Quercetin in Hypoxia-Induced Oxidative Stress: Novel Target for Neuroprotection

Cancer cells are characterized by higher levels of reactive oxygen species (ROS) compared to normal cells as a result of an imbalance between oxidants and antioxidants. However, cancer cells maintain their redox balance due to their high antioxidant capacity. Recently, a high level of oxidative stress is considered a novel target for anticancer therapy. This can be induced by increasing exogenous ROS and/or inhibiting the endogenous protective antioxidant system. Additionally, the immune system has been shown to be a significant ally in the fight against cancer. Since ROS levels are important to modulate the antitumor immune response, it is essential to consider the effects of oxidative stress-inducing treatments on this response. In this review, we provide an overview of the mechanistic cellular responses of cancer cells towards exogenous and endogenous ROS-inducing treatments, as well as the indirect and direct antitumoral immune effects, which can be both immunostimulatory and/or immunosuppressive. For future perspectives, there is a clear need for comprehensive investigations of different oxidative stress-inducing treatment strategies and their specific immunomodulating effects, since the effects cannot be generalized over different treatment modalities. It is essential to elucidate all these underlying immune effects to make oxidative stress-inducing treatments effective anticancer therapy.

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PRDX4 and Its Roles in Various Cancers

Technology in Cancer Research & Treatment ◽

10.1177/1533033819864313 ◽

2019 ◽

Vol 18 ◽

pp. 153303381986431

Author(s):

Wenqiao Jia ◽

Pengxiang Chen ◽

Yufeng Cheng

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Stem Cells ◽

Cell Survival ◽

Redox Regulation ◽

Redox Balance ◽

Vital Role ◽

Research Progress ◽

A Cell ◽

Novel Target

Reactive oxygen species play a vital role in cell survival by regulating physiological metabolism and signal transduction of cells. The imbalance of oxidant and antioxidant states induces oxidative stress within a cell. Redox regulation and oxidative stress are closely related to survival and proliferation of stem cells, cancer cells, and cancer stem cells. Peroxiredoxin 4, a typical endoplasmic reticulum-resident 2-Cys antioxidant of peroxiredoxins, can fine-tune hydrogen peroxide catabolism which affects cell survival by affecting redox balance, oxidative protein folding, and regulation of hydrogen peroxide signaling. Recent studies revealed the overexpression of peroxiredoxin 4 in several kinds of cancers, such as breast cancer, prostate cancer, ovarian cancer, colorectal cancer, and lung cancer. And it has been demonstrated that peroxiredoxin 4 causally contributes to tumorigenesis, therapeutic resistance, metastasis, and recurrence of tumors. In this article, the characteristics of peroxiredoxin 4 in physiological functions and the cancer-related research progress of mammalian peroxiredoxin 4 is reviewed. We believe that peroxiredoxin 4 has the potential of serving as a novel target for multiple cancers.

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Allergen inhalation generates pro-inflammatory oxidised phosphatidylcholine associated with airway dysfunction

European Respiratory Journal ◽

10.1183/13993003.00839-2020 ◽

2020 ◽

pp. 2000839 ◽

Cited By ~ 1

Author(s):

Christopher D. Pascoe ◽

Aruni Jha ◽

Min Hyung Ryu ◽

Mirna Ragheb ◽

Jignesh Vaghasiya ◽

...

Keyword(s):

Oxidative Stress ◽

Smooth Muscle ◽

Airway Smooth Muscle ◽

High Performance ◽

Allergen Challenge ◽

Airway Narrowing ◽

Gm Csf ◽

Liquid Chromatography Tandem Mass ◽

Inflammatory Phenotype ◽

Novel Target

RationaleOxidised phosphatidylcholines (OxPC) are produced under conditions of elevated oxidative stress and can contribute to human disease pathobiology. However, their role in allergic asthma is unexplored.ObjectivesCharacterise the OxPC profile in the airways after allergen challenge of people with airway hyperresponsiveness (AHR) or mild-asthma. Determine the capacity of OxPC to contribute to pathobiology associated with asthma.MethodsUsing bronchoalveolar lavage (BAL) from two human cohorts, OxPC species were quantified using ultra high performance liquid chromatography tandem mass spectrometry. Murine thin cut lung slices (TCLS) were used to measure airway narrowing caused by OxPCs. Human airway smooth muscle (HASM) cells were exposed to OxPCs to assess concentration-associated changes in inflammatory phenotype and activation of signalling networks.Measurements and Main ResultsOxPC profiles were different in the airways of people with or without AHR and correlated with methacholine responsiveness. Exposure of mild-asthmatics to allergens produced unique OxPC signatures that were associated with the late asthma response severity. OxPCs dose-dependently induced 15% airway narrowing in murine TCLS. In HASM, OxPCs dose-dependently increased the biosynthesis of cyclooxygenase-2, IL-6, IL-8, GM-CSF, and the production of oxylipins via protein kinase C-dependent pathways.ConclusionsData from human cohorts and primary HASM culture we show that OxPCs are present in the airways, increase after allergen challenge, and correlate with metrics of a dysfunction. Furthermore, OxPCs may contribute to asthma pathobiology by promoting airway narrowing and inducing a pro-inflammatory phenotype and contraction of airway smooth muscle. OxPCs represent a potential novel target for treating oxidative stress-associated pathobiology in asthma.

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Regulation of the Dimerization and Activity of SARS-CoV-2 Main Protease through Reversible Glutathionylation of Cysteine 300

10.1101/2021.04.09.439169 ◽

2021 ◽

Author(s):

David A Davis ◽

Haydar Bulut ◽

Prabha Shrestha ◽

Amulya Yaparla ◽

Hannah K. Jaeger ◽

...

Keyword(s):

Oxidative Stress ◽

Human Disease ◽

Reducing Agents ◽

Therapeutic Interventions ◽

Primary Target ◽

Analytical Studies ◽

Main Protease ◽

Novel Target

SARS-CoV-2 encodes main protease (Mpro), an attractive target for therapeutic interventions. We show Mpro is susceptible to glutathionylation leading to inhibition of dimerization and activity. Activity of glutathionylated Mpro could be restored with reducing agents or glutaredoxin. Analytical studies demonstrated that glutathionylated Mpro primarily exists as a monomer and that a single modification with glutathione is sufficient to block dimerization and loss of activity. Proteolytic digestions of Mpro revealed Cys300 as a primary target of glutathionylation, and experiments using a C300S Mpro mutant revealed that Cys300 is required for inhibition of activity upon Mpro glutathionylation. These findings indicate that Mpro dimerization and activity can be regulated through reversible glutathionylation of Cys300 and provides a novel target for the development of agents to block Mpro dimerization and activity. This feature of Mpro may have relevance to human disease and the pathophysiology of SARS-CoV-2 in bats, which develop oxidative stress during flight.

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MicroRNA-874-3p Aggravates Doxorubicin-Induced Renal Podocyte Injury via Targeting Methionine Sulfoxide Reductase B3

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/9481841 ◽

2020 ◽

Vol 2020 ◽

pp. 1-18

Author(s):

Yan Dai ◽

Meng Gao ◽

Linxia Li ◽

Zhang Mao ◽

Lina Xu ◽

...

Keyword(s):

Oxidative Stress ◽

Side Effects ◽

Methionine Sulfoxide ◽

Methionine Sulfoxide Reductase ◽

Luciferase Reporter ◽

Renal Diseases ◽

Luciferase Reporter Gene ◽

Podocyte Injury ◽

Novel Target ◽

Related Proteins

Clinical application of doxorubicin (Dox) is limited due to its serious side effects including nephrotoxicity, and kidney podocytes play important roles in renal diseases. MicroRNAs (miRNAs) are critical regulators associated with human diseases. The purpose of this study was to explore a novel target in adjusting Dox-induced renal podocyte injury. Through a double luciferase reporter gene experiment, it was found that miR-874-3p directly targeted methionine sulfoxide reductase B3 (MsrB3). During the tests of miR-874-3p inhibitor and MsrB3 siRNA in human podocytes or miR-874-3p antagomir in mice, we found that the expression levels of downstream oxidative stress and apoptosis-related proteins were regulated by miR-874-3p/MsrB3 signal to alleviate or aggravate renal podocyte injury. The data in the present work showed that miR-874-3p aggravated Dox-caused renal podocyte injury by promoting apoptosis and oxidative damage via inhibiting MsrB3. Therefore, miR-874-3p/MsrB3 should be considered as a new therapeutic target in controlling renal podocyte injury induced by Dox.

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The Emerging Role of Pathogenesis of IgA Nephropathy

Journal of Clinical Medicine ◽

10.3390/jcm7080225 ◽

2018 ◽

Vol 7 (8) ◽

pp. 225 ◽

Cited By ~ 4

Author(s):

Meng-Yu Wu ◽

Chien-Sheng Chen ◽

Giou-Teng Yiang ◽

Pei-Wen Cheng ◽

Yu-Long Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Iga Nephropathy ◽

Immune Complex ◽

Review Article ◽

Molecular Regulation ◽

Therapeutic Approaches ◽

Treatment Interventions ◽

Inflammatory Cascade ◽

Novel Target

IgA nephropathy is an autoimmune disease induced by fthe ormation of galactose-deficient IgA1 and anti-glycans autoantibody. A multi-hit hypothesis was promoted to explain full expression of IgA nephropathy. The deposition of immune complex resulted in activation of the complement, increasing oxidative stress, promoting inflammatory cascade, and inducing cell apoptosis via mesangio-podocytic-tubular crosstalk. The interlinked signaling pathways of immune-complex-mediated inflammation can offer a novel target for therapeutic approaches. Treatments of IgA nephropathy are also summarized in our review article. In this article, we provide an overview of the recent basic and clinical studies in cell molecular regulation of IgAN for further treatment interventions.

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Novel Hematopoietic Target Genes in the NRF2-Mediated Transcriptional Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/120305 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 36

Author(s):

Michelle R. Campbell ◽

Mehmet Karaca ◽

Kelly N. Adamski ◽

Brian N. Chorley ◽

Xuting Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Iron Homeostasis ◽

Target Genes ◽

K562 Cells ◽

Antioxidant Response ◽

Lymphoid Cells ◽

Negative Regulator ◽

Cis Acting ◽

Heme Metabolism ◽

Novel Target

Nuclear factor- (erythroid-derived 2) like 2 (NFE2L2, NRF2) is a key transcriptional activator of the antioxidant response pathway and is closely related to erythroid transcription factorNFE2. Under oxidative stress, NRF2 heterodimerizes with small Maf proteins and binds cis-acting enhancer sequences found near oxidative stress response genes. Using the dietary isothiocyanate sulforaphane (SFN) to activate NRF2, chromatin immunoprecipitation sequencing (ChIP-seq) identified several hundred novel NRF2-mediated targets beyond its role in oxidative stress. Activated NRF2 bound the antioxidant response element (ARE) in promoters of several known and novel target genes involved in iron homeostasis and heme metabolism, including known targetsFTLandFTH1, as well as novel binding in the globin locus control region. Five novel NRF2 target genes were chosen for followup:AMBP, ABCB6, FECH, HRG-1 (SLC48A1), andTBXAS1. SFN-induced gene expression in erythroid K562 and lymphoid cells were compared for each target gene. NRF2 silencing showed reduced expression in lymphoid, lung, and hepatic cells. Furthermore, stable knockdown of NRF2 negative regulator KEAP1 in K562 cells resulted in increasedNQO1, AMBP, andTBXAS1expression. NFE2 binding sites in K562 cells revealed similar binding profiles as lymphoid NRF2 sites in all potential NRF2 candidates supporting a role forNRF2in heme metabolism and erythropoiesis.

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Abstract P70: SPAK/OSR1 Signaling as a Novel Target for Post-Stroke Oxidative Stress Brain Injury

Stroke ◽

10.1161/str.52.suppl_1.p70 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Jun Wang ◽

Victoria M Fiesler ◽

Gulnaz Begum ◽

Mohammad Iqbal H Bhuiyan ◽

Shuying Dong ◽

...

Keyword(s):

Oxidative Stress ◽

Ischemic Stroke ◽

Brain Injury ◽

Neuronal Damage ◽

Recombinant Tissue Plasminogen Activator ◽

Primary Therapy ◽

Post Stroke ◽

Stroke Models ◽

Novel Target

Stroke is the second leading cause of death worldwide, and ischemic stroke accounts for the vast majority of stroke cases. Currently, recombinant tissue plasminogen activator and endovascular thrombectomy are the two primary therapy strategies for acute ischemic stroke patients. Reactive oxygen species (ROS)-mediated oxidative stress can cause brain injury during reperfusion. We have shown that the Ste20/SPS1-related proline-alanine-rich protein kinase/oxidative stress-responsive kinase-1 (SPAK/OSR1) are activated in ischemic stroke brains, resulting in worsened outcomes in murine stroke models. SPAK activation induces the production of pro-inflammatory cytokines. Post-stroke administration of a novel SPAK inhibitor ZT-1a attenuates cerebral edema and protects against brain damage in in vivo model of ischemic stroke. However, whether ROS mediated oxidative stress directly activate SPAK/OSR1 pathway and induces SPAK pro-inflammatory cytokine production in ischemic brains remains unknown. In our extended study, we examined activation of SPAK/OSR1 and its substrate Na-K-Cl cotransporter (NKCC1) in cultured mouse primary neurons in response to hydrogen peroxide (H 2 O 2 )-mediated oxidative stress. We found that exposure of neurons to H 2 O 2 for 24 hrs triggered upregulation of protein expression and phosphorylation activation of SPAK/OSR1 and NKCC1 ( p < 0.05), which are accompanied with an increase in intracellular Na + concentration and neuronal death ( p < 0.01). These changes were blocked by an ROS scavenger ebselen. Interestingly, both novel SPAK inhibitor ZT-1a and NKCC1 inhibitor bumetanide are able to block H 2 O 2 -induced neuronal damage. We are in the process to assess effects of SPAK inhibitor ZT-1a in reducing ROS-mediated inflammation and brain injury in in vivo model of ischemic stroke. Together, our study suggests that ROS can activate SPAK/OSR1 complex during reperfusion injury and the therapeutic potentials of SPAK inhibitor ZT-1a for ischemic stroke.

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