Modulate NADPH Oxidase Research Articles

Ellagic acid protects against angiotensin II-induced hypertrophic responses through ROS-mediated MAPK pathway in H9c2 cells.

The early myocardial response of hypertension is an elevation of angiotensin-II (Ang-II) concentration, leading to heart failure and cardiac hypertrophy. This hypertrophic event of the heart is mediated by the interaction of Ang type 1 receptors (AT-R1), thereby modulating NADPH oxidase activity in cardiomyocytes, which alters redox status in cardiomyocytes. Ellagic acid (EA) has anti-inflammatory and anti-oxidative capacities. Thus, EA has potential preventive effects on cardiovascular diseases and diabetes. In the last decades, because the protective effect of EA on Ang-II-induced hypertrophic responses is unclear, this study aims to investigate the protective effect of EA in cardiomyocytes. H9c2 cells were treated to Ang-II 1 μM for 24 h to induce cellular damage. We found that EA protected against Ang-II-increased cell surface area and pro-hypertrophic gene expression in H9c2. EA reduced Ang-II-caused AT-R1 upregulation, thereby inhibiting oxidative stress NADPH oxidase activation. EA mitigated Ang-II-enhanced p38 and extracellular-signal-regulated kinase (ERK) phosphorylation. Moreover, EA treatment under Ang-II stimulation also reversed NF-κB activity and iNOS expression. This study shows that EA protects against Ang-II-induced myocardial hypertrophy and attenuates oxidative stress through reactive oxygen species-mediated mitogen-activated protein kinase signaling pathways in H9c2 cells. Thus, EA may be an effective compound for preventing Ang-II-induced myocardial hypertrophy.

Retracted: Osthole Attenuates Bleomycin-Induced Pulmonary Fibrosis by Modulating NADPH Oxidase 4-Derived Oxidative Stress in Mice.

[This retracts the article DOI: 10.1155/2021/3309944.].

GC/MS Profiling, In Vitro Antidiabetic Efficacy of Origanum compactum Benth. Essential Oil and In Silico Molecular Docking of Its Major Bioactive Compounds

Diabetes is a global health concern with significant implications for individuals and healthcare systems. Finding effective and safe antidiabetic agents is crucial for the management of this chronic disease. Natural products have emerged as potential alternatives to allopathic drugs, offering a vast source of bioactive compounds. In this study, we conducted an assessment of the antidiabetic potential of Origanum compactum essential oil, employing a two-pronged approach, i.e., experimental investigation and computational docking analysis. The results of gas chromatography–mass spectrometry (GC-MS) showed that thymol (54.6%), carvacrol (23.18%), and p-cymene (7.12%) were the major compounds. Experimental assessments revealed higher IC50 values (150 µg/mL for α-amylase; 120 µg/mL for α-glucosidase) of O. compactum oil, compared to the control drug acarbose. In silico analysis revealed the best binding affinity of the oil components (carvacrol and thymol) with human NADPH oxidase, while the lysosomal acid-α-glucosidase and salivary amylase also demonstrated good binding affinity towards carvacrol and thymol. Our findings highlight the translational potential of O. compactum oil-based treatment for diabetes mellitus and provide a basis for further studies on the modulation of NADPH oxidase, amylase inhibition, and α-glucosidase by antidiabetic natural products. However, further in vivo investigations are strongly required to confirm the results of in vitro antidiabetic effect of O. compactum EO.

Therapeutic potential of NOX inhibitors in neuropsychiatric disorders.

Neuropsychiatric disorders encompass a broad category of medical conditions that include both neurology as well as psychiatry such as major depressive disorder, autism spectrum disorder, bipolar disorder, schizophrenia as well as psychosis. NADPH-oxidase (NOX), which is the free radical generator, plays a substantial part in oxidative stress in neuropsychiatric disorders. It is thought that elevated oxidative stress as well as neuroinflammation plays a part in the emergence of neuropsychiatric disorders. Including two linked with membranes and four with subunits of cytosol, NOX is a complex of multiple subunits. NOX has been linked to a significant source of reactive oxygen species in the brain. NOX has been shown to control memory processing and neural signaling. However, excessive NOX production has been linked to cardiovascular disorders, CNS degeneration, and neurotoxicity. The increase in NOX leads to the progression of neuropsychiatric disorders. Our review mainly emphasized the characteristics of NOX and its various mechanisms, the modulation of NOX in various neuropsychiatric disorders, and various studies supporting the fact that NOX might be the potential therapeutic target for neuropsychiatric disorders. Here, we summarizes various pharmacological studies involving NOX inhibitors in neuropsychiatric disorders.

OsPDIL1-1 controls ROS generation by modulating NADPH oxidase in developing anthers to alter the susceptibility of floret fertility to heat for rice

High temperature (HT) at meiosis induces heat injury to pollen viability and floret fertility, which is closely associated with HT-induced endoplasmic reticulum (ER) stress and ROS damage in developing anthers. Disulfide isomerase like proteins (PDILs) play an essential role in the formation, reduction, and isomerization of disulfide bonds in nascent secretory proteins for the maintenance of cell viability and ER homeostasis. However, the underlying mechanism by which HT induces ROS burst in rice anthers and its relation to ER stress for the varying existence of PDILs is largely unknown. In this paper, we investigated the action of PDILs in the regulation of heat injury to floret fertility and its association with HT-induced ROS generation in developing anthers under well-controlled climatic conditions. Results showed that knock-down of OsPDIL1-1 by RNAi enhanced the activity of NADPH oxidase and caused the excessive ROS accumulation in developing anthers, consequently the up-grading sensitivity of pollen viability and floret fertility to heat stress. RBOHb is the primary site where HT exposure affected NADPH oxidase activity and triggered ROS generation in rice anthers because OsPDIL1-1 was found to interact with RBOHb in the ER-PM junction. Furthermore, HT exposure triggered the RBOHb-mediated ROS generation in a Ca 2+ -dependent manner, while the induction of HT exposure to ER stress was not necessarily associated with ROS generation derived from NADPH oxidase. • PDIL1-1 was essential for maintaining floret fertility at elevated temperatures. • PDIL1-1 directly interacts with RBOHb to modulate ROS generation in rice anthers. • HT triggered the RBOHb-mediated ROS generation in a Ca 2+ -dependent manner. • HT-induced ER stress was not associated with NADPH oxidase-derived ROS. • PDIL1-1 was found to interact with RBOHb in the ER-PM junction.

The possible protective role of oxytocin on hepatic ischemia and reperfusion injury via modulation of NADPH oxidase in adult male rats.

The possible protective role of oxytocin on hepatic ischemia and reperfusion injury via modulation of NADPH oxidase in adult male rats.

Ursolic acid reduces NADPH oxidase expression and ensuing oxidative stress in diabetic kidney

Background and Aims : Diabetic kidney disease (DKD) is a major life-threatening complication of diabetes. Triterpenic acids elicit anti-hyperglycemic effects and prevent the dysfunction of pancreatic beta cells. The molecular basis of triterpenes action is not completely understood, particularly in DKD. This study aimed at investigating the potential of ursolic acid (UA), a pentacyclic triterpenoid, to modulate NADPH oxidase (Nox) expression, the key source of reactive oxygen species (ROS), in experimental DKD.

Molecular Mechanisms Underlying the Acclimation of Chlamydomonas reinhardtii Against Nitric Oxide Stress

The acclimation mechanism of Chlamydomonas reinhardtii to nitric oxide (NO) was studied by exposure to S-nitroso-N-acetylpenicillamine (SNAP), a NO donor. Treatment with 0.1 or 0.3 mM SNAP transiently inhibited photosynthesis within 1 h, followed by a recovery, while 1.0 mM SNAP treatment caused irreversible photosynthesis inhibition and mortality. The SNAP effects are avoided in the presence of the NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-l-oxyl-3-oxide (cPTIO). RNA-seq, qPCR, and biochemical analyses were conducted to decode the metabolic shifts under NO stress by exposure to 0.3 mM SNAP in the presence or absence of 0.4 mM cPTIO. These findings revealed that the acclimation to NO stress comprises a temporally orchestrated implementation of metabolic processes: (1). modulation of NADPH oxidase (respiratory burst oxidase-like 2, RBOL2) and ROS signaling pathways for downstream mechanism regulation, (2). trigger of NO scavenging elements to reduce NO level; (3). prevention of photo-oxidative risk through photosynthesis inhibition and antioxidant defense system induction; (4). acclimation to nitrogen and sulfur shortage; (5). attenuation of transcriptional and translational activity together with degradation of damaged proteins through protein trafficking machinery (ubiquitin, SNARE, and autophagy) and molecular chaperone system for dynamic regulation of protein homeostasis. In addition, the expression of the gene encoding NADPH oxidase, RBOL2, showed a transient increase while that of RBOL1 was slightly decreased after NO challenge. It reflects that NADPH oxidase, a regulator in ROS-mediated signaling pathway, may be involved in the responses of Chlamydomonas to NO stress. In conclusion, our findings provide insight into the molecular events underlying acclimation mechanisms in Chlamydomonas to NO stress.

Osthole Attenuates Bleomycin-Induced Pulmonary Fibrosis by Modulating NADPH Oxidase 4-Derived Oxidative Stress in Mice.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by the extensive accumulation of myofibroblasts and collagens. However, the exact mechanism that underlies this condition is unclear. Growing evidence suggests that NADPH oxidases (NOXs), especially NOX4-derived oxidative stress, play an important role in the development of lung fibrosis. Bleomycin (BLM) is a tumor chemotherapeutic agent, which has been widely employed to establish IPF animal models. Osthole (OST) is an active constituent of the fruit of Cnidium ninidium. Here, we used an in vivo mouse model and found that OST suppressed BLM-induced body weight loss, lung injury, pulmonary index increase, fibroblast differentiation, and pulmonary fibrosis. OST also significantly downregulated BLM-induced NOX4 expression and oxidative stress in the lungs. In vitro, OST could inhibit TGF-β1-induced Smad3 phosphorylation, differentiation, proliferation, collagen synthesis, NOX4 expression, and ROS generation in human lung fibroblasts in a concentration-dependent manner. Moreover, NOX4 overexpression could prevent the above effects of OST. We came to the conclusion that OST could significantly attenuate BLM-induced pulmonary fibrosis in mice, via the mechanism that involved downregulating TGF-β1/NOX4-mediated oxidative stress in lung fibroblasts.

Nox1/4 inhibition exacerbates age dependent perivascular inflammation and fibrosis in a model of spontaneous hypertension

Hypertension is associated with oxidative stress and perivascular inflammation, critical contributors to perivascular fibrosis and accelerated vascular ageing. Oxidative stress can promote vascular inflammation, creating options for potential use of NADPH oxidase inhibitors in pharmacological targeting of perivascular inflammation and its consequences.Accordingly, we characterized age-related changes in oxidative stress and immune cell infiltration in normotensive (WKY) and spontaneously hypertensive rats (SHRs). Subsequently, we used pharmacological inhibitors of Nox1 (ML171) and Nox1/Nox4 (GKT137831; 60 mg/kg), to modulate NADPH oxidase activity at the early stage of spontaneous hypertension and investigated their effects on perivascular inflammation and fibrosis. ResultsAgeing was associated with a progressive increase of blood pressure as well as an elevation of the total number of leukocytes, macrophages and NK cells infiltrating perivascular adipose tissue (PVAT) in SHRs but not in WKY. At 1 month of age, when blood pressure was not yet different, only perivascular NK cells were significantly higher in SHR. Spontaneous hypertension was also accompanied by the higher perivascular T cell accumulation, although this increase was age independent. Aortic Nox1 and Nox2 mRNA expression increased with age only in SHR but not in WKY, while age-related increase of Nox4 mRNA in the vessels has been observed in both groups, it was more pronounced in SHRs. At early stage of hypertension (3-months) the most pronounced differences were observed in Nox1 and Nox4. Surprisingly, GKT137831, dual inhibitor of Nox1/4, therapy increased both blood pressure and perivascular macrophage infiltration. Mechanistically, this was linked to increased expression of proinflammatory chemokines expression (CCL2 and CCL5) in PVAT. This inflammatory response translated to increased perivascular fibrosis. This effect was likely Nox4 dependent as the Nox1 inhibitor ML171 did not affect the development of spontaneous hypertension, perivascular macrophage accumulation, chemokine expression nor adventitial collagen deposition.In summary, spontaneous hypertension promotes ageing-associated perivascular inflammation which is exacerbated by Nox4 but not Nox1 pharmacological inhibition.

A novel danshensu derivative ameliorates experimental colitis by modulating NADPH oxidase 4-dependent NLRP3 inflammasome activation.

We have previously reported a novel compound [4‐(2‐acetoxy‐3‐((R)‐3‐(benzylthio)‐1‐methoxy‐1‐oxopropan‐2‐ylamino)‐3‐oxopropyl)‐1,2‐phenylene diacetate (DSC)], derived from danshensu, exhibits cytoprotective activities in vitro. Here, we investigated the effects and underlying mechanisms of DSC on dextran sodium sulphate (DSS)‐induced experimental colitis. We found that DSC treatment afforded significant protection against the development of colitis, evidencing by suppressed inflammatory responses and enhanced barrier integrity. Intriguingly, DSC specifically down‐regulated DSS‐induced colonic NADPH oxidase 4 (Nox4) expression, accompanied by a balanced redox status, suppressed nuclear factor‐κB (NF‐κB) and NLRP3 inflammasome activation and up‐regulated nuclear factor (erythroid‐derived 2)‐like 2 and haeme oxygenase‐1 expression. In vitro study also demonstrated DSC also markedly decreased Nox4 expression and activity associated with inhibiting reactive oxygen species generation, NF‐κB activation and NLRP3 inflammasome activation in bone marrow‐derived macrophages. Either lentiviral Nox4 shRNA‐mediated Nox4 knockdown or Nox4‐specific small‐interfering RNA mimicked effects of DSC by suppressing NLPR3 inflammasome activation to alleviate experimental colitis or inflammatory macrophage response. Collectively, our results provide the first evidence that DSC ameliorates experimental colitis partly through modulating Nox4‐mediated NLRP3 inflammasome activation.

Modulation of NADPH oxidase and Nrf2/HO-1 pathway by vanillin in cisplatin-induced nephrotoxicity in rats.

To investigate the protective effect of vanillin in cisplatin (CP)-induced nephrotoxicity in rats and elucidate the role of nrf-2 and its downstream antioxidant molecules. Rats received vanillin (100mg/kg orally) for 10 constitutive days and CP (7.5mg/kg, once, ip) on day 6 of vanillin administration. Cisplatin suppressed body weight gain, increased serum urea and creatinine and renal malondialdehyde and nitric oxide while decreased renal total antioxidant capacity. Up-regulation of NADPH oxidase-4 (NOX-4) was marked in renal tissue of CP-treated rats along with down-regulation of the antioxidant genes (nuclear factor erythroid 2-related factor2 (NRF2) and haem oxygenase-1(HO-1)). Increased tumour necrosis factor-α and decreased interleukin-10 with increased myeloperoxidase activity were apparent in renal tissue of CP-treated rats along with marked tubular injury, neutrophil infiltration and increased apoptosis (caspase-3) and some degree of interstitial fibrosis. Vanillin prophylactic administration prevented the deterioration of kidney function, oxidative and nitrosative stress. It also suppressed NOX-4 and up-regulated NRF2 and HO-1 expression in renal tissue. Inflammation, apoptosis and tubular injury were also inhibited by vanillin. The antioxidant mechanism by which vanillin protected against CP-induced nephrotoxicity involved the inhibition of NOX-4 along with the stimulation of Nrf2/HO-1 signalling pathway. These in turn inhibited inflammation and apoptosis.

Quercetin suppressed NADPH oxidase-derived oxidative stress via heme oxygenase-1 induction in macrophages

NADPH oxidase-derived superoxide (O2.-) generation and oxidative stress is usually considered as an important factor to the pathogenesis of inflammatory diseases. Quercetin, widely known for their anti-oxidant and anti-inflammatory properties in vitro and in vivo, is recently identified to induce expression of antioxidant enzyme heme oxygenase-1 (HO-1). Previous studies suggest that HO-1 induction and/or subsequent HO-1 end product generation in vitro and in vivo may suppress NADPH oxidase-derived oxidative stress. In this study, we tested whether quercetin might modulate NADPH oxidase activity in macrophages via induction of HO-1. In RAW264.7 macrophages, quercetin significantly attenuated NADPH oxidase-derived O2.- generation via a HO-1-dependent mechanism. Mechanistically, the protective effects of quercetin were (1) linked to increased expression of HO-1 in the presence or absence of lipopolysaccharide (LPS), (2) similar to that observed with the NADPH oxidase inhibitor apocynin, and (3) could be abolished by the specific small-interfering RNA against HO-1 expression or HO-1 activity inhibitor tin protoporphyrin. The induction of HO-1 by quercetin was associated with the nuclear accumulation of Nrf2 and downregulation of Keap1, a negative regulator of Nrf2. In addition, this flavonoid also inhibited the overproduction of nitric oxide and inflammatory cytokines in LPS-stimulated macrophages via simultaneous induction of HO-1 expression. In agreement with the observations in macrophages, pretreatment with quercetin significantly alleviated LPS-induced inflammation in mice which was concomitant with decreased NADPH oxidase activity and increased HO-1 expression. Our results suggested that quercein could modulate NADPH oxidase-derived O2.- production in macrophages at least partly through HO-1 induction. Suppression of NADPH oxidase-dependent oxidative stress may represent a novel mechanism underlying the anti-oxidant and anti-inflammatory properties of quercetin/HO-1 pathway.

Nitric oxide protected against NADPH oxidase-derived superoxide generation in vascular endothelium: Critical role for heme oxygenase-1

NADPH oxidase-derived superoxide (O2−) generation is usually considered as an important factor to the pathogenesis of cardiovascular diseases. Nitric oxide (NO), previously viewed as a key regulator of cardiovascular function, is identified to induce expression of heme oxygenase-1 (HO-1), an antioxidant enzyme in blood vessels. In this study, we tested whether NO might modulate NADPH oxidase activity in vascular endothelium via HO-1. In vascular endothelial cells, NO donor (diethylenetriamine/nitric oxide adduct) significantly attenuated NADPH oxidase-derived O2− generation via a HO-1-dependent mechanism. Mechanistically, the protective effects of NO were (1) linked to increased expression of HO-1, (2) similar to the effects of NADPH oxidase inhibitor, (3) could be abolished by the specific siRNA against HO-1 expression or HO-1 activity inhibitor and (4) similar to the effects of HO-1 end product bilirubin. Moreover, bilirubin seemed to interrupt the assembly and activation of NADPH oxidase. In addition, NO inhibited H2O2-induced endothelial dysfunction through activation of HO-1. In agreement with these in vitro data, aortic NADPH oxidase activity was increased in NO-deficient mice while the endothelial function was simultaneously impaired. Our results suggested that suppression of NADPH oxidase-dependent oxidative stress may represent a novel mechanism underlying the cardiovascular protection of NO/HO-1 pathway.

P9 - Plant Bioactives and the Intestinal Barrier: Redox Signaling and Implications for Insulin Resistance

Dietary plant bioactives, and in particular flavonoids, can exert actions at the gastrointestinal (GI) tract that can have an impact systemically, e.g. on glucose homeostasis, lipid and energy metabolism. GI barrier permeabilization and the associated increased passage to the circulation of luminal endotoxins underlie in part the pathophysiology of obesity-associated pathologies, including insulin resistance and type 2 diabetes. Endotoxins trigger systemic pro-inflammatory responses that contribute to tissue insulin resistance involving the activation of redox-regulated signals. Among flavonoids, we found that the flavan-3-ol (-)-epicatechin (EC) inhibits high fat (HFD)- and/or high fructose (HFr) diet-induced insulin resistance and steatosis in rodents. These beneficial effects are associated with EC capacity to inhibit HFD-mediated intestinal barrier permeabilization and endotoxemia. In vivo and in vitro studies support intestinal cell NADPH oxidase as a major target involved in EC effects. NADPH oxidase triggers a downstream series of events that cause tight junction disruption: NF-kB and ERK1/2 activation, upregulation of myosin light chain (MLC) kinase, leading to MLC phosphorylation and consequent monolayer permeabilization. Modulation of NADPH oxidase is also involved in the capacity of EC to restore insulin sensitivity in liver and adipose tissues, given that the redox-regulated activation of IKK/NF-kB, JNK1/2 and PKC causes inhibitory serine phosphorylation of the insulin receptor (IR) substrate 1 (IRS1), and upregulation of the IR and IRS1 inhibitory tyrosine phosphatase PTP1B. EC and other structurally related flavonoids (i.e. anthocyanidins (AC)) that directly inhibit NADPH oxidase, share similar chemical structures and capacity to improve insulin sensitivity. Furthermore, inhibition of NF-kB can explain EC-mediated decreased expression of select NADPH isoforms. In summary, the capacity of select bioactives (EC, AC) to improve HFD/HFR-associated insulin resistance is in part mediated through their capacity to modulate NADPH oxidase and redox-regulated pathways, leading to loss of GI tract barrier integrity and downregulation of the insulin pathway.

4-(4-Hydroxy-3-methoxyphenyl)-2-butanone modulates redox signal in gamma-irradiation-induced nephrotoxicity in rats

Cellular exposure to ionising radiation leads to oxidative stress events, which refer to elevated intracellular levels of reactive oxygen species (ROS). The elevated levels of ROS significantly contributed to γ-radiation (IR) induced cytotoxicity. In an attempt to minimise these cytotoxic effects, antioxidant compounds have been identified to counteract radiation- associated toxicities. We mainly aimed to study the protective effect of 4-(4-hydroxy-3-methoxyphenyl)-2-butanone (HMB) on IR-induced nephrotoxicity, whereas it was previously shown to have anti-inflammatory effects in different inflammation models. Animals were treated orally with HMB (25 mg/kg b.wt daily) then performed by whole-body gamma-irradiation of animals with 6 Gy; a single dose applied on the 15th day and animals were sacrificed at the end of the 23rd day. It was found that IR exposure significantly induced renal oxidative injury that accompanied by inflammatory disturbance. Also, NADPH oxidase and iNOS gene expressions were significantly up-regulated, while the mitochondrial enzymes (complex I & II) were significantly down-regulated in IR exposed animals. Additionally, Western immunoblotting analysis of signalling growth factor protein; p38 MAPK was significantly overexpressed. Interestingly, HMB treatment showed statistically significant amelioration in parameters with an improved histological structure upon the IR-induced nephrotoxicity. It can be concluded that modulation of NADPH-oxidase, iNOS and mitochondrial enzymes by HMB might be responsible for the amendment of the antioxidant status and impairment of p38 MAPK signal, thus attenuate the nephrotoxicity induced post IR exposure.

YJI-7 Suppresses ROS Production and Expression of Inflammatory Mediators via Modulation of p38MAPK and JNK Signaling in RAW 264.7 Macrophages.

Chalcone, (2E)-1,3-Diphenylprop-2-en-1-one, and its synthetic derivatives are known to possess anti-oxidative and anti-inflammatory properties. In the present study, we prepared a novel synthetic chalcone compound, (E)-1-(4-hydroxyphenyl)-3-(2-(trifluoromethoxy)phenyl)prop-2-en-1-one name (YJI-7), and investigated its inhibitory effects on endotoxin-stimulated production of reactive oxygen species (ROS) and expression of inflammatory mediators in macrophages. We demonstrated that treatment of RAW 264.7 macrophages with YJI-7 significantly suppressed lipopolysaccharide (LPS)-stimulated ROS production. We also found that YJI-7 substantially decreased NADPH oxidase activity stimulated by LPS, indicating that YJI-7 regulates ROS production via modulation of NADPH oxidase in macrophages. Furthermore, YJI-7 strongly inhibited the expression of a number of inflammatory mediators in a gene-selective manner, suggesting that YJI-7 possesses potent anti-inflammatory properties, as well as anti-oxidative activity. In continuing experiments to investigate the mechanisms that could underlie such biological effects, we revealed that YJI-7 suppressed phosphorylation of p38MAPK and JNK stimulated by LPS, whereas no significant effect on ERK was observed. Furthermore, LPS-stimulated production of ROS, activation of NADPH oxidase and expression of inflammatory mediators were markedly suppressed by treatment with selective inhibitor of p38MAPK (SB203580) and JNK (SP600125). Taken together, these results demonstrated that YJI-7, a novel synthetic chalcone derivative, suppressed LPS-stimulated ROS production via modulation of NADPH oxidase and diminished expression of inflammatory mediators, at least in part, via down-regulation of p38MAPK and JNK signaling in macrophages.

Design, synthesis, and structure-activity relationship study of halogen containing 2-benzylidene-1-indanone derivatives for inhibition of LPS-stimulated ROS production in RAW 264.7 macrophages

As a continuous effort to discover new potential anti-inflammatory agents, we systematically designed and synthesized sixty-one 2-benzylidene-1-indanone derivatives with structural modification of chalcone, and evaluated their inhibitory activity on LPS-stimulated ROS production in RAW 264.7 macrophages. Systematic structure-activity relationship study revealed that hydroxyl group in C-5, C-6, or C-7 position of indanone moiety, and ortho-, meta-, or para-fluorine, trifluoromethyl, trifluoromethoxy, and bromine functionalities in phenyl ring are important for inhibition of ROS production in LPS-stimulated RAW 264.7 macrophages. Among all the tested compounds, 6-hydroxy-2-(2-(trifluoromethoxy) benzylidene)-2,3-dihydro-1H-inden-1-one (compound 44) showed the strongest inhibitory activity of ROS production. Further studies on the mode of action revealed that compound 44 potently suppressed LPS-stimulated ROS production via modulation of NADPH oxidase. The findings of this work could be useful to design 2-benzylidene-indanone based lead compounds as novel anti-inflammatory agents.

L-Carnitine ameliorates the oxidative stress response to angiotensin II by modulating NADPH oxidase through a reduction in protein kinase c activity and NF-κB translocation to the nucleus.

l-Carnitine (LC) exerts beneficial effects in arterial hypertension due, in part, to its antioxidant capacity. We investigated the signalling pathways involved in the effect of LC on angiotensin II (Ang II)-induced NADPH oxidase activation in NRK-52E cells. Ang II increased the generation of superoxide anion from NADPH oxidase, as well as the amount of hydrogen peroxide and nitrotyrosine. Co-incubation with LC managed to prevent these alterations and also reverted the changes in NADPH oxidase expression triggered by Ang II. Cell signalling studies evidenced that LC did not modify Ang II-induced phosphorylation of Akt, p38 MAPK or ERK1/2. On the other hand, a significant decrease in PKC activity, and inhibition of nuclear factor kappa B (NF-kB) translocation, were attributable to LC incubation. In conclusion, LC counteracts the pro-oxidative response to Ang II by modulating NADPH oxidase enzyme via reducing the activity of PKC and the translocation of NF-kB to the nucleus.

The Role of Iodine Deficiency and Subsequent Repletion in Autoimmune Thyroid Disease and Thyroid Cancer

Iodine is an essential trace mineral that is necessary for thyroid hormone production. With the prevalence of iodine deficiency worldwide, universal salt iodization programs were successfully implemented to reduce the incidence of iodine deficiency disorders; however, unexpected increases in the prevalence of thyroid autoimmunity occurred, and iodine excess was implicated as the causative factor. Despite these observations, epidemiological studies are inconsistent, and the etiology of autoimmune thyroid disease remains undefined. A review of observational and in vitro studies revealed that iodine alone is not responsible for thyroid autoimmunity. Experimental models used to explain iodine excess as the culprit in thyroid autoimmunity fail to induce thyroid autoantibodies unless iodine is in the presence of excess inflammatory cytokines (interferon [IFN]-γ) and hydrogen peroxide (H2O2). Within iodine-deficient populations, regulatory mechanisms to limit oxidative stress and excess iodine are lost. Thyroid-stimulating hormone persistently activates the sodium-iodide symporter, while iodine concentrations fail to achieve levels high enough to produce iodolactones, which are responsible for modulating NADPH oxidase and H2O2 production. Subsequently, the thyroid becomes susceptible to oxidative stress as iodine is reintroduced. Oxidation of thyroid peroxidase and thyroglobulin initiate the release of inflammatory cytokines (IFN-γ) and lymphocytic infiltration, which induce autoantibody production and thyroid autoimmunity. Population studies revealed that iodine administration even below the recommended dietary allowance alters thyroid autoimmunity. Despite increases in thyroid antibodies, these changes are found to be transient. Interestingly, reports of iodine in combination with other nutrients and standardized botanical extracts have been used successfully to restore thyroid function. On the basis of our review of the literature, it is apparent that a loss of regulatory mechanisms due to preexisting iodine deficiency followed by iodine repletion, as opposed to iodine excess, is a causal factor in the development of thyroid autoimmunity.