found a cytokines and oxidative stress dysregulation in CRS type 1 patients compared with AHF. Furthermore, we observed a strong positive significant correlation between LPS levels and IL-6 (Spearman's rho = 0.79, p < 0.001), and IL-18 (Spearman's rho = 0.77, p < 0.001) and MPO (Spearman's rho = 0.80, p < 0.001), all confirm by simple linear regression analysis. CRS type 1 patients presented an increased level of LPS, pro-inflammatory cytokines, and MPO. Furthermore, there is a direct correlation between LPS and pro-inflammatory cytokines and stress oxidative marker. LPS may play a role in the pathophysiology of CRS type 1 inducing inflammation, oxidative stress and finally kidney damage.

Early Identification and Intervention of Schizophrenia: Insight From Hypotheses of Glutamate Dysfunction and Oxidative Stress.

Schizophrenia is a severe mental disorder which leads to functional deterioration. Early detection and intervention are vital for better prognosis. However, the diagnosis of schizophrenia still depends on clinical observation to date. Without reliable biomarkers, schizophrenia is difficult to detect in its early phase. Further, there is no approved medication for prodromal schizophrenia because current antipsychotics fail to show satisfactory efficacy and safety. Therefore, to develop an effective early diagnostic and therapeutic approach for schizophrenia, especially in its prodromal phase, is crucial. Glutamate signaling dysfunction and dysregulation of oxidative stress have been considered to play important roles in schizophrenic prodrome. The N-methyl-D-aspartate receptor (NMDAR) is one of three types of ionotropic glutamate receptors. In this article, we reviewed literature regarding NMDAR hypofunction, oxidative stress, and the linkage between both in prodromal schizophrenia. The efficacy of NMDAR enhancers such as D-amino acid oxidase inhibitor was addressed. Finally, we highlighted potential biomarkers related to NMDAR and oxidative stress regulation, and therefore suggested the strategies of early detection and intervention of prodromal schizophrenia. Future larger-scale studies combining biomarkers and novel drug development for early psychosis are warranted.

NNT and NNT-AS1 expression levels are not different between bipolar patients and healthy subjects

Nicotinamide nucleotide transhydrogenase (NNT) participates in redox and energy interconnections. Nnt silencing in N27 dopaminergic cells has changed basal, extra, and greatest mitochondrial oxygen absorption rates and made these cell vulnerable to constant upsurges in H2O2. NNT-antisense RNA1 (NNT-AS1) is transcribed from the opposite stand of NNT gene and is possibly involved in regulation of NNT expression. Based on the reports of previous studies regarding dys-regulation of oxidative stress markers in bipolar patients, we designed the current study to assess peripheral expression of NNT and NNT-AS1 in bipolar patients and healthy subjects. Transcript levels of NNT and NNT-AS1 were not significantly different between bipolar patients and controls. No significant correlation was found between relative expression of genes and age of study participants. Moreover, expression of either gene was correlated with age at disease onset or disease duration in cases. However, significant pairwise correlation was found between expressions of these genes in bipolar patients. Our results imply that NNT does not participate in dys-regulation of oxidative stress in bipolar disease.

Proteomic Analysis of Hippocampus in a Mouse Model of Depression Reveals Neuroprotective Function of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) via Stress-induced Cysteine Oxidative Modifications

Chronic physical restraint stress increases oxidative stress in the brain, and dysregulation of oxidative stress can be one of the causes of major depressive disorder. To understand the underlying mechanisms, we undertook a systematic proteomic analysis of hippocampus in a chronic restraint stress mouse model of depression. Combining two-dimensional gel electrophoresis (2D-PAGE) for protein separation with nanoUPLC-ESI-q-TOF tandem mass spectrometry, we identified sixty-three protein spots that changed in the hippocampus of mice subjected to chronic restraint stress. We identified and classified the proteins that changed after chronic stress, into three groups respectively functioning in neural plasticity, metabolic processes and protein aggregation. Of these, 5 proteins including ubiquitin C-terminal hydrolase L1 (UCH-L1), dihydropyrimidinase-related protein 2 (DPYL2), haloacid dehalogenase-like hydrolase domain-containing protein 2 (HDHD2), actin-related protein 2/3 complex subunit 5 (ARPC5) and peroxiredoxin-2 (PRDX2), showed pI shifts attributable to post-translational modifications. Further analysis indicated that UCH-L1 underwent differential oxidations of 2 cysteine residues following chronic stress. We investigated whether the oxidized form of UCH-L1 plays a role in stressed hippocampus, by comparing the effects of UCH-L1 and its Cys mutants on hippocampal cell line HT-22 in response to oxidative stress. This study demonstrated that UCH-L1 wild-type and cysteine to aspartic acid mutants, but not its cysteine to serine mutants, afforded neuroprotective effects against oxidative stress; there were no discernible differences between wild-type UCH-L1 and its mutants in the absence of oxidative stress. These findings suggest that cysteine oxidative modifications of UCH-L1 in the hippocampus play key roles in neuroprotection against oxidative stress caused in major depressive disorder.