bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2020‒05‒31
five papers selected by
Laia Caja Puigsubira
Uppsala University


  1. Redox Biol. 2020 May 16. pii: S2213-2317(20)30554-1. [Epub ahead of print]34 101575
    Rodríguez C, Contreras C, Sáenz-Medina J, Muñoz M, Corbacho C, Carballido J, García-Sacristán A, Hernandez M, López M, Rivera L, Prieto D.
      AMP-activated protein kinase (AMPK) is a cellular energy sensor activated during energy stress to stimulate ATP production pathways and restore homeostasis. AMPK is widely expressed in the kidney and involved in mitochondrial protection and biogenesis upon acute renal ischemia, AMPK activity being blunted in metabolic disease-associated kidney disease. Since little is known about AMPK in the regulation of renal blood flow, the present study aimed to assess the role of AMPK in renal vascular function. Functional responses to the selective AMPK activator A769662 were assessed in intrarenal small arteries isolated from the kidney of renal tumour patients and Wistar rats and mounted in microvascular myographs to perform simultaneous measurements of intracellular calcium [Ca2+]i and tension. Superoxide (O2.-) and hydrogen peroxide (H2O2) production were measured by chemiluminescence and fluorescence and protein expression by Western blot. Activation of AMPK with A769662 increased AMPKα phosphorylation at Thr-172 and induced potent relaxations compared to AICAR in isolated human and rat intrarenal arteries, through both endothelium-dependent mechanisms involving nitric oxide (NO) and intermediate-conductance calcium-activated potassium (IKCa) channels, as well as activation of ATP-sensitive (KATP) channels and sarcoplasmic reticulum Ca2+-ATPase (SERCA) in vascular smooth muscle (VSM). Furthermore, AMPK activator reduced NADPH oxidase 4 (Nox4) and Nox2-derived reactive oxygen species (ROS) production. These results demonstrate that A769662 has potent vasodilator and antioxidant effects in intrarenal arteries. The benefits of AMPK activation in rat kidney are reproduced in human arteries and therefore vascular AMPK activation might be a therapeutic target in the treatment of metabolic disease-associated kidney injury.
    Keywords:  AMPK activators; IK(Ca) channels; K(ATP) channels; Reactive oxygen species; Renal arteries; SERCA
    DOI:  https://doi.org/10.1016/j.redox.2020.101575
  2. Cell Stress Chaperones. 2020 May 23.
    Vallés PG, Bocanegra V, Costantino VV, Gil Lorenzo AF, Benardon ME, Cacciamani V.
      Angiotensin II exerts a cardinal role in the pathogenesis of hypertension and renal injury via action of angiotensin II type 1 (AT1) receptors. Local renin-angiotensin system (RAS) activity is essential for the mechanisms mediating pathophysiological functions. Proximal tubular angiotensinogen and tubular AT1 receptors are augmented by intrarenal angiotensin II. Caveolin 1 plays an important role as a regulatory molecule for the compartmentalization of redox signaling events through angiotensin II-induced NADPH oxidase activation in the kidney. A role for the renin-angiotensin system in the development and/or maintenance of hypertension has been demonstrated in spontaneously hypertensive rats (SHRs). Many effects of angiotensin II are dependent on the AT1 stimulation of reactive oxygen species (ROS) production by NADPH oxidase. Angiotensin II upregulation stimulates oxidative stress in proximal tubules from SHR. The NADPH oxidase 4 (Nox4) is abundantly expressed in kidney proximal tubule cells. Induction of the stress response includes synthesis of heat shock protein 70, a molecular chaperone that has a critical role in the recovery of cells from stress and in cytoprotection, guarding cells from subsequent insults. HSP70 chaperones function in part by driving the molecular triage decision, which determines whether proteins enter the productive folding pathway or result in client substrate ubiquitination and proteasomal degradation. This review examines regulation of losartan-mediated antioxidative stress responses by the chaperone HSP70 in proximal tubule cells of spontaneously hypertensive rats.
    Keywords:  Angiotensin II; Heat shock proteins 70 (HSP70); Losartan; Nox4 NADPH oxidase; Renal proximal tubule cells
    DOI:  https://doi.org/10.1007/s12192-020-01119-8
  3. Nutrients. 2020 May 22. pii: E1516. [Epub ahead of print]12(5):
    An X, Zhang Y, Cao Y, Chen J, Qin H, Yang L.
      Diabetic nephropathy is a diabetic complication caused by chronic inflammation. As the primary polyphenol in pomegranate, punicalagin is believed to have significant anti-inflammatory properties. In this study, we established a mice model for diabetes induced by high-fat diet (HFD)/ streptozotocin (STZ) to verify the protective effect of punicalagin in vivo. The results show that the blood urea nitrogen (BUN), serum creatinine (CREA), and the urine albumin to creatinine ratio (UACR) were significantly decreased in diabetic mice after punicalagin intervention, and the symptoms of glomerular interstitial hyperplasia and glomerular hypertrophy were alleviated. Pyroptosis is an essential manner of programmed cell death in the inflammatory response; the expression of pyroptosis-related proteins such as interleukin-1 (IL-1β), cysteinyl aspartate-specific protease-1 (caspase-1), gasdermin D (GSDMD), and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing protein 3 (NLRP3) was decreased in our study, which proved that the administration of punicalagin for eight weeks can significantly inhibit pyroptosis in mice. In addition, punicalagin reduced high glucose-mediated protein expressions of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) and alleviated mitochondria damage. Low expression of NOX4 inhibits the dissociation of thioredoxin (Trx) and thioredoxin-interacting protein (TXNIP) and the suppression of NLRP3 inflammasome activation. To summarize, our study provided evidence that punicalagin can alleviate diabetic nephropathy, and the effect is associated with downregulating the expression of NOX4, inhibiting TXNIP/NLRP3 pathway-mediated pyroptosis, suggesting its therapeutic implications for complications of diabetes.
    Keywords:  NLRP3 inflammasome; TXNIP; diabetic nephropathy; punicalagin; pyroptosis
    DOI:  https://doi.org/10.3390/nu12051516
  4. Redox Biol. 2020 May 16. pii: S2213-2317(20)30378-5. [Epub ahead of print]34 101571
    Fan CC, Tsai ST, Lin CY, Chang LC, Yang JC, Chen GY, Sher YP, Wang SC, Hsiao M, Chang WC.
      Recurrence and metastasis remain the major cause of cancer mortality. Even for early-stage lung cancer, adjuvant chemotherapy yields merely slight increase to patient survival. EF-hand domain-containing protein D2 (EFHD2) has recently been implicated in recurrence of patients with stage I lung adenocarcinoma. In this study, we investigated the correlation between EFHD2 and chemoresistance in non-small cell lung cancer (NSCLC). High expression of EFHD2 was significantly associated with poor overall survival of NSCLC patients with chemotherapy in in silica analysis. Ectopic EFHD2 overexpression increased cisplatin resistance, whereas EFHD2 knockdown improved chemoresponse. Mechanistically, EFHD2 induced the production of NADPH oxidase 4 (NOX4) and in turn the increase of intracellular reactive oxygen species (ROS), consequently activating membrane expression of the ATP-binding cassette subfamily C member 1 (ABCC1) for drug efflux. Non-steroidal anti-inflammatory drug (NSAID) ibuprofen suppressed EFHD2 expression by leading to the proteasomal and lysosomal degradation of EFHD2 through a cyclooxygenase (COX)-independent mechanism. Combining ibuprofen with cisplatin enhanced antitumor responsiveness in a murine xenograft model in comparison with the individual treatment. In conclusion, we demonstrate that EFHD2 promotes chemoresistance through the NOX4-ROS-ABCC1 axis and therefore developing EFHD2-targeting strategies may offer a new avenue to improve adjuvant chemotherapy of lung cancer.
    Keywords:  ABCC1; Adjuvant chemotherapy; EFHD2; Ibuprofen; NOX4; Recurrence
    DOI:  https://doi.org/10.1016/j.redox.2020.101571
  5. Int J Endocrinol. 2020 ;2020 3161730
    Ma X, Wang F, Zhen X, Zhao L, Fang L, Dong Z, Chen W, Zhou X.
      Background: gp91phox, the catalytic core of NADPH oxidase (NOX) and biomarker of NOX activation, has been recently recognized as a parameter of systemic oxidative stress in several studies. Subclinical hypothyroidism (SH) is characteristic of elevated level of serum thyroid stimulating hormone (TSH) and is frequently accompanied with cholesterolemia. In this study, the levels of serum soluble gp91phox were measured to assess the oxidative stress in patients with SH. And the relationship among gp91phox, low-density lipoprotein-C (LDL-C), and TSH was also investigated.Methods: A total of 51 subjects were enrolled and categorized into four groups: the healthy controls subjects (n = 13), controls with high level of LDL-C alone (n = 12), SH with normal level of LDL-C (n = 11), and SH with high level of LDL-C (n = 15). The related clinical and laboratory data were collected for statistical analysis. All the patients were newly diagnosed and did not take any medication. The information of lipid profile and thyroid function was extracted, and the concentrations of gp91phox were obtained with ELISA.
    Results: The levels of serum soluble gp91phox evidently increased in the patients with SH with a high level of LDL-C (81.52 ± 37.00 ug/mL) as compared to the healthy controls (54.98 ± 1.83ug/mL, p < 0.001), controls with high level of LDL-C (61.21 ± 4.48 ug/mL, p=0.038) and SH with a normal level of LDL-C (62.82 ± 11.67ug/mL, p=0.027). Additionally, the levels of gp91phox showed a significant positive correlation with both the levels of LDL-C (r = 0.595, p < 0.001) and TSH (r = 0.346, p=0.013) by the Spearman correlation analyses. The correlation remained significant even when the effect of another factor was controlled (TSH: when the effect of LDL-C was controlled, r = 0.453, p=0.001; LDL-C: when the effect of TSH was controlled, r = 0.291, p=0.040). The main effect analysis showed an independent main effect of either LDL-C (p = 0.041) or TSH (p=0.022) on gp91phox without interaction (p=0.299).
    Conclusions: Our work demonstrated that the levels of gp91phox, a novel biomarker for measuring the oxidative stress, were significantly elevated in the patients with SH. And LDL-C and TSH were both independent predictors of gp91phox. Abbreviations. BMI : Body mass index; TC : Total cholesterol; LDL-C : Low-density lipoprotein cholesterol; HDL-C : High-density lipoprotein cholesterol; TG : Triglyceride; FBG : Fasting blood glucose; FT3 : Free triiodothyronine; FT4 : Free thyroxine; TSH: Thyroid stimulating hormone; SBP : Systolic blood pressure; DBP : Diastolic blood pressure; SD : Standard deviation; LSD: Least significant difference.
    DOI:  https://doi.org/10.1155/2020/3161730