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Tiger's Milk Medicinal Mushroom, Lignosus rhinocerotis (Agaricomycetes) Sclerotium Inhibits Nitric Oxide Production in LPS-Stimulated BV2 Microglia

Seow SL, Naidu M, Sabaratnam V, Vidyadaran S, Wong KH

Int J Med Mushrooms, 2017;19(5):405-418.
PMID: 28845770 DOI: 10.1615/IntJMedMushrooms.v19.i5.30

In Malaysia and China, the sclerotium of Lignosus rhinocerotis is used by local communities and traditional medicine practitioners as a general tonic and remedy to treat a variety of ailments, including inflammation-associated disorders. In this study, 10 samples from different preparations of L. rhinocerotis sclerotium, including a hot aqueous extract (HAE), an ethanol extract (EE), fractions from the HAE and EE, and crude polysaccharides, were tested for their in vitro cytotoxic and nitric oxide (NO) inhibitory activities in lipopolysaccharide (LPS)--stimulated BV2 microglia. Of the 10 samples tested, HAE was the least cytotoxic toward BV2 microglia, with a half-maximal inhibitory concentration of 176.23 ± 2.64 mg/mL at 24 hours of incubation and 20.01 ± 1.69 mg/ mL at 48 hours of incubation. The inhibition of NO production was explored by pretreatment of BV2 microglia with samples at 2 incubation time points (4 and 24 hours) before the stimulation by LPS for 24 hours. After 24 hours of pretreatment, 8 of the 10 samples inhibited NO production by 50% or more, and cytotoxic effects were not observed. Among the 8 active samples, 500 µg/mL of HAE, 250 µg/mL of an n-butanol fraction of the HAE, and 250 µg/mL of an ethyl acetate fraction of HAE showed maximum inhibition of NO production by 88.95%, 86.50%, and 85.93%, respectively. These results suggest that the L. rhinocerotis sclerotium may contain secondary metabolites that have the potential to inhibit NO production.

Matched MeSH terms: Nitric Oxide/metabolism*
Fulltext Metabolite Profiling of the Microalgal Diatom Chaetoceros Calcitrans and Correlation with Antioxidant and Nitric Oxide Inhibitory Activities via ¹H NMR-Based Metabolomics

Azizan A, Ahamad Bustamam MS, Maulidiani M, Shaari K, Ismail IS, Nagao N, et al.

Mar Drugs, 2018 May 07;16(5).
PMID: 29735927 DOI: 10.3390/md16050154

Microalgae are promising candidate resources from marine ecology for health-improving effects. Metabolite profiling of the microalgal diatom, Chaetoceros calcitrans was conducted by using robust metabolomics tools, namely ¹H nuclear magnetic resonance (NMR) spectroscopy coupled with multivariate data analysis (MVDA). The unsupervised data analysis, using principal component analysis (PCA), resolved the five types of extracts made by solvents ranging from polar to non-polar into five different clusters. Collectively, with various extraction solvents, 11 amino acids, cholesterol, 6 fatty acids, 2 sugars, 1 osmolyte, 6 carotenoids and 2 chlorophyll pigments were identified. The fatty acids and both carotenoid pigments as well as chlorophyll, were observed in the extracts made from medium polar (acetone, chloroform) and non-polar (hexane) solvents. It is suggested that the compounds were the characteristic markers that influenced the separation between the clusters. Based on partial least square (PLS) analysis, fucoxanthin, astaxanthin, violaxanthin, zeaxanthin, canthaxanthin, and lutein displayed strong correlation to 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging and nitric oxide (NO) inhibitory activity. This metabolomics study showed that solvent extractions are one of the main bottlenecks for the maximum recovery of bioactive microalgal compounds and could be a better source of natural antioxidants due to a high value of metabolites.

Matched MeSH terms: Nitric Oxide/metabolism*
Assessment of Polygonum odoratum Lour. Leaf Extract on Rat's Ileum Contraction and the Mechanisms Involved

Duangjai A, Parseatsook K, Sajjapong W, Saokaew S

J Med Food, 2020 Nov;23(11):1169-1175.
PMID: 32976072 DOI: 10.1089/jmf.2020.4769

Vietnamese coriander (Polygonum odoratum Lour.) is a plant native to northern Thailand. The biological activities of P. odoratum Lour. extract (POE) include antibacterial, antiviral, and expectorant. However, the effect of POE on intestinal smooth muscle motility is unclear. The aim of this study was to evaluate the relaxant effects of POE on isolated rat ileum. Propranolol (1 μM), calcium chloride (1-20 mM), and Nω-nitro-l-arginine methylester (l-NAME, 100 μM) were used to investigate the mechanisms of action. The results showed that POE (0.01-5 mg/mL) reduced KCl-induced contraction. In addition, POE (1 mg/mL) reduced the contraction by propranolol and l-NAME and attenuated CaCl2-induced contractions. Our results indicate that the relaxation effect of POE on ileum contractions seems to involve nitric oxide and β-adrenergic pathways, and blockade of calcium influx. These findings provide a pharmacological basis for the traditional use of POE to treat gastrointestinal disorders such as irritable bowel syndrome or diarrhea.

Matched MeSH terms: Nitric Oxide/metabolism
Fulltext Drug Delivery System for Refractory Cancer Therapy via an Endogenous Albumin Transport System

Ishima Y, Maruyama T, Otagiri M, Ishida T

Chem Pharm Bull (Tokyo), 2020;68(7):583-588.
PMID: 32611995 DOI: 10.1248/cpb.c20-00026

A unique phenomenon in solid tumors, the enhanced permeability and retention (EPR) effect is now well known in the development of macromolecular anticancer therapy. However, cancers with low vascular permeability have posed a challenge for these EPR based therapeutic systems. An intrinsic vascular modulator, such as nitric oxide (NO), could augment the endogenous EPR effect. However, the most important aim has been to construct an effective NO delivery system for cancer. Since it is well known that human serum albumin is one of the most important endogenous NO transport proteins in human circulation, for more than a decade we have demonstrated that S-nitrosated human serum albumin dimer (SNO-HSA-Dimer) becomes an enhancer of the EPR effect. Here, we summarize the enhanced effect of SNO-HSA-Dimer on the anticancer effect of macromolecular anticancer drugs such as PEGylated liposomal doxorubicin (Doxil®). In C26-bearing mice with highly permeable vasculature, SNO-HSA-Dimer is able to increase more 3-fold the tumor accumulation of these anticancer drugs, thereby tripling their anticancer effects. Interestingly, the tumor accumulation of Doxil® in B16-bearing mice, which are characterized by a low permeable vasculature, increased more than 6-fold in the presence of SNO-HSA-Dimer, and the improved accumulation of Doxil® led to both increased survival and decreased tumor volume. These results strongly suggest that the more cancer is refractory, the more the SNO-HSA-Dimer could enhance the EPR effect via an endogenous albumin transport (EAT) system. Accordingly, we conclude that the EAT system is promising as a drug delivery system (DDS) strategy for refractory cancer therapy.

Matched MeSH terms: Nitric Oxide/metabolism
Effects of 14-deoxyandrographolide and 14-deoxy-11,12-didehydroandrographolide on nitric oxide production in cultured human endothelial cells

Zhang CY, Tan BK

Phytother Res, 1999 Mar;13(2):157-9.
PMID: 10190192

14-deoxyandrographolide (DA) and 14-deoxy-11,12-didehydroandrographolide (DDA) are two diterpenoids isolated from A. paniculata, a popular folk medicine used as an antihypertensive drug in Malaysia. We have previously reported that DDA exhibited a greater hypotensive effect in anaesthetized rats and a vasorelaxant activity in isolated rat aorta, compared with DA. Their vasorelaxant activities were mediated through the activation of the enzymes, nitric oxide synthase (NOS) and guanylyl cyclase. The present study demonstrated that both DA and DDA stimulated nitric oxide (NO) release from human endothelial cells. DDA compared with DA caused a greater production of NO; this is in line with the finding of the earlier study that the vasorelaxant effect of DDA was more dependent on endothelium than DA.

Matched MeSH terms: Nitric Oxide/metabolism*
Fulltext Role of rutin on nitric oxide synthesis in human umbilical vein endothelial cells

Ugusman A, Zakaria Z, Chua KH, Nordin NA, Abdullah Mahdy Z

ScientificWorldJournal, 2014;2014:169370.
PMID: 25093198 DOI: 10.1155/2014/169370

Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), is a major antiatherogenic factor in the blood vessel. Oxidative stress plays an important role in the pathogenesis of various cardiovascular diseases, including atherosclerosis. Decreased availability of endothelial NO promotes the progression of endothelial dysfunction and atherosclerosis. Rutin is a flavonoid with multiple cardiovascular protective effects. This study aimed to investigate the effects of rutin on eNOS and NO production in cultured human umbilical vein endothelial cells (HUVEC). HUVEC were divided into four groups: control; oxidative stress induction with 180 μM H₂O₂; treatment with 300 μM rutin; and concomitant induction with rutin and H₂O₂ for 24 hours. HUVEC treated with rutin produced higher amount of NO compared to control (P < 0.01). In the oxidative stress-induced HUVEC, rutin successfully induced cells' NO production (P < 0.01). Rutin promoted NO production in HUVEC by inducing eNOS gene expression (P < 0.05), eNOS protein synthesis (P < 0.01), and eNOS activity (P < 0.05). Treatment with rutin also led to increased gene and protein expression of basic fibroblast growth factor (bFGF) in HUVEC. Therefore, upregulation of eNOS expression by rutin may be mediated by bFGF. The results showed that rutin may improve endothelial function by augmenting NO production in human endothelial cells.

Matched MeSH terms: Nitric Oxide/metabolism*
Nitric oxide (no), citrulline - no cycle enzymes, glutamine synthetase and oxidative stress in anoxia (hypobaric hypoxia) and reperfusion in rat brain

Swamy M, Salleh MJ, Sirajudeen KN, Yusof WR, Chandran G

Int J Med Sci, 2010 May 31;7(3):147-54.
PMID: 20567615

Nitric oxide is postulated to be involved in the pathophysiology of neurological disorders due to hypoxia/ anoxia in brain due to increased release of glutamate and activation of N-methyl-D-aspartate receptors. Reactive oxygen species have been implicated in pathophysiology of many neurological disorders and in brain function. To understand their role in anoxia (hypobaric hypoxia) and reperfusion (reoxygenation), the nitric oxide synthase, argininosuccinate synthetase, argininosuccinate lyase, glutamine synthetase and arginase activities along with the concentration of nitrate /nitrite, thiobarbituric acid reactive substances and total antioxidant status were estimated in cerebral cortex, cerebellum and brain stem of rats subjected to anoxia and reperfusion. The results of this study clearly demonstrated the increased production of nitric oxide by increased activity of nitric oxide synthase. The increased activities of argininosuccinate synthetase and argininosuccinate lyase suggest the increased and effective recycling of citrulline to arginine in anoxia, making nitric oxide production more effective and contributing to its toxic effects. The decreased activity of glutamine synthetase may favor the prolonged availability of glutamic acid causing excitotoxicity leading to neuronal damage in anoxia. The increased formation of thiobarbituric acid reactive substances and decreased total antioxidant status indicate the presence of oxidative stress in anoxia and reperfusion. The increased arginase and sustained decrease of GS activity in reperfusion group likely to be protective.

Matched MeSH terms: Nitric Oxide/metabolism*
Role of nitric oxide in skeletal muscle glucose uptake during exercise

Hong YH, Betik AC, McConell GK

Exp Physiol, 2014 Dec 1;99(12):1569-73.
PMID: 25192731 DOI: 10.1113/expphysiol.2014.079202

Nitric oxide is produced within skeletal muscle fibres and has various functions in skeletal muscle. There is evidence that NO may be essential for normal increases in skeletal muscle glucose uptake during contraction/exercise. Although there have been some discrepant results, it has been consistently demonstrated that inhibition of NO synthase (NOS) attenuates the increase in skeletal muscle glucose uptake during contraction in mouse and rat muscle ex vivo, during in situ contraction in rats and during exercise in humans. The NO-mediated increase in skeletal muscle glucose uptake during contraction/exercise is probably due to the modulation of intramuscular signalling that ultimately increases glucose transporter 4 (GLUT4) translocation and is, surprisingly, independent of blood flow. In this review, we discuss the evidence for and against a role of NO in regulating skeletal muscle glucose uptake during contraction/exercise and outline the possible mechanism(s) involved. Emerging findings regarding the role of neuronal NOS mu (nNOSμ) in this process are also discussed.

Matched MeSH terms: Nitric Oxide/metabolism*
Atherosclerotic cardiovascular disease: a review of initiators and protective factors

Ellulu MS, Patimah I, Khaza'ai H, Rahmat A, Abed Y, Ali F

Inflammopharmacology, 2016 Feb;24(1):1-10.
PMID: 26750181 DOI: 10.1007/s10787-015-0255-y

Atherosclerotic cardiovascular disease (CVD) is a collective term comprising of a group of disorders of the heart and blood vessels. These diseases are the largest cause of morbidity and premature death worldwide. Coronary heart disease and cerebrovascular disease (stroke) are the most frequently occurring diseases. The two major initiators involved in the development of atherosclerotic CVD are vascular production of reactive oxygen species (ROS) and lipid oxidation. In atherosclerosis development, ROS is associated with rapid loss of anti-inflammatory and anti-atherogenic activities of the endothelium-derived nitric oxide (NO(·)) resulting in endothelial dysfunction. In part involving activation of the transcription factor NF-κB, ROS have been involved in signaling cascades leading to vascular pro-inflammatory and pro-thrombotic gene expression. ROS is also a potent activator of matrix metalloproteinases (MMPs), which indicate plaque destabilization and rupture. The second initiator involved in atherosclerotic CVD is the oxidation of low-density lipoproteins (LDL). Oxidation of LDL in vessel wall leads to an inflammatory cascade that activates atherogenic pathway leading to foam cell formation. The accumulation of foam cells leads to fatty streak formation, which is the earliest visible atherosclerotic lesion. In contrast, the cardiac sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a) and hepatic apolipoprotein E (apoE) expression can improve cardiovascular function. SERCA2a regulates the cardiac contractile function by lowering cytoplasmic calcium levels during relaxation, and affecting NO(·) action in vascular cells, while apoE is a critical ligand in the plasma clearance of triglyceride- and cholesterol-rich lipoproteins.

Matched MeSH terms: Nitric Oxide/metabolism
Endothelium dependent hyperpolarization-type relaxation compensates for attenuated nitric oxide-mediated responses in subcutaneous arteries of diabetic patients

Mokhtar SS, Vanhoutte PM, Leung SW, Yusof MI, Wan Sulaiman WA, Mat Saad AZ, et al.

Nitric Oxide, 2016 Feb 29;53:35-44.
PMID: 26768833 DOI: 10.1016/j.niox.2015.12.007

Diabetes impairs endothelium-dependent relaxations. The present study evaluated the contribution of different endothelium-dependent relaxing mechanisms to the regulation of vascular tone in subcutaneous blood vessels of humans with Type 2 diabetes mellitus. Subcutaneous arteries were isolated from tissues of healthy controls and diabetics. Vascular function was determined using wire myography. Expressions of proteins were measured by Western blotting and immunostaining. Endothelium-dependent relaxations to acetylcholine were impaired in arteries from diabetics compared to controls (P = 0.009). Acetylcholine-induced nitric oxide (NO)-mediated relaxations [in the presence of an inhibitor of cyclooxygenases (COX; indomethacin) and small and intermediate conductance calcium-activated potassium channel blockers (UCL1684 and TRAM 34, respectively)] were attenuated in arteries from diabetics compared to controls (P

Matched MeSH terms: Nitric Oxide/metabolism*
Immunomodulatory Effects of Agarwood Leaf Extract on RAW264.7 Murine Macrophages

Pang KL, Chin KY, Nirwana SI

Endocr Metab Immune Disord Drug Targets, 2023;23(7):964-976.
PMID: 36597600 DOI: 10.2174/1871530323666230103153134

BACKGROUND: The immunomodulatory effects of plants have been utilised to enhance the immunity of humans against infections. However, evidence of such effects of agarwood leaves is very limited despite the long tradition of consuming the leaves as tea.
OBJECTIVE: This study aimed to investigate the immuno-modulatory effects of agarwood leaf extract (ALE) derived from Aquilaria malaccensis using RAW264.7 murine macrophages.
METHODS: In this study, RAW264.7 macrophages were incubated with ALE alone for 26 hours or ALE for 2 hours, followed by bacterial lipopolysaccharide for 24 hours. The nitrite and cytokine production (tumour necrosis factor-alpha (TNFα), interleukin (IL)-1β, IL-6, and IL-10), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX2) expression in the macrophages were assayed.
RESULTS: The study showed that ALE alone was immunostimulatory on the macrophages by increasing the nitrite, TNFα, and IL-6 production and COX2 expression (p<0.05 vs. untreated unstimulated cells). Pre-treatment of ALE suppressed nitrite level and iNOS expression but enhanced TNFα and IL-6 production and COX2 expression (p<0.05 vs. untreated lipopolysaccharides (LPS)-stimulated cells). ALE also increased IL-10 production regardless of LPS stimulation (p<0.05 vs. untreated cells).
CONCLUSION: ALE was able to promote the immune response of macrophages by upregulating pro-inflammatory cytokine levels and COX2 expression. It also regulated the extent of the inflammation by reducing iNOS expression and increasing IL-10 levels. Thus, ALE may have a role in enhancing the innate immune system against infection; however, its validation from in vivo studies is still pending.

Matched MeSH terms: Nitric Oxide/metabolism
Fulltext Epigallocatechin gallate (EGCG) alleviates vascular dysfunction in angiotensin II-infused hypertensive mice by modulating oxidative stress and eNOS

Mohd Sabri NA, Lee SK, Murugan DD, Ling WC

Sci Rep, 2022 Oct 21;12(1):17633.
PMID: 36271015 DOI: 10.1038/s41598-022-21107-5

Epigallocatechin gallate (EGCG) has been shown to have antihypertensive activity. However, the role of epigallocatechin gallate (EGCG) in improving vascular function via modulation of endothelial nitric oxide synthase (eNOS) in hypertensive subjects is not well researched. Angiotensin II-infused hypertensive mice (8-10 weeks old) received EGCG (50 mg/kg/day) for 14 days via oral gavage. The arterial systolic blood pressure (SBP) was measured using the tail-cuff method every three days. At the end of the treatment, the vascular reactivity of the isolated aortae was studied using wire myographs. The level of nitric oxide (NO), cyclic guanosine monophosphate (cGMP) and tetrahydrobiopterine (BH4) were determined using assay kits while the presence of proteins (NOS, p-eNOS and NOx-2) were determined using by Western blotting. In vivo treatment with EGCG for 14 days significantly attenuated the increase in SBP, alleviated the vascular dysfunction, increased the vascular cGMP and BH4 level as well as the expression of p-eNOS and decreased elevated ROS level and NOx-2 protein in angiotensin II-infused hypertensive mice. Collectively, treatment with EGCG in hypertensive mice exerts a blood pressure lowering effect which is partly attributed to the improvement in the vascular function due to its ability to reduce vascular oxidative stress in the aortic tissue leading to a decrease in eNOS uncoupling thus increasing NO bioavailability.

Matched MeSH terms: Nitric Oxide/metabolism
Medicinal Tiger Milk Mushroom Lignosus rhinocerus TM02® (Agaricomycetes) Sclerotia Supplementation Mitigates Hypertension and Alleviates Vascular Dysfunction Partly through Oxidative Stress Modulation in Spontaneously Hypertensive Rats

Wong YE, Razif MFM, Ng ST, Tan CS, Fung SY, Murugan DD

Int J Med Mushrooms, 2024;26(11):27-40.
PMID: 39241161 DOI: 10.1615/IntJMedMushrooms.2024055061

Hypertension is a risk factor for cardiovascular diseases such as coronary artery disease, heart failure, and stroke. Lignosus rhinocerus (Cooke) Ryvarden (also known as tiger milk mushroom), has been reported to exhibit a range of pharmacological effects, such as anti-inflammatory, anti-proliferative, antioxidative, immunomodulatory and anti-asthmatic activities. Thus far, there is limited research that has explored its ability to mediate vascular effects in vivo. Therefore, this study investigated the antihypertensive and vascular protective effects of L. rhinocerus TM02® sclerotia supplementation in spontaneously hypertensive rats (SHR). Wistar Kyoto (WKY) rats served as a normotensive control group. SHR were orally administered with L. rhinocerus TM02® sclerotia (100 mg/kg and 300 mg/kg, respectively) for 8 weeks, and blood pressure was monitored every 2 weeks. Vascular function was evaluated using an organ bath (aorta) and wire myograph (renal artery) at the treatment endpoint. The levels of reactive oxygen species (ROS) and nitric oxide (NO) in the aorta and renal artery were evaluated using dihydroethidium (DHE) and difluoro fluorescein acetate (DAF-FM) fluorescence assays, respectively. Total plasma nitrate/nitrite and tumor necrosis factor alpha (TNF-α) levels were evaluated via colorimetric assays. In vivo treatment with L. rhinocerus TM02® sclerotia significantly attenuated the increase in systolic blood pressure (SBP). It also alleviated vascular dysfunction and decreased elevated ROS in the aorta and renal arteries of the treated SHRs. Moreover, L. rhinocerus TM02® sclerotia attenuated plasma TNF-α level but increased total plasma nitrate/nitrite, albeit slightly, coupled with significantly increased NO at the vascular level. Collectively, the present study demonstrated that L. rhinocerus TM02® sclerotia supplementation exerted blood pressure lowering effects, partly attributed to improvements in vascular function via reduction in vascular oxidative stress.

Matched MeSH terms: Nitric Oxide/metabolism
Repurposing Anakinra for Alzheimer's Disease: The In Vitro and In Vivo Effects of Anakinra on LPS- and AC-Induced Neuroinflammation

Retinasamy T, Lee ALY, Lee HS, Lee VLL, Shaikh MF, Yeong KY

ACS Chem Neurosci, 2024 Sep 18;15(18):3298-3310.
PMID: 39213521 DOI: 10.1021/acschemneuro.4c00205

Alzheimer's disease is a significant global health issue, and studies suggest that neuroinflammation plays a vital role in the advancement of this disease. In this study, anakinra has been shown to display a time- and concentration-dependent antineuroinflammatory effect. In the in vitro studies, it diminished the gene expressions of tumor necrosis factor-alpha (TNF-α) and nitric oxide (NO) synthase 2 stimulated by lipopolysaccharide (LPS). Anakinra also reduced the LPS-induced production of NO and reactive oxygen species. Thus, the hypertrophic state of LPS-activated BV2 microglial cells was reversed by anakinra. Furthermore, acrylamide (ACR)-induced activation of nuclear transcription factor-κB, TNF-α, and interleukin-1β was downregulated, while cAMP response element binding protein and brain-derived neurotrophic factor expression levels were markedly enhanced in ACR-treated zebrafish larvae. It was also observed that anakinra improved the uncoordinated swimming behaviors in ACR-exposed zebrafish larvae. Overall, anakinra demonstrated potential antineuroinflammatory and antioxidative effects.

Matched MeSH terms: Nitric Oxide/metabolism
Fulltext The Promising Key Factors Mediating Secondary Neuronal Damage in the Perihematomal Region of Intracerebellar Hemorrhage of Mice

Bhatia S, Paramasivam R, Zolkefley MKIB, Kandasamy R, Muthuraju S, Abdullah JM

J Physiol Investig, 2024 Nov 01;67(6):321-334.
PMID: 39475842 DOI: 10.4103/ejpi.EJPI-D-24-00013

The underlying mechanisms of secondary neuronal damage following intracerebellar hemorrhage (ICbH) have not yet been clearly understood. Our previous study reported apoptotic neuronal damage in the perihematomal region (PH) in mice. However, the possible key factors causing secondary neuronal damage in ICbH are not yet known. Therefore, we aimed to study the vital factors in the mediation of secondary neuronal damage following ICbH induced by collagenase type VII (0.4 U/μL of saline) into the cerebellum of mice. The mice were grouped into four groups: (1) control group ( n = 12), (2) day-1 group ( n = 12), (3) day-3 group ( n = 12), and (4) day-7 group ( n = 12). All mice underwent behavior assessment following induction of ICbH and were subsequently sacrificed on days 1, 3, and 7. Perihaematoma samples were collected to study morphological changes, immunohistochemistry, nitric oxide (NO) estimation, and oxidative stress markers, respectively. Mouse behavior was disturbed following ICbH on days 3 and 7 compared to the control. In addition, neuronal damage was found in the PH region. Glial fibrillary acidic protein (GFAP) and excitatory amino acid transporter 1 (EAAT1) were highly expressed on day 7, while gamma-aminobutyric acid receptor subunit alpha-1 (GABA A α1)-containing receptor subunit was detected on days 1 and 3. NO increased on day 1 post-induction and decreased on days 3 and 7. The expressions of superoxide dismutase (SOD), catalase (CAT), neuronal nitric oxide synthases (nNOSs), glutathione peroxidase 1, and cyclooxygenase-2 (COX-2) were significantly increased on day 3. Morphological studies of the PH and tissue showed that neuronal damage occurred from day 1 onward and peaked on day 3, associated with alterations in NO, reactive astrocytes (GFAP), glutamate transport regulation (EAAT1), and GABA receptor. Briefly, significant changes in the key markers in the PH regions at different time points are possibly crucial factors facilitating secondary neuronal damage in the PH region. Identifying the time window of these vital changes could help prevent secondary damage and optimize the treatment to occur at proper time points.

Matched MeSH terms: Nitric Oxide/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
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*

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