Displaying publications 1 - 20 of 81 in total

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  1. Ismail N, Jambari NN, Zareen S, Akhtar MN, Shaari K, Zamri-Saad M, et al.
    Toxicol Appl Pharmacol, 2012 Mar 1;259(2):257-62.
    PMID: 22266348 DOI: 10.1016/j.taap.2012.01.003
    Asthma is associated with increased pulmonary inflammation and airway hyperresponsiveness. The current use of corticosteroids in the management of asthma has recently raised issues regarding safety and lack of responsiveness in 5-10% of asthmatic individuals. The aim of the present study was to investigate the therapeutic effect of a non-steroidal small molecule that has cysteinyl leukotriene (cysLT) inhibitory activity, upon attenuation of allergic lung inflammation in an acute murine model. Mice were sensitized with ovalbumin (OVA) and treated with several intraperitoneal doses (100, 20, 2 and 0.2mg/kg) of 2,4,6,-trihydroxy-3-geranylacetophenone (tHGA). Bronchoalveolar lavage was performed, blood and lung samples were obtained and respiratory function was measured. OVA sensitization increased pulmonary inflammation and pulmonary allergic inflammation was significantly reduced at doses of 100, 20 and 2mg/kg with no effect at the lowest dose of 0.2mg/kg. The beneficial effects in the lung were associated with reduced eosinophilic infiltration and reduced secretion of Th2 cytokines and cysLTs. Peripheral blood reduction of total IgE was also a prominent feature. Treatment with tHGA significantly attenuated altered airway hyperresponsiveness as measured by the enhanced pause (Penh) response to incremental doses of methacholine. These data demonstrate that tHGA, a synthetic non-steroidal small molecule, can prevent acute allergic inflammation. This proof of concept opens further avenues of research and development of tHGA as an additional option to the current armamentarium of anti-asthma therapeutics.
  2. Ming-Tatt L, Khalivulla SI, Akhtar MN, Mohamad AS, Perimal EK, Khalid MH, et al.
    Basic Clin Pharmacol Toxicol, 2012 Mar;110(3):275-82.
    PMID: 21967232 DOI: 10.1111/j.1742-7843.2011.00804.x
    This study investigated the potential antinociceptive efficacy of a novel synthetic curcuminoid analogue, 2,6-bis-(4-hydroxy-3-methoxybenzylidene)cyclohexanone (BHMC), using chemical- and thermal-induced nociception test models in mice. BHMC (0.03, 0.1, 0.3 and 1.0 mg/kg) administered via intraperitoneal route (i.p.) produced significant dose-related inhibition in the acetic acid-induced abdominal constriction test in mice with an ID(50) of 0.15 (0.13-0.18) mg/kg. It was also demonstrated that BHMC produced significant inhibition in both neurogenic (first phase) and inflammatory phases (second phase) of the formalin-induced paw licking test with an ID(50) of 0.35 (0.27-0.46) mg/kg and 0.07 (0.06-0.08) mg/kg, respectively. Similarly, BHMC also exerted significant increase in the response latency period in the hot-plate test. Moreover, the antinociceptive effect of the BHMC in the formalin-induced paw licking test and the hot-plate test was antagonized by pre-treatment with the non-selective opioid receptor antagonist, naloxone. Together, these results indicate that the compound acts both centrally and peripherally. In addition, administration of BHMC exhibited significant inhibition of the neurogenic nociception induced by intraplantar injections of glutamate and capsaicin with ID(50) of 0.66 (0.41-1.07) mg/kg and 0.42 (0.38-0.51) mg/kg, respectively. Finally, it was also shown that BHMC-induced antinociception was devoid of toxic effects and its antinociceptive effect was associated with neither muscle relaxant nor sedative action. In conclusion, BHMC at all doses investigated did not cause any toxic and sedative effects and produced pronounced central and peripheral antinociceptive activities. The central antinociceptive activity of BHMC was possibly mediated through activation of the opioid system as well as inhibition of the glutamatergic system and TRPV1 receptors, while the peripheral antinociceptive activity was perhaps mediated through inhibition of various inflammatory mediators.
  3. Shaari K, Suppaiah V, Wai LK, Stanslas J, Tejo BA, Israf DA, et al.
    Bioorg Med Chem, 2011 Nov 1;19(21):6340-7.
    PMID: 21958738 DOI: 10.1016/j.bmc.2011.09.001
    A bioassay-guided investigation of Melicope ptelefolia Champ ex Benth (Rutaceae) resulted in the identification of an acyphloroglucinol, 2,4,6-trihydroxy-3-geranylacetophenone or tHGA, as the active principle inhibiting soybean 15-LOX. The anti-inflammatory action was also demonstrated on human leukocytes, where the compound showed prominent inhibitory activity against human PBML 5-LOX, with an IC(50) value of 0.42 μM, very close to the effect produced by the commonly used standard, NDGA. The compound concentration-dependently inhibited 5-LOX product synthesis, specifically inhibiting cysteinyl leukotriene LTC(4) with an IC(50) value of 1.80 μM, and showed no cell toxicity effects. The anti-inflammatory action does not seem to proceed via redox or metal chelating mechanism since the compound tested negative for these bioactivities. Further tests on cyclooxygenases indicated that the compound acts via a dual LOX/COX inhibitory mechanism, with greater selectivity for 5-LOX and COX-2 (IC(50) value of 0.40 μM). The molecular features that govern the 5-LOX inhibitory activity was thus explored using in silico docking experiments. The residues Ile 553 and Hie 252 were the most important residues in the interaction, each contributing significant energy values of -13.45 (electrostatic) and -5.40 kcal/mol (electrostatic and Van der Waals), respectively. The hydroxyl group of the phloroglucinol core of the compound forms a 2.56Å hydrogen bond with the side chain of the carboxylate group of Ile 553. Both Ile 553 and Hie 252 are crucial amino acid residues which chelate with the metal ion in the active site. Distorting the geometry of these ligands could be the reason for the inhibition activity shown by tHGA. The molecular simulation studies supported the bioassay results and served as a good model for understanding the way tHGA binds in the active site of human 5-LOX enzyme.
  4. Perimal EK, Akhtar MN, Mohamad AS, Khalid MH, Ming OH, Khalid S, et al.
    Basic Clin Pharmacol Toxicol, 2011 Mar;108(3):155-62.
    PMID: 20955360 DOI: 10.1111/j.1742-7843.2010.00635.x
    This study investigated the antinociceptive effects of zerumbone in chemical behavioural models of nociception in mice. Zerumbone given through intraperitoneal route (i.p.) produced dose-related antinociception when assessed on acetic acid-induced abdominal writhing test in mice. In addition, the i.p. administration of zerumbone exhibited significant inhibition of the neurogenic pain induced by intraplantar (i.pl.) injection of capsaicin and bradykinin. Likewise, zerumbone given by i.p. route reduced the nociception produced by i.pl. injection of glutamate and phorbol myristate acetate (PMA). The antinociception caused by zerumbone in the acetic acid test was significantly attenuated by i.p. pre-treatment of mice with l-arginine (nitric oxide precursor) and glibenclamide (ATP-sensitive K(+) channel inhibitor). However, the antinociception of zerumbone was enhanced by methylene blue (non-specific gyanylyl cyclase inhibitor). Together, these results indicate that zerumbone produces pronounced antinociception against chemical models of nociception in mice. It also strongly suggests that the l-arginine-nitric oxide-cGMP-PKC-K(+) ATP channel pathways, the TRPV1 and kinin B2 receptors play an important role in the zerumbone-induced antinociception.
  5. Sulaiman MR, Perimal EK, Akhtar MN, Mohamad AS, Khalid MH, Tasrip NA, et al.
    Fitoterapia, 2010 Oct;81(7):855-8.
    PMID: 20546845 DOI: 10.1016/j.fitote.2010.05.009
    The anti-inflammatory activity of zerumbone (1), a natural cyclic sesquiterpene isolated from Zingiber zerumbet Smith was investigated using carrageenan-induced paw edema and cotton pellet-induced granuloma tissue formation test in mice. It was demonstrated that intraperitoneal administration of 1 at a dose of 5, 10, 50 and 100 mg/kg produced significant dose-dependent inhibition of paw edema induced by carrageenan. It was also demonstrated that 1 at similar doses significantly suppressed granulomatous tissue formation in cotton pellet-induced granuloma test.
  6. Ong HM, Mohamad AS, Makhtar N', Khalid MH, Khalid S, Perimal EK, et al.
    J Ethnopharmacol, 2011 Jan 7;133(1):227-33.
    PMID: 20920570 DOI: 10.1016/j.jep.2010.09.030
    Acmella uliginosa (Sw.) Cass. is a medicinal herbaceous plant that is commonly used by the Malay community in Malaysia to relieve pain often associated with mouth ulcers, toothache, sore throat, and stomach ache.
  7. Mohamad AS, Akhtar MN, Zakaria ZA, Perimal EK, Khalid S, Mohd PA, et al.
    Eur J Pharmacol, 2010 Nov 25;647(1-3):103-9.
    PMID: 20826146 DOI: 10.1016/j.ejphar.2010.08.030
    The present study examined the potential antinociceptive activity of flavokawin B (6'-hydroxy-2',4'-dimethoxychalcone), a synthetic chalcone using chemical- and thermal-induced nociception models in mice. It was demonstrated that flavokawin B (FKB; 0.3, 1, 3 and 10 mg/kg) administered via both oral (p.o.) and intraperitoneal (i.p.) routes produced significant and dose-dependent inhibition in the abdominal constrictions induced by acetic acid, with the i.p. route producing antinociception of approximately 7-fold more potent than the p.o. route. It was also demonstrated that FKB produced significant inhibition in the two phases of the formalin-induced paw licking test. In addition, the same treatment of flavokawin B (FKB) exhibited significant inhibition of the neurogenic nociceptive induced by intraplantar injections of glutamate and capsaicin. Likewise, this compound also induced a significant increase in the response latency period to thermal stimuli in the hot plate test and its antinociceptive effect was not related to muscle relaxant or sedative action. Moreover, the antinociception effect of the FKB in the formalin-induced paw licking test and the hot plate test was not affected by pretreatment of non-selective opioid receptor antagonist, naloxone. The present results indicate that FKB produced pronounced antinociception effect against both chemical and thermal models of pain in mice that exhibited both peripheral and central analgesic activity.
  8. Mohamad AS, Akhtar MN, Khalivulla SI, Perimal EK, Khalid MH, Ong HM, et al.
    Basic Clin Pharmacol Toxicol, 2011 Jun;108(6):400-5.
    PMID: 21214864 DOI: 10.1111/j.1742-7843.2010.00670.x
    The possible mechanisms of action in the antinociceptive activity induced by systemic administration (intraperitoneal, i.p.) of flavokawin B (FKB) were analysed using chemical models of nociception in mice. It was demonstrated that i.p. administration of FKB to the mice at 0.3, 1.0, 3.0 and 10 mg/kg produced significant dose-related reduction in the number of abdominal constrictions. The antinociception induced by FKB in the acetic acid test was significantly attenuated by i.p. pre-treatment of mice with L-arginine, the substrate for nitric oxide synthase or glibenclamide, the ATP-sensitive K(+) channel inhibitor, but was enhanced by methylene blue, the non-specific guanylyl cyclase inhibitor. FKB also produced dose-dependent inhibition of licking response caused by intraplantar injection of phorbol 12-myristate 13-acetate, a protein kinase C activator (PKC). Together, these data indicate that the NO/cyclic guanosine monophosphate/PKC/ATP-sensitive K(+) channel pathway possibly participated in the antinociceptive action induced by FKB.
  9. Harasstani OA, Moin S, Tham CL, Liew CY, Ismail N, Rajajendram R, et al.
    Inflamm Res, 2010 Sep;59(9):711-21.
    PMID: 20221843 DOI: 10.1007/s00011-010-0182-8
    OBJECTIVES: We evaluated several flavonoid combinations for synergy in the inhibition of proinflammatory mediator synthesis in the RAW 264.7 cellular model of inflammation.

    METHODS: The inhibitory effect of chrysin, kaempferol, morin, silibinin, quercetin, diosmin and hesperidin upon nitric oxide (NO), prostaglandin E(2) (PGE(2)) and tumour necrosis factor-alpha (TNF-alpha) secretion from the LPS-induced RAW 264.7 monocytic macrophage was assessed and IC(50) values obtained. Flavonoids that showed reasonable inhibitory effects in at least two out of the three assays were combined in a series of fixed IC(50) ratios and reassessed for inhibition of NO, PGE(2) and TNF-alpha. Dose-response curves were generated and interactions were analysed using isobolographic analysis.

    RESULTS: The experiments showed that only chrysin, kaempferol, morin, and silibinin were potent enough to produce dose-response effects upon at least two out of the three mediators assayed. Combinations of these four flavonoids showed that several combinations afforded highly significant synergistic effects.

    CONCLUSIONS: Some flavonoids are synergistic in their anti-inflammatory effects when combined. In particular chrysin and kaempferol significantly synergised in their inhibitory effect upon NO, PGE(2) and TNF-alpha secretion. These findings open further avenues of research into combinatorial therapeutics of inflammatory-related diseases and the pharmacology of flavonoid synergy.

  10. 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.
  11. Ahmad S, Israf DA, Lajis NH, Shaari K, Mohamed H, Wahab AA, et al.
    Eur J Pharmacol, 2006 May 24;538(1-3):188-94.
    PMID: 16650843
    Some chalcones, such as hydroxychalcones have been reported previously to inhibit major pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha) and reactive oxygen species production by suppressing inducible enzyme expression via inhibition of the mitogen-activated protein kinase (MAPK) pathway and nuclear translocation of critical transcription factors. In this report, the effects of cardamonin (2',4'-dihydroxy-6'-methoxychalcone), a chalcone that we have previously isolated from Alpinia rafflesiana, was evaluated upon two cellular systems that are repeatedly used in the analysis of anti-inflammatory bioactive compounds namely RAW 264.7 cells and whole blood. Cardamonin inhibited NO and PGE(2) production from lipopolysaccharide- and interferon-gamma-induced RAW cells and whole blood with IC(50) values of 11.4 microM and 26.8 microM, respectively. Analysis of thromboxane B(2) (TxB(2)) secretion from whole blood either stimulated via the COX-1 or COX-2 pathway revealed that cardamonin inhibits the generation of TxB(2) via both pathways with IC(50) values of 2.9 and 1.1 microM, respectively. Analysis of IC(50) ratios determined that cardamonin was more COX-2 selective in its inhibition of TxB(2) with a ratio of 0.39. Cardamonin also inhibited the generation of intracellular reactive oxygen species and secretion of TNF-alpha from RAW 264.7 cells in a dose responsive manner with IC(50) values of 12.8 microM and 4.6 microM, respectively. However, cardamonin was a moderate inhibitor of lipoxygenase activity when tested in an enzymatic assay system, in which not a single concentration tested was able to cause an inhibition of more than 50%. Our results suggest that cardamonin acts upon major pro-inflammatory mediators in a similar fashion as described by previous work on other closely related synthetic hydroxychalcones and strengthens the conclusion of the importance of the methoxyl moiety substitution on the 4' or 6' locations of the A benzene ring.
  12. Liew CY, Tham CL, Lam KW, Mohamad AS, Kim MK, Cheah YK, et al.
    Immunopharmacol Immunotoxicol, 2010 Sep;32(3):495-506.
    PMID: 20109039 DOI: 10.3109/08923970903575708
    HMP [3-(2-hydroxyphenyl)-1-(5-methyl-furan-2-y-l) propenone] was evaluated for its ability to inhibit the synthesis of major proinflammatory mediators and cytokines in interferon-gamma (IFN-gamma)- and lipopolysaccharide (LPS)-induced RAW 264.7 cells and phorbol myristate acetate (PMA)-differentiated/LPS-induced U937 cells. HMP suppressed the production of nitric oxide (NO) with significant inhibitory effects at doses as low as 0.78 microM (P < 0.05). Prostaglandin E2 (PGE2) secretion was also inhibited at doses of 12.5 microM and above (P < 0.01). The secretion of both TNF-alpha and IL-6 were only inhibited at the highest dose used (25 microM; P < 0.001). IL-1beta secretion was also inhibited from 12.5 microM onwards (P < 0.01). This inhibition was demonstrated to be caused by down-regulation of inducible enzymes, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), without direct effect upon iNOS or COX-2 enzyme activity. HMP only inhibited iNOS (P < 0.001) and IL-1beta (P < 0.05) gene expression at the highest tested concentration. HMP did not affect the secretion of chemokines IL-8 and monocyte chemotactic protein-1 (MCP-1) and the anti-inflammatory cytokine IL-10. The most striking effect of HMP was its NO inhibitory activity and therefore we conclude that HMP is a selective inhibitor of iNOS.
  13. Kamaldin MN, Akhtar MN, Mohamad AS, Lajis N, Perimal EK, Akira A, et al.
    Molecules, 2013 Apr 10;18(4):4209-20.
    PMID: 23612473 DOI: 10.3390/molecules18044209
    Previous studies have shown that systemic administration of 6'-hydroxy-2',4'-dimethoxychalcone (flavokawin B, FKB) exerts significant peripheral and central antinociceptive effects in laboratory animals. However, the mechanisms underlying these peripheral and central antinociceptive effects have yet to be elucidated. Therefore, the objective of the present study was to evaluate the participation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/potassium (K+) channels pathway in the peripheral antinociception induced by FKB. It was demonstrated that intraplantar (i.pl.) administration of FKB (150, 250, 375 and 500 µg/paw) resulted in dose-dependent peripheral antinociception against mechanical hyperalgesia in carrageenan-induced hyperalgesia test model in rats. The possibility of FKB having either a central or a systemic effect was excluded since administration of FKB into the right paw did not elicit antinociception in the contralateral paw. Furthermore, peripheral antinociception induced by FKB (500 µg/paw) was significantly reduced when L-arginine (25 µg/paw, i.pl.), Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 50 µg/paw, i.pl.), glibenclamide (300 µg/paw, i.pl.), tetraethylammonium (300 µg/paw, i.pl.) and charybdotoxin (3 µg/paw, i.pl.) were injected before treatment. Taken together, our present data suggest that FKB elicits peripheral antinociception when assessed in the mechanical hyperalgesia induced by carrageenan. In addition, it was also demonstrated that this effect was mediated through interaction of the NO/cGMP/K+ channels signaling pathway.
  14. Lee KH, Chow YL, Sharmili V, Abas F, Alitheen NB, Shaari K, et al.
    Int J Mol Sci, 2012;13(3):2985-3008.
    PMID: 22489138 DOI: 10.3390/ijms13032985
    Our preliminary screening has shown that curcumin derivative BDMC33 [2,6-bis(2,5-dimethoxybenzylidene)cyclohexanone] exerted promising nitric oxide inhibitory activity in activated macrophages. However, the molecular basis and mechanism for its pharmacological action is yet to be elucidated. The aim of this study was to investigate the anti-inflammatory properties of BDMC33 and elucidate its underlying mechanism action in macrophage cells. Our current study demonstrated that BDMC33 inhibits the secretion of major pro-inflammatory mediators in stimulated macrophages, and includes NO, TNF-α and IL-1β through interference in both nuclear factor kappaB (NF-κB) and mitogen activator protein kinase (MAPK) signaling cascade in IFN-γ/LPS-stimulated macrophages. Moreover, BDMC33 also interrupted LPS signaling through inhibiting the surface expression of CD-14 accessory molecules. In addition, the inhibitory action of BDMC33 not only restricted the macrophages cell (RAW264.7), but also inhibited the secretion of NO and TNF-α in IFN-γ/LPS-challenged microglial cells (BV-2). The experimental data suggests the inflammatory action of BDMC33 on activated macrophage-like cellular systems, which could be used as a future therapeutic agent in the management of chronic inflammatory diseases.
  15. Khalid S, Shaik Mossadeq WM, Israf DA, Hashim P, Rejab S, Shaberi AM, et al.
    Med Princ Pract, 2010;19(4):255-9.
    PMID: 20516700 DOI: 10.1159/000312710
    To study the effects of Tamarindus indica L. aqueous fruit extract on the antinociceptive activities in rodent models.
  16. Tham CL, Lam KW, Rajajendram R, Cheah YK, Sulaiman MR, Lajis NH, et al.
    Eur J Pharmacol, 2011 Feb 10;652(1-3):136-44.
    PMID: 21114991 DOI: 10.1016/j.ejphar.2010.10.092
    We previously showed that 2,6-bis-(4-hydroxyl-3-methoxybenzylidine)cyclohexanone (BHMC), suppressed the synthesis of various proinflammatory mediators. In this study we explain the mechanism of action of BHMC in lipopolysaccharide (LPS)-induced U937 monocytes and further show that BHMC prevents lethality of CLP-induced sepsis. BHMC showed dose-dependent inhibitory effects on p38, JNK and ERK 1/2 activity as determined by inhibition of phosphorylation of downstream transcription factors ATF-2, c-Jun and Elk-1 respectively. Inhibition of these transcription factors subsequently caused total abolishment of AP-1-DNA binding. BHMC inhibited p65 NF-κB nuclear translocation and DNA binding of p65 NF-κB only at the highest concentration used (12.5μM) but failed to alter phosphorylation of JNK, ERK1/2 and STAT-1. Since the inhibition of p38 activity was more pronounced we evaluated the possibility that BHMC may bind to p38. Molecular docking experiments confirmed that BHMC fits well in the highly conserved hydrophobic pocket of p38 MAP kinase. We also show that BHMC was able to improve survival from lethal sepsis in a murine caecal-ligation and puncture (CLP) model.
  17. Shaik Mossadeq WM, Sulaiman MR, Tengku Mohamad TA, Chiong HS, Zakaria ZA, Jabit ML, et al.
    Med Princ Pract, 2009;18(5):378-84.
    PMID: 19648761 DOI: 10.1159/000226292
    OBJECTIVES: To determine the anti-inflammatory and antinociceptive activities of Mitragyna speciosa Korth methanol extract in rodents.
    MATERIALS AND METHODS: Anti-inflammatory activity was evaluated using carrageenan-induced paw edema and cotton pellet-induced granuloma tests in rats. Antinociceptive activity was measured using the writhing test and the hot plate test in mice, and the formalin test in rats. All drugs and extracts were diluted in dH(2)O and administered through the intraperitoneal route. Results were analyzed using one-way ANOVA followed by Dunnett's test for multiple comparisons among groups.
    RESULTS: Results showed that intraperitoneal administration of the extract at doses of 100 and 200 mg/kg produced significant dose-dependent activity in all of the nociceptive models evaluated (p < 0.05). With the formalin test, the antinociceptive activity in mice was inhibited only at the highest dose of the extract (200 mg/kg). The study also showed that intraperitoneal administration of the methanol extract of M. speciosa (100 and 200 mg/kg) significantly and dose-dependently suppressed the development of carrageenan-induced rat paw edema (p < 0.05). In the chronic test, however, significant reduction in granulomatous tissue formation in rats was observed only at the highest dose of the methanol extract of M. speciosa (200 mg/kg, p < 0.05).
    CONCLUSION: The present study suggests the presence of potent antinociceptive and anti-inflammatory principles in the extract, supporting its folkloric use for the treatment of these conditions.
  18. Liew CY, Lam KW, Kim MK, Harith HH, Tham CL, Cheah YK, et al.
    Int Immunopharmacol, 2011 Jan;11(1):85-95.
    PMID: 21035434 DOI: 10.1016/j.intimp.2010.10.011
    We previously showed that 3-(2-hydroxyphenyl)-1-(5-methyl-furan-2-y-l)propenone (HMP), suppressed the synthesis of various proinflammatory mediators. In this study, HMP showed a dose-dependent inhibition of NO synthesis in the RAW 264.7 murine macrophage line. The inhibition of NO synthesis was related to inhibition of p38 phosphorylation and kinase activity that led to significant inhibition of phosphorylation of ATF-2. This effect in turn caused inhibition of AP-1-DNA binding which partially explains the inhibitory effect upon the synthesis of iNOS. HMP had no effect upon phosphorylation of JNK, ERK1/2 and STAT-1. Kinase activity of JNK and ERK1/2 was also not affected by HMP as determined by levels of phosphorylated c-jun and phosphorylated elk-1. Furthermore HMP failed to block phosphorylation of IκBα, and subsequent nuclear translocation and DNA-binding activity of p65 NF-κB in IFN-γ/LPS-induced RAW 264.7 cells. Molecular docking experiments confirmed that HMP fits well in the highly conserved hydrophobic pocket of p38 MAP kinase. We conclude that the synthetic HMP is a chalcone analogue that selectively inhibits the p38/ATF-2 and AP-1 signaling pathways in the NO synthesis by the macrophage RAW 264.7.
  19. Chan YH, Musa NF, Chong YJ, Saat SA, Hafiz F, Shaari K, et al.
    Pharm Biol, 2021 Dec;59(1):732-740.
    PMID: 34155953 DOI: 10.1080/13880209.2021.1933083
    CONTEXT: Lipopolysaccharide (LPS) exacerbates systemic inflammatory responses and causes excessive fluid leakage. 2,4,6-Trihydroxy-3-geranyl acetophenone (tHGA) has been revealed to protect against LPS-induced vascular inflammation and endothelial hyperpermeability in vitro.

    OBJECTIVE: This study assesses the in vivo protective effects of tHGA against LPS-induced systemic inflammation and vascular permeability in endotoxemic mice.

    MATERIALS AND METHODS: BALB/c mice were intraperitoneally pre-treated with tHGA for 1 h, followed by 6 h of LPS induction. Evans blue permeability assay and leukocyte transmigration assay were performed in mice (n = 6) pre-treated with 2, 20 and 100 mg/kg tHGA. The effects of tHGA (20, 40 and 80 mg/kg) on LPS-induced serum TNF-α secretion, lung dysfunction and lethality were assessed using ELISA (n = 6), histopathological analysis (n = 6) and survivability assay (n = 10), respectively. Saline and dexamethasone were used as the negative control and drug control, respectively.

    RESULTS: tHGA significantly inhibited vascular permeability at 2, 20 and 100 mg/kg with percentage of inhibition of 48%, 85% and 86%, respectively, in comparison to the LPS control group (IC50=3.964 mg/kg). Leukocyte infiltration was suppressed at 20 and 100 mg/kg doses with percentage of inhibition of 73% and 81%, respectively (IC50=17.56 mg/kg). However, all tHGA doses (20, 40 and 80 mg/kg) failed to prevent endotoxemic mice from lethality because tHGA could not suppress TNF-α overproduction and organ dysfunction.

    DISCUSSION AND CONCLUSIONS: tHGA may be developed as a potential therapeutic agent for diseases related to uncontrolled vascular leakage by combining with other anti-inflammatory agents.

  20. Ismail NI, Ming-Tatt L, Lajis N, Akhtar MN, Akira A, Perimal EK, et al.
    Molecules, 2016 Aug 22;21(8).
    PMID: 27556438 DOI: 10.3390/molecules21081077
    The antinociceptive effects produced by intraperitoneal administration of a novel synthetic chalcone, 3-(2,3-dimethoxyphenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one (DMFP), were investigated in several mouse models of induced nociception. The administration of DMFP (0.1, 0.5, 1.0 and 5.0 mg/kg) produced significant attenuation on the acetic acid-induced abdominal-writhing test. It also produced a significant increase in response latency time in the hot-plate test and a marked reduction in time spent licking the injected paw in both phases of the formalin-induced paw-licking test. In addition, it was also demonstrated that DMFP exhibited significant inhibition of the neurogenic nociceptive response induced by intraplantar injections of capsaicin and glutamate. Moreover, the antinociceptive effect of DMFP in the acetic acid-induced abdominal-writhing test and the hot-plate test was not antagonized by pretreatment with a non-selective opioid receptor antagonist, naloxone. Finally, DMFP did not show any toxic effects and/or mortality in a study of acute toxicity and did not interfere with motor coordination during the Rota-rod test. Our present results show that DMFP exhibits both peripheral and central antinociceptive effects. It was suggested that its peripheral antinociceptive activity is associated with attenuated production and/or release of NO and various pro-inflammatory mediators, while central antinociceptive activity seems to be unrelated to the opioidergic system, but could involve, at least in part, an interaction with the inhibition of capsaicin-sensitive fibers and the glutamatergic system.
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