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  1. Fulltext TRPC3-Nox2 axis mediates nutritional deficiency-induced cardiomyocyte atrophy
    Sudi SB, Tanaka T, Oda S, Nishiyama K, Nishimura A, Sunggip C, et al.
    Sci Rep, 2019 07 05;9(1):9785.
    PMID: 31278358 DOI: 10.1038/s41598-019-46252-2
    Myocardial atrophy, characterized by the decreases in size and contractility of cardiomyocytes, is caused by severe malnutrition and/or mechanical unloading. Extracellular adenosine 5'-triphosphate (ATP), known as a danger signal, is recognized to negatively regulate cell volume. However, it is obscure whether extracellular ATP contributes to cardiomyocyte atrophy. Here, we report that ATP induces atrophy of neonatal rat cardiomyocytes (NRCMs) without cell death through P2Y2 receptors. ATP led to overproduction of reactive oxygen species (ROS) through increased amount of NADPH oxidase (Nox) 2 proteins, due to increased physical interaction between Nox2 and canonical transient receptor potential 3 (TRPC3). This ATP-mediated formation of TRPC3-Nox2 complex was also pathophysiologically involved in nutritional deficiency-induced NRCM atrophy. Strikingly, knockdown of either TRPC3 or Nox2 suppressed nutritional deficiency-induced ATP release, as well as ROS production and NRCM atrophy. Taken together, we propose that TRPC3-Nox2 axis, activated by extracellular ATP, is the key component that mediates nutritional deficiency-induced cardiomyocyte atrophy.
    Matched MeSH terms: NADPH Oxidase/metabolism
  2. Fulltext Studying neuroprotective effect of Atorvastatin as a small molecule drug on high glucose-induced neurotoxicity in undifferentiated PC12 cells: role of NADPH oxidase
    Rayegan S, Dehpour AR, Sharifi AM
    Metab Brain Dis, 2017 02;32(1):41-49.
    PMID: 27476541 DOI: 10.1007/s11011-016-9883-1
    Overproduction of reactive oxygen species (ROS) by NADPH oxidase (NOX) activation has been considered the essential mechanism induced by hyperglycemia in various tissues. However, there is no comprehensive study on the role of NOXs in high glucose (HG)-induced toxic effect in neural tissues. Recently, a therapeutic strategy in oxidative related pathologies has been introduced by blocking the undesirable actions of NOX enzymes by small molecules. The protective roles of Statins in ameliorating oxidative stress by NOX inhibition have been shown in some tissues except neural. We hypothesized then, that different NOXs may have role in HG-induced neural cell injury. Furthermore, we postulate that Atorvastatin as a small molecule may modulate this NOXs activity to protect neural cells. Undifferentiated PC12 cells were treated with HG (140 mM/24 h) in the presence and absence of Atorvastatin (1 μM/96 h). The cell viability was measured by MTT assay and the gene and protein expressions profile of NOX (1-4) were determined by RT-PCR and western blotting, respectively. Levels of ROS and malondialdehyde (MDA) were also evaluated. Gene and protein expression levels of NOX (1-4) and consequently ROS and MDA levels were elevated in HG-treated PC12 cells. Atorvastatin could significantly decrease HG-induced NOXs, ROS and MDA elevation and improve impaired cell viability. It can be concluded that HG could elevate NOXs activity, ROS and MDA levels in neural tissues and Atorvastatin as a small molecule NOX inhibitor drug may prevent and delay diabetic complications, particularly neuropathy.
    Matched MeSH terms: NADPH Oxidase/metabolism*
  3. Fulltext Defining p47-phox deficient Chronic Granulomatous Disease in a Malay family
    Gill HK, Kumar HC, Dhaliwal JS, Zabidi F, Sendut IH, Noah RM, et al.
    Asian Pac J Allergy Immunol, 2012 Dec;30(4):313-20.
    PMID: 23393912
    BACKGROUND: The most common autosomal form of Chronic Granulomatous Disease, p47-phox deficient CGD, generally features a GT (deltaGT) deletion in the GTGT sequence at the start of exon 2 on the NCF-1 gene. This consistency is due to the coexistence of and the recombination between 2 homologous pseudogenes (psi s) and NCF-1. The GTGT: deltaGT ratio mirrors the NCF-I: NCF-1 psi ratio and is 2:4 in normal individuals.
    OBJECTIVE: To determine the molecular basis of the Autosomal-CGD in a family with 2 children, a male and female, affected by the disease. The female patient suffered recurrent infection, retinitis pigmentosa and discoid lupus.
    METHODS: Chemiluminescence (CL) was used to study the respiratory burst, while genetic analysis was done by RT-PCR, PCR, deltaGT and the 20bp gene scans.
    RESULTS: The CL response of the patient was profoundly low. The patient's p47-phox band was absent in the RT-PCR for NADPH-oxidase component mRNAs. The deltaGT scan showed that the patient's GTGT: deltaGT ratio was 0:6, the parents' and the younger brother's was 1:5 and the younger sister's was 2:4. Examination of other NCF-1/ NCF-1 psi s differences showed that the father had a compound deltaGT allele ie. deltaGT-20bp, inherited by the patient, and that both parents had compound GTGT alleles with a single 30bp segment in intron 1.
    CONCLUSIONS: The patient was a classic, homozygous deltaGT p47-phox deficient CGD with one allele harbouring a compound deltaGT-20bp gene. The deltaGT and 20bp gene scans offer a relatively simple and efficient means of defining a p47-phox deficient CGD patient.
    Key words: Chronic Granulomatous Disease, Primary Immunodeficiency, NCF-1, p47-phox, NADPH-oxidas
    Matched MeSH terms: NADPH Oxidase/metabolism
  4. Fulltext Renal targeting potential of a polymeric drug carrier, poly-l-glutamic acid, in normal and diabetic rats
    Chai HJ, Kiew LV, Chin Y, Norazit A, Mohd Noor S, Lo YL, et al.
    Int J Nanomedicine, 2017;12:577-591.
    PMID: 28144140 DOI: 10.2147/IJN.S111284
    BACKGROUND AND PURPOSE: Poly-l-glutamic acid (PG) has been used widely as a carrier to deliver anticancer chemotherapeutics. This study evaluates PG as a selective renal drug carrier.

    EXPERIMENTAL APPROACH: 3H-deoxycytidine-labeled PGs (17 or 41 kDa) and 3H-deoxycytidine were administered intravenously to normal rats and streptozotocin-induced diabetic rats. The biodistribution of these compounds was determined over 24 h. Accumulation of PG in normal kidneys was also tracked using 5-(aminoacetamido) fluorescein (fluoresceinyl glycine amide)-labeled PG (PG-AF). To evaluate the potential of PGs in ferrying renal protective anti-oxidative stress compounds, the model drug 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) was conjugated to 41 kDa PG to form PG-AEBSF. PG-AEBSF was then characterized and evaluated for intracellular anti-oxidative stress efficacy (relative to free AEBSF).

    RESULTS: In the normal rat kidneys, 17 kDa radiolabeled PG (PG-Tr) presents a 7-fold higher, while 41 kDa PG-Tr shows a 15-fold higher renal accumulation than the free radiolabel after 24 h post injection. The accumulation of PG-AF was primarily found in the renal tubular tissues at 2 and 6 h after an intravenous administration. In the diabetic (oxidative stress-induced) kidneys, 41 kDa PG-Tr showed the greatest renal accumulation of 8-fold higher than the free compound 24 h post dose. Meanwhile, the synthesized PG-AEBSF was found to inhibit intracellular nicotinamide adenine dinucleotide phosphate oxidase (a reactive oxygen species generator) at an efficiency that is comparable to that of free AEBSF. This indicates the preservation of the anti-oxidative stress properties of AEBSF in the conjugated state.

    CONCLUSION/IMPLICATIONS: The favorable accumulation property of 41 kDa PG in normal and oxidative stress-induced kidneys, along with its capabilities in conserving the pharmacological properties of the conjugated renal protective drugs, supports its role as a potential renal targeting drug carrier.

    Matched MeSH terms: NADPH Oxidase/metabolism
  5. Fulltext Antioxidant and pro-oxidant effects of oil palm (Elaeis guineensis) leaves extract in experimental diabetic nephropathy: a duration-dependent outcome
    Varatharajan R, Sattar MZ, Chung I, Abdulla MA, Kassim NM, Abdullah NA
    BMC Complement Altern Med, 2013;13:242.
    PMID: 24074026 DOI: 10.1186/1472-6882-13-242
    Catechins-rich oil palm (Elaeis guineensis) leaves extract (OPLE) is known to have antioxidant activity. Several polyphenolic compounds reported as antioxidants such as quercetin, catechins and gallic acid have been highlighted to have pro-oxidant activity at high doses. Therefore, the present study was conducted to investigate the antioxidant and pro-oxidant effects of chronically administering high dose of OPLE (1000 mg kg⁻¹) in an animal model of diabetic nephropathy (DN).
    Matched MeSH terms: NADPH Oxidase/metabolism
  6. Fulltext Piper sarmentosum inhibits ICAM-1 and Nox4 gene expression in oxidative stress-induced human umbilical vein endothelial cells
    Ugusman A, Zakaria Z, Hui CK, Nordin NA
    BMC Complement Altern Med, 2011;11:31.
    PMID: 21496279 DOI: 10.1186/1472-6882-11-31
    Aqueous extract of Piper sarmentosum (AEPS) is known to possess antioxidant and anti-atherosclerotic activities but the mechanism responsible for it remains unclear. In early part of atherosclerosis, nuclear factor-kappa B (NF-κB) induces the expression of cellular adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) and E-selectin. NADPH oxidase 4 (Nox4) is the predominant source of superoxide in the endothelial cells whereas superoxide dismutase 1 (SOD1), catalase (CAT) and glutathione peroxidase (GPx) are the antioxidant enzymes responsible for inactivating reactive oxygen species. The present study aimed to investigate the effects of AEPS on the gene expression of NF-κB, VCAM-1, ICAM-1, E-selectin, Nox4, SOD1, CAT and GPx in cultured human umbilical vein endothelial cells (HUVECs).
    Matched MeSH terms: NADPH Oxidase/metabolism*
  7. Fulltext Endothelium-Dependent Relaxation Effect of Apocynum venetum Leaf Extract via Src/PI3K/Akt Signalling Pathway
    Lau YS, Ling WC, Murugan D, Kwan CY, Mustafa MR
    Nutrients, 2015 Jul;7(7):5239-53.
    PMID: 26133970 DOI: 10.3390/nu7075220
    Botanical herbs are consumed globally not only as an essential diet but also as medicines or as functional/recreational food supplements. The extract of the Apocynum venetum leaves (AVLE), also known as Luobuma, exerts its antihypertensive effect via dilating the blood vessels in an endothelium- and concentration-dependent manner with optimal effect seen at as low as 10 µg/mL. A commercial Luoboma "antihypertensive tea" is available commercially in the western province of China. The present study seeks to investigate the underlying cellular mechanisms of the nitric oxide (NO)-releasing property of AVLE in rat aortas and human umbilical vein endothelial cells (HUVECs). Endothelium-dependent relaxation induced by AVLE was assessed in organ chambers in the presence or absence of polyethyleneglycol catalase (PP2, 20 µM; inhibitor of Src kinase), wortmannin (30 nM) and LY294002 (20 µM; PI3 (phosphatidylinositol3)-Kinase inhibitor), N(G)-nitro-L-arginine (L-NAME, 100 µM; endothelial NO synthase inhibitor (eNOS)) and ODQ (1 µM; soluble guanylyl cyclase inhibitor). Total nitrite and nitrate (NOx) level and protein expression of p-Akt and p-eNOS were measured. AVLE-induced endothelium-dependent relaxation was reduced by PP2, wortmannin and LY294002 and abolished by L-NAME and ODQ. AVLE significantly increased total NOx level in rat aortas and in HUVECs compared to control. It also instigated phosphorylation of Akt and eNOS in cultured HUVECs in a concentration-dependent manner and this was markedly suppressed by PP2, wortmannin and LY294002. AVLE also inhibited superoxide generated from both NADPH oxidase and xanthine/xanthine oxidase system. Taken together, AVLE causes endothelium-dependent NO mediated relaxations of rat aortas through Src/PI3K/Akt dependent NO signalling pathway and possesses superoxide scavenging activity.
    Matched MeSH terms: NADPH Oxidase/metabolism
  8. Oxidised low density lipoprotein causes human macrophage cell death through oxidant generation and inhibition of key catabolic enzymes
    Katouah H, Chen A, Othman I, Gieseg SP
    Int J Biochem Cell Biol, 2015 Oct;67:34-42.
    PMID: 26255116 DOI: 10.1016/j.biocel.2015.08.001
    Oxidised low density lipoprotein (oxLDL) is thought to be a significant contributor to the death of macrophage cells observed in advanced atherosclerotic plaques. Using human-derived U937 cells we have examined the effect of cytotoxic oxLDL on oxidative stress and cellular catabolism. Within 3h of the addition of oxLDL, there was a rapid, concentration dependent rise in cellular reactive oxygen species followed by the loss of cellular GSH, and the enzyme activity of both glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and aconitase. The loss of these catabolic enzymes was accompanied by the loss of cellular ATP and lower lactate generation. Addition of the macrophage antioxidant 7,8-dihydroneopterin inhibited the ROS generation, glutathione loss and catabolic inactivation. NOX was shown to be activated by oxLDL addition while apocynin inhibited the loss of GSH and cell viability. The data suggests that oxLDL triggers an excess of ROS production through NOX activation, and catabolic failure through thiol oxidation resulting in cell death.
    Matched MeSH terms: NADPH Oxidase/metabolism
  9. Fulltext Rutin Modulates MAPK Pathway Differently from Quercetin in Angiotensin II-Induced H9c2 Cardiomyocyte Hypertrophy
    Siti HN, Jalil J, Asmadi AY, Kamisah Y
    Int J Mol Sci, 2021 May 11;22(10).
    PMID: 34064664 DOI: 10.3390/ijms22105063
    Rutin is a flavonoid with antioxidant property. It has been shown to exert cardioprotection against cardiomyocyte hypertrophy. However, studies regarding its antihypertrophic property are still lacking, whether it demonstrates similar antihypertrophic effect to its metabolite, quercetin. Hence, this study aimed to investigate the effects of both flavonoids on oxidative stress and mitogen-activated protein kinase (MAPK) pathway in H9c2 cardiomyocytes that were exposed to angiotensin II (Ang II) to induce hypertrophy. Cardiomyocytes were exposed to Ang II (600 nM) with or without quercetin (331 μM) or rutin (50 μM) for 24 h. A group given vehicle served as the control. The concentration of the flavonoids was chosen based on the reported effective concentration to reduce cell hypertrophy or cardiac injury in H9c2 cells. Exposure to Ang II increased cell surface area, intracellular superoxide anion level, NADPH oxidase and inducible nitric oxide synthase activities, and reduced cellular superoxide dismutase activity and nitrite level, which were similarly reversed by both rutin and quercetin. Rutin had no significant effects on phosphorylated proteins of extracellular signal-related kinases (ERK1/2) and p38 but downregulated phosphorylated c-Jun N-terminal kinases (JNK1/2), which were induced by Ang II. Quercetin, on the other hand, had significantly downregulated the phosphorylated proteins of ERK1/2, p38, and JNK1/2. The quercetin inhibitory effect on JNK1/2 was stronger than the rutin. In conclusion, both flavonoids afford similar protective effects against Ang II-induced cardiomyocyte hypertrophy, but they differently modulate MAPK pathway.
    Matched MeSH terms: NADPH Oxidase/metabolism
  10. The superoxide dismutase mimetic tempol blunts diabetes-induced upregulation of NADPH oxidase and endoplasmic reticulum stress in a rat model of diabetic nephropathy
    De Blasio MJ, Ramalingam A, Cao AH, Prakoso D, Ye JM, Pickering R, et al.
    Eur J Pharmacol, 2017 Jul 15;807:12-20.
    PMID: 28438648 DOI: 10.1016/j.ejphar.2017.04.026
    Endoplasmic reticulum (ER) stress contributes to progression of diabetic nephropathy, which promotes end-stage renal failure in diabetic patients. This study was undertaken to investigate the actions of tempol and ramipril, pharmacological agents that target the consequences of NADPH oxidase, on diabetic nephropathy in a rat model of type 1 diabetes, with an emphasis on markers of ER stress. Male Sprague-Dawley rats were injected intravenously with a single bolus of streptozotocin (55mg/kg) to induce type 1 diabetes. An additional age-matched group of rats was administered with citrate vehicle as controls. After 4 weeks of untreated diabetes, rats received tempol (1.5mM/kg/day subcutaneously, n=8), ramipril (1mg/kg/day in drinking water, n=8) or remained untreated for an additional 4 weeks (n=7). After 8 weeks of diabetes in total, kidneys were collected for histological analysis, gene expression and protein abundance. Tempol and ramipril blunted diabetes-induced upregulation of NADPH oxidase isoforms (Nox4, Nox2, p47phox), accompanied by an amelioration of diabetes-induced glomerular injury (podocin, nephrin, Kim-1), tubulo-interstitial fibrosis (TGFβ1, TGFβ-R2, pSMAD3, α-SMA) and pro-inflammatory cytokines (TNFα, MCP-1, ANX-A1, FPR2) expression. In addition, the diabetes-induced renal ER stress, evidenced by increased expression of GRP-78 chaperone and stress-associated markers ATF4, TRB3, as well as XBP1s, phospho-p38 mitogen-activated protein kinase (MAPK) and 3-nitrotyrosination, were all attenuated by tempol and ramipril. These observations suggest that antioxidant approaches that blunt NADPH upregulation may attenuate diabetic nephropathy, at least in part by negatively regulating ER stress and inflammation, and hence ameliorating kidney damage.
    Matched MeSH terms: NADPH Oxidase/metabolism*
  11. A critical role of TRPM2 channel in Aβ42 -induced microglial activation and generation of tumor necrosis factor-α
    Alawieyah Syed Mortadza S, Sim JA, Neubrand VE, Jiang LH
    Glia, 2018 03;66(3):562-575.
    PMID: 29143372 DOI: 10.1002/glia.23265
    Amyloid β (Aβ)-induced neuroinflammation plays an important part in Alzheimer's disease (AD). Emerging evidence supports a role for the transient receptor potential melastatin-related 2 (TRPM2) channel in Aβ-induced neuroinflammation, but how Aβ induces TRPM2 channel activation and this relates to neuroinflammation remained poorly understood. We investigated the mechanisms by which Aβ42 activates the TRPM2 channel in microglial cells and the relationships to microglial activation and generation of tumor necrosis factor-α (TNF-α), a key cytokine implicated in AD. Exposure to 10-300 nM Aβ42 induced concentration-dependent microglial activation and generation of TNF-α that were ablated by genetically deleting (TRPM2 knockout ;TRPM2-KO) or pharmacologically inhibiting the TRPM2 channel, revealing a critical role of this channel in Aβ42 -induced microglial activation and generation of TNF-α. Mechanistically, Aβ42 activated the TRPM2 channel via stimulating generation of reactive oxygen species (ROS) and activation of poly(ADPR) polymerase-1 (PARP-1). Aβ42 -induced generation of ROS and activation of PARP-1 and TRPM2 channel were suppressed by inhibiting protein kinase C (PKC) and NADPH oxidases (NOX). Aβ42 -induced activation of PARP-1 and TRPM2 channel was also reduced by inhibiting PYK2 and MEK/ERK. Aβ42 -induced activation of PARP-1 was attenuated by TRPM2-KO and moreover, the remaining PARP-1 activity was eliminated by inhibiting PKC and NOX, but not PYK2 and MEK/ERK. Collectively, our results suggest that PKC/NOX-mediated generation of ROS and subsequent activation of PARP-1 play a role in Aβ42 -induced TRPM2 channel activation and TRPM2-dependent activation of the PYK2/MEK/ERK signalling pathway acts as a positive feedback to further facilitate activation of PARP-1 and TRPM2 channel. These findings provide novel insights into the mechanisms underlying Aβ-induced AD-related neuroinflammation.
    Matched MeSH terms: NADPH Oxidase/metabolism
  12. Fulltext Mechanisms of the antihypertensive effects of Nigella sativa oil in L-NAME-induced hypertensive rats
    Jaarin K, Foong WD, Yeoh MH, Kamarul ZY, Qodriyah HM, Azman A, et al.
    Clinics (Sao Paulo), 2015 Nov;70(11):751-7.
    PMID: 26602523 DOI: 10.6061/clinics/2015(11)07
    This study was conducted to determine whether the blood pressure-lowering effect of Nigella sativa might be mediated by its effects on nitric oxide, angiotensin-converting enzyme, heme oxygenase and oxidative stress markers.
    Matched MeSH terms: NADPH Oxidase/metabolism
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