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Under normal condition, the endothelial cells form a compact monolayer to line the blood vessel. The integrity of this monolayer can be disrupted by lipopolysaccharide (LPS), where LPS could increase the permeability of the endothelium via dissociation of cell-to-cell junctions and rearrangement of cytoskeleton. Prolonged LPS-induced inflammation may lead to excessive plasma leakage and leukocyte migration, leading to fatal outcomes such as shock and multiple organ dysfunctions. Control on this hallmark of inflammation was suggested as a mean of therapeutic interference to improve inflammation. In this study, we investigated the capability of tHGA on maintaining barrier integrity of LPS-induced endothelial cells. tHGA is a phloroglucinol found in Melicope ptelefolia. The compound was previously proven to have strong therapeutic potential with anti-asthma, anti cancer and anti-inflammatory properties. In murine experimental asthma model, tHGA has been shown to inhibit cytokine secretion and leukocyte infiltration, both of which are hallmarks of LPS-induced inflammation. Therefore, it is highly probable that tHGA may have anti-inflammatory effects on LPS-induced inflammation, Human Umbilical Vein Endothelial Cells (HUVECs) were used as an in vitro representative of endothelial cells. HUVECs were seeded to confluence in cell culture insert, where the cells were pretreated with tHGA and induced with LPS. Tracer dyes or monocytes were then allowed to pass the endothelium to examine severity of vascular leakage. To examine F-actin rearrangement, pretreated HUVECs were stained with Alexa-Fluur 488 Phalloidin prior to microscopic examination. The effect of tHGA on preserving junctional protein expression were examined via Western Blot. tHGA reduced permeability and monocyte transendothelial migration at 5µM and 20µM. Furthermore, tHGA inhibited LPS-induced cytoskeletal rearrangement of HUVECs. Additionally, tHGA is able to preserve the protein expression of F-cadherin and O

Pain is an unpleasant sensation associated with body state dysfunction that negatively affects the productivity of patients. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used as over-the-counter pain reliever medication due to its cost effectiveness. However, prolonged usage of NSAIDs usually accompanied with adverse side effects such as ulcer, nausea and even kidney failure. Hence, researchers are now focused on traditional herbal research to search for potential analgesic substances that are with minimal or no adverse effects. Boesenbergia pandurata，it is also known as temu kunci in Malaysia is a perennial herb that belongs to Zingiberaceae family. Boesenbergia pandurata is widely distributed in Southeast Asia and its rhizomes are commonly used as food ingredients or as traditional medicine to treat diseases conditions such as inflammation, cancer, and fungal infection. The aim of this study is to evaluate the inhibitory effect of aqueous extract of Boesenbergia pandurata (AEBP) on formalin-induced nociception test in mice. Mice were pre-treated with AEBP via intraperitoneal injection 30 min before challenged with intraplantar injection of formalin. It was demonstrated that intraperitoneal administration of AEBP at doses (0.3, 1, 3 and 10 mg/kg) produced significant antinociceptive response in both neurogenic and inflammatory phases of pain response induced by formalin. The findings indicated preliminary study on antinociceptive effect of AEBP, but further study should be conducted to explore the exact mechanism of pain inhibition by AEBP.

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.

L-Glutamate plays a crucial role in neuronal cell death, which is known to be associated with various neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. In this study, we investigated the protective effects of biochanin A, a phytoestrogen compound found mainly in Trifolium pratense, against L-glutamate-induced cytotoxicity in a PC12 cell line. Exposure of the cells to 10 mM l-glutamate was found to significantly increase cell viability loss and apoptosis, whereas pretreatment with various concentrations of biochanin A attenuated the cytotoxic effects of l-glutamate. Specifically, the pretreatment led to not only decreases in the release of lactate dehydrogenase, the number of apoptotic cells, and the activity of caspase-3 but also an increase in the total glutathione level in the L-glutamate-treated PC12 cells. These results indicate that biochanin A may be able to exert neuroprotective effects against L-glutamate-induced cytotoxicity. Furthermore, our findings also imply that biochanin A may act as an antiapoptotic agent in order to perform its protective function.

Adapun pokok permasalahan dalam penelitian ini adalah: Perencanaan, pengorganisasian, perencanaan sumber daya manusia, pengawasan dalam peningkatan mutu pendidikan di MTsN 1 Padangsidimpuan. Secara metodologi penelitian ini merupakan penelitian kualitatif dengan mencari, menganalisa, dan membuat intervertasi data yang ditemukan melalui wawancara, observasi ( pengamatan ) dan study dokumen. Data yang telah dikumpulkan diperiksa keabsahannya melalui standar keabsahan data, berupa keterpercayaan, keteralihan ketergantungan dan kepastian. Taknik analisa data yang dilakukan adalah dengan mereduksi data, penyajian data dan menarik kesimpulan dari hasil penelitian. Penelitian ini bertujuan untuk menemukan dan mengkaji lebih mendalam tentang : 1) Mendeskripsikan perencanaan sumber daya manusia dalam peningkatan mutu pendidikan di MTsN 1 Padangsidimpuan.2) Mendeskripsikan pengorganisasian sumber daya manusia di MTsN 1 Padangsidimpuan dalam upaya peningkatan mutu pendidikan. 3) mendeskripsikan pelaksanaan sumber daya manusia di MTsN 1 Padangsidimpuan dalam peningkatan mutu pendidikan. 4) Mendeskripsikan pengawasan sumber daya manusia dalam peningkatan mutu pendidikan di MTsN 1 Padangsidimpuan. Penelitian ini merupakan penelitian deskriptif analitik non statistik dengan menggunakan pendekatan kualitatif dan rancangan studi kasus (case study). Data diperoleh melalui pengamatan, dimana peneliti berfungsi sebagai instrumen untuk melakukan observasi non partisipan, wawancara mendalam dengan sumber data primer dan study dokumentasi. Data dianalisis dengan analisis interaktif melalui 3 kegiatan yaitu reduksi data, penyajian data dan penarikan kesimpulan. Keabsahan data diperoleh dengan perpanjangan keikutsertaan dan triangulasi data. Dari hasil penelitian ini dapat dipaparkan bahwa : 1) Perencanaan SDM dirancang dan disusun secara sistematik dan berdasarkan kemandirian sekolah dengan memperhatikan ciri khas sekolah. 2) Rekrutmen SDM dilakukan secara terbuka, mandiri dan dengan menge

A sensitive and accurate high performance liquid chromatography with ultraviolet/visible light detection (HPLC-UV/VIS) method for the quantification of 2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) in rat plasma was developed and validated. BHMC and the internal standard, harmaline, were extracted from plasma samples by a simple liquid–liquid extraction using 95% ethyl acetate and 5% methanol. Plasma concentration of BHMC and internal standard were analyzed by reversed phase chromatography using a C18 column (150 × 4.6 mm I.D., particle size 5 µm) and elution with a gradient mobile phase of water and methanol at a flow rate of 1.0 mL/min. Detection of BHMC and internal standard was done at a wavelength of 380 nm. The limit of quantification was 0.02 µg/mL. The calibration curves was linear (R2 > 0.999) over the concentration range of 0.02–2.5 µg/mL. Intra- and inter-day precision were less than 2% coefficient of variation. The validated method was then applied to a pharmacokinetic study in rats by intravenous administration of BHMC at a single dose of 10 mg/kg. Pharmacokinetic parameters such as half-life, maximum plasma concentration, volume of distribution, clearance and elimination rate constant for BHMC were calculated.

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 ID50 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 ID50 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 ID50 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 inflamm

The present invention relates to an analog of curcumin, 2,6-bis-(4-hydroxyl-3-methoxybenzylidine)cyclohexanone (BHMC) or a pharmaceutically acceptable salt, solvate or derivative thereof, for use in treating, preventing or managing endothelial dysfunction and/or a disorder associated with endothelial dysfunction. Furthermore provided are methods of treating, preventing or managing endothelial dysfunction and/or a disorder associated with endothelial dysfunction using BHMC or a pharmaceutically acceptable salt, solvate or derivative thereof. The invention provides also a method for attenuating endothelial dysfunction in an endothelial cell and/or attenuating the hallmarks of endothelial dysfunction in an endothelial cell.

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.

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 LTC4 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 2.56 Å 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.

Ethnopharmacological relevance Zingiber zerumbet (L.) Smith, a wild edible ginger species or locally known as “lempoyang”, commonly used in the Malays traditional medicine as an appetizer or to treat stomachache, toothache, muscle sprain and as a cure for swelling sores and cuts. Aim The present study was conducted to investigate the possible mechanism of actions underlying the systemic antinociception activity of the essential oil of Zingiber zerumbet (EOZZ) in chemical-induced nociception tests in mice. Materials and methods Acetic acid-induced abdominal constriction, capsaicin-, glutamate- and phorbol 12-myristate 13-acetate-induced paw licking tests in mice were employed in the study. In all experiments, EOZZ was administered systemically at the doses of 50, 100, 200 and 300 mg/kg. Results It was shown that EOZZ given to mice via intraperitoneal and oral routes at 50, 100, 200 and 300 mg/kg produced significant dose dependent antinociception when assessed using acetic acid-induced abdominal writing test with calculated mean ID50 values of 88.84 mg/kg (80.88–97.57 mg/kg) and 118.8 mg/kg (102.5–137.8 mg/kg), respectively. Likewise, intraperitoneal administration of EOZZ at similar doses produced significant dose dependent inhibition of neurogenic pain induced by intraplantar injection of capsaicin (1.6 μg/paw), glutamate (10 μmol/paw) and phorbol 12-myristate 13-acetate (1.6 μg/paw) with calculated mean ID50 of 128.8 mg/kg (118.6–139.9 mg/kg), 124.8 mg/kg (111.4–139.7 mg/kg) and 40.29 (35.39–45.86) mg/kg, respectively. It was also demonstrated that pretreatment with l-arginine (100 mg/kg, i.p.), a nitric oxide precursor significantly reversed antinociception produced by EOZZ suggesting the involvement of l-arginine/nitric oxide pathway. In addition, methylene blue (20 mg/kg, i.p.) significantly enhanced antinociception produced by EOZZ. Administration of glibenclamide (10 mg/kg, i.p.), an ATP-sensitive K+ channel antagonist significantly reversed antinoci

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.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used for the treatment of inflammation. However, despite their effectiveness, most NSAIDs cause various side effects that negatively affect the management of inflammation and, in part, pain. Thus, there is a need to search for new anti-inflammatory agents with few, or no, side effects. Natural products of plant, animal, or microorganism origin have been good sources of new bioactive compounds. The present study was carried out to evaluate the acute and chronic anti-inflammatory activities of the essential oil of the rhizomes of Zingiber zerumbet (Zingiberaceae) using the carrageenan-induced paw edema and cotton pellet-induced granuloma tests, respectively. The effect of the essential oil on inflammatory- and noninflammatory-mediated pain was also assessed using the formalin test. Essential oil of Z. zerumbet, at doses of 30, 100, and 300 mg/kg, was administered intraperitoneally to rats. The substance exhibited significant anti-inflammatory activity both in acute and chronic animal models. The essential oil also inhibited inflammatory- and noninflammatory-mediated pain when assessed using the formalin test. In conclusion, the essential oil of Z. zerumbet possessed anti-inflammatory activity, in addition to its antinociceptive activity, which may explain its traditional uses to treat inflammatory-related ailments.

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.

The Human Immune System (HIS) is considered as a bank of models, functions, and concepts from where Artificial Immune algorithms are inspired. These algorithms are used to secure both host-based and network-based systems. However, it is not only important to utilize the HIS in producing AIS-based algorithms as much as it is important to introduce an algorithm with high performance. Therefore, creating a balance between utilizing HIS on one side and introducing the required AIS-based intrusion detection algorithm on the other side is a crucial issue which would be valuable to investigate. Securing the mobile ad hoc network (MANET) which is a collection of mobile, decentralized, and self organized nodes is another problem, which adds more challenges to the research. This is because MANET properties make it harder to be secured than the other types of static networks. We claim that AISs’ properties such as being self-healing, self-defensive and self-organizing can meet the challenges of securing the MANET environment. This paper’s objective is to utilize the biological model used in the dendritic cell algorithm (DCA) to introduce a Dendritic Cell Inspired Intrusion Detection Algorithm (DCIIDA). DCIIDA is introduced to detect the Resource Consumption Attack (RCA) over MANET. Furthermore, this paper proposes a DCIIDA architecture which should be applied by each node in MANET.

This invention relates to a method of treating inflammatory disease characterized by the production of an undesirable level on inflammatory mediators such as nitric oxide, thromboxane B₂ , prostaglandin E₂, or hydrogen peroxide. The method comprising of administering to a patient a pharmacologycal effective dose of cardamonin with a pharmaceutically acceptable carrier. The effective dose of cardamonin with a rage between about 0.02uM and 74 uM.

Ethnopharmacological relevance: 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. Aim: The study was carried out to investigate the antinociceptive effect of the methanolic extract of A. uliginosa (Sw.) Cass. flowers (MEAU) using murine models of chemicals and thermal nociception. Materials and methods: Chemicals (acetic acid-induced abdominal constriction and formalin-, capsaicin-, glutamate-induced paw licking test) and thermal models (hot plate test) of nociception in mice were employed to evaluate the MEAU analgesic effect. The extract was given via oral administration at doses of 3, 10, 30 and 100 mg/kg. Results: It was demonstrated that MEAU produced significant antinociceptive response in all the chemical- and thermal-induced nociception models, which indicates the presence of both centrally and peripherally mediated activities. Furthermore, the reversal of antinociception of MEAU by naloxone suggests the involvement of opioid system in its centrally mediated analgesic activity. Moreover, MEAU-treated mice did not show any significant motor performance alterations. No mortality and signs of toxicity were recorded following treatment of the MEAU. Conclusion: The results from the present study appear to support the folkloric belief in the medicinal properties of A. uliginosa (Sw.) Cass. which against pain at both central and peripheral levels, in which the central antinociception is probably due to the participation of the opioid receptors.

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 E2 (PGE2) and tumour necrosis factor-α (TNF-α) secretion from the LPS-induced RAW 264.7 monocytic macrophage was assessed and IC50 values obtained. Flavonoids that showed reasonable inhibitory effects in at least two out of the three assays were combined in a series of fixed IC50 ratios and reassessed for inhibition of NO, PGE2 and TNF-α. 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, PGE2 and TNF-α secretion. These findings open further avenues of research into combinatorial therapeutics of inflammatory-related diseases and the pharmacology of flavonoid synergy.

Melicope ptelefolia is a medicinal herb commonly used in Malaysia to treat fever, pain, wounds, and itches. The present study was conducted to evaluate the antinociceptive activity of the Melicope ptelefolia ethanolic extract (MPEE) using animal models of nociception. The antinociceptive activity of the extract was assessed using acetic acid-induced abdominal writhing, hot-plate, and formalin-induced paw licking tests. Oral administration of MPEE produced significant dose-dependent antinociceptive effects when tested in mice and rats using acetic acid-induced abdominal constriction test and on the second phase of the formalin-induced paw licking test, respectively. It was also demonstrated that MPEE had no effect on the response latency time to the heat stimulus in the thermal model of the hot-plate test. In addition, the antinociception produced by MPEE was not blocked by naloxone. Furthermore, oral administration of MPEE did not produce any effect in motor performance of the rota-rod test and in acute toxicity study no abnormal behaviors as well as mortality were observed up to a dose level of the extract of 5 g/kg. These results indicated that MPEE at all doses investigated which did not produce any sedative and toxic effects exerted pronounce antinociceptive activity that acts peripherally in experimental animals.

Ethnopharmacological relevance: Piper sarmentosum (Piperaceae) is a medicinal plant traditionally used by the Malays to treat headaches, toothaches, coughs, asthma and fever. Aim of the study: In order to establish the pharmacological properties of the leaf of this plant, studies were performed on anti-nociceptive and anti-inflammatory activities. Materials and methods: The aqueous extract of Piper sarmentosum (AEPS) was prepared in the doses of 30, 100 and 300 mg/kg. Anti-nociceptive activity of AEPS was evaluated by abdominal constriction and hot-plate tests. AEPS was also pre-challenged with 5 mg/kg naloxone to determine the involvement of opioid receptors. Anti-inflammatory activity was evaluated using carrageenan-induced paw edema assay. Results: Subcutaneous administration of AEPS exhibited anti-nociceptive activity (P<0.05) in a dose-dependent manner in the abdominal constriction and hot-plate tests. Pre-treatment with naloxone completely (P<0.05) diminished the extract anti-nociceptive activity in both tests. The AEPS, at all doses used, exerted significant (P<0.05) anti-inflammatory activity in a dose-dependent manner. Conclusions: The AEPS exhibits opioid-mediated anti-nociceptive activity at the peripheral and central levels, as well as anti-inflammatory activity, which confirmed the traditional uses of the plant in the treatment of pain- and inflammatory-related ailments.

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.

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.

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.

The present invention relates to a compound for inhibiting cysteinyl leukotrienes (CysLT) which is the most potent bronchoconstrictors. The present invention further relates to methods for producing the compound either from natural product or chemical synthesis. The compound from the present invention is potent for preventing or treating inflammatory disorders such as psoriasis, asthma, rheumatoid arthritis, inflammatory bowel diseases and ischemic renal failure.

Solvent–solvent fractionation of the methanolic extract of the popular Malay traditional vegetable “tenggek burung” (Melicope ptelefolia), followed by nitric oxide inhibition assay on RAW 264.7 cells revealed that the most active components reside mainly in hexane and dichloromethane fractions. Online profiling of the nitric oxide (NO) inhibitive fractions of the tenggek burung using liquid chromatography coupled diode array detection and electrospray ion-trap tandem mass spectroscopy (LC–DAD–ESI-MSn), has identified seven constituents. The compounds were identified as kokusaginine (1), compound 2, [kokusagine, (2a) or 5-methoxymaculine (2b)], 2,4,6-trihydroxy-3-prenylacetophenone (3), 2,4,6-trihydroxy-3-geranylacetophenone (4), 2,4,6-trihydroxy-3-geranylgeranylacetophenone (5), 3-[4-O-(3,7-dimethyl-2,6-octadienyl)phenyl]-2-propenoic acid (6) and 2,4,6-trihydroxy-3-farnesylgeranylacetophenone (7). The identity of compounds 1, 4 and 6 were unequivocally confirmed by isolation and spectroscopic evidences, other constituents are tentatively identified, based on their UV, MS, MSn and comparison with literature data. Kokusaginine (1) demonstrated in vitro activity on NO inhibition in murine peritoneal macrophages.

OBJECTIVE: The present study was carried out to determine the antiinflammatory and antinociceptive activities of a methanol extract of Zingiber zerumbet rhizomes (MEZZ) using various experimental model systems. MATERIALS AND METHODS: The MEZZ was prepared by macerating oven-dried (50 degrees C) powdered rhizomes (1.2 kg) of Z. zerumbet in 80% methanol in a ratio of 1:20 (w/v) for 48 h. The supernatant was collected, filtered and evaporated to dryness under reduced pressure (50 degrees C) yielding approximately 21.0 g of the crude dried extract. The crude dried extract was stored at -20 degrees C prior to use and was dissolved in normal saline (0.9% NaCl) immediately before administration at concentrations required to produce doses of 25, 50 and 100 mg/kg. RESULTS: All dosages of MEZZ showed significant (p < 0.05) antiedema activity when assessed using the carrageenan-induced paw edema test and the cotton-pellet-induced granuloma test. The MEZZ exhibited significant (p < 0.05) antinociceptive activity when assessed by the writhing, hot plate and formalin tests. Pretreatment with naloxone (5 mg/kg) significantly decreased the latency of discomfort produced by the 100 mg/kg dose of MEZZ in the hot plate test. CONCLUSION: MEZZ produced antiinflammatory and antinociceptive activities which may involve the inhibition of bradykinin-, prostaglandin-, histamine- and opioid-mediated processes.

Alpinia conchigera Griff. (Zingiberaceae), locally known to the Malays as "lengkuas ranting", is native to Peninsular Malaysia. The Malays traditionally used it to treat infection and rashes, and as a health drink. This study evaluated the analgesic and anti-inflammatory activities of the ethanol extract of A. conchigera rhizomes in mice and rats, respectively. The analgesic activity was elucidated using the acetic acid-induced writhing test, hot plate test, and formalin test, while the anti-inflammatory activity was determined using carrageenan-induced paw edema. The extract (30, 100, and 300mg/kg) given intraperitoneally (i.p.) exhibited antinociceptive and anti-inflammatory activities in all tests used. The range of percentage of analgesia obtained for all doses of extract in the writhing test was 5092%, and in the early and late phases of the formalin test was 2562% and 6398%, respectively. In addition, naloxone (5mg/kg) given subcutaneously (s.c.) was found to reverse the extract (300mg/kg)-induced antinociceptive activity in the writhing, hot plate, and formalin tests. Based on the results obtained, it can be concluded that the ethanol extract of A. conchigera rhizomes possessed a peripheral and central antinociceptive activity that was mediated, in part, via the opioid receptor, as well as anti-inflammatory activity.

The current study was performed to evaluate the antinociceptive and antiedematogenic properties of andrographolide isolated from the leaves of Andrographis paniculata using two animal models. Antinociceptive activity was evaluated using the acetic acid- induced writhing and the hot-plate tests, while antiedematogenic activity was measured using the carrageenan-induced paw edema test. Subcutaneous (s.c.) administration of andrographolide (10, 25, and 50 mg/kg) did not affect the motor coordination of the experimental animals but produced significant (p <.05) antinociceptive activity when assessed using both tests. However, 2 mg/kg naloxone failed to affect the 25 mg/kg andrographolide activity in both tests, indicating that the activity was modulated via nonopioid mechanisms. Furthermore, andrographolide showed significant (p <.05) antiedematogenic activity. In conclusion, the results obtained suggest that andrographolide has antinociceptive and antiedematogenic activities; it may be useful for treating pain and inflammation once human studies are conducted.

In the present study, the rhizome essential oil from Zingiber zerumbet (Zingiberaceae) was evaluated for antinociceptive activity using chemical and thermal models of nociception, namely, the acetic acid-induced abdominal writhing test, the hot-plate test and the formalin-induced paw licking test. It was demonstrated that intraperitoneal administration of the essential oil of Z. zerumbet (EOZZ) at the doses of 30, 100 and 300mg/kg produced significant dose-dependent inhibition of acetic acid-induced abdominal writhing, comparable to that of obtained with acetylsalicylic acid (100mg/kg). At the same doses, the EOZZ produced significant dose-dependent increases in the latency time in the hot-plate test with respect to controls, and in the formalin-induced paw licking test, the EOZZ also significantly reduced the painful stimulus in both neurogenic and inflammatory phase of the test. In addition, the antinociceptive effect of the EOZZ in the formalin-induced paw licking test as well as hot-plate test was reversed by the nonselective opioid receptor antagonist, naloxone suggesting that the opioid system was involved in its analgesic mechanism of action. On the basis of these data, we concluded that the EOZZ possessed both central and peripheral antinociceptive activities which justifying its popular folkloric use to relieve some pain conditions.

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.

A series of 46 curcumin related diarylpentanoidanalogues were synthesized and evaluated for their anti-inflammatory, antioxidant and anti-tyrosinaseactivities. Among these compounds 2, 13 and 33 exhibited potent NO inhibitory effect on IFN-γ/LPS-activated RAW 264.7 cells as compared to l-NAME and curcumin. However, these series of diarylpentanoidanalogues were not significantly inhibiting NO scavenging, total radical scavenging and tyrosinase enzyme activities. The results revealed that the biologicalactivity of these diarylpentanoidanalogues is most likely due to their action mainly upon inflammatory mediator, inducible nitric oxide synthase (iNOS). The present results showed that compounds 2, 13 and 33 might serve as a useful starting point for the design of improved anti-inflammatory agents.

The methanol extracts of 32 plant parts of 19 species of the genus Garcinia (Guttiferae) were collected from rainforests of the Malaysian Peninsula and the island of Sumatra, Indonesia, for evaluation of their in vitro cytotoxic and nitric oxide inhibitory activities. An end-point MTT cell viability assay was used to determine the 50% inhibitory concentration (IC50) of the extracts in three human tumor cell lines representing tumors of the breast (MCF-7), lung (NCI-H460) and prostate (DU-145). Griess assay was performed to assess the nitric oxide (NO) inhibitory activity. Of the 32 extracts, 27 showed cytotoxic activity in at least one of the three tumor cell lines used in this study. Four extracts, Garcinia opaca King (fruit), Garcinia maingayi Hook.f. (stem), Garcinia penangiana Pierre (leaf) and Garcinia urophylla Scortech.ex King (leaf) extracts showed the most potent and selective cytotoxic activity against MCF-7 cells (IC50 3-8 ?g/mL). The extracts from Garcinia cowa Roxb. (stem), Garcinia bancana Miq. (stem) and Garcinia malaccensis Hook.f. (leaf) showed moderate activity and selectivity towards non-small lung tumor cells. The extracts from Garcinia bancana (stem), Garcinia malaccensis (stem), Garcinia prainiana King (leaf), Garcinia rostrata Hassk.ex Hook.f. (stem and leaf), Garcinia cowa (stem) and Garcinia nervosa Miq. (leaf) exhibited inhibition against NO production without affecting the viability of LPS and IFN-?-induced RAW 264.7 macrophage cells. Among these, the most promising extracts were G. bancana (stem) and G. malaccensis (stem), as they showed the highest selectivity indices (>50) for NO inhibition. In conclusion, these data provide evidence that some of the Garcinia species could potentially contain potent and selective cytotoxic and anti-inflammatory agents.

We have investigated the antinociceptive activity of zerumbone (1), a natural cyclic sesquiterpene isolated from Zingiber zerumbet Smith, in acetic acid-induced abdominal writhing test and hot plate test in mice. 1 given by intraperitoneal route produced significant dose-dependent antinociceptive effect in all the test models used. In addition, the antinociceptive effect of 1 in the hot plate test was reversed by the non-selective opioid receptor antagonist naloxone, suggesting that the opioid system is involved in its analgesic mechanism of action.

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.

Objective: The present study was carried out to explore the antinociceptive as well as the anti-inflammatory effects of an ethanol extract of Stachytarpheta jamaicensis (L.) Vahl (EESJ) using 3 models of nociception and 2 models of inflammation in experimental animals. Materials and Methods: EESJ was prepared by overnight soaking of the oven-dried (50°C; 72 h) ground leaves (500 g) in 80% ethanol (1:5; w/v). The filtrate was evaporated to dryness (50°C), resuspended in distilled water at concentrations to provide the desired doses of 50, 100 and 150 mg/kg. For antinociceptive effects, 3 models were used: acetic acid-induced abdominal writhing, hot-plate- and formalin-induced paw-licking tests; for anti-inflammatory effects, 2 models were used - carrageenan-induced paw edema and cotton-pellet-induced granuloma tests. Appropriate doses were administered intraperitoneally (i.p.) to mice/rats prior to each test. The mechanisms of antinociceptive action of the extract were also investigated by pretreatment with naloxone (5 mg/kg, i.p.). Results: The extract exhibited significant (p < 0.05) antinociceptive activity in all nociceptive models tested with dose-dependent activity observed using the abdominal writhing and formalin tests. Pretreatment with naloxone partially, but significantly (p < 0.05) reversed the antinociceptive activity of the extract when assessed using the abdominal-writhing- and formalin-induced paw-licking tests, and completely inhibited its activity when the hot-plate test was used. The extract also showed significant (p < 0.05) anti-inflammatory activity in both the acute (carrageenan-induced paw edema test) and the chronic (cotton-pellet granuloma test) tests. Conclusion: This study showed the potential of EESJ to exert antinociceptive and anti-inflammatory activities, the former being modulated via peripheral and central mechanisms and involving, in part, activation of the opioid receptor system.

The ethanolic extract of Alpinia conchigera Griff. leaves (EACL) was evaluated for its antinociceptive and anti-inflammatory activities in several in vivo experimental models. Antinociceptive activity was determined using the acetic acid-induced abdominal writhing test, the hot plate test and the formalin test. Anti-inflammatory activity was determined using the carrageenan-induced paw edema test. The extract (30, 100 and 300 mg/kg i.p.) was found to possess significant, dose-dependent inhibitory activity in all test models. In addition, the antinociceptive effect of the extract in the acetic acid-induced writhing and hot plate tests was reversed by naloxone, suggesting that this activity is mediated through activation of the opioid system. These findings suggest that EACL presents notable analgesic and anti-inflammatory activities, which support its folkloric use for painful and inflammatory conditions.

Moringa oleifera L. (Moringaceae) is known to possess high nutritional value and is used in a folklore medicine to treat various ailments related to pain and inflammation. The aim of the present study was to evaluate the antinoCICeptive and anti-inflammatory effects of the aqueous extract of the leaves of M. oleifera in laboratory animals, using the writhing, hot-plate and formalin tests as the antinoCICeptive assays, and carrageenan-induced paw edema test as the anti-inflammatory assay. The extract (10, 30 and 100 mg/kg) exhibited significant (P < 0.05) antinoCICeptive activity, which occurred in a dose-dependent manner, in all tests used. The extract also exhibited significant (P < 0.05) anti-inflammatory activity in a dose-dependent manner. Furthermore, the extract antinoCICeptive activity was suggested to be modulated via opioid receptors at the central, but not peripheral, antinoCICeptive level, based on the ability of 5 mg/kg naloxone to reverse the extract activity in the hot-plate, but not the writhing test. In conclusion, M. oleifera leaves possess peripherally non-opioid mediated and centrally opioid mediated antinoCICeptive and anti-inflammtory activities. This study also confirms the traditional uses of M. oleifera in the treatment of ailments, particularly those related to pain and inflammation.