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Nitric oxide (NO), citrulline-NO cycle enzymes, glutamine synthetase, and oxidative status in kainic acid-mediated excitotoxicity in rat brain

Swamy M, Sirajudeen KN, Chandran G

Drug Chem Toxicol, 2009;32(4):326-31.
PMID: 19793024 DOI: 10.1080/01480540903130641

Neuronal excitation, involving the excitatory glutamate receptors, is recognized as an important underlying mechanism in neurodegenerative disorders. To understand their role in excitotoxicity, the nitric oxide synthase (NOS), argininosuccinate synthetase (AS), argininosuccinate lyase (AL), glutamine synthetase (GS), and arginase activities, along with the concentration of nitrate/nitrite, thiobarbituric acid-reactive substances (TBARS), and total antioxidant status (TAS), were estimated in the cerebral cortex, cerebellum, and brain stem of rats subjected to kainic acid-mediated excitotoxicity. The results of this study clearly demonstrated the increased production of NO by increased activity of NOS. The increased activities of AS and AL suggest the increased and effective recycling of citrulline to arginine in excitotoxicity, making NO production more effective and contributing to its toxic effects. The decreased activity of GS may favor the prolonged availability of glutamic acid, causing excitotoxicity, leading to neuronal damage. The increased formation of TBARS and decreased TAS indicate the presence of oxidative stress in excitotoxicity.

Matched MeSH terms: Nitric Oxide/metabolism*
Flavonoid combinations cause synergistic inhibition of proinflammatory mediator secretion from lipopolysaccharide-induced RAW 264.7 cells

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.

Matched MeSH terms: Nitric Oxide/metabolism
Fulltext Antifungal, anti-inflammatory and cytotoxicity activities of three varieties of labisia pumila benth: from microwave obtained extracts

Karimi E, Jaafar HZ, Ahmad S

BMC Complement Altern Med, 2013;13:20.
PMID: 23347830 DOI: 10.1186/1472-6882-13-20

Labisia pumila, locally known as Kacip Fatimah, is a forest-floor plant that has tremendous potential in the herbal industry. It is one of the five herbal plants identified by the government as one of the national key economic areas to be developed for commercial purposes. There are three varieties of L. pumila namely, L. pumila var. pumila, L. pumila var. alata and L. pumila var. lanceolata and each has its own use.

Matched MeSH terms: Nitric Oxide/metabolism*
Fulltext Preventive Effects of Tocotrienol on Stress-Induced Gastric Mucosal Lesions and Its Relation to Oxidative and Inflammatory Biomarkers

Nur Azlina MF, Kamisah Y, Chua KH, Ibrahim IA, Qodriyah HM

PLoS One, 2015;10(10):e0139348.
PMID: 26465592 DOI: 10.1371/journal.pone.0139348

This study aimed to investigate the possible gastroprotective effect of tocotrienol against water-immersion restraint stress (WIRS) induced gastric ulcers in rats by measuring its effect on gastric mucosal nitric oxide (NO), oxidative stress, and inflammatory biomarkers. Twenty-eight male Wistar rats were randomly assigned to four groups of seven rats. The two control groups were administered vitamin-free palm oil (vehicle) and the two treatment groups were given omeprazole (20 mg/kg) or tocotrienol (60 mg/kg) orally. After 28 days, rats from one control group and both treated groups were subjected to WIRS for 3.5 hours once. Malondialdehyde (MDA), NO content, and superoxide dismutase (SOD) activity were assayed in gastric tissue homogenates. Gastric tissue SOD, iNOS, TNF-α and IL1-β expression were measured. WIRS increased the gastric MDA, NO, and pro-inflammatory cytokines levels significantly when compared to the non-stressed control group. Administration of tocotrienol and omeprazole displayed significant protection against gastric ulcers induced by exposure to WIRS by correction of both ulcer score and MDA content. Tissue content of TNF-α and SOD activity were markedly reduced by the treatment with tocotrienol but not omeprazole. Tocotrienol significantly corrected nitrite to near normal levels and attenuated iNOS gene expression, which was upregulated in this ulcer model. In conclusion, oral supplementation with tocotrienol provides a gastroprotective effect in WIRS-induced ulcers. Gastroprotection is mediated through 1) free radical scavenging activity, 2) the increase in gastric mucosal antioxidant enzyme activity, 3) normalisation of gastric mucosal NO through reduction of iNOS expression, and 4) attenuation of inflammatory cytokines. In comparison to omeprazole, it exerts similar effectiveness but has a more diverse mechanism of protection, particularly through its effect on NO, SOD activity, and TNF-α.

Matched MeSH terms: Nitric Oxide/metabolism
The Molecular Concept of Atheromatous Plaques

Thent ZC, Chakraborty C, Mahakkanukrauh P, Nik Ritza Kosai Nik Mahmood N, Rajan R, Das S

Curr Drug Targets, 2017;18(11):1250-1258.
PMID: 27138760 DOI: 10.2174/1389450117666160502151600

BACKGROUND: Recently, there are scientific attempts to discover new drugs in the biotechnology industry in order to treat various diseases including atherosclerosis.
OBJECTIVE: The main objective of the present review was to highlight the cellular, molecular biology and inflammatory process related to the atheromatous plaques.
METHODS: A thorough literature search of Pubmed, Google and Scopus databases was done.
RESULTS: Atherosclerosis is considered to be a leading cause of death throughout the world. Atherosclerosis involves oxidative damage to the cells with production of reactive oxygen species (ROS). Development of atheromatous plaques in the arterial wall is a common feature. Specific inflammatory markers pertaining to the arterial wall in atherosclerosis may be useful for both diagnosis and treatment. These include Nitric oxide (NO), cytokines, macrophage inhibiting factor (MIF), leucocytes and Pselectin. Modern therapeutic paradigms involving endothelial progenitor cells therapy, angiotensin II type-2 (AT<sub>2</sub>R) and ATP-activated purinergic receptor therapy are notable to mention.
CONCLUSION: Future drugs may be designed aiming three signalling mechanisms of AT<sub>2</sub>R which are (a) activation of protein phosphatases resulting in protein dephosphorylation (b) activation of bradykinin/nitric oxide/cyclic guanosine 3',5'-monophosphate pathway by vasodilation and (c) stimulation of phospholipase A(2) and release of arachidonic acid. Drugs may also be designed to act on ATP-activated purinergic receptor channel type P2X7 molecules which acts on cardiovascular system.

Matched MeSH terms: Nitric Oxide/metabolism
Fulltext Cystathione gamma lyase/Hydrogen Sulphide Pathway Up Regulation Enhances the Responsiveness of α1A and α1B-Adrenoreceptors in the Kidney of Rats with Left Ventricular Hypertrophy

Ahmad A, Sattar MA, Azam M, Abdulla MH, Khan SA, Hashmi F, et al.

PLoS One, 2016;11(5):e0154995.
PMID: 27191852 DOI: 10.1371/journal.pone.0154995

The purpose of the present study was to investigate the interaction between H2S and NO (nitric oxide) in the kidney and to evaluate its impact on the functional contribution of α1A and α1B-adrenoreceptors subtypes mediating the renal vasoconstriction in the kidney of rats with left ventricular hypertrophy (LVH). In rats the LVH induction was by isoprenaline administration and caffeine in the drinking water together with intraperitoneal administration of H2S. The responsiveness of α1A and α1B to exogenous noradrenaline, phenylephrine and methoxaminein the absence and presence of 5-methylurapidil (5-MeU) and chloroethylclonidine (CEC) was studied. Cystathione gamma lyase (CSE), cystathione β synthase (CBS), 3-mercaptopyruvate sulphar transferase (3-MST) and endothelial nitric oxide synthase (eNOS) were quantified. There was significant up regulation of CSE and eNOS in the LVH-H2S compared to the LVH group (P<0.05). Baseline renal cortical blood perfusion (RCBP) was increased (P<0.05) in the LVH-H2S compared to the LVH group. The responsiveness of α1A-adrenergic receptors to adrenergic agonists was increased (P<0.05) after administration of low dose 5-Methylurapidil in the LVH-H2S group while α1B-adrenergic receptors responsiveness to adrenergic agonists were increased (P<0.05) by both low and high dose chloroethylclonidine in the LVH-H2S group. Treatment of LVH with H2S resulted in up-regulation of CSE/H2S, CBS, and 3-MST and eNOS/NO/cGMP pathways in the kidney. These up regulation of CSE/H2S, CBS, and 3-MST and eNOS/NO/cGMP pathways enhanced the responsiveness of α1A and α1B-adrenoreceptors subtypes to adrenergic agonists in LVH-H2S. These findings indicate an important role for H2S in modulating deranged signalling in the renal vasculature resulting from LVH development.

Matched MeSH terms: Nitric Oxide/metabolism
Polyphenol-enriched extract of oil palm fronds (Elaeis guineensis) promotes vascular relaxation via endothelium-dependent mechanisms

Abeywardena M, Runnie I, Nizar M, Suhaila M, Head R, Suhaila Momamed

Asia Pac J Clin Nutr, 2002;11 Suppl 7:S467-72.
PMID: 12492636

Plant-based polyphenolic compounds have been reported to possess cardiovascular health benefits. Several dietary sources, including herbs and spices, fruits and vegetables, and tea and wine, contain an array of biologically active compounds that have been shown to be effective in retarding oxidation of low-density lipoproteins (LDL) and promoting vascular relaxation. In the present study four different plant sources, both edible and non-edible, were evaluated for potential activity. Organic extracts enriched in polyphenols were prepared from palm fronds (Elaesis guineensis); lemongrass (Cymbopogon citrates); papaya shoots (Carica papaya) and green chilli (Capsicum frutescenes) and tested for their ability to prevent in vitro oxidation of LDL, and for potential vascular relaxation actions. Rings of rat thoracic aorta and isolated perfused mesenteric vascular beds were mounted in organ baths, contracted using a half-maximal dose of noradrenaline and exposed to cumulative additions of test extracts. Palm frond extract resulted in considerable relaxation (>75%) in both preparations and was found to be endothelium-dependent as removal of endothelium or inhibition of endogenous nitric oxide (NO) led to a total loss in relaxant activity. Lemongrass extract caused a greater relaxation action in the mesenteric preparation compared to aortic rings, and appears to be mediated via NO-independent and non-prostanoid mechanisms. Of the extracts tested, palm fronds also demonstrated the highest antioxidant capacity, as determined by the ferric reducing activity/potential assay, and resulted in a significant delay (P < 0.05) in the oxidation of LDL. Collectively, these preliminary findings lend further support to the potential cardiovascular actions of plant polyphenols and also identify oil palm fronds as containing constituents that promote vascular relaxation via endothelium-dependent mechanisms.

Matched MeSH terms: Nitric Oxide/metabolism
Nitric oxide production by murine spleen cells stimulated with Porphyromonas gingivalis-derived lipopolysaccharide

Sosroseno W

Asian Pac J Allergy Immunol, 2000 Dec;18(4):209-14.
PMID: 11316041

The aim of the present study was to determine whether Porphyromonas gingivalis-lipopolysaccharide (Pg-LPS) may stimulate nitric oxide (NO) production by murine spleen cells. Spleen cells derived from Balb/c mice were cultured in the presence of Pg-LPS or LPS from Salmonella Typhosa. The cell were also cultured in the presence of Pg-LPS with or without L-arginine, L-arginine plus NG-monomethyl-L-arginine (NMMA), or IFN-gamma. Furthermore, the plastic non-adherent spleen cells were stimulated with Pg-LPS and L-arginine. The results showed that Pg-LPS failed to stimulate splenic NO production by themselves. Exogenous L-arginine or IFN-gamma up-regulated the NO production of Pg-LPS-stimulated spleen cells, but the stimulatory effects of L-arginine were completely blocked by NMMA. It was also demonstrated that in the presence of Pg-LPS and L-arginine, splenic macrophages were the cellular source of NO. These results suggest, therefore, that P. gingivalis-LPS may induce murine splenic macrophages to produce NO in a L-arginine and an IFN-gamma-dependent mechanism.

Matched MeSH terms: Nitric Oxide/metabolism
The anti-inflammatory and anti-nociceptive effects of Korean black ginseng

Lee YY, Saba E, Irfan M, Kim M, Chan JY, Jeon BS, et al.

Phytomedicine, 2019 Feb 15;54:169-181.
PMID: 30668366 DOI: 10.1016/j.phymed.2018.09.186

BACKGROUND: Different processing conditions alter the ginseng bioactive compounds, promoting or reducing its anti-inflammatory effects. We compared black ginseng (BG) - that have been steamed 5 times - with red ginseng (RG).
HYPOTHESIS/ PURPOSE: To compare the anti-inflammatory activities and the anti-nociceptive properties of RG and BG.
METHODS: Nitric Oxide (NO) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay, quantitative Reverse Transcriptase-Polymerase Chain Reaction (qRT-PCR), western blot, xylene-induced ear edema, carrageenan-induced paw edema RESULTS: The ginsenoside contents were confirmed using high-performance liquid chromatography (HPLC) and has been altered through increased processing. The highest concentration of these extracts inhibited NO production to near-basal levels in lipopolysaccharide (LPS)-stimulated RAW 264.7 without exhibiting cytotoxicity. Pro-inflammatory cytokine expression at the mRNA level was investigated using qRT-PCR. Comparatively, BG exhibited better inhibition of pro-inflammatory mediators, iNOS and COX-2 and pro-inflammatory cytokines, IL-1β, IL-6 and TNF-α. Protein expression was determined using western blot analysis and BG exhibited stronger inhibition. Xylene-induced ear edema model in mice and carrageenan-induced paw edema in rats were carried out and tested with the effects of ginseng as well as dexamethasone and indomethacin - commonly used drugs. BG is a more potent anti-inflammatory agent, possesses anti-nociceptive properties, and has a strong potency comparable to the NSAIDs.
CONCLUSION: BG has more potent anti-inflammatory and anti-nociceptive effects due to the change in ginsenoside component with increased processing.

Matched MeSH terms: Nitric Oxide/metabolism
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/metabolism
Fulltext Biological Activities of Selected Plants and Detection of Bioactive Compounds from Ardisia elliptica Using UHPLC-Q-Exactive Orbitrap Mass Spectrometry

Wong PL, Fauzi NA, Mohamed Yunus SN, Abdul Hamid NA, Abd Ghafar SZ, Azizan A, et al.

Molecules, 2020 Jul 06;25(13).
PMID: 32640504 DOI: 10.3390/molecules25133067

Plants and plant-based products have been used for a long time for medicinal purposes. This study aimed to determine the antioxidant and anti-α-glucosidase activities of eight selected underutilized plants in Malaysia: Leucaena leucocephala, Muntingia calabura, Spondias dulcis, Annona squamosa, Ardisia elliptica, Cynometra cauliflora, Ficus auriculata, and Averrhoa bilimbi. This study showed that the 70% ethanolic extract of all plants exhibited total phenolic content (TPC) ranging from 51 to 344 mg gallic acid equivalent (GAE)/g dry weight. A. elliptica showed strong 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide (NO) scavenging activities, with half maximal inhibitory concentration (IC50) values of 2.17 and 49.43 μg/mL, respectively. Most of the tested plant extracts showed higher inhibition of α-glucosidase enzyme activity than the standard, quercetin, particularly A. elliptica, F. auriculata, and M. calabura extracts with IC50 values of 0.29, 0.36, and 0.51 μg/mL, respectively. A total of 62 metabolites including flavonoids, triterpenoids, benzoquinones, and fatty acids were tentatively identified in the most active plant, i.e., A. elliptica leaf extract, by using ultra-high-performance liquid chromatography (UHPLC)-electrospray ionization (ESI) Orbitrap MS. This study suggests a potential natural source of antioxidant and α-glucosidase inhibitors from A. elliptica.

Matched MeSH terms: Nitric Oxide/metabolism
Boldine protects endothelial function in hyperglycemia-induced oxidative stress through an antioxidant mechanism

Lau YS, Tian XY, Huang Y, Murugan D, Achike FI, Mustafa MR

Biochem Pharmacol, 2013 Feb 1;85(3):367-75.
PMID: 23178655 DOI: 10.1016/j.bcp.2012.11.010

Increased oxidative stress is involved in the pathogenesis and progression of diabetes. Antioxidants are therapeutically beneficial for oxidative stress-associated diseases. Boldine ([s]-2,9-dihydroxy-1,10-dimethoxyaporphine) is a major alkaloid present in the leaves and bark of the boldo tree (Peumus boldus Molina), with known an antioxidant activity. This study examined the protective effects of boldine against high glucose-induced oxidative stress in rat aortic endothelial cells (RAEC) and its mechanisms of vasoprotection related to diabetic endothelial dysfunction. In RAEC exposed to high glucose (30 mM) for 48 h, pre-treatment with boldine reduced the elevated ROS and nitrotyrosine formation, and preserved nitric oxide (NO) production. Pre-incubation with β-NAPDH reduced the acetylcholine-induced endothelium-dependent relaxation; this attenuation was reversed by boldine. Compared with control, endothelium-dependent relaxation in the aortas of streptozotocin (STZ)-treated diabetic rats was significantly improved by both acute (1 μM, 30 min) and chronic (20mg/kg/daily, i.p., 7 days) treatment with boldine. Intracellular superoxide and peroxynitrite formation measured by DHE fluorescence or chemiluminescence assay were higher in sections of aortic rings from diabetic rats compared with control. Chronic boldine treatment normalized ROS over-production in the diabetic group and this correlated with reduction of NAD(P)H oxidase subunits, NOX2 and p47(phox). The present study shows that boldine reversed the increased ROS formation in high glucose-treated endothelial cells and restored endothelial function in STZ-induced diabetes by inhibiting oxidative stress and thus increasing NO bioavailability.

Matched MeSH terms: Nitric Oxide/metabolism
Fulltext Methanol Extract of Dicranopteris linearis Leaves Attenuate Pain via the Modulation of Opioid/NO-Mediated Pathway

Zakaria ZA, Roosli RAJ, Marmaya NH, Omar MH, Basir R, Somchit MN

Biomolecules, 2020 02 12;10(2).
PMID: 32059475 DOI: 10.3390/biom10020280

Dicranopteris linearis leaf has been reported to exert antinociceptive activity. The present study elucidates the possible mechanisms of antinociception modulated by the methanol extract of D. linearis leaves (MEDL) using various mouse models. The extract (25, 150, and 300 mg/kg) was administered orally to mice for 30 min priot to subjection to the acetic acid-induced writhing-, hot plate- or formalin-test to establish the antinociceptive profile of MEDL. The most effective dose was then used in the elucidation of possible mechanisms of action stage. The extract was also subjected to the phytochemical analyses. The results confirmed that MEDL exerted significant (p < 0.05) antinociceptive activity in those pain models as well as the capsaicin-, glutamate-, bradykinin- and phorbol 12-myristate 13-acetate (PMA)-induced paw licking model. Pretreatment with naloxone (a non-selective opioid antagonist) significantly (p < 0.05) reversed MEDL effect on thermal nociception. Only l-arginine (a nitric oxide (NO) donor) but not N(ω)-nitro-l-arginine methyl ester (l-NAME; a NO inhibitor) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; a specific soluble guanylyl cyclase inhibitor) significantly (p < 0.05) modified MEDL effect on the writhing test. Several polyphenolics and volatile antinociceptive compounds were detected in MEDL. In conclusion, MEDL exerted the opioid/NO-mediated antinociceptive activity, thus, justify D. linearis as a potential source for new analgesic agents development.

Matched MeSH terms: Nitric Oxide/metabolism*
Fulltext Effect of (R)-salbutamol on the switch of phenotype and metabolic pattern in LPS-induced macrophage cells

Wang S, Liu F, Tan KS, Ser HL, Tan LT, Lee LH, et al.

J Cell Mol Med, 2020 01;24(1):722-736.
PMID: 31680470 DOI: 10.1111/jcmm.14780

Evidence demonstrates that M1 macrophage polarization promotes inflammatory disease. Here, we discovered that (R)-salbutamol, a β2 receptor agonist, inhibits and reprograms the cellular metabolism of RAW264.7 macrophages. (R)-salbutamol significantly inhibited LPS-induced M1 macrophage polarization and downregulated expressions of typical M1 macrophage cytokines, including monocyte chemotactic protein-1 (MCP-1), interleukin-1β (IL-1β) and tumour necrosis factor α (TNF-α). Also, (R)-salbutamol significantly decreased the production of inducible nitric oxide synthase (iNOS), nitric oxide (NO) and reactive oxygen species (ROS), while increasing the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio. In contrast, (S)-salbutamol increased the production of NO and ROS. Bioenergetic profiles showed that (R)-salbutamol significantly reduced aerobic glycolysis and enhanced mitochondrial respiration. Untargeted metabolomics analysis demonstrated that (R)-salbutamol modulated metabolic pathways, of which three metabolic pathways, namely, (a) phenylalanine metabolism, (b) the pentose phosphate pathway and (c) glycerophospholipid metabolism were the most noticeably impacted pathways. The effects of (R)-salbutamol on M1 polarization were inhibited by a specific β2 receptor antagonist, ICI-118551. These findings demonstrated that (R)-salbutamol inhibits the M1 phenotype by downregulating aerobic glycolysis and glycerophospholipid metabolism, which may propose (R)-salbutamol as the major pharmacologically active component of racemic salbutamol for the treatment of inflammatory diseases and highlight the medicinal value of (R)-salbutamol.

Matched MeSH terms: Nitric Oxide/metabolism
Oppositinines A and B: new vasorelaxant beta-carboline alkaloids from Neisosperma oppositifolia

Ahmad K, Thomas NF, Hadi AH, Mukhtar MR, Mohamad K, Nafiah MA, et al.

Chem Pharm Bull (Tokyo), 2010 Aug;58(8):1085-7.
PMID: 20686264

A phytochemical study on the bark of Neisosperma oppositifolia (Apocynaceae) yielded two new beta-carboline indole alkaloids, oppositinines A (1) and B (2), together with five known alkaloids, isoreserpiline, isocarapanaubine, vobasine, 10-methoxydihydrocorynantheol-N-oxide, and ochropposinine oxindole. Structural elucidation of 1 and 2 was performed using 2D NMR methods. Oppositinines A (1) and B (2) showed potent vasorelaxant effects on the rat aorta.

Matched MeSH terms: Nitric Oxide/metabolism
Antinociceptive activity of a synthetic oxopyrrolidine-based compound, ASH21374, and determination of its possible mechanisms

Zakaria ZA, Sani MH, Mohammat MF, Mansor NS, Shaameri Z, Kek TL, et al.

Can J Physiol Pharmacol, 2013 Dec;91(12):1143-53.
PMID: 24289087 DOI: 10.1139/cjpp-2013-0099

This study was carried out to determine the antinociceptive activity of a novel synthetic oxopyrrolidine-based compound, (2R,3R,4S)-ethyl 4-hydroxy-1,2-dimethyl-5-oxopyrrolidine-3-carboxylate (ASH21374), and to elucidate the involvement of the opioid, vanilloid, glutamate, and nitric oxide - cyclic guanosine monophosphate (NO/cGMP) systems in modulating the observed antinociception. ASH21374, in the doses of 2, 10, and 100 mg/kg body mass, was administered orally to mice 60 mins prior to exposure to various antinociceptive assays. From the results obtained, ASH21374 exhibited significant (P < 0.05) antinociceptive activity in the abdominal constriction, hot-plate, and formalin tests that was comparable with 100 mg/kg acetylsalicylic acid or 5 mg/kg morphine, respectively. ASH21374 also attenuated capsaicin- and glutamate-induced paw licking. Pre-treatment with 5 mg/kg naloxone significantly (P < 0.05) inhibited the activity in all assays, while pretreatment with 10 mg/kg β-funaltraxamine, 1 mg/kg naltrindole, or 1 mg/kg nor-binaltorphimine significantly (P < 0.05) reversed the activity in the abdominal constriction test. l-Arginine, N(G)-nitro-l-arginine methyl esters (l-NAME), methylene blue, and their combinations, failed to inhibit the ASH21374 antinociceptive activity. In conclusion, ASH21374 demonstrated antinociceptive activities on the peripheral and central nervous systems, mediated through the activation of opioid receptors, inhibition of the glutamatergic system, and attenuation of vanilloid-mediated nociceptive transmission. Further studies have been planned to determine the pharmacological potential of ASH21374.

Matched MeSH terms: Nitric Oxide/metabolism
Zerumbone from Zingiber zerumbet inhibits innate and adaptive immune responses in Balb/C mice

Jantan I, Haque MA, Ilangkovan M, Arshad L

Int Immunopharmacol, 2019 Aug;73:552-559.
PMID: 31177081 DOI: 10.1016/j.intimp.2019.05.035

Zerumbone exhibited various biological properties including in vitro immunosuppressive effects. However, its modulatory activity on the immune responses in experimental animal model is largely unknown. This investigation was conducted to explore the effects of daily treatment of zerumbone (25, 50, and 100 mg/kg) isolated from Zingiber zerumbet rhizomes for 14 days on various cellular and humoral immune responses in Balb/C mice. For measurement of adaptive immunity, sheep red blood cells (sRBC) were used to immunize the mice on day 0 and orally fed with similar doses of zerumbone for 14 days. The effects of zerumbone on phagocytosis, nitric oxide (NO) release, myeloperoxidase (MPO) activity, proliferation of T and B cells, lymphocyte phenotyping, cytokines release in serum by activated T cells, delayed type hypersensitivity (DTH) and immunoglobulins production (IgG and IgM) were investigated. Zerumbone downregulated the engulfment of E. coli by peritoneal macrophages and the release of NO and MPO in a concentration-dependent manner. Zerumbone showed significant and concentration-dependent suppression of T and B lymphocytes proliferation and inhibition of the Th1 and Th2 cytokines release. At higher concentrations of zerumbone, the % expression of CD4+ and CD8+ in splenocytes was significantly inhibited. Zerumbone also concentration-dependently demonstrated strong suppression on sRBC-triggered swelling of mice paw in DTH. Substantial suppression of anti-sRBC immunoglobulins antibody titer was noted in immunized and zerumbone-treated mice in a concentration-dependent manner. The potent suppressive effects of zerumbone on the immune responses suggest that zerumbone can be a potential candidate for development of immunosuppressive agent.

Matched MeSH terms: Nitric Oxide/metabolism
Fulltext Preparation, characterization and therapeutic properties of gum arabic-stabilized gallic acid nanoparticles

Hassani A, Azarian MMS, Ibrahim WN, Hussain SA

Sci Rep, 2020 10 20;10(1):17808.
PMID: 33082415 DOI: 10.1038/s41598-020-71175-8

Gallic acid (GA) is a natural phenolic compound with therapeutic effects that are often challenged by its rapid metabolism and clearance. Therefore, GA was encapsulated using gum arabic into nanoparticles to increase its bioavailability. The formulated nanoparticles (GANPs) were characterized for physicochemical properties and size and were then evaluated for antioxidant and antihypertensive effects using various established in vitro assays, including 1,1-diphenyl-2-picrylhydrazyl (DPPH), nitric oxide scavenging (NO), β-carotene bleaching and angiotensin-converting enzyme (ACE) inhibitory assays. The GANPs were further evaluated for the in vitro cytotoxicity, cell uptake and cell migration in four types of human cancer cell lines including (MCF-7, MDA-MB231) breast adenocarcinoma, HepG2 hepatocellular cancer, HT-29 colorectal adenocarcinoma, and MCF-10A breast epithelial cell lines. The GANPs demonstrated potent antioxidant effects and have shown promising anti-cancer properties in a dose-dependent manner with a predilection toward HepG2 and MCF7 cancer cells. The uptake of GANPs was successful in the majority of cancer cells with a propensity to accumulate in the nuclear region of the cells. The HepG2 and MCF7 cancer cells also had a significantly higher percentage of apoptosis and were more sensitive to gallic acid nanoparticle treatment in the cell migration assay. This study is the first to confirm the synergistic effects of gum arabic in the encapsulation of gallic acid by increasing the selectivity towards cancer cells and enhancing the antioxidant properties. The formulated nanoparticles also had remarkably low toxicity in normal cells. Based on these findings, GANPs may have promising therapeutic applications towards the development of more effective treatments with a probable targeting precision in cancer cells.

Matched MeSH terms: Nitric Oxide/metabolism
Fulltext Bee Bread Ameliorates Vascular Inflammation and Impaired Vasorelaxation in Obesity-Induced Vascular Damage Rat Model: The Role of eNOS/NO/cGMP-Signaling Pathway

Othman ZA, Zakaria Z, Suleiman JB, Nna VU, Che Romli A, Wan Ghazali WS, et al.

Int J Mol Sci, 2021 Apr 19;22(8).
PMID: 33921777 DOI: 10.3390/ijms22084225

Obesity and hyperlipidemia are major risk factors for developing vascular diseases. Bee bread (BB) has been reported to exhibit some biological actions, including anti-obesity and anti-hyperlipidemic. This study aims to investigate whether bee bread can ameliorate vascular inflammation and impaired vasorelaxation activity through eNOS/NO/cGMP pathway in obese rats. Forty male Sprague-Dawley rats were randomly divided into four groups (n = 10/group), namely: control (normal group), obese rats (OB group), obese rats treated with bee bread (0.5 g/kg/day, OB/BB group) and obese rats treated with orlistat (10 mg/kg/day, OB/OR group). The latter three groups were given a high-fat diet (HFD) for 6 weeks to induced obesity before being administered with their respective treatments for another 6 weeks. After 12 weeks of the total experimental period, rats in the OB group demonstrated significantly higher Lee obesity index, lipid profile (total cholesterol, triglyceride, low-density lipoprotein), aortic proinflammatory markers (tumor necrosis factor-α, nuclear factor-κβ), aortic structural damage and impairment in vasorelaxation response to acetylcholine (ACh). Bee bread significantly ameliorated the obesity-induced vascular damage manifested by improvements in the lipid profile, aortic inflammatory markers, and the impaired vasorelaxation activity by significantly enhancing nitric oxide release, promoting endothelial nitric oxide synthase (eNOS) and cyclic guanosine monophosphate (cGMP) immunoexpression. These findings suggest that the administration of bee bread ameliorates the impaired vasorelaxation response to ACh by improving eNOS/NO/cGMP-signaling pathway in obese rats, suggesting its vascular therapeutic role.

Matched MeSH terms: Nitric Oxide/metabolism*
Vasorelaxant effect of sinensetin via the NO/sGC/cGMP pathway and potassium and calcium channels

Yam MF, Tan CS, Shibao R

Hypertens Res, 2018 Oct;41(10):787-797.
PMID: 30111856 DOI: 10.1038/s41440-018-0083-8

Orthosiphon stamineus Benth. (Lambiaceae) is an important traditional plant for the treatment of hypertension. Previous studies have demonstrated that the sinensetin content in O. stamineus is correlated with its vasorelaxant activity. However, there is still very little information regarding the vasorelaxant effect of sinensetin due to a lack of scientific studies. Therefore, the present study was designed to investigate the underlying mechanism of action of sinensetin in vasorelaxation using an in vitro precontraction aortic ring assay. The changes in the tension of the aortic ring preparations were recorded using a force-displacement transducer and the PowerLab system. The mechanisms of the vasorelaxant effect of sinensetin were determined in the presence of antagonists. Sinensetin caused relaxation of the aortic ring precontracted with PE in the presence and absence of the endothelium and with potassium chloride in endothelium-intact aortic rings. In the presence of Nω-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor), methylene blue (cyclic guanosine monophosphate lowering agent), ODQ (selective soluble guanylate cyclase inhibitor), indomethacin (a nonselective cyclooxygenase inhibitor), tetraethylammonium (nonselective calcium activator K+ channel blocker), 4-aminopyridine (voltage-dependent K+ channel blocker), barium chloride (inwardly rectifying Kir channel blocker), glibenclamide (nonspecific ATP-sensitive K+ channel blocker), atropine (muscarinic receptor blocker), or propranolol (β-adrenergic receptor blocker), the relaxation stimulated by sinensetin was significantly reduced. Sinensetin was also active in reducing Ca2+ release from the sarcoplasmic reticulum (via IP3R) and in blocking calcium channels (VOCC). The present study demonstrates the vasorelaxant effect of sinensetin, which involves the NO/sGC/cGMP and indomethacin pathways, calcium and potassium channels, and muscarinic and beta-adrenergic receptors.

Matched MeSH terms: Nitric Oxide/metabolism*

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