bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2019‒10‒13
eight papers selected by
Laia Caja Puigsubira
Uppsala University


  1. Antioxid Redox Signal. 2019 Oct 05.
    Henríquez-Olguín C, Boronat S, Cabello-Verrugio C, Jaimovich E, Hidalgo E, Jensen TE.
      Significance Skeletal muscle is a crucial tissue to whole-body locomotion and metabolic health. Reactive oxygen species (ROS) have emerged as intracellular messengers participating in both physiological and pathological adaptations in skeletal muscle. A complex interplay between ROS-producing enzymes and antioxidant networks exists in different subcellular compartments of mature skeletal muscle. Recent evidence suggests that NADPH oxidases (NOX) are a major source of contraction- and insulin-stimulated oxidants production, but may paradoxically also contribute to muscle insulin resistance and atrophy. Recent Advances Pharmacological and molecular biological tools, including redox-sensitive probes and transgenic mouse models, have generated novel insights into compartmentalized redox signaling and suggested that NOX2 contributes to redox control of skeletal muscle metabolism. Critical Issues Major outstanding questions in skeletal muscle include where NOX2 activation occurs under different conditions in health and disease, how NOX2 activation is regulated, how superoxide/ H2O2 generated by NOX2 reaches the cytosol, what the signaling mediators are downstream of NOX2, and the role of NOX2 for different physiological and pathophysiological processes. Future Directions Future research should utilize and expand the current redox-signaling toolbox to clarify the NOX2-dependent mechanisms in skeletal muscle and determine whether the proposed functions of NOX2 in cells and animal models are conserved into man.
    DOI:  https://doi.org/10.1089/ars.2018.7678
  2. Clin Exp Pharmacol Physiol. 2019 Oct 06.
    Wang Y, Li X, Huang X, Ma S, Xing Y, Geng X, He X.
      Hypertension is a common type of cardiovascular disease that remains a major cause of death in the world. Vascular remodeling is an important complication of hypertension, and vascular smooth muscle cells (VSMCs) play a major role in vascular remodeling. Sauchinone is one of the active lignin, which has been found to possess vascular protective effect. However, the functional role of sauchinone in hypertension has not been investigated. The aim of this study was to evaluate the role of sauchinone in the angiotensin II (Ang II)-induced vascular remodeling model in VSMCs. The results showed that treatment of sauchinone inhibited Ang II-inducedVSMCs proliferation and migration in VSMCs. Sauchinone treatment suppressed the reactive oxygen species (ROS) production and NADPH oxidase (NOX) activity in Ang II-induced VSMCs. The inhibitory effects of Ang II on expressions of VSMCs phenotype markers including α-smooth muscle actin (α-SMA), calponin, osteopontin were mitigated by sauchinone treatment. Furthermore, sauchinone inhibitedAng II-induced over-activation of TGF-β1/Smad3 signaling pathway in VSMCs.Taken together, this study identified sauchinone as a potential agent for preventing vascular remodeling in hypertension.
    Keywords:  Hypertension; migration; phenotypic switching; proliferation; sauchinone; vascular remodeling; vascular smooth muscle cells (VSMCs)
    DOI:  https://doi.org/10.1111/1440-1681.13187
  3. Nat Commun. 2019 Oct 11. 10(1): 4623
    Henríquez-Olguin C, Knudsen JR, Raun SH, Li Z, Dalbram E, Treebak JT, Sylow L, Holmdahl R, Richter EA, Jaimovich E, Jensen TE.
      Reactive oxygen species (ROS) act as intracellular compartmentalized second messengers, mediating metabolic stress-adaptation. In skeletal muscle fibers, ROS have been suggested to stimulate glucose transporter 4 (GLUT4)-dependent glucose transport during artificially evoked contraction ex vivo, but whether myocellular ROS production is stimulated by in vivo exercise to control metabolism is unclear. Here, we combined exercise in humans and mice with fluorescent dyes, genetically-encoded biosensors, and NADPH oxidase 2 (NOX2) loss-of-function models to demonstrate that NOX2 is the main source of cytosolic ROS during moderate-intensity exercise in skeletal muscle. Furthermore, two NOX2 loss-of-function mouse models lacking either p47phox or Rac1 presented striking phenotypic similarities, including greatly reduced exercise-stimulated glucose uptake and GLUT4 translocation. These findings indicate that NOX2 is a major myocellular ROS source, regulating glucose transport capacity during moderate-intensity exercise.
    DOI:  https://doi.org/10.1038/s41467-019-12523-9
  4. Nat Rev Cardiol. 2019 Oct 07.
    Zhang Y, Murugesan P, Huang K, Cai H.
      Reactive oxygen species (ROS)-dependent production of ROS underlies sustained oxidative stress, which has been implicated in the pathogenesis of cardiovascular diseases such as hypertension, aortic aneurysm, hypercholesterolaemia, atherosclerosis, diabetic vascular complications, cardiac ischaemia-reperfusion injury, myocardial infarction, heart failure and cardiac arrhythmias. Interactions between different oxidases or oxidase systems have been intensively investigated for their roles in inducing sustained oxidative stress. In this Review, we discuss the latest data on the pathobiology of each oxidase component, the complex crosstalk between different oxidase components and the consequences of this crosstalk in mediating cardiovascular disease processes, focusing on the central role of particular NADPH oxidase (NOX) isoforms that are activated in specific cardiovascular diseases. An improved understanding of these mechanisms might facilitate the development of novel therapeutic agents targeting these oxidase systems and their interactions, which could be effective in the prevention and treatment of cardiovascular disorders.
    DOI:  https://doi.org/10.1038/s41569-019-0260-8
  5. J Burn Care Res. 2019 Sep 07. pii: irz162. [Epub ahead of print]
    Korkmaz HI, Ulrich MMW, Çelik G, Van Wieringen WN, Van Zuijlen PPM, Krijnen PAJ, Niessen HWM.
      Reepithelialization is crucial for effective wound repair in burn wounds. Reactive oxygen species (ROS) have shown to be important in this. Recent studies suggest that NOX proteins produce ROS in keratinocytes. In the present study, we have studied NOX proteins in burn wounds, including the effect of C1-esterase inhibitor (C1inh) hereon, which is the endogenous inhibitor of complement activity whereof we have shown previously that it also increased the rate of reepithelialization in burn wounds. Skin tissue derived from healthy control Wistar rats (n = 6) were compared with burn-injured rats, with (n = 7) or without C1inh treatment (n = 7). After 14 days, rats were terminated. From the burn-injured rats, the entire wound and nonburned skin from the hind leg, that is, internal control was excised. From the control rats, dorsal skin was excised. In these skin samples, NOX2 and NOX4 were analyzed immunohistochemically. In nonburned rats, NOX2 was found in keratinocytes in both the basal layer and suprabasal layer of the epidermis; and the number of NOX2-positive keratinocytes was 367/mm2 (254-378). In burned rats, the number of NOX2-positive keratinocytes was significantly increased in the newly forming epidermis in the burned area to 1019/mm2 (649-1172), especially in the suprabasal layer, but significantly decreased in remote nonburned skin to 22/mm2 (6-89). C1inh treatment counteracted these changes in epidermal NOX2 expression in burned rats, both in the burned area as in remote nonburned skin. No NOX4 expression was found in the epidermis in none of the groups. NOX2 expression was increased in keratinocytes in newly forming epidermis after burn injury. C1inh, a drug that increases the rate of reepithelialization, counteracted this effect. These results suggest a role for NOX2 in the reepithelialization of burn wounds.
    DOI:  https://doi.org/10.1093/jbcr/irz162
  6. Eur J Pharmacol. 2019 Oct 03. pii: S0014-2999(19)30675-2. [Epub ahead of print] 172723
    Gupta AP, Syed AA, Garg R, Goand UK, Singh P, Riyazuddin M, Valicherla GR, Husain A, Gayen JR.
      Pancreastatin (PST), a chromograninA derived peptide has anti-insulin effects and plays a significant role in obesity-induced insulin resistance. In obesity and type 2 diabetes mellitus, both insulin and PST level are elevated, but it is not clearly understood how anti-insulin effect of PST get regulated in hyperinsulinemic state. Simultaneously we have explored pancreastatin inhibitor PSTi8 against the native PST in the same hyperinsulinemic state. In in-vitro studies, we found that PST treatment increases lipid droplets and reactive oxygen species production in 3T3L1 adipocyte cells and theses effects of PST was found synergistic with chronic-insulin treatment. Treatment of PSTi8 in 3T3L1 adipocytes attenuates PST effect on lipid droplet formation and reactive oxygen species production. We further validated these findings in epididymal white adipose tissue of C57BL/6 mice, implanted with mini-osmotic insulin pump with and without PSTi8 for 4 weeks. We found that chronic hyperinsulinemia enhanced PST levels in circulation which in turn induces expression of various pro-inflammatory cytokines and oxidative stress. In addition, it also stimulated the expression of lipogenic genes, fat mass and body weight gain through the regulation of circulating adiponectin level. The change in PST mediated inflammatory and lipogenic parameters were attenuated by PSTi8 treatment, leading to enhanced insulin sensitivity and improved glucose homeostasis. PSTi8 rescue from PST mediated insulin resistance in adipose via inhibition of MAPK and NOX3-JNK stress signalling pathway which stimulates GLUT4 expression through activation of AKT-AS160 pathway. Thus PSTi8 may be a novel therapeutic agent for the treatment of hyperinsulinemia induced obesity and inflammation mediated insulin resistance.
    Keywords:  CHGA; CI; DAG; Diabetes; GAPDH; GLUT4; Glucose transporter 4; Glyceraldehyde 3-phosphate dehydrogenase; HDL; Hyperinsulinemia; IL6; IP3; IRS; Inflammation; Insulin resistance; Interleukin 6; JNK; MAPK; MCP-1; Mitogen-activated protein kinase; Monocyte chemoattractant protein-1; NADPH oxidase 3; NOX-3; Obesity; PST; Pancreastatin; TBST; TNFα; Tumor necrosis factor alpha; c-Jun N-terminal kinases; cPKC; chromogranin A; chronic hyperinsulinemia; conventional protein kinase C; diacylglycerol; inositol 3 phosphate; insulin receptor substrate; pancreastatin; tris-buffered saline tween
    DOI:  https://doi.org/10.1016/j.ejphar.2019.172723
  7. Int J Mol Sci. 2019 Oct 05. pii: E4936. [Epub ahead of print]20(19):
    Fan C, Ma Q, Xu M, Qiao Y, Zhang Y, Li P, Bi Y, Tang M.
      (1) Aims: The present study aimed to observe the effects of Ginsenoside Rb1 on high glucose-induced endothelial damage in rat retinal capillary endothelial cells (RCECs) and to investigate the underlying mechanism. (2) Methods: Cultured RCECs were treated with normal glucose (5.5 mM), high glucose (30 mM glucose), or high glucose plus Rb1 (20 μM). Cell viability, lactate dehydrogenase (LDH) levels, the mitochondrial DNA copy number, and the intracellular ROS content were measured to evaluate the cytotoxicity. Superoxide dismutase (SOD), catalase (CAT), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), poly(ADP-ribose) polymerase (PARP), and sirtuin (SIRT) activity was studied in cell extracts. Nicotinamide adenine dinucleotide (NAD+)/NADH, NADPH/NADP+, and glutathione (GSH)/GSSG levels were measured to evaluate the redox state. The expression of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), SIRT1, and SIRT3 was also evaluated after Rb1 treatment. (3) Results: Treatment with Rb1 significantly increased the cell viability and mtDNA copy number, and inhibited ROS generation. Rb1 treatment increased the activity of SOD and CAT and reduced the activity of NOX and PARP. Moreover, Rb1 enhanced both SIRT activity and SIRT1/SIRT3 expression. Additionally, Rb1 was able to re-establish the cellular redox balance in RCECs. However, Rb1 showed no effect on NMNAT1 expression in RCECs exposed to high glucose. (4) Conclusion: Under high glucose conditions, decreases in the reducing power may be linked to DNA oxidative damage and apoptosis via activation of the NMNAT-NAD-PARP-SIRT axis. Rb1 provides an advantage during high glucose-induced cell damage by targeting the NAD-PARP-SIRT signaling pathway and modulating the redox state in RCECs.
    Keywords:  Ginsenoside Rb1; NAD+; PARP; high glucose; retinal capillary endothelial cells; sirtuin
    DOI:  https://doi.org/10.3390/ijms20194936
  8. PLoS One. 2019 ;14(10): e0223551
    Yamada T, Ashida Y, Tatebayashi D, Himori K.
      Although there is good evidence to indicate a major role of intrinsic impairment of the contractile apparatus in muscle weakness seen in several pathophysiological conditions, the factors responsible for control of myofibrillar function are not fully understood. To investigate the role of mechanical load in myofibrillar function, we compared the skinned fiber force between denervated (DEN) and dexamethasone-treated (DEX) rat skeletal muscles with or without neuromuscular electrical stimulation (ES) training. DEN and DEX were induced by cutting the sciatic nerve and daily injection of dexamethasone (5 mg/kg/day) for 7 days, respectively. For ES training, plantarflexor muscles were electrically stimulated to produce four sets of five isometric contractions each day. In situ maximum torque was markedly depressed in the DEN muscles compared to the DEX muscles (-74% vs. -10%), whereas there was not much difference in the degree of atrophy in gastrocnemius muscles between DEN and DEX groups (-24% vs. -17%). Similar results were obtained in the skinned fiber preparation, with a greater reduction in maximum Ca2+-activated force in the DEN than in the DEX group (-53% vs. -16%). Moreover, there was a parallel decline in myosin heavy chain (MyHC) and actin content per muscle volume in DEN muscles, but not in DEX muscles, which was associated with upregulation of NADPH oxidase (NOX) 2, neuronal nitric oxide synthase (nNOS), and endothelial NOS expression, translocation of nNOS from the membrane to the cytosol, and augmentation of mRNA levels of muscle RING finger protein 1 (MuRF-1) and atrogin-1. Importantly, mechanical load evoked by ES protects against DEN- and DEX-induced myofibrillar dysfunction and these molecular alterations. Our findings provide novel insights regarding the difference in intrinsic contractile properties between DEN and DEX and suggest an important role of mechanical load in preserving myofibrillar function in skeletal muscle.
    DOI:  https://doi.org/10.1371/journal.pone.0223551