Displaying publications 1 - 20 of 26 in total

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  1. A Cyclic Peptide Inhibitor of the iNOS-SPSB Protein-Protein Interaction as a Potential Anti-Infective Agent
    Sadek MM, Barlow N, Leung EWW, Williams-Noonan BJ, Yap BK, Shariff FM, et al.
    ACS Chem. Biol., 2018 10 19;13(10):2930-2938.
    PMID: 30226743 DOI: 10.1021/acschembio.8b00561
    SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, and SPSB4 interact with inducible nitric oxide synthase (iNOS), causing the iNOS to be polyubiquitinated and targeted for degradation. Inhibition of this interaction increases iNOS levels, and consequently cellular nitric oxide (NO) concentrations, and has been proposed as a potential strategy for killing intracellular pathogens. We previously described two DINNN-containing cyclic peptides (CP1 and CP2) as potent inhibitors of the murine SPSB-iNOS interaction. In this study, we report the crystal structures of human SPSB4 bound to CP1 and CP2 and human SPSB2 bound to CP2. We then used these structures to design a new inhibitor in which an intramolecular hydrogen bond was replaced with a hydrocarbon linkage to form a smaller macrocycle while maintaining the bound geometry of CP2 observed in the crystal structures. This resulting pentapeptide SPSB-iNOS inhibitor (CP3) has a reduced macrocycle ring size, fewer nonbinding residues, and includes additional conformational constraints. CP3 has a greater affinity for SBSB2 ( KD = 7 nM as determined by surface plasmon resonance) and strongly inhibits the SPSB2-iNOS interaction in macrophage cell lysates. We have also determined the crystal structure of CP3 in complex with human SPSB2, which reveals the structural basis for the increased potency of CP3 and validates the original design.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism*
  2. A synthetic curcuminoid derivative inhibits nitric oxide and proinflammatory cytokine synthesis
    Tham CL, Liew CY, Lam KW, Mohamad AS, Kim MK, Cheah YK, et al.
    Eur J Pharmacol, 2010 Feb 25;628(1-3):247-54.
    PMID: 19958764 DOI: 10.1016/j.ejphar.2009.11.053
    Curcumin is a highly pleiotropic molecule with significant regulatory effects upon inflammation and inflammatory related diseases. However curcumin has one major important limitation in which it has poor bioavailability. Design of synthetic structural derivatives of curcumin is but one approach that has been used to overcome its poor bioavailability while retaining, or further enhancing, its drug-like effects. We have synthesized a series of curcumin analogues and describe the effects of 2,6-bis-4-(hydroxyl-3-methoxy-benzylidine)-cyclohexanone or BHMC upon nitric oxide and cytokine synthesis in cellular models of inflammation. BHMC showed a significant dose-response inhibitory action upon the synthesis of NO and we have shown that this effect was due to suppression of both iNOS gene and enzyme expression without any effects upon scavenging of nitrite. We also demonstrated that BHMC has a very minimal effect upon iNOS activity with no effect at all upon the secretion of PGE(2) but has a strong inhibitory effect upon MCP-1 and IL-10 secretion and gene expression. Secretion and gene expression of TNF-alpha and IL-6 were moderately inhibited whereas IL-8 and IL-1beta were not altered. We conclude that BHMC selectively inhibits the synthesis of several inflammatory mediators. BHMC should be considered a promising drug lead for preclinical and further pharmacological studies.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  3. Arginine glutamate improves healing of radiation-induced skin ulcers in guinea pigs
    Khalin I, Kocherga G
    Int J Radiat Biol, 2013 Dec;89(12):1108-15.
    PMID: 23786463 DOI: 10.3109/09553002.2013.817698
    The increase in the incidence of the radiation-induced skin injury cases and the absence of standard treatments escalate the interest in finding new and effective drugs for these lesions. We studied the effect of a 40% solution of arginine glutamate on the healing of radiation-induced skin ulcers in guinea pigs.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  4. Attenuation of COX-2 enzyme by modulating H2O2-mediated NF-κB signaling pathway by monoamine oxidase inhibitor (MAOI): a further study on the reprofiling of MAOI in acute inflammation
    Sur D, Mondal C, Balaraman AK, Haldar PK, Maji HS, Bala A
    Inflammopharmacology, 2023 Jun;31(3):1305-1317.
    PMID: 36826724 DOI: 10.1007/s10787-023-01165-5
    OBJECTIVE: This study aims to investigate the anti-inflammatory mechanism of monoamine oxidase inhibitor (MAOI) in carrageenan (CARR) induced inflammation models to reprofile their use. We also aimed to explore the role of monoamine oxidase (MAO)-mediated H2O2-NF-κB-COX-2 pathway in acute inflammation.

    METHODS: In vitro anti-inflammatory activity and hydrogen peroxide (H2O2) scavenging activity were performed according to the established procedure. Inflammation was induced using CARR in BALB/c mice at the foot paw and peritoneal cavity. Hourly measurement of paw swelling was performed. The level of nitric oxide (NO), myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and nuclear factor κB (NF-κB) was determined using enzyme-linked immunosorbent assay (ELISA). Peritoneal fluid was collected to investigate total count, differential count of leukocytes, and capillary permeability.

    RESULTS: In vitro anti-inflammatory evaluations revealed the potential role of MAOI to inhibit heat-induced protein denaturation and human red cell membrane destabilization. H2O2 inhibition activity of MAOI also proved their powerful role as an H2O2 scavenger. Treatment with MAOI in CARR-induced mice significantly reduced paw edema, leukocyte extravasation, and total and differential leukocyte count. The result of ELISA showed MAOI effectively reduce the level of COX-2, PGE2 and NF-κB in inflamed tissue.

    CONCLUSIONS: In short, this study demonstrates that inhibition of H2O2 by MAOI alleviates CARR-induced paw edema possibly by inhibiting the H2O2-mediated NF-κB-COX-2 pathway. The present investigation identifies MAOI might reprofile for the treatment of acute inflammation also, the MAO enzyme may use as a novel therapeutic target to design and develop new class of anti-inflammatory agents.

    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  5. Fulltext Brewers' rice modulates oxidative stress in azoxymethane-mediated colon carcinogenesis in rats
    Tan BL, Norhaizan ME, Huynh K, Yeap SK, Hazilawati H, Roselina K
    World J Gastroenterol, 2015 Aug 7;21(29):8826-35.
    PMID: 26269672 DOI: 10.3748/wjg.v21.i29.8826
    To investigate the mechanistic action of brewers' rice in regulating the Wnt/nuclear factor-kappa B (NF-κB)/Nrf2-signaling pathways during colon carcinogenesis in male Sprague-Dawley rats.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  6. Fulltext Capgermacrenes A and B, Bioactive Secondary Metabolites from a Bornean Soft Coral, Capnella sp
    Phan CS, Ng SY, Kim EA, Jeon YJ, Palaniveloo K, Vairappan CS
    Mar Drugs, 2015 May;13(5):3103-15.
    PMID: 25996100 DOI: 10.3390/md13053103
    Two new bicyclogermacrenes, capgermacrenes A (1) and B (2), were isolated with two known compounds, palustrol (3) and litseagermacrane (4), from a population of Bornean soft coral Capnella sp. The structures of these metabolites were elucidated based on spectroscopic data. Compound 1 was found to inhibit the accumulation of the LPS-induced pro-inflammatory IL-1b and NO production by down-regulating the expression of iNOS protein in RAW 264.7 macrophages.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  7. Cardamonin inhibits COX and iNOS expression via inhibition of p65NF-kappaB nuclear translocation and Ikappa-B phosphorylation in RAW 264.7 macrophage cells
    Israf DA, Khaizurin TA, Syahida A, Lajis NH, Khozirah S
    Mol Immunol, 2007 Feb;44(5):673-9.
    PMID: 16777230
    Cardamonin, a chalcone isolated from the fruits of a local plant Alpinia rafflesiana, has demonstrated anti-inflammatory activity in cellular models of inflammation. In this report, we evaluated the ability of cardamonin to suppress both NO and PGE2 synthesis, iNOS and COX-2 expression and enzymatic activity, and key molecules in the NF-kappaB pathway in order to determine its molecular target. Cardamonin suppressed the production of NO and PGE2 in interferon-gamma (IFN-gamma)- and lipopolysaccharide (LPS)-induced RAW 264.7 cells. This inhibition was demonstrated to be caused by a dose-dependent down-regulation of both inducible enzymes, iNOS and COX-2, without direct effect upon iNOS or COX-2 enzyme activity. Subsequently we determined that the inhibition of inducible enzyme expression was due to a dose-dependent inhibition of phosphorylation and degradation of I-kappaBalpha, which resulted in a reduction of p65NF-kappaB nuclear translocation. We conclude that cardamonin is a potential anti-inflammatory drug lead that targets the NF-kappaB pathway.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  8. Cellular uptake and anti-inflammatory effects of palm oil-derived delta (δ)-tocotrienol in microglia
    Tan SW, Israf Ali DAB, Khaza'ai H, Wong JW, Vidyadaran S
    Cell Immunol, 2020 11;357:104200.
    PMID: 32979761 DOI: 10.1016/j.cellimm.2020.104200
    Tocopherols long dominated studies on vitamin E, although interest has shifted to tocotrienols. It was previously shown that δ-tocotrienol derived from palm oil reduced nitric oxide released by BV2 microglia as early as 18 h after lipopolysaccharide stimulation. The current study measured δ-tocotrienol uptake by BV2 over a 24 h incubation period and its anti-inflammatory effects on primary microglia. Uptake of 17.5 μg/mL δ-tocotrienol by BV2 microglia began as early as 5 min and rose steeply to 21 ± 3% of the amount administered at 24 h. The amount of δ-tocotrienol retained in the lipopolysaccharide-stimulated microglia at 24 h was 14 ± 2%, with no substantial difference seen in unstimulated microglia. The same δ-tocotrienol regimen reduced nitric oxide levels by 82% at 24 h after lipopolysaccharide stimulation (p nitric oxide synthase protein expression by 67 ± 5% compared to untreated controls (p 
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  9. Dietary cocoa protects against colitis-associated cancer by activating the Nrf2/Keap1 pathway
    Pandurangan AK, Saadatdoust Z, Esa NM, Hamzah H, Ismail A
    Biofactors, 2015 Jan-Feb;41(1):1-14.
    PMID: 25545372 DOI: 10.1002/biof.1195
    Colorectal cancer (CRC) is the third most common malignancy in males and the second most common cancer worldwide. Chronic colonic inflammation is a known risk factor for CRC. Cocoa contains many polyphenolic compounds that have beneficial effects in humans. The objective of this study is to explore the antioxidant properties of cocoa in the mouse model of azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated cancer, focusing on the activation of Nrf2 signaling. Mice were treated with AOM/DSS and randomized to receive either a control diet or a 5 and 10% cocoa diet during the study period. On day 62 of the experiment, the entire colon was processed for biochemical and histopathological examination and further evaluations. Increased levels of malondialdehyde (MDA) were observed in AOM/DSS-induced mice; however, subsequent administration of cocoa decreased the MDA. Enzymatic and nonenzymatic antioxidants, such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, were decreased in the AOM/DSS mice. Cocoa treatment increases the activities/levels of enzymatic and nonenzymatic antioxidants. Inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, were elevated during AOM/DSS-induction, and treatment with 5 and 10% cocoa effectively decreases the expression of iNOS and COX-2. The NF-E2-related factor 2 and its downstream targets, such as NQO1 and UDP-GT, were increased by cocoa treatment. The results of our study suggest that cocoa may merit further clinical investigation as a chemopreventive agent that helps prevent CAC.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  10. Effect of L-N6-(1-iminoethyl)-lysine, an inducible nitric oxide synthase inhibitor, on murine immune response induced by Actinobacillus actinomycetemcomitans lipopolysaccharide
    Sosroseno W, Musa M, Ravichandran M, Fikri Ibrahim M, Bird PS, Seymour GJ
    J Periodontal Res, 2007 Apr;42(2):124-30.
    PMID: 17305870
    Inducible nitric oxide synthase (iNOS) activity is known to regulate the immune response. The present study was carried out to determine the effect of L-N6-(1-iminoethyl)-lysine (L-NIL), an iNOS inhibitor, on the induction of immune response to Actinobacillus actinomycetemcomitans lipopolysaccharide in mice.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  11. Effects of topically applied tocotrienol on cataractogenesis and lens redox status in galactosemic rats
    Abdul Nasir NA, Agarwal R, Vasudevan S, Tripathy M, Alyautdin R, Ismail NM
    Mol Vis, 2014;20:822-35.
    PMID: 24940038
    Oxidative and nitrosative stress underlies cataractogenesis, and therefore, various antioxidants have been investigated for anticataract properties. Several vitamin E analogs have also been studied for anticataract effects due to their antioxidant properties; however, the anticataract properties of tocotrienols have not been investigated. In this study, we investigated the effects of topically applied tocotrienol on the onset and progression of cataract and lenticular oxidative and nitrosative stress in galactosemic rats.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  12. Eucophylline, a Tetracyclic Vinylquinoline Alkaloid from Leuconotis eugenifolius
    Deguchi J, Shoji T, Nugroho AE, Hirasawa Y, Hosoya T, Shirota O, et al.
    J Nat Prod, 2010 Oct 22;73(10):1727-9.
    PMID: 20836516 DOI: 10.1021/np100458b
    Eucophylline (1), a new tetracyclic vinylquinoline alkaloid, was isolated from the bark of Leuconotis eugenifolius together with leucophyllidine (2). The structure and absolute configuration of 1 were elucidated on the basis of 2D NMR correlations and simulated CD analysis. Leucophyllidine (2) showed iNOS inhibitory activity and decreased the iNOS protein expression dose-dependently.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  13. Evaluation of antiarthritic activity of nimbolide against Freund's adjuvant induced arthritis in rats
    Cui X, Wang R, Bian P, Wu Q, Seshadri VDD, Liu L
    Artif Cells Nanomed Biotechnol, 2019 Dec;47(1):3391-3398.
    PMID: 31394949 DOI: 10.1080/21691401.2019.1649269
    Nimbolide, a triterpenoid isolated from flower of neem tree possess various therapeutic properties. The objective of the study was to assess the anti-arthritic activity of nimbolide in arthritis induced rats. Nimbolide (20 mg/kg per day) was given orally to arthritic rats induced with Complete Freund's Adjuvant and changes in paw volume, body weight, organ indices (thymus and spleen), arthritic score, biochemical parameters and proinflammatory cytokines levels were determined. Histopathological analysis was also performed. Western blot analysis was also performed. Rats treated with nimbolide displayed marked reduction in arthritic score, organ indices, volume of paw, edema formation, along with substantial enhancement in body weight. Histopathological findings showed significant reduction in destruction of joints and inflammation following nimbolide treatment. The protective action of arthritic rats treated with nimbolide was also substantiated by molecular and biochemical studies. The results of the study show that nimbolide treatment has markedly enhanced health and reduced inflammation via lessening the proinflammatory cytokines expression in arthritic rats. Hence, nimbolide may be used as a potent therapeutic drug in treating rheumatoid arthritis.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  14. Fulltext Gelam honey scavenges peroxynitrite during the immune response
    Kassim M, Mansor M, Suhaimi A, Ong G, Yusoff KM
    Int J Mol Sci, 2012;13(9):12113-29.
    PMID: 23109904 DOI: 10.3390/ijms130912113
    Monocytes and macrophages are part of the first-line defense against bacterial, fungal, and viral infections during host immune responses; they express high levels of proinflammatory cytokines and cytotoxic molecules, including nitric oxide, reactive oxygen species, and their reaction product peroxynitrite. Peroxynitrite is a short-lived oxidant and a potent inducer of cell death. Honey, in addition to its well-known sweetening properties, is a natural antioxidant that has been used since ancient times in traditional medicine. We examined the ability of Gelam honey, derived from the Gelam tree (Melaleuca spp.), to scavenge peroxynitrite during immune responses mounted in the murine macrophage cell line RAW 264.7 when stimulated with lipopolysaccharide/interferon-γ (LPS/IFN-γ) and in LPS-treated rats. Gelam honey significantly improved the viability of LPS/IFN-γ-treated RAW 264.7 cells and inhibited nitric oxide production-similar to the effects observed with an inhibitor of inducible nitric oxide synthase (1400W). Furthermore, honey, but not 1400W, inhibited peroxynitrite production from the synthetic substrate 3-morpholinosydnonimine (SIN-1) and prevented the peroxynitrite-mediated conversion of dihydrorhodamine 123 to its fluorescent oxidation product rhodamine 123. Honey inhibited peroxynitrite synthesis in LPS-treated rats. Thus, honey may attenuate inflammatory responses that lead to cell damage and death, suggesting its therapeutic uses for several inflammatory disorders.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  15. Fulltext In vitro and in vivo anti-inflammatory activity of 17-O-acetylacuminolide through the inhibition of cytokines, NF-κB translocation and IKKβ activity
    Achoui M, Appleton D, Abdulla MA, Awang K, Mohd MA, Mustafa MR
    PLoS One, 2010;5(12):e15105.
    PMID: 21152019 DOI: 10.1371/journal.pone.0015105
    17-O-acetylacuminolide (AA), a diterpenoid labdane, was isolated for the first time from the plant species Neouvaria foetida. The anti-inflammatory effects of this compound were studied both in vitro and in vivo.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  16. Fulltext Malaysian endophytic fungal extracts-induced anti-inflammation in Lipopolysaccharide-activated BV-2 microglia is associated with attenuation of NO production and, IL-6 and TNF-α expression
    Harun A, Vidyadaran S, Lim SM, Cole AL, Ramasamy K
    BMC Complement Altern Med, 2015;15:166.
    PMID: 26047814 DOI: 10.1186/s12906-015-0685-5
    Excessive production of inflammatory mediators such as nitric oxide (NO) and proinflammatory cytokines like tumour necrosis factor-alpha (TNF-α) from activated microglia contributes to uncontrolled inflammation in neurodegenerative diseases. This study investigated the protective role of five endophytic extracts (HAB16R12, HAB16R13, HAB16R14, HAB16R18 and HAB8R24) against LPS-induced inflammatory events in vitro. These endophytic extracts were previously found to exhibit potent neuroprotective effect against LPS-challenged microglial cells.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  17. Nitric oxide production by a human osteoblast cell line stimulated with Aggregatibacter actinomycetemcomitans lipopolysaccharide
    Sosroseno W, Bird PS, Seymour GJ
    Oral Microbiol. Immunol., 2009 Feb;24(1):50-5.
    PMID: 19121070 DOI: 10.1111/j.1399-302X.2008.00475.x
    Human osteoblasts induced by inflammatory stimuli express an inducible nitric oxide synthase (iNOS). The aim of the present study was to test the hypothesis that Aggregatibacter actinomycetemcomitans lipopolysaccharide stimulates the production of nitric oxide (NO) by a human osteoblast-like cell line (HOS cells).
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism*
  18. Nitric oxide production by a murine macrophage cell line (RAW264.7 cells) stimulated with Aggregatibacter actinomycetemcomitans surface-associated material
    Sosroseno W, Bird PS, Seymour GJ
    Anaerobe, 2011 Oct;17(5):246-51.
    PMID: 21736946 DOI: 10.1016/j.anaerobe.2011.06.006
    Nitric oxide (NO) may play a crucial role in the pathogenesis of periodontal disease and, hence, the aim of the present study was to test the hypothesis that Aggregatibacter actinomycetemcomitans surface-associated material (SAM) stimulates inducible nitric oxide synthase (iNOS) activity and NO production by the murine macrophage cell line RAW264.7. Cells were stimulated with untreated or heat-treated A. actinomycetemcomitans SAM and with or without pre-treatment with L-N(6)-(1-Iminoethyl)-lysine (L-NIL) (an iNOS inhibitor), polymyxin B, interferon-gamma (IFN-γ) and Interleukin-4 (IL-4), IL-10, genistein [a protein tyrosine kinase (PTK) inhibitor], bisindolylmaleimide [a protein kinase C (PKC) inhibitor], bromophenacyl bromide (BPB) [a phospholipase A(2) (PLA2) inhibitor] or wortmannin [phosphatidylinositol 3-kinase (PI-3K) inhibitor]. The iNOS activity and nitrite production in the cell cultures were determined. Untreated but not heat-treated A. actinomycetemcomitans SAM-stimulated both iNOS activity and nitrite production in RAW264.7 cells. L-NIL, IL-4, IL-10, genistein, bisindolylmaleimide, or BPB, suppressed but IFN-γ enhanced both iNOS activity and nitrite production by A. actinomycetemcomitans SAM-stimulated cells. Wortmannin and polymyxin B failed to alter both iNOS activity or nitrite production by A. actinomycetemcomitans SAM treated cells. Therefore, the present study suggests that a heat-sensitive protein constituent(s) of A. actinomycetemcomitans SAM stimulates both iNOS activity and nitrite production by RAW264.7 cells in a cytokine, PTK, PKC, and PLA(2) but not PI-3K-dependent fashion.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  19. Fulltext Palm kernel cake extract exerts hepatoprotective activity in heat-induced oxidative stress in chicken hepatocytes
    Oskoueian E, Abdullah N, Idrus Z, Ebrahimi M, Goh YM, Shakeri M, et al.
    BMC Complement Altern Med, 2014;14:368.
    PMID: 25273634 DOI: 10.1186/1472-6882-14-368
    Palm kernel cake (PKC), the most abundant by-product of oil palm industry is believed to contain bioactive compounds with hepatoprotective potential. These compounds may serve as hepatoprotective agents which could help the poultry industry to alleviate adverse effects of heat stress on liver function in chickens.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
  20. Fulltext Pleurotus giganteus (Berk. Karun & Hyde), the giant oyster mushroom inhibits NO production in LPS/H2O2 stimulated RAW 264.7 cells via STAT 3 and COX-2 pathways
    Baskaran A, Chua KH, Sabaratnam V, Ravishankar Ram M, Kuppusamy UR
    BMC Complement Altern Med, 2017 Jan 13;17(1):40.
    PMID: 28086773 DOI: 10.1186/s12906-016-1546-6
    Pleurotus giganteus (Berk. Karunarathna and K.D. Hyde), has been used as a culinary mushroom and is known to have medicinal properties but its potential as an anti-inflammatory agent to mitigate inflammation triggered diseases is untapped. In this study, the molecular mechanism underlying the protective effect of ethanol extract of P. giganteus (EPG) against lipopolysaccharide (LPS) and combination of LPS and hydrogen peroxide (H2O2)-induced inflammation on RAW 264.7 macrophages was investigated.
    Matched MeSH terms: Nitric Oxide Synthase Type II/metabolism
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