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Fulltext In Vivo Antioxidant and Hypolipidemic Effects of Fermented Mung Bean on Hypercholesterolemic Mice

Yeap SK, Beh BK, Ho WY, Mohd Yusof H, Mohamad NE, Ali NM, et al.

Evid Based Complement Alternat Med, 2015;2015:508029.
PMID: 26074993 DOI: 10.1155/2015/508029

Legumes have previously been reported with hypolipidemic effect caused by the presence of flavonoid. This study was carried out to evaluate the antioxidant and hypolipidemic effects of fermented mung bean on hypercholesterolemic mice. Blood from all mice was collected and subjected to serum lipid and liver profiles biochemical analysis and quantitative RT-PCR for atherosclerosis related gene expressions. Besides, livers were collected for antioxidant assays and histopathology evaluation. Fermented mung bean was found to reduce the level of serum lipid and liver enzyme profiles of hypercholesterolemic mice. Furthermore, liver antioxidant and nitric oxide levels were also significantly restored by fermented mung bean in a dosage dependent manner. The gene expression study indicated that Apoe and Bcl2a1a were upregulated while Npy and Vwf expressions were downregulated after the treatment. The effects of fermented mung bean were greater than nonfermented mung bean. These results indicated that fermented mung bean possessed antioxidants that lead to its hypolipidemic effect on hypercholesterolemic mice.

Matched MeSH terms: Nitric Oxide
Fulltext Role of endothelium-dependent hyperpolarisation and prostacyclin in diabetes

Mokhtar SS, Rasool AH

Malays J Med Sci, 2015 Mar-Apr;22(2):8-17.
PMID: 26023290 MyJurnal

The endothelium plays a crucial role in maintaining vascular homeostasis by producing several vasodilating factors, including nitric oxide (NO), prostacyclin (PGI2), and endothelium-dependent hyperpolarisation (EDH); however, the balance between endothelial relaxing and contracting factors is disrupted in disease states such as diabetes mellitus and hypertension. Most reported studies of endothelial dysfunction in diabetes focused on the actions of NO; however, there is accumulating evidence demonstrating that in addition to NO, PGI2 and EDH are likely to contribute to the vasodilatation of blood vessels. EDH plays an important role as a regulator of vascular tone and reactivity in resistance and conduit arteries of animal models and humans. PGI2 only plays a minimal role in endothelium-dependent vasodilatation but may serve as an important compensatory mechanism in conditions in which NO and EDH activities are decreased. Further studies are needed to determine the exact roles of EDH and PGI2 in the development of endothelial dysfunction and clinical vasculopathy in humans with type 1 and type 2 diabetes.

Matched MeSH terms: Nitric Oxide
Fulltext Malaysian endophytic fungal extracts-induced anti-inflammation in Lipopolysaccharide-activated BV-2 microglia is associated with attenuation of NO production and, IL-6 and TNF-α expression

Harun A, Vidyadaran S, Lim SM, Cole AL, Ramasamy K

BMC Complement Altern Med, 2015;15:166.
PMID: 26047814 DOI: 10.1186/s12906-015-0685-5

Excessive production of inflammatory mediators such as nitric oxide (NO) and proinflammatory cytokines like tumour necrosis factor-alpha (TNF-α) from activated microglia contributes to uncontrolled inflammation in neurodegenerative diseases. This study investigated the protective role of five endophytic extracts (HAB16R12, HAB16R13, HAB16R14, HAB16R18 and HAB8R24) against LPS-induced inflammatory events in vitro. These endophytic extracts were previously found to exhibit potent neuroprotective effect against LPS-challenged microglial cells.

Matched MeSH terms: Nitric Oxide/metabolism; Nitric Oxide Synthase Type II/metabolism
Fulltext Glucose uptake during contraction in isolated skeletal muscles from neuronal nitric oxide synthase μ knockout mice

Hong YH, Frugier T, Zhang X, Murphy RM, Lynch GS, Betik AC, et al.

J Appl Physiol (1985), 2015 May 1;118(9):1113-21.
PMID: 25749441 DOI: 10.1152/japplphysiol.00056.2015

Inhibition of nitric oxide synthase (NOS) significantly attenuates the increase in skeletal muscle glucose uptake during contraction/exercise, and a greater attenuation is observed in individuals with Type 2 diabetes compared with healthy individuals. Therefore, NO appears to play an important role in mediating muscle glucose uptake during contraction. In this study, we investigated the involvement of neuronal NOSμ (nNOSμ), the main NOS isoform activated during contraction, on skeletal muscle glucose uptake during ex vivo contraction. Extensor digitorum longus muscles were isolated from nNOSμ(-/-) and nNOSμ(+/+) mice. Muscles were contracted ex vivo in a temperature-controlled (30°C) organ bath with or without the presence of the NOS inhibitor N(G)-monomethyl-l-arginine (L-NMMA) and the NOS substrate L-arginine. Glucose uptake was determined by radioactive tracers. Skeletal muscle glucose uptake increased approximately fourfold during contraction in muscles from both nNOSμ(-/-) and nNOSμ(+/+) mice. L-NMMA significantly attenuated the increase in muscle glucose uptake during contraction in both genotypes. This attenuation was reversed by L-arginine, suggesting that L-NMMA attenuated the increase in muscle glucose uptake during contraction by inhibiting NOS and not via a nonspecific effect of the inhibitor. Low levels of NOS activity (~4%) were detected in muscles from nNOSμ(-/-) mice, and there was no evidence of compensation from other NOS isoform or AMP-activated protein kinase which is also involved in mediating muscle glucose uptake during contraction. These results indicate that NO regulates skeletal muscle glucose uptake during ex vivo contraction independently of nNOSμ.

Matched MeSH terms: Nitric Oxide/metabolism; Nitric Oxide Synthase Type I/metabolism*
Fulltext Virgin coconut oil prevents blood pressure elevation and improves endothelial functions in rats fed with repeatedly heated palm oil

Nurul-Iman BS, Kamisah Y, Jaarin K, Qodriyah HM

Evid Based Complement Alternat Med, 2013;2013:629329.
PMID: 23861707 DOI: 10.1155/2013/629329

This study was performed to explore the effects of virgin coconut oil (VCO) in male rats that were fed with repeatedly heated palm oil on blood pressure, plasma nitric oxide level, and vascular reactivity. Thirty-two male Sprague-Dawley rats were divided into four groups: (i) control (basal diet), (ii) VCO (1.42 mL/kg, oral), (iii) five-times-heated palm oil (15%) (5HPO), and (iv) five-times-heated palm oil (15%) and VCO (1.42 mL/kg, oral) (5HPO + VCO). Blood pressure was significantly increased in the group that was given the 5HPO diet compared to the control group. Blood pressure in the 5HPO + VCO group was significantly lower than the 5HPO group. Plasma nitric oxide (NO) level in the 5HPO group was significantly lower compared to the control group, whereas in the 5HPO + VCO group, the plasma NO level was significantly higher compared to the 5HPO group. Aortic rings from the 5HPO group exhibited attenuated relaxation in response to acetylcholine and sodium nitroprusside as well as increased vasoconstriction to phenylephrine compared to the control group. Aortic rings from the 5HPO + VCO group showed only attenuated vasoconstriction to phenylephrine compared to the 5HPO group. In conclusion, VCO prevents blood pressure elevation and improves endothelial functions in rats fed with repeatedly heated palm oil.

Matched MeSH terms: Nitric Oxide
Fulltext α -Mangostin from Cratoxylum arborescens (Vahl) Blume Demonstrates Anti-Ulcerogenic Property: A Mechanistic Study

Sidahmed HM, Abdelwahab SI, Mohan S, Abdulla MA, Mohamed Elhassan Taha M, Hashim NM, et al.

Evid Based Complement Alternat Med, 2013;2013:450840.
PMID: 23634169 DOI: 10.1155/2013/450840

Cratoxylum arborescens (Vahl) Blume is an Asian herbal medicine with versatile ethnobiological properties including treatment of gastric ulcer. This study evaluated the antiulcerogenic mechanism(s) of α -mangostin (AM) in a rat model of ulcer. AM is a prenylated xanthone derived through biologically guided fractionation of C. arborescens. Rats were orally pretreated with AM and subsequently exposed to acute gastric lesions induced by ethanol. Following treatment, ulcer index, gastric juice acidity, mucus content, histological and immunohistochemical analyses, glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO), and nonprotein sulfhydryl groups (NP-SH) were evaluated. The anti-Helicobacter pylori, cyclooxygenase-2 (COX-2) inhibitory effect, and antioxidant activity of AM were also investigated in vitro. AM (10 and 30 mg/kg) inhibited significantly (P < 0.05) ethanol-induced gastric lesions by 66.04% and 74.39 %, respectively. The compound induces the expression of Hsp70, restores GSH levels, decreases lipid peroxidation, and inhibits COX-2 activity. The minimum inhibitory concentration (MIC) of AM showed an effective in vitro anti-H. pylori activity. The efficacy of the AM was accomplished safely without presenting any toxicological parameters. The results of the present study indicate that the antioxidant properties and the potent anti-H. pylori, in addition to activation of Hsp70 protein, may contribute to the gastroprotective activity of α -mangostin.

Matched MeSH terms: Nitric Oxide
The bioflavonoid quercetin synergises with PPAR-γ agonist pioglitazone in reducing angiotensin-II contractile effect in fructose-streptozotocin induced diabetic rats

Kunasegaran T, Mustafa MR, Murugan DD, Achike FI

Biochimie, 2016 Jun;125:131-9.
PMID: 27012965 DOI: 10.1016/j.biochi.2016.03.008

This study investigated the effects of combined minimal concentrations of quercetin and pioglitazone on angiotensin II-induced contraction of the aorta from fructose-streptozotocin (F-STZ)-induced type 2 diabetic rats and the possible role of superoxide anions (O2(-)) and nitric oxide (NO) in their potential therapeutic interaction. Contractile responses to Ang II of aortic rings from Sprague-Dawley (SD) and F-STZ rats were tested following pre-incubation of the tissues in the vehicle (DMSO; 0.05%), quercetin (Q, 0.1 μM), pioglitazone (P, 0.1 μM) or their combination (P + Q; 0.1 μM each). The amount of superoxide anion was evaluated by lucigenin-enhanced chemiluminescence and dihydroethidium fluorescence, and NO by assay of total nitrate/nitrite, and 4-Amino-5-Methylamino-2',7'-Difluorofluorescein (DAF-FM) diacetate. The synergistic reduction of Ang II-induced contraction of diabetic but not normal aorta with minimally effective concentrations of P + Q occurs through inhibiting O2(-) and increasing NO bioavailability. This finding opens the possibility of maximal vascular protective/antidiabetic effects with low dose pioglitazone combined with quercetin, thus minimizing the risk of adverse effects.

Matched MeSH terms: Nitric Oxide
Reduced nitric oxide-mediated relaxation and endothelial nitric oxide synthase expression in the tail arteries of streptozotocin-induced diabetic rats

Mokhtar SS, Vanhoutte PM, Leung SW, Suppian R, Yusof MI, Rasool AH

Eur J Pharmacol, 2016 Feb 15;773:78-84.
PMID: 26825543 DOI: 10.1016/j.ejphar.2016.01.013

Diabetes is associated with endothelial dysfunction, which is characterized by impaired endothelium-dependent relaxations. The present study aimed to examine the role of nitric oxide (NO), prostacyclin and endothelium-dependent hyperpolarization (EDH), in the relaxation of ventral tail arteries of rats under diabetic conditions. Relaxations of tail arteries of control and diabetic rats were studied in wire myograph. Western blotting and immunostaining were used to determine the presence of proteins. Acetylcholine-induced relaxations were significantly smaller in arteries of diabetic compared to control rats (Rmax; 70.81 ± 2.48% versus 85.05 ± 3.15%). Incubation with the combination of non-selective cyclooxygenase (COX) inhibitor, indomethacin and potassium channel blockers, TRAM 34 and UCL 1684, demonstrated that NO-mediated relaxation was attenuated significantly in diabetic compared to control rats (Rmax; 48.47 ± 5.84% versus 68.39 ± 6.34%). EDH-type (in the presence of indomethacin and NO synthase inhibitor, LNAME) and prostacyclin-mediated (in the presence of LNAME plus TRAM 34 and UCL 1684) relaxations were not significantly reduced in arteries of diabetic compared to control rats [Rmax: (EDH; 17.81 ± 6.74% versus 34.16 ± 4.59%) (prostacyclin; 15.85 ± 3.27% versus 17.23 ± 3.75%)]. Endothelium-independent relaxations to sodium nitroprusside, salbutamol and prostacyclin were comparable in the two types of preparations. Western blotting and immunostaining indicated that diabetes diminished the expression of endothelial NO synthase (eNOS), while increasing those of COX-1 and COX-2. Thus, since acetylcholine-induced NO-mediated relaxation was impaired in diabetes because of reduced eNOS protein expression, pharmacological intervention improving NO bioavailability could be useful in the management of diabetic endothelial dysfunction.

Matched MeSH terms: Nitric Oxide/metabolism*; Nitric Oxide Synthase Type III/metabolism*
Fulltext The effect and action mechanism of resveratrol on the vascular endothelial cell by high glucose treatment

Liu X, Tian J, Bai Q, Ashraf MA, Sarfraz M, Zhao B

Saudi J Biol Sci, 2016 Jan;23(1):S16-21.
PMID: 26858561 DOI: 10.1016/j.sjbs.2015.06.021

To investigate the effect and action mechanism of resveratrol on the vascular endothelial cell by high glucose treatment. Primarily cultured human umbilical vein endothelial cells (HUVECs) were pretreated by resveratrol (0.2 μmol/L) and holding for 6 h, and then cultured in Dulbecco Modified Eagle Medium (DMEM) within 0.45 mmol/L of palmimte acid and 32.8 mmol/L of glucose, which is holding for 12 h. The cells were collected to analyze the expression of E-selected element. Supernatant of cultured cells, induced by 100 nmol/L insulin for 30 min, was used to analyze the nitric oxide content. Compared with normal control cells, the secretion of nitric oxide is stimulated by insulin decrease, however, the expression of E-selected element increased in HUVEC. Resveratrol treatment increased the secretion of nitric oxide stimulated by insulin and decreased the expression of E-selected element and partly counteracts the impairment of high glucose and palmitate acid on the function of endothelial cells. Resveratrol can improve and protect the function of high glucose and fatty acid cultured endothelial cell, and therefore may be a promising medicine in the prevention or therapy of diabetic macrovascular diseases.

Matched MeSH terms: Nitric Oxide
Fulltext Angiotensin 1-7 Protects against Angiotensin II-Induced Endoplasmic Reticulum Stress and Endothelial Dysfunction via Mas Receptor

Murugan D, Lau YS, Lau CW, Lau WC, Mustafa MR, Huang Y

PLoS One, 2015;10(12):e0145413.
PMID: 26709511 DOI: 10.1371/journal.pone.0145413

Angiotensin 1-7 (Ang 1-7) counter-regulates the cardiovascular actions of angiotensin II (Ang II). The present study investigated the protective effect of Ang 1-7 against Ang II-induced endoplasmic reticulum (ER) stress and endothelial dysfunction. Ex vivo treatment with Ang II (0.5 μM, 24 hours) impaired endothelium-dependent relaxation in mouse aortas; this harmful effect of Ang II was reversed by co-treatment with ER stress inhibitors, l4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) as well as Ang 1-7. The Mas receptor antagonist, A779, antagonized the effect of Ang 1-7. The elevated mRNA expression of CHOP, Grp78 and ATF4 or protein expression of p-eIF2α and ATF6 (ER stress markers) in Ang II-treated human umbilical vein endothelial cells (HUVECs) and mouse aortas were blunted by co-treatment with Ang 1-7 and the latter effect was reversed by A779. Furthermore, Ang II-induced reduction in both eNOS phosphorylation and NO production was inhibited by Ang 1-7. In addition, Ang 1-7 decreased the levels of ER stress markers and augmented NO production in HUVECs treated with ER stress inducer, tunicamycin. The present study provides new evidence for functional antagonism between the two arms of the renin-angiotensin system in endothelial cells by demonstrating that Ang 1-7 ameliorates Ang II-stimulated ER stress to raise NO bioavailability, and subsequently preserves endothelial function.

Matched MeSH terms: Nitric Oxide/biosynthesis; Nitric Oxide Synthase Type III/metabolism
Fulltext Endothelium-Dependent Relaxation Effect of Apocynum venetum Leaf Extract via Src/PI3K/Akt Signalling Pathway

Lau YS, Ling WC, Murugan D, Kwan CY, Mustafa MR

Nutrients, 2015 Jul;7(7):5239-53.
PMID: 26133970 DOI: 10.3390/nu7075220

Botanical herbs are consumed globally not only as an essential diet but also as medicines or as functional/recreational food supplements. The extract of the Apocynum venetum leaves (AVLE), also known as Luobuma, exerts its antihypertensive effect via dilating the blood vessels in an endothelium- and concentration-dependent manner with optimal effect seen at as low as 10 µg/mL. A commercial Luoboma "antihypertensive tea" is available commercially in the western province of China. The present study seeks to investigate the underlying cellular mechanisms of the nitric oxide (NO)-releasing property of AVLE in rat aortas and human umbilical vein endothelial cells (HUVECs). Endothelium-dependent relaxation induced by AVLE was assessed in organ chambers in the presence or absence of polyethyleneglycol catalase (PP2, 20 µM; inhibitor of Src kinase), wortmannin (30 nM) and LY294002 (20 µM; PI3 (phosphatidylinositol3)-Kinase inhibitor), N(G)-nitro-L-arginine (L-NAME, 100 µM; endothelial NO synthase inhibitor (eNOS)) and ODQ (1 µM; soluble guanylyl cyclase inhibitor). Total nitrite and nitrate (NOx) level and protein expression of p-Akt and p-eNOS were measured. AVLE-induced endothelium-dependent relaxation was reduced by PP2, wortmannin and LY294002 and abolished by L-NAME and ODQ. AVLE significantly increased total NOx level in rat aortas and in HUVECs compared to control. It also instigated phosphorylation of Akt and eNOS in cultured HUVECs in a concentration-dependent manner and this was markedly suppressed by PP2, wortmannin and LY294002. AVLE also inhibited superoxide generated from both NADPH oxidase and xanthine/xanthine oxidase system. Taken together, AVLE causes endothelium-dependent NO mediated relaxations of rat aortas through Src/PI3K/Akt dependent NO signalling pathway and possesses superoxide scavenging activity.

Matched MeSH terms: Nitric Oxide/metabolism; Nitric Oxide Synthase Type III/metabolism
Renoprotective and antihypertensive mechanism of action of Clinacanthus nutans bioactive polysaccharides by suppression of reactive oxygen species/ nuclear factor/ matrix metalloproteinase (ROS/NF-ΚB/MMP-9) and upregulation of endothelial nitric oxide synthase/nitric oxide (eNOS/NO) pathways

Chia TY, Gan CY, Cheah PS, Murugaiyah V, Fatima T, Haji EM, et al.

J Mol Histol, 2025 Jun 28;56(4):209.
PMID: 40580398 DOI: 10.1007/s10735-025-10481-9

Clinacanthus nutans (C. nutans) Lindau, is classified as a top herb which are investigated for different biological activities like antioxidant, anti-inflammatory and vasodilatory effects. Hitherto, no dedicated study has been investigated on the role of C. nutans in L-NAME [N(ω)-nitro-L-arginine methyl ester] in-vivo rat model to explore its antihypertensive and renoprotective mechanism by modulating the ROS/NF-κB/MMP-9 pathways both globally in the plasma as well as locally in the kidney by using in-vitro expression study. Present study hypothesized that bioactive polysaccharides leaves of the alcoholic extract of C. nutans (CNBP) could improve the functions of the kidney by its antioxidant, anti-inflammatory, antihypertensive actions by suppression of ROS/NF-κB/MMP-9 and upregulation of eNOS/NO pathways in the plasma and kidney. Thirty male Sprague-Dawley (SD) rats (n = 6) were randomised into five groups namely: Control (C), L-NAME (L) administered in drinking water, L-NAME + 500 mg/kg of C. nutans bioactive polysaccharides (CNBP) (LCN500), L-NAME + 1000 mg/kg of CNBP (LCN1000) and L-NAME + 2000 mg/kg of CNBP (LCN2000) respectively. All treatments were continued for the period of 14 days and physiological data like water intake, urine output, body weight was collected on days 0, 7 and 14. Acute in-vivo study was performed after cannulation of the femoral and carotid arteries where renal cortical blood perfusion (RCBP) was measured along with pulse wave velocity (PWV). Plasma and renal malondialdehyde (MDA), tumour necrosis factor-α(TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9), intercellular adhesion molecule-1 (ICAM-1), nitric oxide synthase-1 (NOS1) and superoxide dismutase (SOD) were measured. Histopathological studies were done on the kidney tissue at the termination of experiment. Administrations of L-NAME to L group for 14 days resulted in significantly reduced levels of SOD and NOS while significantly elevated levels of MDA, TNF-α, IL-6 and MMP-9 in both plasma and kidney tissue when compared to control group (C). Conversely, treatment of 500, 1000 and 2000 mg/kg of CNBP has significantly reversed the values when same was compared to normal control ( C) group. Administration of L-NAME to L group for 14 days caused significantly increased systolic blood pressure (SBP) and arterial stiffness by increasing the pulse wave velocity (PWV) along with reduced creatinine clearance and renal cortical blood perfusion (RCBP) when compared to C group. Nevertheless, treatment of 500, 1000 and 2000 mg/kg CNBP has significantly reduced the SBP and PWV and raised the creatine clearance and RCBP functions when compared to (L) group. This study devised with the novel findings of 14 days CNBP treatment has suppressed ROS/TNF-α/MMP-9 pathway in the plasma and kidney which is pathological pathway for the kidney injury and hypertension while upregulated eNOS/NO pathways in plasma and kidney which is renoprotective and antihypertensive pathway in L-NAME rat model of hypertension and kidney injury.

Matched MeSH terms: Nitric Oxide/metabolism; Nitric Oxide Synthase Type III/metabolism
Fulltext Dengue Virus-Induced Reactive Oxygen Species Production in Rat Microglial Cells

Suwanprinya L, Morales NP, Sanvarinda P, Dieng H, Okabayashi T, Morales Vargas RE

Jpn J Infect Dis, 2017 07 24;70(4):383-387.
PMID: 28003593 DOI: 10.7883/yoken.JJID.2016.236

Encephalitis has been described worldwide as a severe complication in patients infected by dengue virus. Reactive oxygen species (ROS) production is a key mechanism involved in the neuronal damage caused by viral encephalitis. In the present study, the capability of dengue virus serotypes 2 (DENV2) and DENV4 to induce ROS production was investigated in a rat microglial cell line, HAPI cells. The cells were infected with DENV2 and DENV4 at a multiplicity of infection of 0.1 for a 2-h adsorption period. Japanese encephalitis virus (JEV) was used as the reference. DENV2- and DENV4-induced microglial activation and significantly increased ROS production corresponded to decreased cell viability. The activity of DENV4 was significantly higher than the activities of DENV2 and JEV at 48 and 72 h post infection. DENV4 partly induced ROS production via an iron-induced Fenton reaction, as demonstrated by the treatment with an iron chelator, deferiprone. Despite the induction of increased inducible nitric oxide synthase expression and nitric oxide (NO) production by JEV, DENV2, and DENV4 did not induce NO production, suggesting the activation of different pathways in response to infections by different viruses. In conclusion, DENV2 and DENV4 have the capability to induce ROS production and activate microglia, which have been reported as the key components of neuronal damage.

Matched MeSH terms: Nitric Oxide/metabolism
Mechanisms of Action of Uncaria rhynchophylla Ethanolic Extract for Its Vasodilatory Effects

Loh YC, Ch'ng YS, Tan CS, Ahmad M, Asmawi MZ, Yam MF

J Med Food, 2017 Sep;20(9):895-911.
PMID: 28771084 DOI: 10.1089/jmf.2016.3804

Uncaria rhynchophylla is one of the major components included in Traditional Chinese Medicine prescriptions for hypertensive treatment. Previous studies have suggested that U. rhynchophylla might contain vasodilation-mediating active compounds, especially indole alkaloids. Hence, this study was carried out to determine the vasodilatory effects of U. rhynchophylla, which was extracted by different solvents. The most effective extract was then further studied for its signaling mechanism pathways. The authenticity of U. rhynchophylla was assured by using modernized tri-step Fourier transform infrared (FTIR), including conventional 1D FTIR, second derivative scanning combined with 2D-correlated IR spectroscopy. Results obtained proved that the fingerprint of U. rhynchophylla used was identical to the atlas. Isolated aortic rings from male Sprague-Dawley rats were preconstricted with phenylephrine (PE) followed by cumulative addition of U. rhynchophylla extracts. The signaling mechanism pathways were studied by incubation with different receptor antagonists before the PE precontraction. In conclusion, the 95% ethanolic U. rhynchophylla extract (GT100) was found to be most effective with an EC50 value of 0.028 ± 0.002 mg/mL and an Rmax value of 101.30% ± 2.82%. The signaling mechanism pathways employed for exerting its vasodilatory effects included nitric oxide/soluble guanylyl cylcase/cyclic guanosine monophosphate (NO/sGC/cGMP) and PGI2 (endothelium-derived relaxing factors), G protein-coupled M3- and β2 receptors, regulation of membrane potential through voltage-operated calcium channel, intracellular Ca2+ released from inositol triphosphate receptor (IP3R), and all potassium channels except the Kca channel.

Matched MeSH terms: Nitric Oxide/metabolism
Mechanism of vasorelaxation induced by 3'-hydroxy-5,6,7,4'-tetramethoxyflavone in the rats aortic ring assay

Tan CS, Yam MF

Naunyn Schmiedebergs Arch Pharmacol, 2018 06;391(6):561-569.
PMID: 29552696 DOI: 10.1007/s00210-018-1481-9

Previous studies have demonstrated that 3'-hydroxy-5,6,7,4'-tetramethoxyflavone (TMF) content in Orthosiphon stamineus fractions correlate with its vasorelaxation activity. Even with the availability of previous studies, there is still very little information on the vasorelaxation effect of TMF, and few scientific studies have been carried out. Therefore, the present study was designed to investigate the vasorelaxation activity and mechanism of action of the TMF. The vasorelaxation activity and the underlying mechanisms of TMF were evaluated on thoracic aortic rings isolated from Sprague Dawley rats. TMF caused the relaxation of aortic rings with endothelium pre-contracted with phenylephrine. However, the vasorelaxant effect of TMF was significantly decreased in PE-primed endothelium-denuded and potassium chloride-primed endothelium-intact aortic rings. In the presence of Nω-nitro-L-arginine methyl ester, methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, indomethacin, tetraethylammonium, 4-aminopyridine, barium chloride, atropine and propranolol, the relaxation stimulated by TMF was significantly reduced. TMF was also found to reduce Ca2+ release from sarcoplasmic reticulum (via IP3R) and block calcium channels (VOCC). The present study demonstrates the vasorelaxant effect of TMF involves NO/sGC/cGMP and prostacyclin pathways, calcium and potassium channels and muscarinic and beta-adrenergic receptors.

Matched MeSH terms: Nitric Oxide/physiology
Fulltext Betulinic acid‑induced expression of nicotinamide adenine dinucleotide phosphate‑diaphorase in the immune organs of mice: A possible role of nitric oxide in immunomodulation

Pang KL, Vijayaraghavan K, Al Sayed B, Seyed MA

Mol Med Rep, 2018 Feb;17(2):3035-3041.
PMID: 29257292 DOI: 10.3892/mmr.2017.8262

The aim of the present study was to investigate the effects of betulinic acid (BetA) on the expression and distribution pattern of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH‑d), an indirect indicator of nitric oxide (NO) synthase in the thymus and spleen of mice. Mice were randomly assigned to four main groups (n=48 per group): Experimental group (BetA), positive control group (goniothalamin), vehicle control group (dimethyl sulfoxide) and control group (without vehicle). Each group was further divided into three equal subgroups according to the treatment length (4, 8 and 12 days). BetA treatment induced the expression of NADPH‑d activity in the thymus and spleen without any significant changes in the morphology of the organs. Furthermore, the expression pattern of NADPH‑d in BetA‑treated animals was significantly increased compared with that in the control animals. NADPH‑d expression in the thymus and spleen suggests that NO signaling may be a potential mechanism underlying the BetA‑induced immunomodulation in these organs. These findings are of direct clinical relevance and may contribute to the further development of BetA as a therapeutic drug.

Matched MeSH terms: Nitric Oxide/immunology*
Fulltext Suppression of Proinflammatory Cytokines and Mediators in LPS-Induced RAW 264.7 Macrophages by Stem Extract of Alternanthera sessilis via the Inhibition of the NF-κB Pathway

Muniandy K, Gothai S, Badran KMH, Suresh Kumar S, Esa NM, Arulselvan P

J Immunol Res, 2018;2018:3430684.
PMID: 30155492 DOI: 10.1155/2018/3430684

Alternanthera sessilis, an edible succulent herb, has been widely used as herbal drug in many regions around the globe. Inflammation is a natural process of the innate immune system, accompanied with the increase in the level of proinflammatory mediators, for example, nitric oxide (NO) and prostaglandin (PGE2); cytokines such as interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor alpha (TNFα); and enzymes including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) via the activation and nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) subunit p65 due to the phosphorylation of inhibitory protein, IκBα. Inflammation over a short period of time is essential for its therapeutic effect. However, prolonged inflammation can be detrimental as it is related to many chronic diseases such as delayed wound healing, cardiovascular disease, arthritis, and autoimmune disorders. Therefore, ways to curb chronic inflammation have been extensively investigated. In line with that, in this present study, we attempted to study the suppression activity of the proinflammatory cytokines and mediators as a characteristic of anti-inflammatory action, by using stem extract of A. sessilis in the lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophage cell line. The results showed that the extract has significantly inhibited the production of the proinflammatory mediators including NO and PGE2; cytokines comprising IL-6, IL-1β, and TNFα; and enzymes covering the iNOS and COX-2 by preventing the IκBα from being degraded, to inhibit the nuclear translocation of NF-κB subunit p65 in order to hinder the inflammatory pathway activation. These results indicated that the stem extract of A. sessilis could be an effective candidate for ameliorating inflammatory-associated complications.

Matched MeSH terms: Nitric Oxide/metabolism
Fulltext Antinociceptive activity of petroleum ether fraction obtained from methanolic extract of Clinacanthus nutans leaves involves the activation of opioid receptors and NO-mediated/cGMP-independent pathway

Zakaria ZA, Abdul Rahim MH, Mohd Sani MH, Omar MH, Ching SM, Abdul Kadir A, et al.

BMC Complement Altern Med, 2019 Apr 02;19(1):79.
PMID: 30940120 DOI: 10.1186/s12906-019-2486-8

BACKGROUND: Methanol extract (MECN) of Clinacanthus nutans Lindau leaves (family Acanthaceae) demonstrated peripherally and centrally mediated antinociceptive activity via the modulation of opioid/NO-mediated, but cGMP-independent pathway. In the present study, MECN was sequentially partitioned to obtain petroleum ether extract of C. nutans (PECN), which was subjected to antinociceptive study with aims of establishing its antinociceptive potential and determining the role of opioid receptors and L-arginine/nitric oxide/cyclic-guanosine monophosphate (L-arg/NO/cGMP) pathway in the observed antinociceptive activity.
METHODS: The antinociceptive potential of orally administered PECN (100, 250, 500 mg/kg) was studied using the abdominal constriction-, hot plate- and formalin-induced paw licking-test in mice (n = 6). The effect of PECN on locomotor activity was also evaluated using the rota rod assay. The role of opioid receptors was determined by pre-challenging 500 mg/kg PECN (p.o.) with antagonist of opioid receptor subtypes, namely β-funaltrexamine (β-FNA; 10 mg/kg; a μ-opioid antagonist), naltrindole (NALT; 1 mg/kg; a δ-opioid antagonist) or nor-binaltorphimine (nor-BNI; 1 mg/kg; a κ-opioid antagonist) followed by subjection to the abdominal constriction test. In addition, the role of L-arg/NO/cGMP pathway was determined by prechallenging 500 mg/kg PECN (p.o.) with L-arg (20 mg/kg; a NO precursor), 1H-[1, 2, 4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ; 2 mg/kg; a specific soluble guanylyl cyclase inhibitor), or the combinations thereof (L-arg + ODQ) for 5 mins before subjection to the abdominal constriction test. PECN was also subjected to phytoconstituents analyses.
RESULTS: PECN significantly (p 0.05) affect the locomotor activity of treated mice. The antinociceptive activity of PECN was significantly (p 0.05) affected by ODQ. HPLC analysis revealed the presence of at least cinnamic acid in PECN.
CONCLUSION: PECN exerted antinocicpetive activity at peripheral and central levels possibly via the activation of non-selective opioid receptors and modulation of the NO-mediated/cGMP-independent pathway partly via the synergistic action of phenolic compounds.

Matched MeSH terms: Nitric Oxide/metabolism*
Therapeutic Implications of Nitrite in Hypertension

Ling WC, Mustafa MR, Murugan DD

J Cardiovasc Pharmacol, 2020 02;75(2):123-134.
PMID: 31651673 DOI: 10.1097/FJC.0000000000000771

Nitrite, an anion produced from the oxidative breakdown of nitric oxide (NO), has traditionally been viewed as an inert molecule. However, this dogma has been challenged with the findings that nitrite can be readily reduced to NO under pathological conditions, hence representing a physiologically relevant storage reservoir of NO either in the blood or tissues. Nitrite administration has been demonstrated to improve myocardial function in subjects with heart failure and to lower the blood pressure in hypertensive subjects. Thus, extensive amount of work has since been carried out to investigate the therapeutic potential of nitrite in treating cardiovascular diseases, especially hypertension. Studies done on several animal models of hypertension have demonstrated the efficacy of nitrite in preventing and ameliorating the pathological changes associated with the disease. This brief review of the current findings aims to re-evaluate the use of nitrite for the treatment of hypertension and in particular to highlight its role in improving endothelial function.

Matched MeSH terms: Nitric Oxide/metabolism*
The endothelial nitric oxide synthase gene G894T, glutathione S-transferase (GSTM1 and GSTT1) polymorphisms as a risk factor in the patient with nephrolithiasis

Mehdi WA, Mehde AA, Yusof F, Raus RA, Resen AK, Ghazali H

Int J Biol Macromol, 2019 Nov 01;140:719-726.
PMID: 31445152 DOI: 10.1016/j.ijbiomac.2019.08.184

BACKGROUND: The genetic features indicate a crucial role in nephrolithiasis. The present study was aimed to investigate the role of Glutathione-S-transferase Mu (GSTM1), Glutathione-S- transferase Theta (GSTT1) and endothelial nitric oxide synthase (eNOs) gene polymorphism in nephrolithiasis.
METHODS: We involved a case-control study in which 480 individuals were divided into 240 healthy control and 240 patients with nephrolithiasis. For each patient and control, we measured biochemical criteria, levels of glutathione S-transferase, eNOs, GSTM1, GSTT1genes and eNOS genes polymorphism by PCR-RFLP.
RESULTS: GSTM1 and GSTT1 null genotypes are not a risk features for nephrolithiasis. The eNOS frequency GG, GT, and TT genotypes by using Ban II enzyme as restriction enzyme were found to be (48.33, 36.67, and 15.00) %. The eNOS frequency TT, GT, and GG genotypes by using the Ban II enzyme as restriction enzyme were found to be 15.84, 25.83, and 58.33%, respectively. The result showed an increase in serum eNOs levels were in the patient's group comparing to control.
CONCLUSIONS: This work is the first in the literature to study the relation between eNOs genes polymorphisms and nephrolithiasis. The results conclude that TT genotypes in the eNOs genes are associated with an increase the oxidative stress in patients.

Matched MeSH terms: Nitric Oxide Synthase Type III/genetics*

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