bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2022‒02‒13
six papers selected by
Laia Caja Puigsubira
Uppsala University
  1. The role of reactive oxygen species derived from different NADPH oxidase isoforms and mitochondria in oxalate-induced oxidative stress and cell injury.
  2. Poldip2/Nox4 Mediates Lipopolysaccharide-Induced Oxidative Stress and Inflammation in Human Lung Epithelial Cells.
  3. TGF-β1 Disrupts redox balance in PCCL3 thyroid cell and is sexually dimorphic expressed in rat thyroid gland.
  4. Glucagon-like peptide-1 receptor activation by liraglutide promotes breast cancer through NOX4/ROS/VEGF pathway.
  5. Melatonin alleviates PM2.5-triggered macrophage M1 polarization and atherosclerosis via regulating NOX2-mediated oxidative stress homeostasis.
  6. Involvement of NOX-4/JAK/STAT pathway in the protective effect of aprepitant against diclofenac-induced renal toxicity.
  1. Urolithiasis. 2022 Feb 06.
    The role of reactive oxygen species derived from different NADPH oxidase isoforms and mitochondria in oxalate-induced oxidative stress and cell injury.
    Xiaoyuan Qian, Weisong Wu, Henglong Hu, Xiao Yu, Shaogang Wang, Jianning Zhu, Jiaqiao Zhang.
      Hyperoxaluria is a risk factor for urolithiasis and can cause renal epithelial cell injury secondary to oxidative stress. Reactive oxygen species (ROS) produced during cell damage originate from different sources and play different roles. Here, we explored the potential sources of ROS production and investigated the role of ROS from various sources in oxalate-induced oxidative stress and cell injury in normal rat kidney-52 epithelial (NRK-52E) cells. Oxalate-induced injury was assessed by lactate dehydrogenase (LDH) release experiments. 2,7-dichlorodihydrofluorescein diacetate and mitoSOX Red were used to determine the intracellular and mitochondrial ROS (mtROS) production, respectively. The expression level of Nox4, Nox2, and p22 protein was detected by Western blotting to observe the effect of oxalate on nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase (Nox). Furthermore, a specific NADPH oxidase subtype inhibitor and targeted mitochondrial antioxidants were used to preliminarily identify the role of ROS from different sources in renal tubular epithelial cell injury induced by oxalate. We found that oxalate inhibited cell viability, induced LDH release, and prompted intracellular and mitochondrial ROS (mtROS) production. Oxalate also decreased the protein expression level of Nox4 and increased the protein expression level of p22. Mitochondria were also a source of ROS production. In addition, Nox2 inhibitor or mtROS scavenging prevented oxalate-induced cell injury, reversed by an inhibitor of Nox4/1. We concluded that ROS from different sources might play different roles in oxalate-induced renal tubular epithelial cell injury. We also identified new potential targets for preventing or alleviating oxalate-induced renal tubular epithelial cell injury.
    Keywords:  Mitochondria; NADPH oxidase; Oxalate; Reactive oxygen species; Urolithiasis
    DOI:  https://doi.org/10.1007/s00240-022-01309-2
  2. Mediators Inflamm. 2022 ;2022 6666022
    Poldip2/Nox4 Mediates Lipopolysaccharide-Induced Oxidative Stress and Inflammation in Human Lung Epithelial Cells.
    Yueguo Wang, Zhenxing Ding, Youhui Tu, Xu Wu, Wenying Zhang, Shuang Ji, Jilong Shen, Li Zhang, Huimei Wu, Guanghe Fei.
      NADPH oxidase 4 (Nox4) is an important source of reactive oxygen species (ROS) production, and its expression is increased in lipopolysaccharide- (LPS-) stimulated lung epithelial cells. Polymerase δ-interacting protein 2 (Poldip2) has been proved to bind Nox4 and participates in oxidative stress and inflammation. However, the role of Poldip2/Nox4 in LPS-induced oxidative stress and inflammation in lung epithelial cells remains unclear. Cell viability was measured via MTT assays. The expression of Poldip2, Nox4, heme oxygenase-1 (HO-1), cyclooxygenase-2 (COX-2), AKT, and p-AKT was detected by Western blotting and/or immunofluorescence. Poldip2 and Nox4 interaction was analyzed via coimmunoprecipitation (Co-IP) assay. NADPH enzymatic activity and production of ROS, prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were assessed simultaneously. The small interfering RNA (siRNA) or plasmid targeting Nox4 was used to downregulate or upregulate Nox4, and the lentiviral vector encoding Poldip2 was used to downregulate or upregulate Poldip2. The present study demonstrated that LPS stimulation significantly increased the protein levels of Poldip2 and Nox4 and proved that Poldip2 interacted with Nox4 proved by Co-IP. Importantly, Poldip2 acted as an upstream regulator of Nox4. The increased expression of Nox4 and COX-2; NADPH enzymatic activity; production of ROS, PGE2, TNF-α, and IL-1β; and decreased HO-1 expression were significantly suppressed by lentiviral Poldip2 shRNA downregulation but were increased by lentiviral upregulation of Poldip2. Furthermore, inhibiting of PI3K-AKT signaling notably attenuated LPS-induced Poldip2/Nox4 activation. Our study demonstrated that Poldip2 mediates LPS-induced oxidative stress and inflammation via interaction with Nox4 and was regulated by the PI3K-AKT signaling. Targeting Poldip2 could be a beneficial therapeutic strategy for the treatment of ALI.
    DOI:  https://doi.org/10.1155/2022/6666022
  3. Mol Cell Endocrinol. 2022 Feb 06. pii: S0303-7207(22)00040-5. [Epub ahead of print]546 111593
    TGF-β1 Disrupts redox balance in PCCL3 thyroid cell and is sexually dimorphic expressed in rat thyroid gland.
    Caroline Coelho de Faria, Fabio Hecht Castro Medeiros, Juliana Cazarin Menezes, Victor Hugo Ortenzi de Andrade Silva, Andrea Claudia Freitas Ferreira, Denise Pires de Carvalho, Rodrigo Soares Fortunato.
      Thyroid diseases are more prevalent in women, and this difference seems to be associated with the oxidative stress found in the thyroid of females. Thyroid NADPH Oxidase 4 (NOX4) was shown to respond to estrogen, which can also modulate TGF-β1, a potent stimulator of NOX4. This study aimed to investigate the effects of TGF-β1 on redox homeostasis parameters in the rat thyroid cell PCCL3 and the interrelationship between estrogen and TGF-β1. TGF-β1 treatment increased both intra- and extracellular ROS generation along with NOX4 expression and reduced GPX and catalase activities, extracellular H2O2 scavenging capacity, and reduced thiol content. TGF-β1 mRNA and protein expression are higher in female thyroid glands of rats in comparison to males. Moreover, 17β-estradiol treatment enhanced TGF-β1 mRNA in PCCL3 cells, decreased extracellular bioavailability but did not activate Smad pathway. Our data suggest that higher levels of TGF-β1 in females are potentially related to higher ROS availability which may be associated with the sex disparity in thyroid disorders.
    Keywords:  Estrogen; NOX4; ROS; TGF-β1; Thyroid
    DOI:  https://doi.org/10.1016/j.mce.2022.111593
  4. Life Sci. 2022 Feb 03. pii: S0024-3205(22)00070-4. [Epub ahead of print]294 120370
    Glucagon-like peptide-1 receptor activation by liraglutide promotes breast cancer through NOX4/ROS/VEGF pathway.
    Zhan-Zhao Liu, Xian-Xian Duan, Meng-Ci Yuan, Jing Yu, Xiao Hu, Xiao Han, Lan Lan, Bo-Wei Liu, Yue Wang, Jun-Fang Qin.
      AIMS: Scientific evidence imply the strong correlation between diabetes and breast cancer. Glucagon-like peptide-1 (GLP-1) and its analogue liraglutide, have been widely used for diabetes treatment. However, the role of GLP-1 receptor (GLP-1R) in breast cancer requires further elucidation. This study aimed to investigate the risk and the molecular mechanisms of liraglutide using in breast cancer.MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction, western blot or immunohistochemistry were used to detect the expressions of GLP-1R, NADPH oxidase 4 (NOX4) and vascular endothelial growth factor (VEGF) in human triple negative breast cancer (TNBC) cells (MDA-MB-231 and MDA-MB-468) and tissues derived from BALB/cfC3H mouse bearing 4T1 cells inoculation. Cell proliferation and migration was detected using the Cell Counting Kit-8, adenosine triphosphate assay, and transwell assay, respectively. Flow cytometry was used to measure the level of reactive oxygen species (ROS).
    KEY FINDINGS: We found that the expression of GLP-1R increased after liraglutide treatment in breast cancer cells and the transplanted tumors. Liraglutide, at a slightly higher concentration, accelerated breast cancer progress in vitro (100 nM) and in vivo (400μg/kg) through the NOX4/ROS/VEGF signal pathway after activating GLP-1R. The GLP-1R inhibitor, Exendin (9-39), significantly inhibited the effect of liraglutide, inducing a reversed function of GLP-1R activation.
    SIGNIFICANCE: Our study illustrated that in an approximately toxicology context, liraglutide may promote the malignant progression of TNBC. The dosage and the phenotype of the breast cancer should be considered as important factors for the rational administration of antidiabetic drugs, especially that of liraglutide in breast cancer patients.
    Keywords:  Breast cancer; Glucagon-like peptide-1 receptor (GLP-1R); Liraglutide; NADPH oxidases 4 (NOX4); Reactive oxygen species (ROS); VEGF
    DOI:  https://doi.org/10.1016/j.lfs.2022.120370
  5. Free Radic Biol Med. 2022 Feb 08. pii: S0891-5849(22)00058-2. [Epub ahead of print]
    Melatonin alleviates PM2.5-triggered macrophage M1 polarization and atherosclerosis via regulating NOX2-mediated oxidative stress homeostasis.
    Jiangyan Liu, Qinglin Sun, Mengqi Sun, Lisen Lin, Xiaoke Ren, Tianyu Li, Qing Xu, Zhiwei Sun, Junchao Duan.
      It is reported that oxidative stress homeostasis was involved in PM2.5-induced foam cell formation and progression of atherosclerosis, but the exact molecular mechanism is still unclear. Melatonin is an effective antioxidant that could reverse the cardiopulmonary injury. The main purpose of this study is to investigate the latent mechanism of PM2.5-triggered atherosclerosis development and the protective role of melatonin administration. Vascular Doppler ultrasound showed that PM2.5 exposure reduced aortic elasticity in ApoE-/- mice. Meanwhile, blood biochemical and pathological analysis demonstrated that PM2.5 exposure caused dyslipidemia, elicited oxidative damage of aorta and was accompanied by an increase in atherosclerotic plaque area; while the melatonin administration could effectively alleviate PM2.5-induced macrophage M1 polarization and atherosclerosis in mice. Further investigation verified that NADPH oxidase 2 (NOX2) and mitochondria are two prominent sources of PM2.5-induced ROS production in vascular macrophages. Whereas, the combined use of two ROS-specific inhibitors and adopted with melatonin markedly rescued PM2.5-triggered macrophage M1 polarization and foam cell formation by inhibiting NOX2-mediated crosstalk of Keap1/Nrf2/NF-κB and TLR4/TRAF6/NF-κB signaling pathways. Our results demonstrated that NOX2-mediated oxidative stress homeostasis is critical for PM2.5-induced atherosclerosis and melatonin might be a potential treatment for air pollution-related cardiovascular diseases.
    Keywords:  Atherosclerosis; Macrophage M1 polarization; NADPH oxidase 2; Oxidative stress homeostasis; PM(2.5)
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.02.005
  6. Life Sci. 2022 Feb 07. pii: S0024-3205(22)00081-9. [Epub ahead of print] 120381
    Involvement of NOX-4/JAK/STAT pathway in the protective effect of aprepitant against diclofenac-induced renal toxicity.
    Heba M Hafez, Shaimaa Waz, Rehab Ahmed Rifaai, Mervat Z Mohamed.
      AIMS: Aprepitant, a neurokinin-1 (NK1) receptor antagonist, is a clinically approved anti-emetic drug. Recently, inhibition of the NK1 receptor has been reported as a potential nephroprotective strategy. We aimed to assess the pharmacological mechanisms of aprepitant against diclofenac (DIC)-induced renal toxicity.MAIN METHODS: An in vivo study was conducted using twenty-four male Wistar rats, divided into 4 groups. Aprepitant was administered for 5 days (5 mg/kg/day) with or without DIC which was given on the 4th and 5th days (50 mg/kg, i.p.). At the end of the study, renal function biomarkers, renal oxidative parameters, prostaglandin E (PGE-2), and NADPH oxidase (NOX-4) were measured. Histopathological changes as well as expression of renal inflammatory and apoptotic markers (tumor necrosis factor alpha (TNF-α) and caspase-3) were investigated.
    KEY FINDINGS: DIC caused significant renal damage, as evidenced by deterioration of renal functions, oxidative stress, inflammatory and apoptotic markers, and confirmed by histopathological findings. Pretreatment with aprepitant successfully ameliorated and improved all biochemical and molecular parameters induced by DIC. Moreover, aprepitant restored the decrease in renal PGE-2 concentration and inhibited DIC-activated Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling in renal tissues.
    SIGNIFICANCE: The protective effect of aprepitant is possibly attributed to its anti-oxidant and anti-inflammatory roles via the NOX-4/JAK/STAT pathway.
    Keywords:  Aprepitant; Diclofenac; JAK/STAT; NADPH oxidase; Nephrotoxicity
    DOI:  https://doi.org/10.1016/j.lfs.2022.120381
This page is being maintained by Thomas Krichel. It was last updated on 2022‒02‒14 at 15:04:33.