scholarly journals NF-κB-Dependent Production of ROS and Restriction of HSV-1 Infection in U937 Monocytic Cells

Viruses ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 428 ◽  
Author(s):  
Francesca Marino-Merlo ◽  
Emanuela Papaianni ◽  
Caterina Frezza ◽  
Silvana Pedatella ◽  
Mauro De Nisco ◽  
...  
Keyword(s):  
Cell Types ◽  
Dominant Negative ◽  
Ros Generation ◽  
Neural Cells ◽  
Ros Production ◽  
U937 Cells ◽  
Herpes Simplex Virus 1 ◽  
Monocytic Cells ◽  
Wide Range ◽  
Hsv 1

Herpes simplex virus 1 (HSV-1) can infect a wide range of cell types, including cells of the adaptive and innate immunity but, normally, it completes a fully-permissive replication cycle only in epithelial or neural cells. Complex mechanisms controlling this delicate balance in immune cells and consequent restriction of HSV-1 infection in these cells have not been completely elucidated. We have recently demonstrated that the transcription factor nuclear factor kappa B (NF-κB) can act as a main permissiveness regulator of HSV-1 infection in monocytic cells, however, mediators involved in this regulation have not been identified. To better define mechanisms involved in this phenomenon and, particularly, the possible involvement of ROS, wild type U937 cells or U937 cells stably transfected with a dominant-negative (DN) IκB-mutant and selenium-containing compounds, as anti-oxidants, were utilized. The main results can be summarized as follows. HSV-1 infection induces an immediate ROS production in U937 monocytic cells that can efficiently activate NF-κB but not in DN-IκB-mutant cells. Treatment with selenium-containing antioxidants efficiently inhibited HSV-1-induced ROS generation while producing increased levels of HSV-1 replication and a reduction of HSV-1-induced NF-κB activation in U937 monocytic cells. Our results suggest a scenario in which an efficient NF-κB-dependent ROS production in response to infection could contribute in limiting HSV-1 replication in monocytes/macrophages, thus avoiding possible irreparable damage to the innate immune system of the host during HSV-1 infection.

scholarly journals A novel role for phagocytosis-like uptake in herpes simplex virus entry

2006 ◽  
Vol 174 (7) ◽  
pp. 1009-1021 ◽  
Author(s):  
Christian Clement ◽  
Vaibhav Tiwari ◽  
Perry M. Scanlan ◽  
Tibor Valyi-Nagy ◽  
Beatrice Y.J.T. Yue ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Dominant Negative ◽  
Endocytic Pathway ◽  
Herpes Simplex Virus 1 ◽  
Mode Of Entry ◽  
Virion Envelope ◽  
Membrane Protrusions ◽  
Simplex Virus ◽  
Hsv 1

It is becoming increasingly clear that herpesviruses can exploit the endocytic pathway to infect cells, yet several important features of this process remain poorly defined. Using herpes simplex virus-1 (HSV-1) as a model, we demonstrate that endocytosis of the virions mimic many features of phagocytosis. During entry, HSV-1 virions associated with plasma membrane protrusions followed by a phagocytosis-like uptake involving rearrangement of actin cytoskeleton and trafficking of the virions in large phagosome-like vesicles. RhoA GTPase was activated during this process and the mode of entry was cell type–specific. Clathrin-coated vesicles had no detectable role in virion trafficking as Eps15 dominant-negative mutants failed to affect HSV-1 uptake. Binding and fusion of the virion envelope with the phagosomal membrane is likely facilitated by clustering of nectin-1 (or HVEM) in phagosomes, which was observed in infected cells. Collectively, our data suggests a novel mode of uptake by which the virus can infect both professional and nonprofessional phagocytes.

scholarly journals Binding of Herpes Simplex Virus 1 UL20 to GODZ (DHHC3) Affects Its Palmitoylation and Is Essential for Infectivity and Proper Targeting and Localization of UL20 and Glycoprotein K

2017 ◽  
Vol 91 (19) ◽  
Author(s):  
Shaohui Wang ◽  
Kevin R. Mott ◽  
Kolja Wawrowsky ◽  
Konstantin G. Kousoulas ◽  
Bernhard Luscher ◽  
...  
Keyword(s):  
Golgi Apparatus ◽  
Envelope Protein ◽  
Zinc Finger Protein ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Herpes Simplex Virus 1 ◽  
Finger Protein ◽  
Glycoprotein K ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Herpes simplex virus 1 (HSV-1) UL20 plays a crucial role in the envelopment of the cytoplasmic virion and its egress. It is a nonglycosylated envelope protein that is regulated as a γ1 gene. Two-hybrid and pulldown assays demonstrated that UL20, but no other HSV-1 gene-encoded proteins, binds specifically to GODZ (also known as DHHC3), a cellular Golgi apparatus-specific Asp-His-His-Cys (DHHC) zinc finger protein. A catalytically inactive dominant-negative GODZ construct significantly reduced HSV-1 replication in vitro and affected the localization of UL20 and glycoprotein K (gK) and their interactions but not glycoprotein C (gC). GODZ is involved in palmitoylation, and we found that UL20 is palmitoylated by GODZ using a GODZ dominant-negative plasmid. Blocking of palmitoylation using 2-bromopalmitate (2-BP) affected the virus titer and the interaction of UL20 and gK but did not affect the levels of these proteins. In conclusion, we have shown that binding of UL20 to GODZ in the Golgi apparatus regulates trafficking of UL20 and its subsequent effects on gK localization and virus replication. We also have demonstrated that GODZ-mediated UL20 palmitoylation is critical for UL20 membrane targeting and thus gK cell surface expression, providing new mechanistic insights into how UL20 palmitoylation regulates HSV-1 infectivity. IMPORTANCE HSV-1 UL20 is a nonglycosylated essential envelope protein that is highly conserved among herpesviruses. In this study, we show that (i) HSV-1 UL20 binds to GODZ (also known as DHHC3), a Golgi apparatus-specific Asp-His-His-Cys (DHHC) zinc finger protein; (ii) a GODZ dominant-negative mutant and an inhibitor of palmitoylation reduced HSV-1 titers and altered the localization of UL20 and glycoprotein K; and (iii) UL20 is palmitoylated by GODZ, and this UL20 palmitoylation is required for HSV-1 infectivity. Thus, blocking of the interaction of UL20 with GODZ, using a GODZ dominant-negative mutant or possibly GODZ shRNA, should be considered a potential alternative therapy in not only HSV-1 but also other conditions in which GODZ processing is an integral component of pathogenesis.

Abstract 152: Urotensin-II Activates Rac-1 And ROS Production In Pulmonary Artery Smooth Muscle Cells Involving GPR14 And Gα I3 Proteins

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Talija Djordjevic ◽  
Nicola Schaefer ◽  
Michael Weitnauer ◽  
John Hess ◽  
Agnes Görlach
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Nadph Oxidase ◽  
Smooth Muscle Cells ◽  
Dominant Negative ◽  
Ros Generation ◽  
Ros Production ◽  
Urotensin Ii ◽  
Pulmonary Artery Smooth Muscle

Human urotensin II (hU-II) has recently been described as a potent vasoactive peptide associated with remodelling processes within the vasculature, thus contributing to various cardiovascular diseases including pulmonary hypertension. hU-II acts via the G-protein coupled receptor GPR14. However, the mechanisms mediating GPR14 signalling remain unclear. ROS have been shown to act as signalling molecules in vascular cells, and NADPH oxidases which are activated by Rac-1, are important sources of ROS generation. Therefore, we investigated whether hU-II and GPR14 can activate Rac-1 and NADPH oxidase-mediated ROS production in pulmonary artery smooth muscle cells (PASMC). Urotensin-II activated Rac-1 within 15 seconds and this response was abolished by treatment of PASMC with the GPR14 antagonist urantide. In line, urotensin-II induced a rapid increase in ROS levels within 5 minutes of application, which was prevented by urantide or transfection of a dominant-negative mutant of Rac-1 (RacT17N). Furthermore, in cells overexpressing GPR14 or constitutively active Rac-1 (RacG12V), hU-II-stimulated ROS generation was further enhanced. Interestingly, in the presence of Pertussis toxin, hU-II-induced Rac-1 activation and ROS generation were abolished, indicating coupling of GPR14 to Gα i proteins. Indeed, transfection of dominant-negative G α i3 completely diminished hU-II-stimulated ROS generation in PASMC. Similar effects were observed upon depletion of the NADPH oxidase subunit NOX4. Furthermore, hU-II, RacG12V and NOX4 stimulated proliferation of PASMC, whereas antioxidants, RacT17N or NOX4 depletion had opposite effects.These results show that hU-II is a potent activator of Rac-1 leading to rapid activation of NADPH oxidase and ROS generation involving GPR14 and Gα i3 proteins, and subsequent stimulation of PASMC proliferation. Thus, activation of NADPH oxidase by GPR14 and Rac-1 provides a novel mechanism how hU-II can promote vascular remodelling processes and may provide a novel therapeutic target for pulmonary vasculopathies associated with pulmonary hypertension.

scholarly journals Analysis of Human Alphaherpesvirus MicroRNA Expression in Latently Infected Human Trigeminal Ganglia

2009 ◽  
Vol 83 (20) ◽  
pp. 10677-10683 ◽  
Author(s):  
Jennifer L. Umbach ◽  
Maria A. Nagel ◽  
Randall J. Cohrs ◽  
Donald H. Gilden ◽  
Bryan R. Cullen
Keyword(s):  
Trigeminal Ganglia ◽  
Herpes Simplex Virus 1 ◽  
Viral Mirnas ◽  
Varicella Zoster ◽  
Wide Range ◽  
Latently Infected ◽  
Infected Cells ◽  
Virally Encoded ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Analysis of cells infected by a wide range of herpesviruses has identified numerous virally encoded microRNAs (miRNAs), and several reports suggest that these viral miRNAs are likely to play key roles in several aspects of the herpesvirus life cycle. Here we report the first analysis of human ganglia for the presence of virally encoded miRNAs. Deep sequencing of human trigeminal ganglia latently infected with two pathogenic alphaherpesviruses, herpes simplex virus 1 (HSV-1) and varicella-zoster virus (VZV), confirmed the expression of five HSV-1 miRNAs, miR-H2 through miR-H6, which had previously been observed in mice latently infected with HSV-1. In addition, two novel HSV-1 miRNAs, termed miR-H7 and miR-H8, were also identified. Like four of the previously reported HSV-1 miRNAs, miR-H7 and miR-H8 are encoded within the second exon of the HSV-1 latency-associated transcript. Although VZV genomic DNA was readily detectable in the three human trigeminal ganglia analyzed, we failed to detect any VZV miRNAs, suggesting that VZV, unlike other herpesviruses examined so far, may not express viral miRNAs in latently infected cells.

Abstract 930: NADPH Oxidase 2 is Responsible for α1-Adrenergic Receptor-Dependent Reactive Oxygen Species Production in Adult Rat Ventricular Myocytes

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Steve Lancel ◽  
Ellen O Weinberg ◽  
Eugene B Valsky ◽  
Mark Y Jeong ◽  
Zareen Farukhi ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Ventricular Myocytes ◽  
Dominant Negative ◽  
Regulatory Proteins ◽  
Ros Generation ◽  
Ros Production ◽  
Oxygen Species ◽  
Inhibitory Peptide ◽  
Rat Ventricular Myocytes ◽  
Adult Rat

Background: Five NAPDH oxidase (NOX) isoforms have been implicated in reactive oxygen species (ROS) generation in a cell type- and agonist-specific manner. We previously showed that α 1 -adrenoreceptor (α 1 -AR) stimulation in cultured adult rat ventricular myocytes (ARVM) leads to NADPH-dependent ROS-production, suggesting that a NOX may be responsible. The goal of this project was to determine whether NOX mediates α 1 -AR-stimulated ROS production in ARVM, and if so, which isoform(s) is responsible. Methods and Results: ROS production, assessed by dichlorofluoresceine (DCF) fluorescence, was increased by 51±7 % in ARVM subjected to α 1 -AR stimulation (norepinephrine 1μM + propranolol 2 μM; 30 min; p=0.002, n=3/group). Apocynin (Apo, 50 μM), a broad-spectrum NOX inhibitor, prevented α1-AR-mediated ROS generation (+19±8% vs Apo-treated/α 1 -AR-unstimulated cells, n=4, NS), suggesting a role for NOX. Expression of NOX1, 2 and 4, as well as regulatory proteins p22 phox , p47 phox , Rac1 and Rac2, but not NOX3, was detected by RT-PCR in ARVM. Neither the inhibitory Nox4-tat peptide (+56±7% vs NOX4-tat-treated/α 1 -AR-unstimulated cells) nor adenovirus-mediated overexpression of NOX4 dominant-negative protein (+84±17% vs NOX4DN-infected/α 1 -AR-unstimulated cells) reduced α 1 -AR-induced DCF fluorescence increase (n=4/ group, both p<0.01 vs α 1 -AR-unstimulated cells). In contrast, adenovirus-mediated overexpression of dominant negative p47 phox , p67 phox and Rac1 proteins prevented α 1 -AR-mediated ROS production, suggesting that the responsible NOX requires each of these proteins. NOX2-tat inhibitory peptide (+18.4±7.3% vs NOX2-tat-treated/α 1 -AR-unstimulated cells, n=6, NS), but not NOX1-tat inhibitory peptide (+51±8% vs NOX1-tat-treated/α 1 -AR-unstimulated cells, n=3, p<0.01), prevented α 1 -AR-mediated ROS production. Conclusion: The NOX2 complex, including the catalytic subunit gp91 phox , and the regulatory proteins p47 phox , p67 phox and Rac1, is directly responsible for α 1 -adrenergic-receptor induced ROS production in adult rat ventricular myocytes.

scholarly journals The ESCRT-Related ATPase Vps4 Is Modulated by Interferon during Herpes Simplex Virus 1 Infection

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Jorge Ruben Cabrera ◽  
Richard Manivanh ◽  
Brian J. North ◽  
David A. Leib
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Viral Infections ◽  
Cell Types ◽  
Primary Neurons ◽  
Herpes Simplex Virus 1 ◽  
Escrt Machinery ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTInterferons (IFNs) and autophagy are critical neuronal defenses against viral infection. IFNs alter neuronal autophagy by promoting the accumulation of IFN-dependent LC3-decorated autophagic structures, termed LC3 clusters. Here, we analyzed LC3 clusters in sensory ganglia following herpes simplex virus 1 (HSV-1) infection. In the vicinity of acutely infected neurons, antigen-negative neurons contained structures resembling accumulated autophagosomes and autolysosomes that culminated in LC3 clusters. This accumulation reflects a delayed completion of autophagy. Theendosomalsortingcomplexesrequired fortransport (ESCRT) machinery participates in autophagosome closure and is also required for HSV-1 replication. In this study, our results showed that HSV-1 infectionin vivoand in primary neurons caused a decrease in Vps4 (a key ESCRT pathway ATPase) RNA and protein with concomitant Stat1 activation and LC3 cluster induction. We also observed that IFNs were sufficient to decrease RNA and protein levels of Vps4 in primary neurons and in other cell types. The accumulation of ubiquitin was also observed at the LC3 cluster sites. Together, our results show that IFNs modulate the ESCRT machinery in neurons in response to HSV-1 infections.IMPORTANCENeurons rely on IFNs and autophagy as major defenses against viral infections, and HSV must overcome such defenses in order to replicate. In addition to controlling host immunity, HSV must also control host membranes in order to complete its life cycle. HSV uses the host ESCRT membrane scission machinery for viral production and transport. Here we present evidence of a new IFN-dependent mechanism used by the host to prevent ESCRT subversion by HSV. This activity also impacts the dynamics of autophagy, possibly explaining the presence of recently described LC3 clusters in the HSV-infected nervous system. The induced accumulations of ubiquitin observed in these LC3 clusters resembled those observed in certain neurodegenerative diseases, suggesting possible mechanistic parallels between these conditions.

scholarly journals In Vitro Analysis of the Antioxidant and Antiviral Activity of Embelin against Herpes Simplex Virus-1

2021 ◽  
Vol 9 (2) ◽  
pp. 434
Author(s):  
Tony Elias ◽  
Lee H. Lee ◽  
Miriam Rossi ◽  
Francesco Caruso ◽  
Sandra D. Adams
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Time Course ◽  
Early Stage ◽  
Vero Cells ◽  
Host Cells ◽  
Herpes Simplex Virus 1 ◽  
Wide Range ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus-1 (HSV-1) causes a wide range of infections from mild to life-threatening in the human population. There are effective treatments for HSV-1 infections that are limited due HSV-1 latency and development of resistance to current therapeutics. The goal of this study was to investigate the antioxidant and antiviral effects of embelin on HSV-1 in cultured Vero cells. Oxidative stress was verified by an extensive production of a reactive oxygen species (ROS) H2O2. Vero cells were infected with a recombinant strain of HSV-1 and antiviral assays, time course attachment, penetration, and post penetration assays, confocal microscopy, qPCR, and antioxidant assays were conducted. Our results lead to the conclusion that embelin is noncytotoxic at concentrations tested ranging from 20 to 70 µM. Treatment of HSV-1 virions with embelin resulted in 98.7–100% inhibition and affected the early stage of HSV-1 infection of Vero cells, by inhibiting the attachment and penetration of HSV-1 virions to host cells. Treatment of virions with concentrations of embelin ranging from 35 to 60 µM significantly reduced the production of H2O2. In conclusion, embelin reduces oxidative damage caused by HSV-1 infection and is an effective antiviral to reduce the infection of HSV-1 in cultured Vero cells. Further studies are needed to explore the possibility of embelin as a medicinal agent.

scholarly journals Characterization of a complement-fragment-C5a-stimulated calcium-influx mechanism in U937 monocytic cells

1993 ◽  
Vol 295 (3) ◽  
pp. 679-684 ◽  
Author(s):  
P N Monk ◽  
L J Partridge
Keyword(s):  
Cell Line ◽  
Pertussis Toxin ◽  
Inositol Phosphates ◽  
Calcium Influx ◽  
Cell Types ◽  
U937 Cells ◽  
Monocytic Cell ◽  
Monocytic Cell Line ◽  
Monocytic Cells

The mechanism by which complement fragment C5a elevates intracellular Ca2+ ([Ca2+]i) levels in two cell types, a monocytic cell line, U937, and neutrophils, has been investigated by the use of fluorometric and radiometric techniques. In U937 cells the influx of extracellular Ca2+ can be distinguished from the release of intracellular Ca2+ stores in terms of dose-responsiveness to C5a and sensitivity to pertussis-toxin poisoning. This suggests that the mechanism of Ca2+ influx in these cells is at least partially independent of both the production of inositol phosphates and elevation of internal Ca2+ concentration. The C5a-stimulated influx of 45Ca2+ into U937 cells is inhibited by a series of metal ions (Zn2+ > Co2+ > Mn2+ > Sr2+ approximately equal to Ni2+ > La3+). The stimulated influx of Ca2+ into neutrophils is inhibited differently (Ni2 >> Co2+ > Zn2+ approximately equal to La3+ > Mn2+ approximately equal to Sr2+), is less sensitive to C5a and both the influx of extracellular Ca2+ and the release of intracellular stores are equally sensitive to pertussis toxin treatment. Taken together these results indicate that [Ca2+]i is controlled in U937 monocytes by mechanisms distinct from those which appear to operate in other myeloid cells, such as neutrophils, stimulated with C5a and formylpeptide.

scholarly journals Histone deacetylase inhibitors reduce the number of herpes simplex virus-1 genomes initiating expression in individual cells

2016 ◽  
Author(s):  
Shapira Lev ◽  
Ralph Maya ◽  
Tomer Enosh ◽  
Cohen Shai ◽  
Kobiler Oren
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cell Types ◽  
Nuclear Bodies ◽  
Host Proteins ◽  
Herpes Simplex Virus 1 ◽  
Viral Genomes ◽  
Early Protein ◽  
Simplex Virus ◽  
Hsv 1

AbstractAlthough many viral particles can enter a single cell, the number of viral genomes per cell that establish infection is limited. However, mechanisms underlying this restriction were not explored in depth. For herpesviruses, one of the possible mechanisms suggested is chromatinization and silencing of the incoming genomes. To test this hypothesis, we followed infection with three herpes simplex virus 1 (HSV-1) fluorescence-expressing recombinants in the presence or absence of histone deacetylases inhibitors (HDACi’s). Unexpectedly, a lower number of viral genomes initiated expression in the presence of these inhibitors. This phenomenon was observed using several HDACi: Trichostatin A (TSA), Suberohydroxamic Acid (SBX), Valporic Acid (VPA) and Suberoylanilide Hydoxamic Acid (SAHA). We found that HDACi presence did not change the progeny outcome from the infected cells but did alter the kinetic of the infection. Different cell types (HFF, Vero and U2OS), which vary in their capability to activate intrinsic and innate immunity, show a cell specific basal average number of viral genomes establishing infection. Importantly, in all cell types, treatment with TSA reduced the number of viral genomes. ND10 nuclear bodies are known to interact with the incoming herpes genomes and repress viral replication. The viral immediate early protein, ICP0, is known to disassemble the ND10 bodies and to induce degradation of some of the host proteins in these domains. HDACi treated cells expressed higher levels of some of the host ND10 proteins (PML and ATRX), which may down regulate the number of viral genomes initiating expression per cell. Corroborating this hypothesis, infection with three HSV-1 recombinants carrying a deletion in the gene coding for ICP0, show a reduction in the number of genomes being expressed in U2OS cells. We suggest that alterations in the levels of host proteins involved in intrinsic antiviral defense may result in differences in the number of genomes that initiate expression.

PKC-δ-dependent activation of oxidative stress in adipocytes of obese and insulin-resistant mice: role for NADPH oxidase

2005 ◽  
Vol 288 (2) ◽  
pp. E405-E411 ◽  
Author(s):  
Ilana Talior ◽  
Tamar Tennenbaum ◽  
Toshio Kuroki ◽  
Hagit Eldar-Finkelman
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Oxidase Inhibitor ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Ros Generation ◽  
Ros Production ◽  
Insulin Resistant ◽  
Glucose Depletion ◽  
Causative Factors

Oxidative stress is thought to be one of the causative factors contributing to insulin resistance and type 2 diabetes. Previously, we showed that reactive oxygen species (ROS) production is significantly increased in adipocytes from high-fat diet-induced obese and insulin-resistant mice (HF). ROS production was also associated with the increased activity of PKC-δ. In the present studies, we hypothesized that PKC-δ contributes to ROS generation and determined their intracellular source. NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) reduced ROS levels by 50% in HF adipocytes, and inhibitors of NO synthase (l-NAME, 1 mM), xanthine oxidase (allopurinol, 100 μM), AGE formation (aminoguanidine, 10 μM), or the mitochondrial uncoupler (FCCP, 10 μM) had no effect. Rottlerin, a selective PKC-δ inhibitor, suppressed ROS levels by ∼50%. However, neither GÖ-6976 nor LY-333531, effective inhibitors toward conventional PKC or PKC-β, respectively, significantly altered ROS levels in HF adipocytes. Subsequently, adenoviral-mediated expression of wild-type PKC-δ or its dominant negative mutant (DN-PKC-δ) in HF adipocytes resulted in either a twofold increase in ROS levels or their suppression by 20%, respectively. In addition, both ROS levels and PKC-δ activity were sharply reduced by glucose depletion. Taken together, these results suggest that PKC-δ is responsible for elevated intracellular ROS production in HF adipocytes, and this is mediated by high glucose and NADPH oxidase.

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