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1

Constituents of the stem barks of Ailanthus altissima and their potential to inhibit LPS-induced nitric oxide production.  

PubMed

Three new canthinone type alkaloids, canthin-6-one-1-O-?-d-apiofuranosyl-(1?2)-?-d-glucopyranoside (1), canthin-6-one-1-O-[6-O-(3-hydroxy-3-methylglutaryl)]-?-d-glucopyranoside (2) and canthin-6-one-1-O-[2-?-d-apiofuranosyl-6-O-(3-hydroxy-3-methylglutaryl)]-?-d-glucopyranoside (3) were isolated from the stem barks of Ailanthus altissima together with four quassinoids (4-7), seven phenylpropanoids (8-14) and a lignan of previously known structure (15). The inflammatory activities of the 15 isolates were screened on LPS-induced nitric oxide (NO), a proinflammatory mediator, in RAW 264.7 cells. PMID:25666824

Kim, Hye Mi; Kim, Su Jung; Kim, Ha-Yeong; Ryu, Byeol; Kwak, Hokwang; Hur, Jonghyun; Choi, Jung-Hye; Jang, Dae Sik

2015-03-01

2

Melampolides from the leaves of Smallanthus sonchifolius and their inhibitory activity of lps-induced nitric oxide production.  

PubMed

Two new melampolide-type sesquiterpene lactones, 8beta-epoxyangeloyloxy-9alpha-ethoxy-14-oxo-acanthospermolide (1) and 8beta-angeloyloxy-9alpha-ethoxy-14-oxo-acanthospermolide (2), were isolated from the leaves of yacon [Smallanthus sonchifolia (POEPP. et ENDL.) H. Robinson] along with eleven known melampolides, allo-schkuhriolide (3), enhydrin (4), polymatin A (5), fluctuanin (6), 8beta-angeloyloxy-9alpha-acetoxy-14-oxo-acanthospermolide (7), 8beta-angeloyloxy-14-oxo-acanthospermolide (8), 8beta-methacryloyloxymelampolid-14-oic acid methyl ester (9), uvedalin (10), polymatin B (11), 8beta-tigloyloxymelampolid-14-oic acid methyl ester (12), and sonchifolin (13). Their structures were established on the basis of spectroscopic evidence including 1D- and 2D-NMR experiments. All isolates were evaluated for inhibition of LPS-induced nitric oxide production in murine macrophage RAW 264.7 cells. PMID:18239309

Hong, Seong Su; Lee, Seon A; Han, Xiang Hua; Lee, Min Hee; Hwang, Ji Sang; Park, Jeong Sook; Oh, Ki-Wan; Han, Kun; Lee, Myung Koo; Lee, Heesoon; Kim, Wook; Lee, Dongho; Hwang, Bang Yeon

2008-02-01

3

Furanoligularenone, an eremophilane from Ligularia fischeri, inhibits the LPS-induced production of nitric oxide and prostaglandin E2 in macrophage RAW264.7 cells.  

PubMed

Furanoligularenone (1), a known eremophilane, was identified from Ligularia fischeri (Compositae) together with 3-oxo-8alpha-hydroxy-10alphaH-eremophila-1,7(11)-dien-12,8beta-olide (2) and 3-oxo-8alpha-methoxy-10alphaH-eremophila-1,7(11)-dien-12,8beta-olide (3), by its potent inhibition of LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in RAW 264.7 cells. Compound 1 also suppressed the expression of iNOS and COX-2 mRNA and protein in a dose-dependent manner. Taken together, compound 1 inhibits the production of NO and PGE2 at the transcription of iNOS and COX-2 genes, and would be responsible for the anti-inflammatory activities of the Ligularia fischeri. PMID:11859456

Hwang, Bang Yeon; Lee, Jeong-Hyung; Koo, Tae Hyeon; Kim, Hang Sub; Hong, Young Soo; Ro, Jai Seup; Lee, Kyong Soon; Lee, Jung Joon

2002-02-01

4

Pheophytin a Inhibits Inflammation via Suppression of LPS-Induced Nitric Oxide Synthase-2, Prostaglandin E2, and Interleukin-1? of Macrophages  

PubMed Central

Inflammation is a serious health issue worldwide that induces many diseases such as sepsis. There has been a vast search for potentially effective drugs to decrease mortality from sepsis. Pheophytin a is a chlorophyll-related compound derived from green tea. We found that pre-treatment with pheophytin a suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO), prostaglandin E2 (PGE2), and interleukin-1? in RAW 264.7 macrophages. NO synthase-2 (NOS2) and cyclooxygenase-2 (COX-2) expression levels were repressed by pre-treatment with pheophytin a at both the transcriptional and translational levels. Pheophytin a inhibited NOS2 promoter activity, but not its mRNA stability, through extracellular signal-regulated kinase (ERK1/2). This suppression was reversed by ERK1/2 inhibitor (U0126). Pheophytin a reduced signal transducers and activators of transcription 1 (STAT-1) activation, without an obvious influence on activator protein-1 (AP-1) and nuclear factor ?B (NF-?B). These results suggest that pheophytin a functions by down-regulating the transcriptional levels of inflammatory mediators and blocking the ERK and STAT-1 pathways. PMID:25501336

Lin, Chun-Yu; Lee, Chien-Hsing; Chang, Yu-Wei; Wang, Hui-Min; Chen, Chung-Yi; Chen, Yen-Hsu

2014-01-01

5

Pheophytin a Inhibits Inflammation via Suppression of LPS-Induced Nitric Oxide Synthase-2, Prostaglandin E2, and Interleukin-1? of Macrophages.  

PubMed

Inflammation is a serious health issue worldwide that induces many diseases such as sepsis. There has been a vast search for potentially effective drugs to decrease mortality from sepsis. Pheophytin a is a chlorophyll-related compound derived from green tea. We found that pre-treatment with pheophytin a suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO), prostaglandin E2 (PGE2), and interleukin-1? in RAW 264.7 macrophages. NO synthase-2 (NOS2) and cyclooxygenase-2 (COX-2) expression levels were repressed by pre-treatment with pheophytin a at both the transcriptional and translational levels. Pheophytin a inhibited NOS2 promoter activity, but not its mRNA stability, through extracellular signal-regulated kinase (ERK1/2). This suppression was reversed by ERK1/2 inhibitor (U0126). Pheophytin a reduced signal transducers and activators of transcription 1 (STAT-1) activation, without an obvious influence on activator protein-1 (AP-1) and nuclear factor ?B (NF-?B). These results suggest that pheophytin a functions by down-regulating the transcriptional levels of inflammatory mediators and blocking the ERK and STAT-1 pathways. PMID:25501336

Lin, Chun-Yu; Lee, Chien-Hsing; Chang, Yu-Wei; Wang, Hui-Min; Chen, Chung-Yi; Chen, Yen-Hsu

2014-01-01

6

Withaferin A inhibits iNOS expression and nitric oxide production by Akt inactivation and down-regulating LPS-induced activity of NF-kappaB in RAW 264.7 cells.  

PubMed

Induction of inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production is thought to have beneficial immunomodulatory effects in acute and chronic inflammatory disorders. In Raw 264.7 cells stimulated with lipopolysaccharide (LPS) to mimic inflammation, withaferin A inhibited LPS-induced expression of both iNOS protein and mRNA in a dose-dependent manner. To investigate the mechanism by which withaferin A inhibits iNOS gene expression, we examined activation of mitogen-activated protein kinases (MAPKs) and Akt in Raw 264.7 cells. We did not observe any significant changes in the phosphorylation of p38 MAPK in cells treated with LPS alone or LPS plus withaferin A. However, LPS-induced Akt phosphorylation was markedly inhibited by withaferin A, while the phosphorylation of p42/p44 extracellular signal-regulated kinases (ERKs) was slightly inhibited by withaferin A treatment. Withaferin A prevented IkappaB phosphorylation, blocking the subsequent nuclear translocation of nuclear factor-kappaB (NF-kappaB) and inhibiting its DNA binding activity. LPS-induced p65 phosphorylation, which is mediated by extracellular signal-regulated kinase (ERK) and Akt pathways, was attenuated by withaferin A treatment. Moreover, LPS-induced NO production and NF-kappaB activation were inhibited by SH-6, a specific inhibitor of Akt. Taken together, these results suggest that withaferin A inhibits inflammation through inhibition of NO production and iNOS expression, at least in part, by blocking Akt and subsequently down-regulating NF-kappaB activity. PMID:18838070

Oh, Jung Hwa; Lee, Tae-Jin; Park, Jong-Wook; Kwon, Taeg Kyu

2008-12-01

7

Inhibition of LPS-induced pulmonary inflammation by specific flavonoids  

Microsoft Academic Search

In the present study, the anti-inflammatory effects of the flavonoids flavone, fisetin and tricetin were evaluated in a mouse model of LPS-induced acute pulmonary inflammation. The flavonoid fisetin significantly reduced lung myeloperoxidase-levels and gene-expression of inflammatory mediators such as IL-6, TNF-?, IL-1?, MIP-1? and MIP-2. The LPS-induced gene transcription of HO-1 and SOD2 was also significantly reduced by fisetin. Overall,

Liesbeth Geraets; Astrid Haegens; Karen Brauers; Jane A. Haydock; Juanita H. J. Vernooy; Emiel F. M. Wouters; Aalt Bast; Geja J. Hageman

2009-01-01

8

Catalpol protects dopaminergic neurons from LPS-induced neurotoxicity in mesencephalic neuron-glia cultures.  

PubMed

Inflammation plays an important role in the pathogenesis of Parkinson's disease (PD). Microglia, the resident immune cells in the central nervous system, are pivotal in the inflammatory reaction. Activated microglia can induce expression of inducible nitric-oxide synthase (iNOS) and release significant amounts of nitric oxide (NO) and TNF-alpha, which can damage the dopaminergic neurons. Catalpol, an iridoid glycoside, contained richly in the roots of Rehmannia glutinosa, was found to be neuroprotective in gerbils subjected to transient global cerebral ischemia. But the effect of catalpol on inflammation-mediated neurodegeneration has not been examined. In this study, microglia in mesencephalic neuron-glia cultures were activated with lipopolysaccharide (LPS) and the aim of the study was to examine whether catalpol could protect dopaminergic neurons from LPS-induced neurotoxicity. The results showed that catalpol significantly reduced the release of reactive oxygen species (ROS), TNF-alpha and NO after LPS-induced microglial activation. Further, catalpol attenuated LPS-induced the expression of iNOS. As determined by immunocytochemical analysis, pretreatment by catalpol dose-dependently protected dopaminergic neurons against LPS-induced neurotoxicity. These results suggest that catalpol exerts its protective effect on dopaminergic neurons by inhibiting microglial activation and reducing the production of proinflammatory factors. Thus, catalpol may possess therapeutic potential against inflammation-related neurodegenerative diseases. PMID:17049947

Tian, Yuan-Yuan; An, Li-Jia; Jiang, Lan; Duan, Yan-Long; Chen, Jun; Jiang, Bo

2006-12-23

9

Silibinin ameliorates LPS-induced memory deficits in experimental animals.  

PubMed

Neuroinflammation is considered as one of the predisposing factor in the etiology of several neurodegenerative disorders. Therefore, the objective of the present study was to evaluate the protective effect of silibinin (SIL) in the lipopolysaccharide (LPS)-induced neuroinflammatory model. The effect of SIL on memory function was also evaluated on normal rats without LPS administration. In the first experiment, male rats were divided into five groups. Except control group animals, all rats received bilateral intracerebroventricular injection of LPS (5?g/5?l) into lateral ventricles on the first day of the experimental schedule. Control rats received bilateral intracerebroventricular injection of artificial cerebrospinal fluid into lateral ventricles. SIL in doses of 50, 100 and 200mg/kg, p.o. was administered 1h before LPS injection and continued for 7days. On Day-7, SIL attenuated the LPS-induced long-term and working memory loss in elevated plus and Y-maze test respectively. Further, SIL dose-dependently attenuated LPS-induced decrease in acetylcholine level and increase in the acetylcholinestrase activity in hippocampus and pre-frontal cortex. SIL ameliorated LPS-induced decrease in the mitochondrial complex activity (I, IV and V) and integrity, increase in lipid peroxidation and decrease in the activity of superoxide dismutase in both the brain regions. SIL attenuated amyloidogenesis in the hippocampus, while it decreased the LPS-induced increase in the level of NF?B in the pre-frontal cortex. In another study, SIL dose-dependently, enhanced memory functions in the normal rats, indicating its nootropic activity. Hence, SIL could be a potential candidate in the management of neuroinflammation-related memory disorders. PMID:25444719

Joshi, Ritu; Garabadu, Debapriya; Teja, Gangineni Ravi; Krishnamurthy, Sairam

2014-12-01

10

Tetrahydrocoptisine protects rats from LPS-induced acute lung injury.  

PubMed

Recent studies show that nuclear factor-kappa B (NF-?B) signaling pathway plays a key role in contributing to the development of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Tetrahydrocoptisine is one of the main active components of Chelidonium majus L. and has been described to be effective in suppressing inflammation. The aim of the present study is to evaluate the protective effect of tetrahydrocoptisine on LPS-induced ALI in rats and clarify its underlying mechanisms of action. We found that in vivo pretreatment with tetrahydrocoptisine to rats 30 min before inducing ALI by LPS markedly decreased the mortality rate, lung wet weight to dry weight ratio, and ameliorated lung pathological changes. Meanwhile, tetrahydrocoptisine significantly inhibited the increase of the amounts of inflammatory cells, total protein content, tumor necrosis factor-? (TNF-?) and interleukin-6 (IL-6) secretion in the bronchoalveolar lavage fluids (BALFs). Furthermore, tetrahydrocoptisine inhibited myeloperoxidase (MPO) accumulation in lung tissue and alleviated TNF-? and IL-6 production in serum. Additionally, immunohistochemistry showed that tetrahydrocoptisine efficiently reduced nuclear factor-kappa B (NF-?B) activation by inhibiting the translocation of NF-?Bp65. In conclusion, our results demonstrate that tetrahydrocoptisine possesses a protective effect on LPS-induced ALI through inhibiting of NF-?B signaling pathways, which may involve the inhibition of pulmonary inflammatory process. PMID:24928630

Li, Weifeng; Huang, Huimin; Niu, Xiaofeng; Fan, Ting; Hu, Hua; Li, Yongmei; Yao, Huan; Li, Huani; Mu, Qingli

2014-12-01

11

The effect of linarin on LPS-induced cytokine production and nitric oxide inhibition in murine macrophages cell line RAW264.7.  

PubMed

The herb, Chrysanthemum zawadskii var, latilobum commomly known as Gu-Jul-Cho in Korea, used in traditional medicine to treat pneumonia, bronchitis, cough, common cold, pharyngitis, bladder-related disorders, gastroenteric disorders, and hypertension. Linarin is the main active compound and the biological mechanisms of its activity are unclear. It is believed that effects of this herb may be exerted through the pluripotent effectors of linarin due to its ability to treat a variety of afflictions. In this study, the effects of linarin on the mouse macrophages cell line, RAW 264.7, were investigated. It was found that linarin could activate macrophages by producing cytokines. Monocytes and tissue macrophages produce at least two groups of protein mediators of inflammation, interleukin 1 (IL-1) and the tumor necrosis factor (TNF). Recent studies have shown that TNF and IL-1 modulate the inflammatory function of endothelial cells, leukocytes, and fibroblasts. TNF-alpha production by macrophages treated with linarin occured in a dose dependent manner. However, IL-1 production was largely unaffected by this natural product. This study demonstrated the ability of linarin to activate macrophages both directly and indirectly. Linarin also affect both cytokine production and nitric oxide inhibition, in addition to the expression of some surface molecules. Nitric oxide (NO), derived from L-argin-ine, is produced by two forms(constitutive and inducible) of nitric oxide synthase (NOS). The NO produced in large amounts by inducible NOS is known to be responsible for the vasodilation and hypotension observed in septic shock. Linarin was found to inhibit NO production in the LPS-activated RAW 264.7 cells. Linarin may be a useful candidate as a new drug for treating endotoxemia and the inflammation accompanied by NO overproduction. The linarin-treated total lymphocytes exhibited cytotoxicity in a dose dependent manner between 20 microg/ml and 40 microg/ml. These results suggest that linarin may function through macrophage activation. PMID:12009031

Han, Shinha; Sung, Ki-Hyun; Yim, Dongsool; Lee, Sookyeon; Lee, Chong-Kil; Ha, Nam-ju; Kim, Kyungjae

2002-04-01

12

Achillea millefolium L. Essential Oil Inhibits LPS-Induced Oxidative Stress and Nitric Oxide Production in RAW 264.7 Macrophages  

PubMed Central

Achillea millefolium L. is a member of the Asteraceae family and has been used in folk medicine in many countries. In this study, 19 compounds in A. millefolium essential oil (AM-EO) have been identified; the major components are artemisia ketone (14.92%), camphor (11.64%), linalyl acetate (11.51%) and 1,8-cineole (10.15%). AM-EO can suppress the inflammatory responses of lipopolysaccharides (LPS)-stimulated RAW 264.7 macrophages, including decreased levels of cellular nitric oxide (NO) and superoxide anion production, lipid peroxidation and glutathione (GSH) concentration. This antioxidant activity is not a result of increased superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities, but rather occurs as a result of the down-regulation of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-? (TNF-?), interleukin-6 (IL-6) and heme oxygenase-1 (HO-1) expression, thus reducing the inflammatory response. Therefore, AM-EO can be utilized in many applications, including the treatment of inflammatory diseases in the future. PMID:23797659

Chou, Su-Tze; Peng, Hsin-Yi; Hsu, Jaw-Cherng; Lin, Chih-Chien; Shih, Ying

2013-01-01

13

Stevioside protects LPS-induced acute lung injury in mice.  

PubMed

Stevioside, a diterpene glycoside component of Stevia rebaudiana, has been known to exhibit anti-inflammatory properties. To evaluate the effect and the possible mechanism of stevioside in lipopolysaccharide (LPS)-induced acute lung injury, male BALB/c mice were pretreated with stevioside or dexamethasone 1 h before intranasal instillation of LPS. Seven hours later, tumor necrosis factor-?, interleukin-1?, and interleukin-6 in bronchoalveolar lavage fluid (BALF) were measured by using enzyme-linked immunosorbent assay. The number of total cells, neutrophils, and macrophages in the BALF were also determined. The right lung was excised for histological examination and analysis of myeloperoxidase activity and nitrate/nitrite content. Cyclooxygenase 2 (COX-2), inducible NO synthase (iNOS), nuclear factor-kappa B (NF-?B), inhibitory kappa B protein were detected by western blot. The results showed that stevioside markedly attenuated the LPS-induced histological alterations in the lung. Stevioside inhibited the production of pro-inflammatory cytokines and the expression of COX-2 and iNOS induced by LPS. In addition, not only was the wet-to-dry weight ratio of lung tissue significantly decreased, the number of total cells, neutrophils, and macrophages in the BALF were also significantly reduced after treatment with stevioside. Moreover, western blotting showed that stevioside inhibited the phosphorylation of I?B-? and NF-?B caused by LPS. Taken together, our results suggest that anti-inflammatory effect of stevioside against the LPS-induced acute lung injury may be due to its ability of inhibition of the NF-?B signaling pathway. Stevioside may be a promising potential therapeutic reagent for acute lung injury treatment. PMID:22968433

Yingkun, Nie; Zhenyu, Wang; Jing, Lin; Xiuyun, Lu; Huimin, Yu

2013-02-01

14

2-Phenoxychromones and prenylflavonoids from Epimedium koreanum and their inhibitory effects on LPS-induced nitric oxide and interleukin-1? production.  

PubMed

Two new 2-phenoxychromones 1 and 2 and two prenylflavonoids 3 and 4 along with 12 known compounds (5-16) were isolated from the CH2Cl2-soluble fraction of a methanol extract of Epimedium koreanum. Compounds 1, 4, 6, 7, 9, 10, 12, and 15 exhibit inhibitory effects on nitric oxide production with IC50 values ranging from 16.8 to 49.3 ?M. Compounds 1, 4, 7, and 12 also showed inhibitory effects on interleukin-1? production with IC50 values ranging from 8.6 to 38.9 ?M in RAW 264.7 macrophages. PMID:24963714

Jin, Qinghao; Lee, Chul; Lee, Jin Woo; Yeon, Eung Tae; Lee, Dongho; Han, Sang Bae; Hong, Jin Tae; Kim, Youngsoo; Lee, Mi Kyeong; Hwang, Bang Yeon

2014-07-25

15

Carabrol suppresses LPS-induced nitric oxide synthase expression by inactivation of p38 and JNK via inhibition of I-{kappa}B{alpha} degradation in RAW 264.7 cells  

SciTech Connect

Carabrol, isolated from Carpesium macrocephalum, showed anti-inflammatory potential in LPS-induced RAW 264.7 murine macrophages. In present study, carabrol demonstrated the inhibitory activity on pro-inflammatory cytokines such as IL-1{beta}, IL-6 and TNF-{alpha}. In addition, mRNA and protein levels of iNOS and COX-2 were reduced by carabrol. Molecular analysis revealed that these suppressive effects were correlated with the inactivation of p38 and JNK via inhibition of NF-{kappa}B activation. Immunoblotting showed that carabrol suppressed LPS-induced degradation of I-{kappa}B{alpha} and decreased nuclear translocation of p65. Taken together, these results suggest that carabrol can be a modulator of pro-inflammatory signal transduction pathway in RAW 264.7 cells.

Lee, Hwa Jin [Department of Life Science, Research Center for Women's Diseases, Sookmyung Women's University, Seoul 140-742 (Korea, Republic of)] [Department of Life Science, Research Center for Women's Diseases, Sookmyung Women's University, Seoul 140-742 (Korea, Republic of); Lim, Hyo Jin; Lee, Da Yeon [College of Pharmacy, Sookmyung Women's University, Seoul 140-742 (Korea, Republic of)] [College of Pharmacy, Sookmyung Women's University, Seoul 140-742 (Korea, Republic of); Jung, Hyeyoun [Department of Life Science, Research Center for Women's Diseases, Sookmyung Women's University, Seoul 140-742 (Korea, Republic of)] [Department of Life Science, Research Center for Women's Diseases, Sookmyung Women's University, Seoul 140-742 (Korea, Republic of); Kim, Mi-Ran; Moon, Dong-Cheul [College of Pharmacy, Chungbuk National University, Cheungju 361-763 (Korea, Republic of)] [College of Pharmacy, Chungbuk National University, Cheungju 361-763 (Korea, Republic of); Kim, Keun Il; Lee, Myeong-Sok [Department of Life Science, Research Center for Women's Diseases, Sookmyung Women's University, Seoul 140-742 (Korea, Republic of)] [Department of Life Science, Research Center for Women's Diseases, Sookmyung Women's University, Seoul 140-742 (Korea, Republic of); Ryu, Jae-Ha, E-mail: ryuha@sookmyung.ac.kr [College of Pharmacy, Sookmyung Women's University, Seoul 140-742 (Korea, Republic of)] [College of Pharmacy, Sookmyung Women's University, Seoul 140-742 (Korea, Republic of)

2010-01-15

16

Amelioration of LPS-Induced Inflammation Response in Microglia by AMPK Activation  

PubMed Central

Adenosine 5?-monophosphate-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis via modulating metabolism of glucose, lipid, and protein. In addition to energy modulation, AMPK has been demonstrated to associate with several important cellular events including inflammation. The results showed that ENERGI-F704 identified from bamboo shoot extract was nontoxic in concentrations up to 80??M and dose-dependently induced phosphorylation of AMPK (Thr-172) in microglia BV2 cells. Our findings also showed that the treatment of BV2 with ENERGI-F704 ameliorated the LPS-induced elevation of IL-6 and TNF-? production. In addition, ENERGI-F704 reduced increased production of nitric oxide (NO) and prostaglandin E2 (PGE2) via downregulating the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2), respectively. Moreover, ENERGI-F704 decreased activated nuclear translocation and protein level of NF-?B. Inhibition of AMPK with compound C restored decreased NF-?B translocation by ENERGI-F704. In conclusion, ENERGI-F704 exerts inhibitory activity on LPS-induced inflammation through manipulating AMPK signaling and exhibits a potential therapeutic agent for neuroinflammatory disease. PMID:25025067

Chen, Chin-Chen; Lin, Jiun-Tsai; Cheng, Yi-Fang; Kuo, Cheng-Yi; Huang, Chun-Fang; Kao, Shao-Hsuan; Liang, Yao-Jen; Cheng, Ching-Yi; Chen, Han-Min

2014-01-01

17

The Effect of the Aerial Part of Lindera akoensis on Lipopolysaccharides (LPS)-Induced Nitric Oxide Production in RAW264.7 Cells  

PubMed Central

Four new secondary metabolites, 3?-((E)-Dodec-1-enyl)-4?-hydroxy-5?-methyldihydrofuran-2-one (1), linderinol (6), 4?-O-methylkaempferol 3-O-?-l-(4?-E-p-coumaroyl)rhamnoside (11) and kaempferol 3-O-?-l-(4?-Z-p-coumaroyl) rhamnoside (12) with eleven known compounds—3-epilistenolide D1 (2), 3-epilistenolide D2 (3), (3Z,4?,5?)-3-(dodec-11-ynylidene)-4-hydroxy-5-methylbutanolide (4), (3E,4?,5?)-3-(dodec-11-ynylidene)-4-hydroxy-5-methylbutanolide (5), matairesinol (7), syringaresinol (8), (+)-pinoresinol (9), salicifoliol (10), 4?-p-coumaroylafzelin (13), catechin (14) and epicatechin (15)—were first isolated from the aerial part of Lindera akoensis. Their structures were determined by detailed analysis of 1D- and 2D-NMR spectroscopic data. All of the compounds isolated from Lindera akoensis showed that in vitro anti-inflammatory activity decreases the LPS-stimulated production of nitric oxide (NO) in RAW 264.7 cell, with IC50 values of 4.1–413.8 ?M. PMID:23624606

Yang, Chung-Ping; Huang, Guan-Jhong; Huang, Hui-Chi; Chen, Yu-Chang; Chang, Chi-I; Wang, Sheng-Yang; Chang, Hsun-Shuo; Tseng, Yen-Hsueh; Chien, Shih-Chang; Kuo, Yueh-Hsiung

2013-01-01

18

Fermented guava leaf extract inhibits LPS-induced COX-2 and iNOS expression in Mouse macrophage cells by inhibition of transcription factor NF-kappaB.  

PubMed

The goal of this study was to elucidate the antiinflammatory activities of Psidium guajava L. (guava) leaf. To improve the functionality of guava leaf, it was fermented with Phellinus linteus mycelia, Lactobacillus plantarum and Saccharomyces cerevisiae. The ethanol extract from fermented guava leaf inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production. Western blot analysis showed that fermented guava leaf extract decreased LPS-induced inducible nitric oxide synthase (iNOS) and the cyclooxygenase-2 (COX-2) protein level in RAW 264.7 cells. To investigate the mechanism involved, the study examined the effect of fermented guava leaf extract on LPS-induced nuclear factor-kappaB (NF-kappaB) activation. Fermented guava leaf extract significantly inhibited LPS-induced NF-kappaB transcriptional activity. Immunochemical analysis revealed that fermented guava leaf extract suppressed LPS-induced degradation of I-kappaBalpha. Taken together, the data indicate that fermented guava leaf extract is involved in the inhibition of iNOS and COX-2 via the down-regulation of NF-kappaB pathway, revealing a partial molecular basis for the antiinflammatory properties of fermented guava leaf extract. PMID:18618521

Choi, Soo-Youn; Hwang, Joon-Ho; Park, Soo-Young; Jin, Yeong-Jun; Ko, Hee-Chul; Moon, Sang-Wook; Kim, Se-Jae

2008-08-01

19

Oenothein B Suppresses Lipopolysaccharide (LPS)-Induced Inflammation in the Mouse Brain  

PubMed Central

Oenothein B has been recently evaluated for its ability to affect inflammatory responses in peripheral tissues. In this study, we examined its effect on the damage to the central nervous system due to systemic inflammation. For this purpose, ICR mice were injected with an intraperitoneal (i.p.) dose of lipopolysaccharide (LPS; 1 mg/kg mouse). When oenothein B was administered per os (p.o.), it suppressed (1) LPS-induced abnormal behavior in open field; (2) LPS-induced microglial activation in the hippocampus and striatum; and (3) LPS-induced cyclooxygenase (COX)-2 production in the hippocampus and striatum of these mice. These results suggest that oenothein B had the ability to reduce neuroinflammation in the brain during systemic inflammation. PMID:23652834

Okuyama, Satoshi; Makihata, Nahomi; Yoshimura, Morio; Amakura, Yoshiaki; Yoshida, Takashi; Nakajima, Mitsunari; Furukawa, Yoshiko

2013-01-01

20

ATF3 Protects against LPS-Induced Inflammation in Mice via Inhibiting HMGB1 Expression  

PubMed Central

Lipopolysaccharide (LPS) triggers innate immunity mainly via TLR4 signaling. ATF3 is a negative regulator of TLR4 signaling. HMGB1 plays a critical role in the final step of sepsis. However, the mechanisms of ATF3 and the role of HMGB1 in regulating innate immunity-induced sepsis are incompletely understood. In this study, we found that serum HMGB1 levels were 10-fold higher in patients with sepsis than normal controls. We further demonstrated that ATF3 gene knockout in mice subjected to LPS-induced endotoxemia correlates with an increase in the mortality rate and the elevated expression of IL-6, TNF-?, NO, MCP-1, and HMGB1 in the lung tissues or serum. The biochemical effects of ATF3 were observed in in vitro macrophages and blocked by ATF3 siRNA treatment. We have also shown that adeno-associated virus-mediated ATF3 gene transfer protected ATF3 knockout mice from LPS-induced mortality. In addition, ATF3 knockdown increased LPS-induced release of HMGB1. In conclusion, upregulation of ATF3 contributes to the reduced release of inflammatory molecules, especially HMGB1, which induced lung injury and increased the survival rate of mice after LPS challenge. Therefore, suppressing LPS-induced inflammation with ATF3 induction or ATF3 mimetics may be an important strategy for sepsis therapy. PMID:24062788

Lai, Pei-Fang; Cheng, Ching-Feng; Lin, Heng; Tseng, Tzu-Ling; Chen, Hsi-Hsien; Chen, Sung-Ho

2013-01-01

21

Low-Level Laser Therapy Attenuates LPS-Induced Rats Mastitis by Inhibiting Polymorphonuclear Neutrophil Adhesion  

PubMed Central

ABSTRACT The aim of this study was to investigate the effects of low-level laser therapy (LLLT) on a rat model of lipopolysaccharide (LPS)-induced mastitis and its underlying molecular mechanisms. The rat model of mastitis was induced by inoculation of LPS through the canals of the mammary gland. The results showed that LPS-induced secretion of IL-1? and IL-8 significantly decreased after LLLT (650 nm, 2.5 mW, 30 mW/cm2). LLLT also inhibited intercellular adhesion molecule-1 (ICAM-1) expression and attenuated the LPS-induced decrease of the expression of CD62L and increase of the expression of CD11b. Moreover, LLLT also suppressed LPS-induced polymorphonuclear neutrophils (PMNs) entering the alveoli of the mammary gland. The number of PMNs in the mammary alveolus and the myeloperoxidase (MPO) activity were decreased after LLLT. These results suggested that LLLT therapy is beneficial in decreasing the somatic cell count and improving milk nutritional quality in cows with an intramammary infection. PMID:25452258

WANG, Yueqiang; HE, Xianjing; HAO, Dandan; YU, Debin; LIANG, Jianbin; QU, Yanpeng; SUN, Dongbo; YANG, Bin; YANG, Keli; WU, Rui; WANG, Jianfa

2014-01-01

22

Low-level laser therapy attenuates LPS-induced rats mastitis by inhibiting polymorphonuclear neutrophil adhesion.  

PubMed

The aim of this study was to investigate the effects of low-level laser therapy (LLLT) on a rat model of lipopolysaccharide (LPS)-induced mastitis and its underlying molecular mechanisms. The rat model of mastitis was induced by inoculation of LPS through the canals of the mammary gland. The results showed that LPS-induced secretion of IL-1? and IL-8 significantly decreased after LLLT (650 nm, 2.5 mW, 30 mW/cm(2)). LLLT also inhibited intercellular adhesion molecule-1 (ICAM-1) expression and attenuated the LPS-induced decrease of the expression of CD62L and increase of the expression of CD11b. Moreover, LLLT also suppressed LPS-induced polymorphonuclear neutrophils (PMNs) entering the alveoli of the mammary gland. The number of PMNs in the mammary alveolus and the myeloperoxidase (MPO) activity were decreased after LLLT. These results suggested that LLLT therapy is beneficial in decreasing the somatic cell count and improving milk nutritional quality in cows with an intramammary infection. PMID:25452258

Wang, Yueqiang; He, Xianjing; Hao, Dandan; Yu, Debin; Liang, Jianbin; Qu, Yanpeng; Sun, Dongbo; Yang, Bin; Yang, Keli; Wu, Rui; Wang, Jianfa

2014-12-01

23

Protective effect of taraxasterol against LPS-induced endotoxic shock by modulating inflammatory responses in mice.  

PubMed

Taraxasterol, a pentacyclic-triterpene, was isolated from the Chinese medicinal herb Taraxacum officinale. In the present study, we investigated the protective effect of taraxasterol on murine model of endotoxic shock and the mechanism of its action. Mice were treated with 2.5, 5 and 10 mg/kg of taraxasterol prior to a lethal dose of lipopolysaccharide (LPS) challenge. Survival of mice was monitored twice a day for 7 days. To further understand the mechanism, the serum levels of inflammatory cytokine tumor necrosis factor-? (TNF-?), interferon-? (IFN-?), interleukin-1? (IL-1?), interleukin-6 (IL-6) and mediator nitric oxide (NO), prostaglandin E? (PGE?) as well as histology of lungs were examined. The results showed that taraxasterol significantly improved mouse survival and attenuated tissue injury of the lungs in LPS-induced endotoxemic mice. Further studies revealed that taraxasterol significantly reduced TNF-?, IFN-?, IL-1?, IL-6, NO and PGE? levels in sera from mice with endotoxic shock. These results indicate that taraxasterol has a protective effect on murine endotoxic shock induced by LPS through modulating inflammatory cytokine and mediator secretion. This finding might provide a new strategy for the treatment of endotoxic shock and associated inflammation. PMID:24286370

Zhang, Xuemei; Xiong, Huanzhang; Li, Hongyu; Cheng, Yao

2014-02-01

24

NEUTROPHILS PLAY A CRITICAL ROLE IN THE DEVELOPMENT OF LPS-INDUCED AIRWAY DISEASE  

EPA Science Inventory

ETD-02-045 (GAVETT) GPRA # 10108 Neutrophils Play a Critical Role in the Development of LPS-Induced Airway Disease. Jordan D. Savov, Stephen H. Gavett*, David M. Brass, Daniel L. Costa*, and David A. Schwartz ABSTRACT We investigated the role of neutrophils...

25

EFFECTS OF SYSTEMIC NEUTROPHIL DEPLETION ON LPS-INDUCED AIRWAY DISEASE  

EPA Science Inventory

Effects of Systemic Neutrophil Depletion on LPS-induced Airway Disease Jordan D. Savov, Stephen H. Gavett*, David M. Brass, Daniel L. Costa*, David A. Schwartz Pulmonary and Critical Care Division, Dept of Medicine ? Duke University Medical Center * National Health and E...

26

Emodin inhibits LPS-induced inflammatory response by activating PPAR-? in mouse mammary epithelial cells.  

PubMed

Emodin, an anthraquinone derivative isolated from the rhizomes of Rheum palmatum, has been reported to have a protective effect against lipopolysaccharide (LPS)-induced mastitis. However, the underlying molecular mechanisms are not well understood. The aim of this study was to investigate the molecular mechanisms of emodin in modifying lipopolysaccharide (LPS)-induced signaling pathways in mouse mammary epithelial cells (MEC). The pro-inflammatory cytokines were determined by ELISA. Nuclear factor-?B (NF-?B), inhibitory kappa B (I?B?) protein, p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and PPAR-? were determined by Western blotting. The results showed that emodin suppressed tumor necrosis factor-alpha (TNF-?), interleukin-6 (IL-6), iNOS and COX-2 expression. We also found that emodin inhibited LPS-induced NF-?B activation, I?B? degradation, phosphorylation of ERK, JNK and P38. Furthermore, emodin could activate PPAR-? and the anti-inflammatory effects of emodin can be reversed by GW9662, a specific antagonist for PPAR-?. In conclusion, our results demonstrate that emodin activates PPAR-?, thereby attenuating LPS-induced inflammatory response. PMID:24874440

Yang, Zhengtao; Zhou, Ershun; Wei, Dong; Li, Depeng; Wei, Zhengkai; Zhang, Wen; Zhang, Xichen

2014-08-01

27

In vitro and in vivo therapeutics of ?-thujaplicin on LPS-induced inflammation in macrophages and septic shock in mice.  

PubMed

?-thujaplicin, an active constituent from Chamaecyparis obtusa, has been shown to have acaricidal and antimicrobial effects. Very few studies have focused on the potential of the anti-inflammatory effect of ?-thujaplicin. Moreover, its capability of inhibiting inflammatory mediators e.g. TNF-a gene transcription, nitric oxide (NO) and prostaglandin E2, remains unknown. Besides those molecular mechanisms behind the anti-inflammatory effect of ?-thujaplicin, solid proof of its effectiveness in vivo has not yet been studied. In our study, in vitro effects of ? thujaplicin were verified on RAW 264.7 macrophages which were stimulated by LPS. Indomethacin was used as a positive control. The inducible NO production after stimulation was measured by Griess reagent. PGE2, IL-6 and TNF-? were measured by ELISA methods. Protein expressions of iNOS, COX2, and NF-?B were evaluated by Western blotting. Septic ICR mice were administered 20 mg/kg of LPS and then the mortality rate was monitored. Within the concentration range which was devoid of cytotoxicty, ?-thujaplicin exhibited a clear dose-dependent inhibition on LPS-induced NO production. Furthermore, ?-thujaplicin inhibited LPS-induced PGE2, IL-6, and TNF-? production as well as iNOS, COX2, and NF- ?B protein expression more substantially potent than indomethacin. In agreement with the in vitro study, ?-thujaplicin was shown to be effective in vivo for inhibiting LPS-induced NO and TNF-? production and a significant decrease in mortality rate of mice suffering from septic shock was observed. This study demonstrates the potential of ?-thujaplicin in treatment of inflammation and sepsis. These effects occur through an efficient blockage of TNF-? and iNOS production. ?-thujaplicin efficacy is comparable to that of indomethacin thus it can be a substitution but bear less depletion of PGE2, making this compound very promising in clinical applications. ?-thujaplicin, an active constituent from Chamaecyparis obtusa, has been shown to have acaricidal and antimicrobial effects. Very few studies have focused on the potential of the anti-inflammatory effect of ?-thujaplicin. Moreover, its capability of inhibiting inflammatory mediators e.g. TNF-alpha gene transcription, nitric oxide (NO) and prostaglandin E2, remains unknown. Besides those molecular mechanisms behind the anti-inflammatory effect of ?-thujaplicin, solid proof of its effectiveness in vivo has not yet been studied. In our study, in vitro effects of ?-thujaplicin were verified on RAW 264.7 macrophages which were stimulated by LPS. Indomethacin was used as a positive control. The inducible NO production after stimulation was measured by Griess reagent. PGE2, IL-6 and TNF-alpha were measured by ELISA methods. Protein expressions of iNOS, COX2, and NF-kB were evaluated by Western blotting. Septic ICR mice were administered 20 mg/kg of LPS and then the mortality rate was monitored. Within the concentration range which was devoid of cytotoxicty, ?-thujaplicin exhibited a clear dose-dependent inhibition on LPS-induced NO production. Furthermore, ?-thujaplicin inhibited LPS-induced PGE2, IL-6, and TNF-alpha production as well as iNOS, COX2, and NF-kB protein expression more substantially potent than indomethacin. In agreement with the in vitro study, ?-thujaplicin was shown to be effective in vivo for inhibiting LPS-induced NO and TNF-alpha production and a significant decrease in mortality rate of mice suffering from septic shock was observed. This study demonstrates the potential of ?-thujaplicin in treatment of inflammation and sepsis. These effects occur through an efficient blockage of TNF-alpha and iNOS production. ?-thujaplicin efficacy is comparable to that of indomethacin thus it can be a substitution but bear less depletion of PGE2, making this compound very promising in clinical applications. PMID:22507316

Shih, M-F; Chen, L-Y; Tsai, P-J; Cherng, J-Y

2012-01-01

28

Euscaphic acid isolated from roots of Rosa rugosa inhibits LPS-induced inflammatory responses via TLR4-mediated NF-?B inactivation in RAW 264.7 macrophages.  

PubMed

As an attempt to search for bioactive natural products exerting anti-inflammatory activity, we have evaluated the anti-inflammatory effects of euscaphic acid (19?-hydroxyursane-type triterpenoids, EA) isolated from roots of Rosa rugosa and its underlying molecular mechanisms in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. EA concentration-dependently reduced the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-? (TNF-?), and interleukin-1? (IL-1?) induced by LPS in RAW 264.7 macgophages. Consistent with these data, expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein and iNOS, COX-2, TNF-?, and IL-1? mRNA were inhibited by EA in a concentration-dependent manner. In addition, EA attenuated LPS-induced DNA binding and transcriptional activity of nuclear factor-kappa B (NF-?B), which was accompanied by a parallel reduction of degradation and phosphorylation of inhibitory kappa B? (I?B?) and consequently by decreased nuclear translocation of p65 subunit of NF-?B. Pretreatment with EA significantly inhibited the LPS-induced phosphorylation of I?B kinase ? (IKK?), p38, and JNK, whereas the phosphorylation of ERK1/2 was unaffected. Furthermore, EA interfered with the LPS-induced clustering of TNF receptor-associated factor 6 (TRAF6) with interleukin receptor associated kinase 1 (IRAK1) and transforming growth factor-?-activated kinase 1 (TAK1). Taken together, these results suggest that EA inhibits LPS-induced inflammatory responses by interference with the clustering of TRAF6 with IRAK1 and TAK1, resulting in blocking the activation of IKK and MAPKs signal transduction to downregulate NF-?B activations. PMID:22234926

Kim, In-Tae; Ryu, Suran; Shin, Ji-Sun; Choi, Jung-Hye; Park, Hee-Juhn; Lee, Kyung-Tae

2012-06-01

29

Oroxylin-A Rescues LPS-Induced Acute Lung Injury via Regulation of NF-?B Signaling Pathway in Rodents  

PubMed Central

Background and Purpose Successful drug treatment for sepsis-related acute lung injury (ALI) remains a major clinical problem. This study was designed to assess the beneficial effects of post-treatment of oroxylin A (OroA), a flavonoid, in ameliorating lipopolysaccharides (LPS)-induced lung inflammation and fatality. Experimental Approach Rats were injected with LPS (10 mg/kg, iv) to induce ALI, and OroA was given (15 mg/kg, iv) 1 hr or 6 hrs after LPS challenge. Twenty four hrs after LPS challenge, biochemical changes in the blood and lung tissues, and morphological/histological alterations in the lung associated with inflammation and injury were examined. Therapeutic effect of OroA was assessed by measuring the survival rate in endotoxemic mice. Key Results LPS (10 mg/kg, iv) significantly altered WBC counts, elevated plasma tumor necrosis factor (TNF)-? and nitric oxide (NO), increased pulmonary edema, thickened alveolar septa, and decreased survival rate. These changes were ameliorated by OroA (15 mg/kg, iv) administered 1 hr or 6 hrs after LPS challenge. This post-treatment also significantly attenuated LPS-induced activation of nuclear factor-?B (NF-?B) and the release of high mobility group box 1 (HMGB1) in lung tissues. Furthermore, post-treatment with OroA (60 mg/kg, ip) administered 1 hr or 6 hrs after LPS challenge in mice significantly increased survival rate. Conclusion and Implication OroA administered after induction of ALI by LPS significantly prevent and revere lung tissues injuries with increased survival rate. Positive post-treatment effects of OroA suggest that OroA is a potentially useful candidate for managing lung inflammation in LPS-induced endotoxemia and septic shock. PMID:23071799

Tseng, Tzu-Ling; Chen, Mei-Fang; Tsai, Ming-Jen; Hsu, Yung-Hsiang; Chen, Chin-Piao; Lee, Tony J. F.

2012-01-01

30

Augmentation of LPS-induced vascular endothelial cell growth factor production in macrophages by transforming growth factor-?1.  

PubMed

The effect of LPS on the production of vascular endothelial growth factor (VEGF) was examined using RAW 264.7 macrophage cells. LPS induced VEGF production in RAW 264.7 cells and mouse peritoneal cells. LPS induced VEGF production via the expression of hypoxia inducible factor-1? and LPS-induced VEGF production was dependent on the activation of p38 MAPK and NF-?B activation· Transforming growth factor (TGF)-?1 augmented LPS-induced VEGF production, although TGF-?1 alone did not induce VEGF production. The augmentation of LPS-induced VEGF production by TGF-?1 was inhibited by a p38 MAPK inhibitor and was correlated with the phosphorylation of Smad3. The enhancing effect of TGF-?1 on LPS-induced VEGF production was observed in vivo in the skin lesions of mice receiving a subcutaneous injection of LPS. Taken together, it is suggested that LPS induced the VEGF production in macrophages and that it was augmented by TGF-?1 in vitro and in vivo. PMID:24225655

Koide, Naoki; Odkhuu, Erdenezaya; Naiki, Yoshikazu; Tsolmongyn, Bilegtsaikhan; Ito, Kiyoaki; Komatsu, Takayuki; Yoshida, Tomoaki; Yokochi, Takashi

2014-11-01

31

Leonurine exerts anti-inflammatory effect by regulating inflammatory signaling pathways and cytokines in LPS-induced mouse mastitis.  

PubMed

Bovine mastitis is defined as the inflammation of mammary gland and is the most multiple diseases in dairy cattle. There is still no effective treatment now. Leonurine, extracted from Leonurus cardiaca, has been proved to have anti-inflammatory effect. In the present study, we utilized a mouse mastitis model to study the effect of leonurine on LPS-induced mastitis. Leonurine was administered three times during the 24 h after inducing infection in the mammary gland. The results showed that leonurine significantly alleviated LPS-induced histopathological changes, downregulated the levels of pro-inflammatory cytokines tumor necrosis factor-? (TNF-?), interleukin-6 (IL-6), upregulated the level of anti-inflammatory cytokine interleukin-10 (IL-10), and inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Further study revealed that leonurine inhibited the expression of Toll-like receptor 4 (TLR4) and the activation of nuclear factor-kappaB (NF-?B) and the phosphorylation of p38, extracellular signal-regulated kinase (ERK), and Jun N-terminal kinase (JNK). Therefore, the results demonstrated that leonurine could downregulate the expression of TNF-?, IL-6, iNOS, and COX-2 and upregulate the expression of IL-10 mainly by inhibiting the expression of TLR4 and the activation of NF-?B and the phosphorylation of p38, ERK, and JNK. Leonurine may be a potential agent for mastitis therapy. PMID:25189466

Song, Xiaojing; Wang, Tiancheng; Zhang, Zecai; Jiang, Haichao; Wang, Wei; Cao, Yongguo; Zhang, Naisheng

2015-02-01

32

Agmatine prevents LPS-induced spatial memory impairment and hippocampal apoptosis.  

PubMed

Neuroinflammation is associated with a number of neurodegenerative diseases. It is known that lipopolysaccharide (LPS) treatment induces neuroinflammation and memory deterioration. Agmatine, the metabolite of arginine by arginine decarboxylase, is suggested to be a neuroprotective agent. The aim of this study was to explore if agmatine can prevent LPS-induced spatial memory impairment and hippocampal apoptosis. Adult male Wistar rats (200-250 g) were trained in water maze for 4 days (3 days in hidden platform and the last day in visible platform task). Saline, LPS (250 microg/kg/ip) or (and) agmatine (5 or 10 mg/kg) were administered 4h before every training session. LPS treatment impaired water maze place learning while agmatine co-administration prevented it. Also western blot studies revealed that LPS induces hippocampal caspase-3 activation while agmatine treatment prevented it. PMID:20184876

Zarifkar, Asadollah; Choopani, Samira; Ghasemi, Rasoul; Naghdi, Nasser; Maghsoudi, Amir Hossein; Maghsoudi, Nader; Rastegar, Karim; Moosavi, Maryam

2010-05-25

33

Effects of ginsenoside Re on LPS-induced inflammatory mediators in BV2 microglial cells  

PubMed Central

Background Microglial activation plays an important role in neurodegenerative diseases by producing several pro-inflammatory enzymes and pro-inflammatory cytokines. Lipopolysaccharide (LPS)-induced inflammation leads to the activation of microglial cells in the central nervous system (CNS) and is associated with the pathological mechanisms of neurodegenerative diseases, including PD, AD, and ALS. Ginseng is a natural antioxidant used in herbal medicine and contains ginsenosides (Rb1, Rg1, Rg3, Re, and Rd), which have anti-neoplastic and anti-stress properties. This study demonstrates the involvement of the anti-inflammatory signaling pathway, ginsenoside-Re (G-Re), which is one of the ginsenosides mediated by LPS-induced neuroinflammation in BV2 microglial cells. Methods BV2 microglial cells were pretreated with 2 ?g/ml G-Re and stimulated with 1 ?g/ml LPS to induce neuroinflammation. To investigate the effect of G-Re on LPS-induced cell signaling, we performed western blotting and immunofluorescence using specific antibodies, such as phospho-p38, COX2, and iNOS. Results Pretreatment with 2 ?g/ml G-Re was neuroprotective against 1 ?g/ml LPS-treated microglial cells. The neuroprotective events induced by G-Re treatment in neuroinflammation occurred via the phospho-p38, iNOS, and COX2 signaling pathways in BV2 cells. Conclusion Taken together, we suggest that G-Re exerts a beneficial effect on neuroinflammatory events in neurodegenerative diseases. PMID:23102375

2012-01-01

34

Protection against LPS-induced cartilage inflammation and degradation provided by a biological extract of Mentha spicata  

PubMed Central

Background A variety of mint [Mentha spicata] has been bred which over-expresses Rosmarinic acid (RA) by approximately 20-fold. RA has demonstrated significant anti-inflammatory activity in vitro and in small rodents; thus it was hypothesized that this plant would demonstrate significant anti-inflammatory activity in vitro. The objectives of this study were: a) to develop an in vitro extraction procedure which mimics digestion and hepatic metabolism, b) to compare anti-inflammatory properties of High-Rosmarinic-Acid Mentha spicata (HRAM) with wild-type control M. spicata (CM), and c) to quantify the relative contributions of RA and three of its hepatic metabolites [ferulic acid (FA), caffeic acid (CA), coumaric acid (CO)] to anti-inflammatory activity of HRAM. Methods HRAM and CM were incubated in simulated gastric and intestinal fluid, liver microsomes (from male rat) and NADPH. Concentrations of RA, CA, CO, and FA in simulated digest of HRAM (HRAMsim) and CM (CMsim) were determined (HPLC) and compared with concentrations in aqueous extracts of HRAM and CM. Cartilage explants (porcine) were cultured with LPS (0 or 3 ?g/mL) and test article [HRAMsim (0, 8, 40, 80, 240, or 400 ?g/mL), or CMsim (0, 1, 5 or 10 mg/mL), or RA (0.640 ?g/mL), or CA (0.384 ?g/mL), or CO (0.057 ?g/mL) or FA (0.038 ?g/mL)] for 96 h. Media samples were analyzed for prostaglandin E2 (PGE2), interleukin 1? (IL-1), glycosaminoglycan (GAG), nitric oxide (NO) and cell viability (differential live-dead cell staining). Results RA concentration of HRAMsim and CMsim was 49.3 and 0.4 ?g/mL, respectively. CA, FA and CO were identified in HRAMsim but not in aqueous extract of HRAM. HRAMsim (? 8 ?g/mL) inhibited LPS-induced PGE2 and NO; HRAMsim (? 80 ?g/mL) inhibited LPS-induced GAG release. RA inhibited LPS-induced GAG release. No anti-inflammatory or chondroprotective effects of RA metabolites on cartilage explants were identified. Conclusions Our biological extraction procedure produces a substance which is similar in composition to post-hepatic products. HRAMsim is an effective inhibitor of LPS-induced inflammation in cartilage explants, and effects are primarily independent of RA. Further research is needed to identify bioactive phytochemical(s) in HRAMsim. PMID:20459798

2010-01-01

35

Endocannabinoid 2-arachidonylglycerol protects primary cultured neurons against LPS-induced impairments in rat caudate nucleus.  

PubMed

Inflammation plays a pivotal role in the pathogenesis of many diseases in the central nervous system. Caudate nucleus (CN), the largest nucleus in the brain, is also implicated in many neurological disorders. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid and the true natural ligand for CB1 receptors, has been shown to exhibit neuroprotective effects through its anti-inflammatory action from proinflammatory stimuli in hippocampus. However, it is still not clear whether 2-AG is also able to protect CN neurons from proinflammation stimuli. In the present study, we discovered that 2-AG significantly protects CN neurons in culture against lipopolysaccharide (LPS)-induced inflammatory response. 2-AG is capable of suppressing elevation of LPS-induced cyclooxygenase-2 expression associated with ERK/p38MAPK/NF-?B signaling pathway in CB1 receptor-dependant manner in primary cultured CN neurons. Moreover, 2-AG inhibits LPS-induced increase in voltage-gated sodium channel currents and hyperpolarizing shift of activation curves through CB1 receptor-dependant pathway. Our study suggests the therapeutic potential of 2-AG for the treatment of some inflammation-induced neurological disorders and pain. PMID:24510751

Lu, Yongli; Peng, Fang; Dong, Manman; Yang, Hongwei

2014-09-01

36

Impact of LPS-Induced Cardiomyoblast Cell Apoptosis Inhibited by Earthworm Extracts.  

PubMed

Dilong is an earthworm extract with a dense nutritional content, widely used in Chinese herbal medicine to remove stasis and stimulate wound healing. Earthworm extracts are traditionally used by indigenous people throughout the world. How this Dilong inhibits Lipopolysaccharide (LPS)-induced cardiomyoblast cell apoptosis is still unclear. This study investigates the Dilong extract effect on LPS-induced apoptosis in H9c2 cardiomyoblast cells. LPS (1 ?g/ml) administration for 24 h induced apoptosis in H9c2 cells. Cell apoptosis was detected using MTT, LDH, TUNEL assay and JC-1 staining. Western blot analysis was used to detect pro-apoptotic and anti-apoptotic proteins. Dilong extract totally blocked the LPS impact, leading to the activation of anti-apoptotic proteins, Bcl-2 and Bcl-xL, stabilized the mitochondria membrane and down-regulated the extrinsic and intrinsic pro-apoptotic proteins, TNF-?, active caspase-8, t-Bid, Bax, active caspase-9 and active caspase-3. Dilong could potentially serve as a cardio protective agent against LPS-induced H9c2 cardiomyoblast cell apoptosis. PMID:25249212

Li, Ping-Chun; Tien, Yun-Chen; Day, Cecilia Hsuan; Pai, Peiying; Kuo, Wei-Wen; Chen, Tung-Sheng; Kuo, Chia-Hua; Tsai, Chang-Hai; Ju, Da-Tong; Huang, Chih-Yang

2014-09-24

37

Inhibitory effects of orally administrated liposomal bovine lactoferrin on the LPS-induced osteoclastogenesis  

Microsoft Academic Search

Bovine lactoferrin (bLF) modulates the production of proinflammatory cytokines including tumor necrosis factor (TNF)-?, and may thus control alveolar bone destruction associated with periodontitis. In this study, the effects of bLF on mRNA expression in lipopolysaccharide (LPS)-stimulated osteoblasts (OBs) and on LPS-induced osteoclastogenesis were examined. The inhibitory effects of oral administration of liposomal-bLF (L-bLF), which improved the robustness of bLF

Eizo Yamano; Mutsumi Miyauchi; Hisako Furusyo; Aki Kawazoe; Atsushi Ishikado; Taketoshi Makino; Kazuo Tanne; Eiji Tanaka; Takashi Takata

2010-01-01

38

Tim-3 Negatively Mediates Natural Killer Cell Function in LPS-Induced Endotoxic Shock  

PubMed Central

Sepsis is an exaggerated inflammatory condition response to different microorganisms with high mortality rates and extremely poor prognosis. Natural killer (NK) cells have been reported to be the major producers of IFN-? and key players in promoting systematic inflammation in lipopolysaccharide (LPS)-induced endotoxic shock. T-cell immunoglobulin and mucin domain (Tim)-3 pathway has been demonstrated to play an important role in the process of sepsis, however, the effect of Tim-3 on NK cell function remains largely unknown. In this study, we observed a dynamic inverse correlation between Tim-3 expression and IFN-? production in NK cells from LPS-induced septic mice. Blockade of the Tim-3 pathway could increase IFN-? production and decrease apoptosis of NK cells in vitro, but had no effect on the expression of CD107a. Furthermore, NK cell cytotoxicity against K562 target cells was enhanced after blocking Tim-3 pathway. In conclusion, our results suggest that Tim-3 pathway plays an inhibitory role in NK cell function, which might be a potential target in modulating the excessive inflammatory response of LPS-induced endotoxic shock. PMID:25337993

Hou, Hongyan; Liu, Weiyong; Wu, Shiji; Lu, Yanjun; Peng, Jing; Zhu, Yaowu; Lu, Yanfang; Wang, Feng; Sun, Ziyong

2014-01-01

39

Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury.  

PubMed

Abstract We have previously shown that the prophylactic treatment with cannabidiol (CBD) reduces inflammation in a model of acute lung injury (ALI). In this work we analyzed the effects of the therapeutic treatment with CBD in mice subjected to the model of lipopolysaccharide (LPS)-induced ALI on pulmonary mechanics and inflammation. CBD (20 and 80?mg/kg) was administered (i.p.) to mice 6?h after LPS-induced lung inflammation. One day (24?h) after the induction of inflammation the assessment of pulmonary mechanics and inflammation were analyzed. The results show that CBD decreased total lung resistance and elastance, leukocyte migration into the lungs, myeloperoxidase activity in the lung tissue, protein concentration and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) in the bronchoalveolar lavage supernatant. Thus, we conclude that CBD administered therapeutically, i.e. during an ongoing inflammatory process, has a potent anti-inflammatory effect and also improves the lung function in mice submitted to LPS-induced ALI. Therefore the present and previous data suggest that in the future cannabidiol might become a useful therapeutic tool for the attenuation and treatment of inflammatory lung diseases. PMID:25356537

Ribeiro, A; Almeida, V I; Costola-de-Souza, C; Ferraz-de-Paula, V; Pinheiro, M L; Vitoretti, L B; Gimenes-Junior, J A; Akamine, A T; Crippa, J A; Tavares-de-Lima, W; Palermo-Neto, J

2015-02-01

40

A G protein-associated ERK pathway is involved in LPS-induced proliferation and a PTK-associated p38 MAPK pathway is involved in LPS-induced differentiation in resting B cells  

Microsoft Academic Search

We, previously, showed that PKC-dependent ERK\\/p38 MAPK activation was inhibited by treating the resting B cell line 38B9 with an anti-MHC class II antibody. Further studies in this work demonstrated that PKA was involved in lipopolysaccharide (LPS)-induced proliferation of the cells, such that the PKC inhibitor activated PKA with concomitant LPS-induced proliferation but not IgG secretion. Consequently, the PKA inhibitor

Ju Kim; Hee-Young Yang; Yong-Suk Jang

2006-01-01

41

Protection of mice from LPS-induced shock by CD14 antisense oligonucleotide.  

PubMed

CD14 is a pattern recognition receptor on myeloid cells and plays a pivotal role in an innate immune system that is responsible for Gram-negative and Gram-positive bacteria infection. Lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, can induce production of a large quantity of proinflammatory cytokines into the circulation mediated by CD14-mediated macrophages and monocytes. These cytokines eventually cause septic shock. Several in vitro and in vivo studies have shown that suppression of a CD14 function by a CD14 antibody led to an inhibition of the production of proinflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-8. In the present study, we found that CD14 antisense oligonucleotide (ODN) can prevent lethal LPS shock in D-galactosamine-sensitized mice. This ODN inhibited CD14 expression in a mouse macrophage cell line, RAW264.7, and suppressed production of TNF-alpha in LPS-stimulated RAW264.7 cells. Furthermore, we designed a consensus antisense ODN that could hybridize human and mouse CD14 RNA, and we evaluated its efficacy. The consensus antisense ODN rescued mice primed with Mycobacterium bovis bacillus Calmette-Guerin (BCG) from the LPS-induced lethal shock. In this model, the CD14 antisense ODN down-regulated LPS-elicited CD14 expression in the liver, resulting in a decrease in LPS-induced TNF-alpha production. These findings suggest that the CD14 antisense ODN is distributed in the liver and efficiently suppresses LPS-induced TNF-alpha production by reducing CD14 expression on Kupffer cells. This CD14 antisense ODN may be useful for the development of a therapeutic agent against sepsis and septic shock. PMID:11332197

Furusako, S; Takahashi, T; Mori, S; Takahashi, Y; Tsuda, T; Namba, M; Mochizuki, H

2001-04-01

42

Pathophysiology of LPS-induced gastrointestinal injury in the rat: role of secretory phospholipase A2.  

PubMed

A hydrophobic layer of phosphatidylcholine (PC) overlies and protects the surface of the gastrointestinal (GI) tract, contributing to barrier integrity. During critical illness such as sepsis, gut barrier integrity is compromised, which could be related to degradation of PC. The purpose of this study was to investigate a role for luminal (secretory) phospholipase A2 (sPLA(2)) in LPS-induced GI injury. Rats were treated with LPS (5 mg/kg) or saline for 0.5, 1, 3, and 5 h. The gastric and ileal luminal contents were collected for determination of sPLA(2) activity, and the luminal lipids were analyzed using thin layer chromatography for lyso-PC content. The GI permeability was assessed in vivo with fluorescein-isothiocyanate dextran 4000 and rats were tested with or without a specific sPLA(2) inhibitor. LPS induced significant increases in sPLA(2) activity and lyso-PC content in the gastric and ileal lumens at 5 h. In addition, LPS treated rats showed a significant increase in GI permeability to fluorescein-isothiocyanate dextran in both the stomach and ileum at 5 h, which was prevented by pretreatment with the sPLA(2) inhibitor. In response to LPS, sPLA(2) activity increases in the GI tract lumen where it may degrade the extracellular protective phospholipid layer and membranes, producing injurious lyso-PC and increased GI permeability. Pretreatment with an orally active sPLA(2) inhibitor blocks the LPS-induced increase in GI permeability, and may suggest a new approach to fortify the GI mucosal barrier and prevent complications from endotoxin in trauma and other patients. PMID:18180698

Zayat, Mayssa; Lichtenberger, Lenard M; Dial, Elizabeth J

2008-08-01

43

Molecular Hydrogen Reduces LPS-Induced Neuroinflammation and Promotes Recovery from Sickness Behaviour in Mice  

PubMed Central

Molecular hydrogen has been shown to have neuroprotective effects in mouse models of acute neurodegeneration. The effect was suggested to be mediated by its free-radical scavenger properties. However, it has been shown recently that molecular hydrogen alters gene expression and protein phosphorylation. The aim of this study was to test whether chronic ad libitum consumption of molecular hydrogen-enriched electrochemically reduced water (H-ERW) improves the outcome of lipopolysaccharide (LPS)-induced neuroinflammation. Seven days after the initiation of H-ERW treatment, C57Bl/6 mice received a single injection of LPS (0.33 mg/kg i.p.) or an equivalent volume of vehicle. The LPS-induced sickness behaviour was assessed 2 h after the injection, and recovery was assessed by monitoring the spontaneous locomotor activity in the homecage for 72 h after the administration of LPS. The mice were killed in the acute or recovery phase, and the expression of pro- and antiinflammatory cytokines in the hippocampus was assessed by real-time PCR. We found that molecular hydrogen reduces the LPS-induced sickness behaviour and promotes recovery. These effects are associated with a shift towards anti-inflammatory gene expression profile at baseline (downregulation of TNF- ? and upregulation of IL-10). In addition, molecular hydrogen increases the amplitude, but shortens the duration and promotes the extinction of neuroinflammation. Consistently, molecular hydrogen modulates the activation and gene expression in a similar fashion in immortalized murine microglia (BV-2 cell line), suggesting that the effects observed in vivo may involve the modulation of microglial activation. Taken together, our data point to the regulation of cytokine expression being an additional critical mechanism underlying the beneficial effects of molecular hydrogen. PMID:22860058

Spulber, Stefan; Edoff, Karin; Hong, Lie; Morisawa, Shinkatsu; Shirahata, Sanetaka; Ceccatelli, Sandra

2012-01-01

44

Molecular hydrogen reduces LPS-induced neuroinflammation and promotes recovery from sickness behaviour in mice.  

PubMed

Molecular hydrogen has been shown to have neuroprotective effects in mouse models of acute neurodegeneration. The effect was suggested to be mediated by its free-radical scavenger properties. However, it has been shown recently that molecular hydrogen alters gene expression and protein phosphorylation. The aim of this study was to test whether chronic ad libitum consumption of molecular hydrogen-enriched electrochemically reduced water (H-ERW) improves the outcome of lipopolysaccharide (LPS)-induced neuroinflammation. Seven days after the initiation of H-ERW treatment, C57Bl/6 mice received a single injection of LPS (0.33 mg/kg i.p.) or an equivalent volume of vehicle. The LPS-induced sickness behaviour was assessed 2 h after the injection, and recovery was assessed by monitoring the spontaneous locomotor activity in the homecage for 72 h after the administration of LPS. The mice were killed in the acute or recovery phase, and the expression of pro- and antiinflammatory cytokines in the hippocampus was assessed by real-time PCR. We found that molecular hydrogen reduces the LPS-induced sickness behaviour and promotes recovery. These effects are associated with a shift towards anti-inflammatory gene expression profile at baseline (downregulation of TNF- ? and upregulation of IL-10). In addition, molecular hydrogen increases the amplitude, but shortens the duration and promotes the extinction of neuroinflammation. Consistently, molecular hydrogen modulates the activation and gene expression in a similar fashion in immortalized murine microglia (BV-2 cell line), suggesting that the effects observed in vivo may involve the modulation of microglial activation. Taken together, our data point to the regulation of cytokine expression being an additional critical mechanism underlying the beneficial effects of molecular hydrogen. PMID:22860058

Spulber, Stefan; Edoff, Karin; Hong, Lie; Morisawa, Shinkatsu; Shirahata, Sanetaka; Ceccatelli, Sandra

2012-01-01

45

General Anesthetics Inhibit LPS-Induced IL-1? Expression in Glial Cells  

PubMed Central

Background Glial cells, including microglia and astrocytes, are considered the primary source of proinflammatory cytokines in the brain. Immune insults stimulate glial cells to secrete proinflammatory cytokines that modulate the acute systemic response, which includes fever, behavioral changes, and hypothalamic-pituitary-adrenal (HPA) axis activation. We investigated the effect of general anesthetics on proinflammatory cytokine expression in the primary cultured glial cells, the microglial cell line BV-2, the astrocytic cell line A-1 and mouse brain. Methodology/Principal Findings Primary cultured glial cells were exposed to lipopolysaccharide (LPS) in combination with general anesthetics including isoflurane, pentobarbital, midazolam, ketamine, and propofol. Following this treatment, we examined glial cell expression of the proinflammatory cytokines interleukin (IL)-1?, IL-6, and tumor necrosis factor-alpha (TNF-?). LPS-induced expression of IL-1? mRNA and protein were significantly reduced by all the anesthetics tested, whereas IL-6 and TNF-? mRNA expression was unaffected. The anesthetics suppressed LPS-induced extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation, but did not affect nuclear factor-kappaB and activator protein-1 activation. The same effect was observed with BV-2, but not with A-1 cells. In the mouse experiments, LPS was injected intraperitoneally, and isoflurane suppressed IL-1? in the brain and adrenocorticotropic hormone in plasma, but not IL-1? in plasma. Conclusions/Significance Taken together, our results indicate that general anesthetics inhibit LPS-induced IL-1? upregulation in glial cells, particularly microglia, and affects HPA axis participation in the stress response. PMID:24349401

Tanaka, Tomoharu; Kai, Shinichi; Matsuyama, Tomonori; Adachi, Takehiko; Fukuda, Kazuhiko; Hirota, Kiichi

2013-01-01

46

Manganese Potentiates LPS-Induced Heme-Oxygenase 1 in Microglia but not Dopaminergic Cells: Role in Controlling Microglial Hydrogen Peroxide and Inflammatory Cytokine Output  

PubMed Central

Excessive manganese (Mn) exposure increases output of glial-derived inflammatory products, which may indirectly contribute to the neurotoxic effects of this essential metal. In microglia, Mn increases hydrogen peroxide (H2O2) release and potentiates lipopolysaccharide (LPS)-induced cytokines (TNF-?, IL-6) and nitric oxide (NO). Inducible heme-oxygenase (HO-1) plays a role in the regulation of inflammation and its expression is upregulated in response to oxidative stressors, including metals and LPS. Because Mn can oxidatively affect neurons both directly and indirectly, we investigated the effect of Mn exposure on the induction of HO-1 in resting and LPS-activated microglia (N9) and dopaminergic neurons (N27). In microglia, 24 h exposure to Mn (up to 250 ?M) had minimal effects on its own, but it markedly potentiated LPS (100 ng/ml)-induced HO-1protein and mRNA. Inhibition of microglial HO-1 activity with two different inhibitors indicated that HO-1 is a positive regulator of the Mn-potentiated cytokine output and a negative regulator of the Mn-induced H2O2 output. Mn enhancement of LPS-induced HO-1 does not appear to be dependent on H2O2 or NO, as Mn+LPS-induced H2O2 release was not greater than the increase induced by Mn alone and inhibition of iNOS did not change Mn potentiation of HO-1. However, because Mn exposure potentiated the LPS-induced nuclear expression of small Maf proteins, this may be one mechanism Mn uses to affect the expression of HO-1 in activated microglia. Finally, the potentiating effects of Mn on HO-1 appear to be glia-specific for Mn, LPS, or Mn+LPS did not induce HO-1 in N27 neuronal cells. PMID:21963524

Dodd, Celia A.; Filipov, Nikolay M.

2012-01-01

47

Lactoferrin prevents LPS-induced decrease of the iron exporter ferroportin in human monocytes/macrophages.  

PubMed

Iron balance is tightly linked to inflammation and it has been demonstrated that many proteins involved in cellular iron management are up- or down-regulated by inflammatory stimuli, ultimately leading to iron retention in the reticuloendothelial system. Ferroportin is a key player in maintenance of correct iron homeostasis, because it is the only known mammalian cellular iron exporter. In this work we show that incubation of THP-1 monocytes/macrophages with lactoferrin prevents the LPS-induced decrease of ferroportin by reducing secretion of IL-6. PMID:24793588

Cutone, Antimo; Frioni, Alessandra; Berlutti, Francesca; Valenti, Piera; Musci, Giovanni; Bonaccorsi di Patti, Maria Carmela

2014-10-01

48

Hemopexin down-regulates LPS-induced proinflammatory cytokines from macrophages  

PubMed Central

Detection of LPS in tissues is an integral component of innate immunity that acts to protect against invasion by Gram-negative bacteria. Plasma down-regulates LPS-induced cytokine production from macrophages, thereby limiting systemic inflammation in blood and distant tissues. To identify the protein(s) involved in this process, we used classical biochemical chromatographic techniques to identify fractions of mouse sera that suppress LPS-induced TNF from bone marrow-derived macrophages (BMDMs). Fractionation yielded microgram quantities of a protein that was identified by MS to be hemopexin (Hx). Mouse Hx purified on hemin-agarose beads and rhHx decreased the production of cytokines from BMDMs and peritoneal macrophages induced by LPS. Preincubation of LPS with Hx did not affect the activity of LPS on LAL, whereas preincubation of Hx with macrophages followed by washing resulted in decreased activity of these cells in response to LPS, suggesting that Hx acts on macrophages rather than LPS. Heme-free Hx did not stimulate HO-1 in the macrophages. Purified Hx also decreased TNF and IL-6 from macrophages induced by the synthetic TLR2 agonist Pam3Cys. Our data suggest that Hx, which is an acute-phase protein that increases during inflammation, limits TLR4 and TLR2 agonist-induced macrophage cytokine production directly through a mechanism distinct from HO-1. PMID:19395472

Liang, Xueya; Lin, Tian; Sun, Guangjie; Beasley-Topliffe, Laura; Cavaillon, Jean-Marc; Warren, H. Shaw

2009-01-01

49

Critical role of endothelial CXCR2 in LPS-induced neutrophil migration into the lung  

PubMed Central

In models of acute lung injury, CXC chemokine receptor 2 (CXCR2) mediates migration of polymorphonuclear leukocytes (PMNs) into the lung. Since CXCR2 ligands, including CXCL1 and CXCL2/3, are chemotactic for PMNs, CXCR2 is thought to recruit PMNs by inducing chemotactic migration. In a model of PMN recruitment to the lung, aerosolized bacterial LPS inhalation induced PMN recruitment to the lung in wild-type mice, but not in littermate CXCR2–/– mice. Surprisingly, lethally irradiated wild-type mice reconstituted with CXCR2–/– BM still showed about 50% PMN recruitment into bronchoalveolar lavage fluid and into lung interstitium, but CXCR2–/– mice reconstituted with CXCR2–/– BM showed no PMN recruitment. Conversely, CXCR2–/– mice reconstituted with wild-type BM showed a surprisingly large defect in PMN recruitment, inconsistent with a role of CXCR2 on PMNs alone. Cell culture, immunohistochemistry, flow cytometry, and real-time RT-PCR were used to show expression of CXCR2 on pulmonary endothelial and bronchial epithelial cells. The LPS-induced increase in lung microvascular permeability as measured by Evans blue extravasation required CXCR2 on nonhematopoietic cells. Our data revealed what we believe to be a previously unrecognized role of endothelial and epithelial CXCR2 in LPS-induced PMN recruitment and lung injury. PMID:16485040

Reutershan, Jörg; Morris, Margaret A.; Burcin, Tracy L.; Smith, David F.; Chang, Daniel; Saprito, Mary S.; Ley, Klaus

2006-01-01

50

Monoammonium glycyrrhizinate inhibited the inflammation of LPS-induced acute lung injury in mice.  

PubMed

Monoammonium glycyrrhizinate (MAG) was the aglycone of glycyrrhizin derived from licorice. In this study, the anti-inflammatory effects of MAG on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and the possible mechanisms involved in this protection were investigated. Pretreatment with MAG prior to the administration of intratracheal LPS significantly induced a decrease in lung wet weight/dry weight ratio, in total leukocyte number and neutrophil percent in the BALF, and in myeloperoxidase (MPO) activity of lung in dose-dependent manners. At the same time, pretreatment with MAG also significantly improved the super oxide dismutase (SOD) activity and induced the malondialdehyde (MDA) content in the bronchoalveolar lavage fluid (BALF). Importantly, pretreatment with MAG prevented an increase in cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE) activity of lung in a dose-dependent manner. In addition, it can up-regulate the interleukin-10 (IL-10) level and down-regulate the tumor neurosis factor-? (TNF-?) level in the lung tissue of ALI mice. These results showed that anti-inflammatory effects of MAG against the LPS-induced ALI may be due to its ability of primary inhibition of cAMP-PDE activity, oxidative stress and its regulation of cytokine effects. Thus the results support that use of MAG is beneficial in the treatment of ALI and ARDS. PMID:20637836

Shi, Jian-Rong; Mao, Lian-Gen; Jiang, Ruo-An; Qian, Yun; Tang, Hui-Fang; Chen, Ji-Qiang

2010-10-01

51

Effects of PPAR-? agonist treatment on LPS-induced mastitis in rats.  

PubMed

PPAR-?, a member of the nuclear receptor superfamily, plays an important role in lipid metabolism and inflammation. The aim of this study was to investigate the preventive effects of synthetic PPAR-? agonist rosiglitazone on lipopolysaccharide (LPS)-induced mastitis in rats. The mouse model of mastitis was induced by the injection of LPS through the duct of the mammary gland. Rosiglitazone was injected 1 h before the induction of LPS intraperitoneally. The results showed that rosiglitazone attenuated the infiltration of inflammatory cells, the activity of myeloperoxidase (MPO), and the production of tumor necrosis factor-? (TNF-?), interleukin-6 (IL-6), and interleukin-1? (IL-1?) in a dose-dependent manner. Additionally, Western blotting showed that rosiglitazone inhibited the phosphorylation of I?B-? and NF-?B p65. These results indicated that rosiglitazone has a protective effect on mastitis, and the anti-inflammatory mechanism of rosiglitazone on LPS-induced mastitis in rats may be due to its ability to inhibit NF-?B signaling pathways. PPAR-? may be a potential therapeutic target against mastitis. PMID:24839089

Mingfeng, Ding; Xiaodong, Ming; Yue, Liu; Taikui, Piao; Lei, Xiao; Ming, Liu

2014-12-01

52

Cannabidiol (CBD) Enhances Lipopolysaccharide (LPS)-Induced Pulmonary Inflammation in C57BL/6 Mice  

PubMed Central

Cannabidiol (CBD) is a plant-derived cannabinoid that has been predominantly characterized as anti-inflammatory. However, it is clear that immune effects of cannabinoids can vary with cannabinoid concentration, or type or magnitude of immune stimulus. The present studies demonstrate that oral administration of CBD enhanced lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice. The enhanced inflammatory cell infiltrate as observed in bronchoalveolar lavage fluid (BALF) was comprised mainly of neutrophils, with some monocytes. Concomitantly, CBD enhanced pro-inflammatory cytokine mRNA production, including tumor necrosis factor-? (Tnfa), interleukins (IL) 6 and 23 (Il6, Il23), and granulocyte colony stimulating factor (Gcsf). These results demonstrate that the CBD-mediated enhancement of LPS-induced pulmonary inflammation is mediated at the level of transcription of a variety of pro-inflammatory genes. The significance of these studies is that CBD is part of a therapeutic currently in use for spasticity and pain in multiple sclerosis patients, and therefore it is important to further understand mechanisms by which CBD alters immune function. PMID:23173851

Karmaus, Peer W. F.; Wagner, James G.; Harkema, Jack R.; Kaminski, Norbert E.; Kaplan, Barbara L.F.

2012-01-01

53

BHBA Suppresses LPS-Induced Inflammation in BV-2 Cells by Inhibiting NF-?B Activation  

PubMed Central

?-Hydroxybutyric acid (BHBA) has neuroprotective effects, but the underlying molecular mechanisms are unclear. Microglial activation plays an important role in neurodegenerative diseases by producing several proinflammatory enzymes and proinflammatory cytokines. The current study investigates the potential mechanisms whereby BHBA affects the expression of potentially proinflammatory proteins by cultured murine microglial BV-2 cells stimulated with lipopolysaccharide (LPS). The results showed that BHBA significantly reduced LPS-induced protein and mRNA expression levels of iNOS, COX-2, TNF-?, IL-1?, and IL-6. Blocking of GPR109A by PTX resulted in a loss of this anti-inflammatory effect in BV-2 cells. Western blot analysis showed that BHBA reduced LPS-induced degradation of I?B-? and translocation of NF-?B, while no effect was observed on MAPKs phosphorylation. All results imply that BHBA significantly reduces levels of proinflammatory enzymes and proinflammatory cytokines by inhibition of the NF-?B signaling pathway but not MAPKs pathways, and GPR109A is essential to this function. Overall, these data suggest that BHBA has a potential as neuroprotective drug candidate in neurodegenerative diseases. PMID:24803746

Fu, Shou-Peng; Li, Su-Nan; Wang, Jian-Fa; Li, Yang; Xie, Shan-Shan; Xue, Wen-Jing; Liu, Hong-Mei; Huang, Bing-Xu; Lv, Qing-Kang; Lei, Lian-Cheng; Liu, Guo-Wen; Wang, Wei; Liu, Ju-Xiong

2014-01-01

54

Calorie restriction attenuates lipopolysaccharide (LPS)-induced microglial activation in discrete regions of the hypothalamus and the subfornical organ.  

PubMed

Calorie restriction (CR) has been shown to increase longevity and elicit many health promoting benefits including delaying immunosenescence and attenuating neurodegeneration in animal models of Alzheimer's disease and Parkinson's disease. CR also suppresses microglial activation following cortical injury and aging. We previously demonstrated that CR attenuates lipopolysaccharide (LPS)-induced fever and shifts hypothalamic signaling pathways to an anti-inflammatory bias; however, the effects of CR on LPS-induced microglial activation remain largely unexplored. The current study investigated regional changes in LPS-induced microglial activation in mice exposed to 50% CR for 28days. Immunohistochemistry was conducted to examine changes in ionized calcium-binding adapter molecule-1 (Iba1), a protein constitutively expressed by microglia, in a total of 27 brain regions involved in immunity, stress, and/or thermoregulation. Exposure to CR attenuated LPS-induced fever, and LPS-induced microglial activation in a subset of regions: the arcuate nucleus (ARC) and ventromedial nucleus of the hypothalamus (VMH) and the subfornical organ (SFO). Microglial activation in the ARC and VMH was positively correlated with body temperature. These data suggest that CR exerts effects on regionally specific populations of microglia; particularly, in appetite-sensing regions of the hypothalamus, and/or regions lacking a complete blood brain barrier, possibly through altered pro- and anti-inflammatory signaling in these regions. PMID:24291211

Radler, Morgan E; Hale, Matthew W; Kent, Stephen

2014-05-01

55

Inhibition of LPS-induced inflammatory biomarkers by ethyl acetate fraction of Patrinia scabiosaefolia through suppression of NF-?B activation in RAW 264.7 cells.  

PubMed

Patrinia scabiosaefolia (PS) has been used for curing various types of inflammatory-related disorders. However, the precise mechanism of the anti-inflammatory activity of PS remains unclear. Here, we investigated the anti-inflammatory effects of several fractions isolated from the PS in RAW 264.7 macrophages. The results indicated that the ethyl acetate fraction of PS (EAPS) concentration highly suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO) and IL-6 productions without a cytotoxic effect on RAW 264.7 cells. EAPS inhibited the expressions of LPS-induced iNOS and COX-2 protein and their mRNA in a dose-dependent manner. Particularly, EAPS suppressed the level of nuclear factor-?B (NF-?B) activity, which was linked with the suppression of LPS-induced phosphorylation of p65 at serine 276 and p65 translocation into nuclei, but not MAPK signaling. In addition, treatment with EAPS inhibited the production of TNF-? in LPS-injected mice and suppressed the production of IL-6 and TNF-? in LPS-stimulated splenocytes from BALB/c mice. Therefore, we demonstrate here that Patrinia scabiosaefolia potentially inhibits the biomarkers related to inflammation through the blocking of NF-?B p65 activation, and it may be a potential therapeutic candidate for the treatment of inflammatory diseases. PMID:21854107

Lee, Eun-Jung; Kim, Chulwon; Kim, Jin-Young; Kim, Sung-Moo; Nam, Dongwoo; Jang, Hyeung-Jin; Kim, Sung-Hoon; Shim, Bum Sang; Ahn, Kyoo Seok; Choi, Seung-Hoon; Jung, Sang Hoon; Ahn, Kwang Seok

2012-04-01

56

Alpinia katsumadai H(AYATA) seed extract inhibit LPS-induced inflammation by induction of heme oxygenase-1 in RAW264.7 cells.  

PubMed

In the present study, we investigated the effects of Alpinia katsumadai H(AYATA) (Zingiberaceae) seed ethanolic extract (AKEE) and its three components on the production of inflammatory mediators and some potential underlying mechanisms in lipopolysaccharide (LPS)-induced inflammation RAW264.7 cells. The whole formula, AKEE, and three major component compounds were then evaluated for their effects on inflammation-related parameters using LPS-induced RAW264.7 cells. Production of namely nitric oxide (NO) and cytokine levels were measured by the Griess reagent and ELISA, respectively. To investigate the underlying mechanisms of anti-inflammatory activities of AKEE, protein expression of nitric oxide synthase (inducible nitric oxide synthase, iNOS), heme oxygenase-1 (HO-1), and nuclear factor-kappa B (NF-?B) were evaluated by western blot analysis. AKEE and the major group of compounds in AKEE (alpinetin, cardamonin, and pinocembrin) complement exert anti-inflammatory effects for NO and PGE(2) production. In addition, AKEE treatment significantly inhibited the LPS-induced production of interleukin-6 and tumor necrosis factor (TNF)-?, as well as the expression of iNOS. AKEE also induced HO-1 expression in RAW264.7 cells and inhibited the nuclear translocation of NF-?B by preventing degradation of the inhibitor kappa B-alpha. We also demonstrated that the effects of AKEE on TNF-? production were partially reversed by the HO-1 inhibitor tin protoporphyrin. These results indicate that AKEE and its major component may have anti-inflammatory activity via induction of HO-1 expression was partly responsible for the anti-inflammatory effects. PMID:21830094

Lee, Mee-Young; Seo, Chang-Seob; Lee, Jin-Ah; Shin, In-Sik; Kim, Su-Jeong; Ha, HeyKyung; Shin, Hyeun-Kyoo

2012-04-01

57

Protective effect of suberoylanilide hydroxamic acid against LPS-induced septic shock in rodents.  

PubMed

We have recently found that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improves survival in a lethal model of hemorrhagic shock in rats. The purpose of the present study was to determine whether SAHA treatment would prevent LPS-induced septic shock and improve the survival in a murine model. C57BL/6J mice were randomly divided into two groups. Experimental mice were given intraperitoneal SAHA (50 mg/kg) in vehicle dimethyl sulfoxide fluid (n = 10). The control mice (n = 10) received vehicle dimethyl sulfoxide only. They were injected with LPS (20 mg/kg, i.p.) 2 h later, and the animals from the treatment group were given a second dose of SAHA. Survival was monitored during the next 7 days. In a parallel study, mice treated with or without SAHA were subjected to LPS insult while normal (sham) mice serviced as controls. 1) Lungs were harvested at 3 and 48 h for analysis of gene expression and pathologic changes, respectively; 2) spleens were isolated for analysis of neutrophilic cell population. In addition, RAW264.7 mouse macrophages were cultured to assess the effects of SAHA on LPS-induced inflammation in vitro. All mice in the control group that were subjected to LPS challenge died in less than 48 h. However, SAHA-treated animals displayed a significantly higher 1-week survival rate (87.5%) compared with the control group (0%). Moreover, LPS insult decreased the acetylation of histone proteins (H2A, H2B, and H3), elevated the levels of TNF-alpha in vivo (circulation) and in vitro (culture medium), increased the neutrophilic cell population in the spleen, enhanced the expression of TNF-alpha and IL-1beta genes in lung tissue, and augmented the pulmonary neutrophil infiltration. In contrast, SAHA treatment markedly attenuated all of these LPS-induced alterations. We report for the first time that administration of SAHA (50 mg/kg) significantly attenuates a variety of inflammatory markers and improves long-term survival after a lethal LPS insult. PMID:19295477

Li, Yongqing; Liu, Baoling; Zhao, Hang; Sailhamer, Elizabeth A; Fukudome, Eugene Y; Zhang, Xiaobo; Kheirbek, Tareq; Finkelstein, Robert A; Velmahos, George C; deMoya, Marc; Hales, Charles A; Alam, Hasan B

2009-11-01

58

Protein tyrosine phosphatase-1B contributes to LPS-induced leptin resistance in male rats.  

PubMed

Leptin resistance is induced by the feedback inhibitors tyrosine phosphatase-1B (PTP1B) and decreased Src homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) signaling. To investigate the participation of PTP1B and SHP-2 in LPS-induced leptin resistance, we injected repeated (6-LPS) intraperitoneal LPS doses (100 ?g/kg ip) for comparison with a single (1-LPS) treatment and evaluated the expression of SHP-2, PTP1B, p-ERK1/2, and p-STAT3 in the hypothalamus of male Wistar rats. The single LPS treatment increased the expression of p-STAT3 and PTP1B but not SHP-2. The repeated LPS treatment reduced SHP-2, increased PTP1B, and did not change p-STAT3. We observed that the PTP1B expression induced by the endotoxin was highly colocalized with leptin receptor cells in the hypothalamus of LepRb-IRES-Cre-tdTomato reporter mice. The single, but not the repeated, LPS treatment decreased the food intake and body weight. Leptin had no stimulatory effect on the hypophagia, body weight loss, or pSTAT3 expression in 6-LPS rats, indicating leptin unresponsiveness. Notably, the PTP1B inhibitor (3.0 nmol/rat in 5 ?l icv) restored the LPS-induced hypophagia in 6-LPS rats and restored the ability of leptin to reduce food intake and body weight as well as to phosphorylate STAT3 in the arcuate, paraventricular, and ventromedial nuclei of the hypothalamus. The present data suggest that an increased PTP1B expression in the hypothalamus underlies the development of leptin resistance during repeated exposure to LPS. Our findings contribute to understanding the mechanisms involved in leptin resistance during low-grade inflammation as seen in obesity. PMID:25352433

Borges, Beatriz de Carvalho; Rorato, Rodrigo C; Uchoa, Ernane Torres; Marangon, Paula B; Elias, Carol F; Antunes-Rodrigues, Jose; Elias, Lucila L K

2015-01-01

59

Sulfur dioxide attenuates LPS-induced acute lung injury via enhancing polymorphonuclear neutrophil apoptosis  

PubMed Central

Aim: We speculated that the enhanced apoptosis of polymorphonuclear neutrophil (PMN) might be responsible for the inhibition of PMN infiltration in the lung. This study was designed to investigate the effects of sulfur dioxide (SO2) on PMN apoptosis in vivo and in vitro, which may mediate the protective action of SO2 on pulmonary diseases. Methods: Acute lung injury (ALI) was induced by intratracheally instillation of lipopolysaccharide (LPS, 100 ?g/100 g, in 200 ?L saline) in adult male SD rats. SO2 solution (25 ?mol/kg) was administered intraperitoneally 30 min before LPS treatment. The rats were killed 6 h after LPS treatment. Lung tissues were collected for histopathologic study and SO2 concentration assay. Bronchoalveolar lavage fluid (BALF) was collected for the measurement of PMN apoptosis. For in vitro experiments, rat peripheral blood PMNs were cultured and treated with LPS (30 mg/L) and SO2 (10, 20 and 30 ?mol/L) for 6 h, and apoptosis-related protein expression was detected by Western blotting, and apoptosis rate was measured with flow cytometry. Results: LPS treatment significantly reduced the SO2 concentrations in the lung tissue and peripheral blood, as compared with the control group. Pretreatment with SO2 prevented LPS-induced reduction of the SO2 concentration in the lung tissue and peripheral blood. LPS treatment significantly reduced PMN apoptosis both in vivo and in vitro, which could be prevented by the pretreatment with SO2. The protein levels of Caspase-3 and Bax was significantly increased, but Bcl-2 was decreased by the pretreatment with SO2, as compared with LPS administration alone. Conclusion: SO2 plays an important role as the modulator of PMN apoptosis during LPS-induced ALI, which might be one of the mechanisms underlying the protective action of SO2 on pulmonary diseases. PMID:22796764

Ma, Hui-jie; Huang, Xin-li; Liu, Yan; Fan, Ya-min

2012-01-01

60

Andrographolide Protects against LPS-Induced Acute Lung Injury by Inactivation of NF-?B  

PubMed Central

Background Nuclear factor-?B (NF-?B) is a central transcriptional factor and a pleiotropic regulator of many genes involved in acute lung injury. Andrographolide is found in the plant of Andrographis paniculata and widely used in Traditional Chinese Medicine, exhibiting potently anti-inflammatory property by inhibiting NF-?B activity. The purpose of our investigation was designed to reveal the effect of andrographolide on various aspects of LPS induced inflammation in vivo and in vitro. Methods and Results In vivo, BALB/C mice were subjected to LPS injection with or without andrographolide treatments to induce ALI model. In vitro, MLE-12 cells were stimulated with LPS in the presence and absence of andrographolide. In vivo, pulmonary inflammation, pulmonary edema, ultrastructure changes of type II alveolar epithelial cells, MPO activity, total cells, neutrophils, macrophages, TNF-?, IL-6 and IL-1? in BALF, along with the expression of VCAM-1 and VEGF were dose-dependently attenuated by andrographolide. Meanwhile, in vitro, the expression of VCAM-1 and VEGF was also reduced by andrographolide. Moreover, our data showed that andrographolide significantly inhibited the ratios of phospho-IKK?/total IKK?, phospho-I?B?/total I?B? and phospho-NF-?B p65/total NF-?B p65, and NF-?B p65 DNA binding activities, both in vivo and in vitro. Conclusions These results indicate that andrographolide dose-dependently suppressed the severity of LPS-induced ALI, more likely by virtue of andrographolide-mediated NF-?B inhibition at the level of IKK? activation. These results suggest andrographolide may be considered as an effective and safe drug for the potential treatment of ALI. PMID:23437127

Zhu, Tao; Wang, Dao-xin; Zhang, Wei; Liao, Xiu-qing; Guan, Xian; Bo, Hong; Sun, Jia-yang; Huang, Ni-wen; He, Jing; Zhang, Yun-kun; Tong, Jing; Li, Chang-yi

2013-01-01

61

LPS-induced IL8 activation in human intestinal epithelial cells is accompanied by specific histone H3 acetylation and methylation changes  

Microsoft Academic Search

BACKGROUND: The release of LPS by bacteria stimulates both immune and specific epithelial cell types to release inflammatory mediators. It is known that LPS induces the release of IL-8 by intestinal mucosal cells. Because it is now emerging that bacteria may induce alteration of epigenetic patterns in host cells, we have investigated whether LPS-induced IL-8 activation in human intestinal epithelial

Tiziana Angrisano; Raffaela Pero; Silvia Peluso; Simona Keller; Silvana Sacchetti; Carmelo B Bruni; Lorenzo Chiariotti; Francesca Lembo

2010-01-01

62

Tanshinone IIA protects rabbits against LPS-induced disseminated intravascular coagulation (DIC)  

PubMed Central

Aim: To evaluate the effects of tanshinone IIA (Tan IIA), a lipophilic diterpene from the Chinese herb Salvia miltiorrhiza, on lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC) in rabbits. Methods: LPS-induced DIC model was made in adult male New Zealand rabbits by continuous intravenous infusion of LPS (0.5 mg/kg) via marginal ear vein for 6 h. The animals were simultaneously administered with Tan IIA (1, 3 and 10 mg/kg) or heparin (500 000 IU/kg) through continuous infusion via the contralateral marginal ear vein for 6 h. Before and 2 and 6 h after the start of LPS infusion, blood samples were taken for biochemical analyses. Results: Continuous infusion of LPS into the rabbits gradually impaired the hemostatic parameters, damaged renal and liver functions, increased the plasma TNF-? level, and led to a high mortality rate (80%). Treatment of the rabbits with Tan IIA dose-dependently attenuated the increase in activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrin-fibrinogen degradation products (FDP); ameliorated the decrease in plasma levels of fibrinogen and platelets; and reversed the decline in activity of protein C and antithrombin III. Meanwhile, the treatment significantly suppressed the increase in the plasma levels of aminotransferase, creatinine and TNF-?, and led to much lower mortality (46.7% and 26.7% for the medium- and high-dose groups). Treatment of the rabbits with the high dose of heparin also effectively improved the hemostatic parameters, ameliorated liver and renal injuries, and reduced the plasma level of TNF-?, and significantly reduced the mortality (33.3%). Conclusion: Tan IIA exerts a protective effect against DIC in rabbits. PMID:22983394

Wu, Liang-cai; Lin, Xi; Sun, Hao

2012-01-01

63

IGF-1 attenuates LPS induced pro-inflammatory cytokines expression in buffalo (Bubalus bubalis) granulosa cells.  

PubMed

Interaction between immune and endocrine system is a diverse process influencing cellular function and homeostasis in animals. Negative energy balance (NEB) during postpartum period in dairy animals usually suppresses these systems resulting in reproductive tract infection and infertility. These negative effects could be due to competition among endocrine and immune signaling pathways for common signaling molecules. The present work studied the effect of IGF-1 (50ng/ml) on LPS (1?g/ml) mediated pro-inflammatory cytokine expression (IL-1?, TNF-?, IL-6) and aromatase (CYP19A1) genes' expressions as well as proliferation of buffalo granulosa cells. The crosstalk between LPS and IGF-1 was also demonstrated through studying the activities of downstream signaling molecules (ERK1/2, Akt, NF-?B) by western blot and immunostaining. Gene expression analysis showed that IGF-1 significantly reduced the LPS induced expression of IL-1?, TNF-? and IL-6. LPS alone inhibited the CYP19A1 expression. However, co-treatment with IGF-1 reversed the inhibitory effect of LPS on CYP19A1 expression. LPS alone did not affect granulosa cell proliferation, but co-treatment with IGF-1, and IGF-1 alone enhanced the proliferation. Western blot results demonstrated that LPS caused the nuclear translocation of the NF-?B and increased the phosphorylation of ERK1/2 and Akt maximum at 15min and 60min, respectively. Nonetheless, co-treatment with IGF-1 delayed LPS induced phosphorylation of ERK1/2 (peak at 120min), while promoting early Akt phosphorylation (peak at 5min) with no effect on NF-?B translocation. Overall, IGF-1 delayed and reversed the effects of LPS, suggesting that high IGF-1 levels may combat infection during critical periods like NEB in postpartum dairy animals. PMID:25433435

Onnureddy K; Ravinder; Onteru, Suneel Kumar; Singh, Dheer

2015-03-01

64

Persistence of LPS-Induced Lung Inflammation in Surfactant Protein-C–Deficient Mice  

PubMed Central

Pulmonary surfactant protein-C (SP-C) gene–targeted mice (Sftpc?/?) develop progressive lung inflammation and remodeling. We hypothesized that SP-C deficiency reduces the ability to suppress repetitive inflammatory injury. Sftpc+/+ and Sftpc?/? mice given three doses of bacterial LPS developed airway and airspace inflammation, which was more intense in the Sftpc?/? mice at 3 and 5 days after the final dose. Compared with Sftpc+/+mice, inflammatory injury persisted in the lungs of Sftpc?/? mice 30 days after the final LPS challenge. Sftpc?/? mice showed LPS-induced airway goblet cell hyperplasia with increased detection of Sam pointed Ets domain and FoxA3 transcription factors. Sftpc?/? type II alveolar epithelial cells had increased cytokine expression after LPS exposure relative to Sftpc+/+ cells, indicating that type II cell dysfunction contributes to inflammatory sensitivity. Microarray analyses of isolated type II cells identified a pattern of enhanced expression of inflammatory genes consistent with an intrinsic low-level inflammation resulting from SP-C deficiency. SP-C–containing clinical surfactant extract (Survanta) or SP-C/phospholipid vesicles blocked LPS signaling through the LPS receptor (Toll-like receptor [TLR] 4/CD14/MD2) in human embryonic kidney 293T cells, indicating that SP-C blocks LPS-induced cytokine production by a TLR4-dependent mechanism. Phospholipid vesicles alone did not modify the TLR4 response. In vivo deficiency of SP-C leads to inflammation, increased cytokine production by type II cells, and persistent inflammation after repetitive LPS stimulation. PMID:23795648

Maxfield, Melissa D.; Ruetschilling, Teah L.; Akinbi, Henry T.; Baatz, John E.; Kitzmiller, Joseph A.; Page, Kristen; Xu, Yan; Bao, Erik L.; Korfhagen, Thomas R.

2013-01-01

65

Dental monomers inhibit LPS-induced cytokine release from the macrophage cell line RAW264.7.  

PubMed

Methacrylate monomers have been identified in aqueous extracts of freshly cured dental fillings. The hypothesis tested presently was that low concentrations of triethyleneglycol dimethacrylate (TEGDMA) and 2-hydroxyethyl methacrylate (HEMA) alone or in combination interfere with the LPS-induced release of cytokines from the macrophage cell line RAW264.7. The cells were exposed to 5-200 ?M of monomers for 24 h followed by a 24 h combined exposure to monomers and LPS. TEGDMA reduced LPS-induced release of interleukin-1? (IL-1?) and tumor necrosis factor-? (TNF-?), whereas HEMA only reduced IL-1? release. Co-exposure to the two monomers indicated an additive effect. Moreover, the reduced cytokine release persisted for 24 h after termination of the monomer exposure. The LPS-induced activation of proteins in pre-transcriptional signaling pathways (CD14, p-ERK1/2, p-p38, p-JNK, p-I?B-? and p-NF?B-p65) was not altered by monomer exposure, neither were the levels of IL-1? and TNF-? mRNA. However, the LPS-induced level of pro-IL-1? was decreased by the monomer treatment. Thus, HEMA and TEGDMA may interfere with post-transcriptional regulation of synthesis and release of these cytokines. Overall, the results suggest that low concentrations of monomers may cause impaired macrophage responses, and that these effects can persist for up to 24 h after exposure. PMID:23182953

Břlling, Anette Kocbach; Samuelsen, Jan Tore; Morisbak, Else; Ansteinsson, Vibeke; Becher, Rune; Dahl, Jon Einar; Mathisen, Gro Haarklou

2013-02-01

66

Moringa fruit inhibits LPS-induced NO/iNOS expression through suppressing the NF-? B activation in RAW264.7 cells.  

PubMed

In this study, we evaluated the anti-inflammatory effects of moringa (Moringa oleifera Lam.), a natural biologically active substance, by determining its inhibitory effects on pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated macrophage RAW264.7 cells. Extracts from different parts of moringa (root, leaf, and fruit) reduced LPS-induced nitric oxide (NO) release in a dose-dependent manner. The moringa fruit extract most effectively inhibited LPS-induced NO production and levels of inducible nitric oxide synthase (iNOS). The moringa fruit extract also was shown to suppress the production of inflammatory cytokines including IL-1?, TNF-?, and IL-6. Furthermore, moringa fruit extract inhibited the cytoplasmic degradation of I ? B -? and the nuclear translocation of p65 proteins, resulting in lower levels of NF -? B transactivation. Collectively, the results of this study demonstrate that moringa fruit extract reduces the levels of pro-inflammatory mediators including NO , IL-1?, TNF-?, and IL-6 via the inhibition of NF -? B activation in RAW264.7 cells. These findings reveal, in part, the molecular basis underlying the anti-inflammatory properties of moringa fruit extract. PMID:24117072

Lee, Hyo-Jin; Jeong, Yun-Jeong; Lee, Tae-Sung; Park, Yoon-Yub; Chae, Whi-Gun; Chung, Il-Kyung; Chang, Hyeun-Wook; Kim, Cheorl-Ho; Choi, Yung-Hyun; Kim, Wun-Jae; Moon, Sung-Kwon; Chang, Young-Chae

2013-01-01

67

p52-independent nuclear translocation of RelB promotes LPS-induced attachment  

SciTech Connect

The NF-{kappa}B signaling pathways have a critical role in the development and progression of various cancers. In this study, we demonstrated that the small cell lung cancer cell line (SCLC) H69 expressed a unique NF-{kappa}B profile as compared to other cancer cell lines. The p105/p50, p100/p52, c-Rel, and RelB protein and mRNA transcripts were absent in H69 cells but these cells expressed RelA/p65. The activation of H69 cells by lipopolysaccharide (LPS) resulted in the induction of RelB and p100 expression. The treatment also induced the nuclear translocation of RelB without the processing of p100 to p52. Furthermore, LPS-induced {beta}1 integrin expression and cellular attachment through an NF-{kappa}B-dependent mechanism. Blocking RelB expression prevented the increase in the expression of {beta}1 integrin and the attachment of H69. Taken together, the results suggest that RelB was responsible for the LPS-mediated attachment and may play an important role in the progression of some cancers.

Saito, T. [Laboratory of Immunology, National Institute on Aging, NIH Biomedical Research Center, Baltimore, MD 21224 (United States)] [Laboratory of Immunology, National Institute on Aging, NIH Biomedical Research Center, Baltimore, MD 21224 (United States); Sasaki, C.Y., E-mail: sasakic@grc.nia.nih.gov [Laboratory of Immunology, National Institute on Aging, NIH Biomedical Research Center, Baltimore, MD 21224 (United States); Rezanka, L.J.; Ghosh, P.; Longo, D.L. [Laboratory of Immunology, National Institute on Aging, NIH Biomedical Research Center, Baltimore, MD 21224 (United States)] [Laboratory of Immunology, National Institute on Aging, NIH Biomedical Research Center, Baltimore, MD 21224 (United States)

2010-01-01

68

Granzyme K synergistically potentiates LPS-induced cytokine responses in human monocytes  

PubMed Central

Granzymes are serine proteases released by cytotoxic lymphocytes to induce apoptosis in virus-infected cells and tumor cells. Evidence is emerging that granzymes also play a role in controlling inflammation. Granzyme serum levels are elevated in patients with autoimmune diseases and infections, including sepsis. However, the function of extracellular granzymes in inflammation largely remains unknown. Here, we show that granzyme K (GrK) binds to Gram-negative bacteria and their cell-wall component lipopolysaccharide (LPS). GrK synergistically enhances LPS-induced cytokine release in vitro from primary human monocytes and in vivo in a mouse model of LPS challenge. Intriguingly, these extracellular effects are independent of GrK catalytic activity. GrK disaggregates LPS from micelles and augments LPS–CD14 complex formation, thereby likely boosting monocyte activation by LPS. We conclude that extracellular GrK is an unexpected direct modulator of LPS–TLR4 signaling during the antimicrobial innate immune response. PMID:24711407

Wensink, Annette C.; Kemp, Vera; Fermie, Job; García Laorden, M. Isabel; van der Poll, Tom; Hack, C. Erik; Bovenschen, Niels

2014-01-01

69

1,8-cineol attenuates LPS-induced acute pulmonary inflammation in mice.  

PubMed

Eucalyptol, also known as 1,8-cineol, is a monoterpene and has been shown to exert anti-inflammatory and antioxidant effect. It is traditionally used to treat respiratory disorders due to its secretolytic properties. In the present study, we evaluated the effect of 1,8-cineol on pulmonary inflammation in a mouse model of acute lung injury. We found that 1,8-cineol significantly decreased the level of TNF-? and IL-1?, and increased the level of IL-10 in lung tissues after acute lung injury induced by lipopolysaccharide (LPS). It also reduced the expression of nuclear factor kappa B (NF-?B) p65 and toll-like receptor 4 (TLR4), and myeloperoxidase activity in lung tissues. In addition, 1,8-cineol reduced the amounts of inflammatory cells in bronchoalveolar lavage fluid (BALF), including neutrophils and macrophages, and significantly decreased the protein content in BALF and the lung wet/dry weight (W/D) ratio. Its effect on LPS-induced pulmonary inflammation was associated with suppression of TLR4 and NF-?B expressions. Our results provide evidence that 1,8-cineol inhibits acute pulmonary inflammation, indicating its potential for the treatment of acute lung injury. PMID:24197825

Zhao, Chunzhen; Sun, Jianbo; Fang, Chunyan; Tang, Fadi

2014-04-01

70

Protective Effects of Baicalin on Decidua Cells of LPS-Induced Mice Abortion  

PubMed Central

The study was carried out to investigate the protective effects of Baicalin on decidual cells of LPS-induced abortion mice. In the in vitro experiment, the decidual cells were cultured by uterus tissue mass cultivation sampled at day 6 of pregnancy, and gradient concentrations of LPS were used to determine the optimal LPS concentration of the injured decidual cells model. The injured decidual cells were treated with Baicalin (4??g/mL) to determine the protective role of Baicalin. In the in vivo experiment, lipopolysaccharide (LPS) was injected intravenously via the tail vein to induce abortion at day 6 of pregnancy, and the mice were given different concentrations of Baicalin by oral gavage consecutively at days 7 to 8 of pregnancy. On day 9 of gestation, the mice were sacrificed. The TNF and progesterone contents in the serum were assayed by ELISA. The results clearly revealed that Baicalin can prevent the injury to decidual cells from LPS dose dependently, TNF was decreased significantly (P < 0.01) compared to LPS group, and there was no effect on the progesterone. These findings suggest that Baicalin has protective effects on the injured decidual cells in the pregnant mice. PMID:25386564

Wang, Xiaodan; Zhao, Yantao; Zhong, Xiuhui

2014-01-01

71

Granzyme K synergistically potentiates LPS-induced cytokine responses in human monocytes.  

PubMed

Granzymes are serine proteases released by cytotoxic lymphocytes to induce apoptosis in virus-infected cells and tumor cells. Evidence is emerging that granzymes also play a role in controlling inflammation. Granzyme serum levels are elevated in patients with autoimmune diseases and infections, including sepsis. However, the function of extracellular granzymes in inflammation largely remains unknown. Here, we show that granzyme K (GrK) binds to Gram-negative bacteria and their cell-wall component lipopolysaccharide (LPS). GrK synergistically enhances LPS-induced cytokine release in vitro from primary human monocytes and in vivo in a mouse model of LPS challenge. Intriguingly, these extracellular effects are independent of GrK catalytic activity. GrK disaggregates LPS from micelles and augments LPS-CD14 complex formation, thereby likely boosting monocyte activation by LPS. We conclude that extracellular GrK is an unexpected direct modulator of LPS-TLR4 signaling during the antimicrobial innate immune response. PMID:24711407

Wensink, Annette C; Kemp, Vera; Fermie, Job; García Laorden, M Isabel; van der Poll, Tom; Hack, C Erik; Bovenschen, Niels

2014-04-22

72

Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-?B pathways.  

PubMed

Activation of microglia cells in the brain contributes to neurodegenerative processes promoted by many neurotoxic factors such as pro-inflammatory cytokines and nitric oxide (NO). Reactive oxygen species (ROS) actively affect microglia-associated neurodegenerative diseases through their role as pro-inflammatory molecules and modulators of pro-inflammatory processes. Although the ROS which involved in microglia activation are thought to be generated primarily by NADPH oxidase (NOX) and involved in the immune response, mitochondrial ROS have also been proposed as important regulators of the inflammatory response in the innate immune system. However, the role of mitochondrial ROS in microglial activation has yet to be fully elucidated. In this study, we demonstrate that inhibition of mitochondrial ROS by treatment with Mito-TEMPO effectively suppressed the level of mitochondrial and intracellular ROS. Mito-TEMPO treatment also significantly prevented LPS-induced increase in the TNF-?, IL-1?, IL-6, iNOS and Cox-2 in BV-2 and primary microglia cells. Furthermore, LPS-induced suppression of mitochondrial ROS generation not only affected LPS-stimulated activation of MAPKs, including ERK, JNK, and p38, but also regulated I?B activation and NF-?B nuclear localization. These results indicate that mitochondria constitute a major source of ROS generation in LPS-mediated activated microglia cells. Additionally, suppression of LPS-induced mitochondrial ROS plays a role in modulating the production of pro-inflammatory mediators by preventing MAPK and NF-?B activation in microglia cells. Our findings suggest that a potential strategy in the development of therapy for inflammation-associated degenerative neurological diseases involves targeting the regulation of mitochondrial ROS in microglial cells. PMID:25459294

Park, Junghyung; Min, Ju-Sik; Kim, Bokyung; Chae, Un-Bin; Yun, Jong Won; Choi, Myung-Sook; Kong, Il-Keun; Chang, Kyu-Tae; Lee, Dong-Seok

2015-01-01

73

Polyphenols from blueberries modulate inflammation cytokines in LPS-induced RAW264.7 macrophages.  

PubMed

Polyphenols including 3-glucoside/arabinoside/galactoside-based polymers of delphinidins, petunidins, peonidins, malvidins and cyanidins are one type of biological macromolecules, which are extraordinarily rich in blueberries. Anti-inflammatory activity of blueberry polyphenols (BPPs) was investigated by using lipopolysaccharide (LPS) induced RAW264.7 macrophages. The results showed that BPPs suppressed the gene expression of IL-1? (interleukin-1?), IL-6 and IL-12p35. The inhibition effect on IL-1? and IL-6 mRNA was most obvious at the concentration of 10-200?g/mL BPPs. But the inhibition effect on IL-12p35 mRNA was increased with the increasing concentration of BPPs. When fixed at 100?g/mL BPPs, the most significant inhibition on IL-1?, IL-6 and IL-12p35 mRNA expression was detected at 12-48h. In conclusion, BPPs exhibit anti-inflammation activity by mediating and modulating the balances in pro-inflammatory cytokines of IL-1?, IL-6, and IL-12. PMID:24905959

Cheng, Anwei; Yan, Haiqing; Han, Caijing; Wang, Wenliang; Tian, Yaoqi; Chen, Xiangyan

2014-08-01

74

Effect of Pluchea lanceolata bioactives in LPS-induced neuroinflammation in C6 rat glial cells.  

PubMed

Neuroinflammation plays a significant role in various chronic and acute pathological conditions of the central nervous system. In the Indian system of medicine, Pluchea lanceolata is used to treat the neurological disorders. We investigated the effect of major pentacyclic triterpene and its naturally occurring acetate derivative isolated from P. lanceolata on lipopolysaccharide (LPS)-stimulated neuroinflammatory condition associated to inflammatory cytokine production in rat astrocytoma cell line (C6). The log concentration dependence of Pluchea bioactive taraxasterol (Tx) significantly (p?LPS-induced IL-6 production at lower concentration (p?>?0.05). Surflex-Dock molecular modeling study was performed to simulate the binding capacity of compounds into the active site of the TNF-? (2AZ5), tumor protein P53 (2VUK), and NF-kappa-B (1RAM). The differential inhibition of cytokines by Tx and TxAc was further confirmed by high docking scores showing the high affinity to target proteins. Findings of the study demonstrated the comparatively greater role of Pluchea triterpene than its in situ produced acetate derivate in neuroinflammation-associated disorders. PMID:24101125

Srivastava, Pooja; Mohanti, Shilpa; Bawankule, Dnyaneshwar Umrao; Khan, Feroz; Shanker, Karuna

2014-02-01

75

Exogenous rhTRX reduces lipid accumulation under LPS-induced inflammation  

PubMed Central

Redox-regulating molecule, recombinant human thioredoxin (rhTRX) which shows anti-inflammatory, and anti-oxidative effects against lipopolysaccharide (LPS)-stimulated inflammation and regulate protein expression levels. LPS-induced reactive oxygen intermediates (ROI) and NO production were inhibited by exogenous rhTRX. We identified up/downregulated intracellular proteins under the LPS-treated condition in exogenous rhTRX-treated A375 cells compared with non-LPS-treated cells via 2-DE proteomic analysis. Also, we quantitatively measured cytokines of in vivo mouse inflammation models using cytometry bead array. Exogenous rhTRX inhibited LPS-stimulated production of ROI and NO levels. TIP47 and ATP synthase may influence the inflammation-related lipid accumulation by affecting lipid metabolism. The modulation of skin redox environments during inflammation is most likely to prevent alterations in lipid metabolism through upregulation of TIP47 and ATP synthase and downregulation of inflammatory cytokines. Our results demonstrate that exogenous rhTRX has anti-inflammatory properties and intracellular regulatory activity in vivo and in vitro. Monitoring of LPS-stimulated pro-inflammatory conditions treated with rhTRX in A375 cells could be useful for diagnosis and follow-up of inflammation reduction related with candidate proteins. These results have a therapeutic role in skin inflammation therapy. PMID:24406320

Han, Gi-Yeon; Lee, Eun-Kyung; Park, Hey-won; Kim, Hyun-Jung; Kim, Chan-Wha

2014-01-01

76

Eukaryotic elongation factor 2 controls TNF-? translation in LPS-induced hepatitis.  

PubMed

Bacterial LPS (endotoxin) has been implicated in the pathogenesis of acute liver disease through its induction of the proinflammatory cytokine TNF-?. TNF-? is a key determinant of the outcome in a well-established mouse model of acute liver failure during septic shock. One possible mechanism for regulating TNF-? expression is through the control of protein elongation during translation, which would allow rapid cell adaptation to physiological changes. However, the regulation of translational elongation is poorly understood. We found that expression of p38?/? MAPK proteins is required for the elongation of nascent TNF-? protein in macrophages. The MKK3/6-p38?/? pathway mediated an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) kinase, which in turn promoted eEF2 activation (dephosphorylation) and subsequent TNF-? elongation. These results identify a new signaling pathway that regulates TNF-? production in LPS-induced liver damage and suggest potential cell-specific therapeutic targets for liver diseases in which TNF-? production is involved. PMID:23202732

González-Terán, Bárbara; Cortés, José R; Manieri, Elisa; Matesanz, Nuria; Verdugo, Ángeles; Rodríguez, María E; González-Rodríguez, Águeda; Valverde, Ángela M; Valverde, Ángela; Martín, Pilar; Davis, Roger J; Sabio, Guadalupe

2013-01-01

77

Eukaryotic elongation factor 2 controls TNF-? translation in LPS-induced hepatitis  

PubMed Central

Bacterial LPS (endotoxin) has been implicated in the pathogenesis of acute liver disease through its induction of the proinflammatory cytokine TNF-?. TNF-? is a key determinant of the outcome in a well-established mouse model of acute liver failure during septic shock. One possible mechanism for regulating TNF-? expression is through the control of protein elongation during translation, which would allow rapid cell adaptation to physiological changes. However, the regulation of translational elongation is poorly understood. We found that expression of p38?/? MAPK proteins is required for the elongation of nascent TNF-? protein in macrophages. The MKK3/6-p38?/? pathway mediated an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) kinase, which in turn promoted eEF2 activation (dephosphorylation) and subsequent TNF-? elongation. These results identify a new signaling pathway that regulates TNF-? production in LPS-induced liver damage and suggest potential cell-specific therapeutic targets for liver diseases in which TNF-? production is involved. PMID:23202732

González-Terán, Bárbara; Cortés, José R.; Manieri, Elisa; Matesanz, Nuria; Verdugo, ?ngeles; Rodríguez, María E.; González-Rodríguez, ?gueda; Valverde, ?ngela; Martín, Pilar; Davis, Roger J.; Sabio, Guadalupe

2012-01-01

78

Involvement of mitogen-activated protein kinases and NF{kappa}B in LPS-induced CD40 expression on human monocytic cells  

SciTech Connect

CD40 is a costimulatory molecule linking innate and adaptive immune responses to bacterial stimuli, as well as a critical regulator of functions of other costimulatory molecules. The mechanisms regulating lipopolysaccharide (LPS)-induced CD40 expression have not been adequately characterized in human monocytic cells. In this study we used a human monocytic cell line, THP-1, to investigate the possible mechanisms of CD40 expression following LPS exposure. Exposure to LPS resulted in a dose- and time-dependent increase in CD40 expression. Further studies using immunoblotting and pharmacological inhibitors revealed that mitogen-activated protein kinases (MAPKs) and NF{kappa}B were activated by LPS exposure and involved in LPS-induced CD40 expression. Activation of MAPKs was not responsible for LPS-induced NF{kappa}B activation. TLR4 was expressed on THP-1 cells and pretreatment of cells with a Toll-like receptor 4 (TLR4) neutralizing antibody (HTA125) significantly blunted LPS-induced MAPK and NF{kappa}B activation and ensuing CD40 expression. Additional studies with murine macrophages expressing wild type and mutated TLR4 showed that TLR4 was implicated in LPS-induced ERK and NF{kappa}B activation, and CD40 expression. Moreover, blockage of MAPK and NF{kappa}B activation inhibited LPS-induced TLR4 expression. In summary, LPS-induced CD40 expression in monocytic cells involves MAPKs and NF{kappa}B.

Wu Weidong [Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina, Chapel Hill, North Carolina 27599 (United States)]|[Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina 27599 (United States)], E-mail: Weidong_Wu@med.unc.edu; Alexis, Neil E. [Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina, Chapel Hill, North Carolina 27599 (United States)]|[Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina 27599 (United States); Chen Xian [Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599 (United States)]|[Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599 (United States); Bromberg, Philip A. [Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina, Chapel Hill, North Carolina 27599 (United States)]|[Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599 (United States); Peden, David B. [Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina, Chapel Hill, North Carolina 27599 (United States)]|[Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina 27599 (United States)]|[Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599 (United States)

2008-04-15

79

Progesterone Is Essential for Protecting against LPS-Induced Pregnancy Loss. LIF as a Potential Mediator of the Anti-inflammatory Effect of Progesterone  

PubMed Central

Lipopolysaccharide (LPS) administration to mice on day 7 of gestation led to 100% embryonic resorption after 24 h. In this model, nitric oxide is fundamental for the resorption process. Progesterone may be responsible, at least in part, for a Th2 switch in the feto-maternal interface, inducing active immune tolerance against fetal antigens. Th2 cells promote the development of T cells, producing leukemia inhibitory factor (LIF), which seems to be important due to its immunomodulatory action during early pregnancy. Our aim was to evaluate the involvement of progesterone in the mechanism of LPS-induced embryonic resorption, and whether LIF can mediate hormonal action. Using in vivo and in vitro models, we provide evidence that circulating progesterone is an important component of the process by which infection causes embryonic resorption in mice. Also, LIF seems to be a mediator of the progesterone effect under inflammatory conditions. We found that serum progesterone fell to very low levels after 24 h of LPS exposure. Moreover, progesterone supplementation prevented embryonic resorption and LPS-induced increase of uterine nitric oxide levels in vivo. Results show that LPS diminished the expression of the nuclear progesterone receptor in the uterus after 6 and 12 h of treatment. We investigated the expression of LIF in uterine tissue from pregnant mice and found that progesterone up-regulates LIF mRNA expression in vitro. We observed that LIF was able to modulate the levels of nitric oxide induced by LPS in vitro, suggesting that it could be a potential mediator of the inflammatory action of progesterone. Our observations support the view that progesterone plays a critical role in a successful pregnancy as an anti-inflammatory agent, and that it could have possible therapeutic applications in the prevention of early reproductive failure associated with inflammatory disorders. PMID:23409146

Aisemberg, Julieta; Vercelli, Claudia A.; Bariani, María V.; Billi, Silvia C.; Wolfson, Manuel L.; Franchi, Ana M.

2013-01-01

80

A critical role for increased labile zinc in reducing sensitivity of cultured sheep pulmonary artery endothelial cells to LPS-induced apoptosis.  

PubMed

We previously noted an important signaling role for decreased labile intracellular zinc ([ Zn ] (i)) in LPS-induced apoptosis in cultured sheep pulmonary artery endothelial cells (SPAEC) (Tang ZL, Wasserloos KJ, Liu X, Stitt MS, Reynolds IJ, Pitt BR, St Croix CM. Mol Cell Biochem 234-235: 211-217, 2002; Thambiayya K, Wasserloos KJ, Huang Z, Kagan VE, St Croix CM, Pitt BR. Am J Physiol Lung Cell Mol Physiol 300: L624-632, 2011). In the present study, we used small interfering RNA (siRNA) to important contributors of zinc homeostasis [ SLC39A14 or Zrt/Irt-like protein 14 (ZIP14), a zinc importer; metallothionein (MT), a zinc binding protein ] to define molecular pathways by which extracellular zinc or nitric oxide (NO) increase labile [ Zn ] (i) [ e.g., zinc-sensitive fluorophore (FluoZin-3) detectable and/or chelatable by N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine ] and reduce the sensitivity of SPAEC to LPS. Addition of 10 ?M zinc to serum-free medium of SPAEC increased [ Zn ] (i) and abolished LPS-induced apoptosis (e.g., increased annexin V binding). The increase in [ Zn ] (i) and the protective effect of extracellular zinc were sensitive to reduction in ZIP14 expression (by siRNA), but not affected by collectively knocking down major isoforms of sheep MT (sMT-Ia, -Ib, -Ic, and -II). Pretreatment of wild-type SPAEC with 250 ?M of the NO donor S-nitroso-N-acetylpenicillamine (SNAP) increased labile zinc in a relatively similar fashion to addition of extracellular zinc and reduced sensitivity of SPAEC to LPS-induced apoptosis (e.g., caspase-3/7 activation) in a N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine-sensitive fashion. The antiapoptotic effects of SNAP were insensitive to siRNA knockdown of ZIP14, but were abolished (along with SNAP-induced increase in [ Zn ] (i)) when SPAEC were pretreated with siRNA to sheep MT. Zinc was able to directly inhibit recombinant caspase-3 activity in an in vitro assay. Collectively, these data show that increases in labile [ Zn ] (i) are an important component of ZIP14- or NO-mediated resistance to LPS-induced apoptosis. Cytoprotection via ZIP14 appeared to be secondary to transcellular movement of extracellular zinc, whereas NO-mediated protection was secondary to S-nitrosation of MT and redistribution of [ Zn ] (i). PMID:22523284

Thambiayya, Kalidasan; Wasserloos, Karla; Kagan, Valerian E; Stoyanovsky, Detcho; Pitt, Bruce R

2012-06-15

81

LPS-Induced Delayed Preconditioning Is Mediated by Hsp90 and Involves the Heat Shock Response in Mouse Kidney  

PubMed Central

Introduction We and others demonstrated previously that preconditioning with endotoxin (LPS) protected from a subsequent lethal LPS challenge or from renal ischemia-reperfusion injury (IRI). LPS is effective in evoking the heat shock response, an ancient and essential cellular defense mechanism, which plays a role in resistance to, and recovery from diseases. Here, by using the pharmacological Hsp90 inhibitor novobiocin (NB), we investigated the role of Hsp90 and the heat shock response in LPS-induced delayed renal preconditioning. Methods Male C57BL/6 mice were treated with preconditioning (P: 2 mg/kg, ip.) and subsequent lethal (L: 10 mg/kg, ip.) doses of LPS alone or in combination with NB (100 mg/kg, ip.). Controls received saline (C) or NB. Results Preconditioning LPS conferred protection from a subsequent lethal LPS treatment. Importantly, the protective effect of LPS preconditioning was completely abolished by a concomitant treatment with NB. LPS induced a marked heat shock protein increase as demonstrated by Western blots of Hsp70 and Hsp90. NB alone also stimulated Hsp70 and Hsp90 mRNA but not protein expression. However, Hsp70 and Hsp90 protein induction in LPS-treated mice was abolished by a concomitant NB treatment, demonstrating a NB-induced impairment of the heat shock response to LPS preconditioning. Conclusion LPS-induced heat shock protein induction and tolerance to a subsequent lethal LPS treatment was prevented by the Hsp90 inhibitor, novobiocin. Our findings demonstrate a critical role of Hsp90 in LPS signaling, and a potential involvement of the heat shock response in LPS-induced preconditioning. PMID:24646925

Kaucsár, Tamás; Bodor, Csaba; Godó, Mária; Szalay, Csaba; Révész, Csaba; Németh, Zalán; Mózes, Miklós; Szénási, Gábor; Rosivall, László; S?ti, Csaba; Hamar, Péter

2014-01-01

82

Wogonin inhibits LPS-induced tumor angiogenesis via suppressing PI3K/Akt/NF-?B signaling.  

PubMed

Wogonin has been shown to have anti-angiogenesis and anti-tumor effects. However, whether wogonin inhibits LPS-induced tumor angiogenesis is not well known. In this study, we investigated the effect of wogonin on inhibiting LPS-induced tumor angiogenesis and further probed the underlying mechanisms. ELISA results revealed that wogonin could suppress LPS-induced VEGF secretion from tumor cells. Transwell assay, tube formation assay, rat aortic ring assay and CAM model were used to evaluate the effect of wogonin on angiogenesis induced by MCF-7 cell (treated with LPS) in vitro and in vivo. The inhibitory effect of wogonin on angiogenesis in LPS-treated MCF-7 cells was then confirmed by the above in vitro and in vivo assays. The study of the molecular mechanism showed that wogonin could suppress PI3K/Akt signaling activation. Moreover, wogonin inhibited nuclear translocation of NF-?B and its binding to DNA. The result of real-time PCR and luciferase reporter assay suggested that VEGF expression was down-regulated by wogonin primarily at the transcriptional level. IGF-1 and p65 expression plasmid were used to activate PI3K/Akt and NF-?B pathways, and to observe the effect of wogonin on the simualtion of PI3K/Akt/NF-?B signaling. Taken together, the result suggested that wogonin was a potent inhibitor of tumor angiogenesis and provided a new insight into the mechanisms of wogonin against cancer. PMID:24858369

Zhao, Kai; Song, Xiuming; Huang, Yujie; Yao, Jing; Zhou, Mi; Li, Zhiyu; You, Qidong; Guo, Qinglong; Lu, Na

2014-08-15

83

Ethylacetate extract from Draconis Resina inhibits LPS-induced inflammatory responses in vascular smooth muscle cells and macrophages via suppression of ROS production.  

PubMed

Draconis Resina (DR) is a type of dragon's blood resin obtained from Daemomorops draco BL. (Palmae). DR has long been used as a traditional Korean herbal medicine, and is currently used in traditional clinics to treat wounds, tumors, diarrhea, and rheumatism, insect bites and other conditions. In this study, we evaluated fractionated extracts of DR to determine if they inhibited the production of interleukin-1beta (IL-1beta) and the expression of cyclooxygenase (COX)-2. The results of this analysis revealed that the ethylacetate extract of Draconis Resina (DREA) was more potent than that of other extracts. Moreover, DREA inhibited the production of nitric oxide (NO), reactive oxygen species (ROS), prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha), IL-8 and IL-6 in lipopolysaccharide (LPS)-treated human aortic smooth muscle cells (HASMC) and RAW 264.7 macrophages. Furthermore, treatment with an NADPH oxidase assembly inhibitor, AEBSF, efficiently blocked LPS-induced mitogen-activated protein kinases (MAPKs) activation, as did DREA. These findings indicate that DREA inhibits the production of NO, PGE(2), TNF-alpha, IL-8, and IL-6 by LPS via the inhibition of ROS production, which demonstrates that DREA inhibits LPS-induced inflammatory responses via the suppression of ROS production. Taken together, these results indicate that DREA has the potential for use as an anti-atherosclerosis agent. PMID:19577610

Heo, Sook-Kyoung; Yi, Hyo-Seung; Yun, Hyun-Jeong; Ko, Chang-Hyun; Choi, Jae-Woo; Park, Sun-Dong

2010-05-01

84

Lactoferrin down-regulates the LPS-induced cytokine production in monocytic cells via NF-?B  

Microsoft Academic Search

Lactoferrin, a glycoprotein present in milk, mucosal secretions and neutrophils contributes to host defense. We have previously shown that orally given milk lactoferrin (LF) mediates anti-infectious and anti-inflammatory activities in vivo. Moreover, we have shown that LF could inhibit the LPS-induced IL-6 secretion in a human monocytic cell line, THP-1. This observation was expanded in the present study investigating the

Liliana Hĺversen; Bertil G Ohlsson; Mirjana Hahn-Zoric; Lars Ĺ Hanson; Inger Mattsby-Baltzer

2002-01-01

85

Role of p38 MAP kinase in LPS-induced airway inflammation in the rat  

PubMed Central

We investigated the effect of the p38 kinase inhibitor SB 203580 on airway inflammation induced by aerosolized lipopolysaccharide (LPS) in male Wistar rats. SB 203580 significantly inhibited (ED50=15.8?mg?kg?1) plasma levels of TNF-? in rats challenged with LPS (1.5?mg?kg?1, i.p.).Aerosolized LPS induced a peak in TNF-? levels and the initiation of a neutrophilic response in bronchoalveolar lavage (BAL) fluid at the 2?h time point. Furthermore, the 4?h time point was associated with the peak in IL-1? levels and the initial plateau of neutrophilia observed in the BAL fluid.SB 203580 (100?mg?kg?1), had no effect on peak TNF-? levels or the associated neutrophilia in the BAL. Interestingly, the PDE 4 inhibitor RP 73401 (100?mg?kg?1) significantly reduced both TNF-? levels and neutrophilic inflammation. However, the BAL fluid from rats pre-treated with either compound significantly inhibited TNF-? release from cultured human monocytes 18?h after LPS treatment (83.6 and 44.5% inhibition, respectively).Alternatively, SB 203580 (100?mg?kg?1) produced dose-related inhibition of BAL IL-1? levels (67.5% inhibition, P<0.01) and BAL neutrophilia (45.9% inhibition, P<0.01) 4?h after LPS challenge.P38 protein was present in lung tissue and the level of expression was not affected by LPS treatment.P38 kinase appears to be involved in the release of IL-1? and the sustained neutrophilic response in the BAL fluid. This data may suggest a role for p38 inhibitors in the treatment of airway inflammatory diseases in which neutrophilia is a feature of the lung pathology. PMID:11309243

Haddad, El-Bdaoui; Birrell, Mark; McCluskie, Kerryn; Ling, Andrea; Webber, Stephen E; Foster, Martyn L; Belvisi, Maria G

2001-01-01

86

LPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice  

PubMed Central

Inflammation and microglial activation are associated with Alzheimer's disease (AD) pathology. Somewhat surprisingly, injection of a prototypical inflammatory agent, lipopolysaccharide (LPS) into brains of amyloid precursor protein (APP) transgenic mice clears some of the pre-existing amyloid deposits. It is less well understood how brain inflammation modulates tau pathology in the absence of A?. These studies examined the role of LPS-induced inflammation on tau pathology. We used transgenic rTg4510 mice, which express the P301L mutation (4R0N TauP301L) and initiate tau pathology between 3-5 months of age. First, we found an age-dependent increase in several markers of microglial activation as these rTg4510 mice aged and tau tangles accumulated. LPS injections into the frontal cortex and hippocampus induced significant activation of CD45 and arginase 1 in rTg4510 and non-transgenic mice. In addition, activation of YM1 by LPS was exaggerated in transgenic mice relative to non-transgenic animals. Expression of Ser199/202 and phospho-tau Ser396 was increased in rTg4510 mice that received LPS compared to vehicle injections. However, the numbers of silver-positive neurons, implying presence of more pre- and mature tangles, was not significantly affected by LPS administration. These data suggest that inflammatory stimuli can facilitate tau phosphorylation. Coupled with prior results demonstrating clearance of A? by similar LPS injections, these results suggest that brain inflammation may have opposing effects on amyloid and tau pathology, possibly explaining the failures (to date) of anti-inflammatory therapies in AD patients. PMID:20846376

2010-01-01

87

Signaling pathways involved in LPS induced TNFalpha production in human adipocytes  

PubMed Central

Background The development of obesity has been linked to an inflammatory process, and the role of adipose tissue in the secretion of pro-inflammatory molecules such as IL-6 or TNFalpha has now been largely confirmed. Although TNFalpha secretion by adipose cells is probably induced, most notably by TLR ligands, the activation and secretion pathways of this cytokine are not yet entirely understood. Moreover, given that macrophagic infiltration is a characteristic of obesity, it is difficult to clearly establish the level of involvement of the different cellular types present within the adipose tissue during inflammation. Methods Primary cultures of human adipocytes and human peripheral blood mononuclear cells were used. Cells were treated with a pathogen-associated molecular pattern: LPS, with and without several kinase inhibitors. Western blot for p38 MAP Kinase was performed on cell lysates. TNFalpha mRNA was detected in cells by RT-PCR and TNFalpha protein was detected in supernatants by ELISA assays. Results We show for the first time that the production of TNFalpha in mature human adipocytes is mainly dependent upon two pathways: NFkappaB and p38 MAP Kinase. Moreover, we demonstrate that the PI3Kinase pathway is clearly involved in the first step of the LPS-pathway. Lastly, we show that adipocytes are able to secrete a large amount of TNFalpha compared to macrophages. Conclusion This study clearly demonstrates that the LPS induced activation pathway is an integral part of the inflammatory process linked to obesity, and that adipocytes are responsible for most of the secreted TNFalpha in inflamed adipose tissue, through TLR4 activation. PMID:20148136

2010-01-01

88

Disparate roles of marrow- and parenchymal cell-derived TLR4 signaling in murine LPS-induced systemic inflammation  

PubMed Central

Systemic inflammatory response syndrome (SIRS) occurs in a range of infectious and non-infectious disease processes. Toll-like receptors (TLRs) initiate such responses. We have shown that parenchymal cell TLR4 activation drives LPS-induced systemic inflammation; SIRS does not develop in mice lacking TLR4 expression on parenchymal cells. The parenchymal cell types whose TLR4 activation directs this process have not been identified. Employing a bone marrow transplant model to compartmentalize TLR4 signaling, we characterized blood neutrophil and cytokine responses, NF-?B1 activation, and Tnf-?, Il6, and Ccl2 induction in several organs (spleen, aorta, liver, lung) near the time of LPS-induced symptom onset. Aorta, liver, and lung gene responses corresponded with both LPS-induced symptom onset patterns and plasma cytokine/chemokine levels. Parenchymal cells in aorta, liver, and lung bearing TLR4 responded to LPS with chemokine generation and were associated with increased plasma chemokine levels. We propose that parenchymal cells direct SIRS in response to LPS. PMID:23213355

Juskewitch, Justin E.; Platt, Jeffrey L.; Knudsen, Bruce E.; Knutson, Keith L.; Brunn, Gregory J.; Grande, Joseph P.

2012-01-01

89

NF-?B Regulates the LPS-Induced Expression of Interleukin 12 p40 in Murine Peritoneal Macrophages: Roles of PKC, PKA, ERK, p38 MAPK, and Proteasome  

Microsoft Academic Search

NF-?B plays a critical role in coordinating the control of gene expression during monocyte\\/macrophage activation. In this report we describe our investigation of the mechanisms of LPS-induced NF-?B activation and IL-12 expression in murine peritoneal suppressor macrophages. Treatment of these macrophages with LPS induced I?B? degradation and NF-?B activation. EMSAs demonstrated that NF-?B bound to a cis-acting element located in

Jin-Song Zhang; Wei-Guo Feng; Chang-Ling Li; Xing-Yu Wang; Zong-Liang Chang

2000-01-01

90

2-phenylethynesulfonamide Prevents Induction of Pro-inflammatory Factors and Attenuates LPS-induced Liver Injury by Targeting NHE1-Hsp70 Complex in Mice.  

PubMed

The endotoxin-mediated production of pro-inflammatory cytokines plays an important role in the pathogenesis of liver disorders. Heat shock protein (Hsp70) overexpression has established functions in lipopolysaccharide (LPS)-mediated inflammatory response. However, little is known about the role of Hsp70 activity in LPS signaling. We hypothesized that inhibition of Hsp70 substrate binding activity can ameliorate LPS-induced liver injury by decreasing induction of pro-inflammatory factors. In this study, C57/BL6 mice were injected intraperitoneally with LPS and 2-phenylethynesulfonamide (PES), an inhibitor of Hsp70 substrate binding activity. We found that i. PES prevented LPS-induced increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, infiltration of inflammatory cells, and liver cell apoptosis; ii. PES reduced inducible nitric oxide synthase (iNOS) protein expression as well as serum nitric oxide (NO), tumor necrosis factor-? (TNF-?), and interleukin-6 (IL-6) content in LPS-stimulated mice; iii. PES reduced the mRNA level of iNOS, TNF-?, and IL-6 in LPS-stimulated liver. iiii. PES attenuated the degradation of inhibitor of ?B-? (I?B-?) as well as the phosphorylation and nuclear translocation of nuclear factor-?B (NF-?B) in LPS-stimulated liver. Similar changes in the protein expression of inflammatory markers, I?B-? degradation, and NF-?B phosphorylation and nuclear translocation were observed in RAW 264.7 cells. Further mechanistic studies revealed that PES remarkably reduced the elevation of [Ca(2+)]i and intracellular pH value (pHi) in LPS-stimulated RAW 264.7 cells. Furthermore, PES significantly reduced the increase in Na(+)/H(+) exchanger 1 (NHE1) association to Hsp70 in LPS-stimulated macrophages and liver, suggesting that NHE1-Hsp70 interaction is required for the involvement of NHE1 in the inflammation response. In conclusion, inhibition of Hsp70 substrate binding activity in vivo reduces the induction of pro-inflammatory factors and prevents LPS-induced liver injury likely by disrupting NHE1-Hsp70 interaction which consequently reduces the activation of I?B-?-NF-?B pathway in liver. PMID:23805318

Huang, Chao; Wang, Jia; Chen, Zhuo; Wang, Yuzhe; Zhang, Wei

2013-01-01

91

Ghrelin inhibits LPS-induced release of IL-6 from mouse dopaminergic neurones  

PubMed Central

Background Ghrelin is an orexigenic stomach hormone that acts centrally to increase mid-brain dopamine neurone activity, amplify dopamine signaling and protect against neurotoxin-induced dopamine cell death in the mouse substantia nigra pars compacta (SNpc). In addition, ghrelin inhibits the lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines from peripheral macrophages, T-cells and from LPS stimulated microglia. Here we sought to determine whether ghrelin attenuates pro-inflammatory cytokine release from dopaminergic neurones. Findings The dopaminergic SN4741 cell-line, which derives from the mouse substantia nigra (SN) and expresses the ghrelin-receptor (growth hormone secretagogue receptor (GHS-R)) and the ghrelin-O-acyl transferase (GOAT) enzyme, was used to determine the neuro-immunomodulatory action of ghrelin. We induced innate immune activation via LPS challenge (1 ?g/ml) of SN4741 neurones that had been pre-cultured in the presence or absence of ghrelin (1, 10, 100 nM) for 4 h. After 24 h supernatants were collected for detection of IL-1 beta (IL-1? ), TNF alpha (TNF-?) and IL-6 cytokines via enzyme linked immunosorbent assay (ELISA) analysis. Nuclear translocation of the transcription factor nuclear factor kappa B (NF-?B) was analyzed by Western blotting, and to determine viability of treatments a cell viability assay and caspase-3 immunohistochemistry were performed. We provide evidence that while IL-1? and TNF-? were not detectable under any conditions, SN4741 neurones constitutively released IL-6 under basal conditions and treatment with LPS significantly increased IL-6 secretion. Pre-treatment of neurones with ghrelin attenuated LPS-mediated IL-6 release at 24 h, an affect that was inhibited by the GHS-R antagonist [D-Lys3]-GHRP-6. However, while ghrelin pre-treatment attenuated the LPS-mediated increase in NF-?B, there was no alteration in its nuclear translocation. Cell viability assay and caspase-3 immunocytochemistry demonstrated that the results were independent from activation of cytotoxic and/or apoptotic mechanisms in the neuronal population, respectively. Conclusion Our results provide evidence that the gut-hormone, ghrelin, attenuates IL-6 secretion to LPS challenge in mid-brain dopaminergic neurones. These data suggest that ghrelin may protect against dopaminergic SN nerve cell damage or death via modulation of the innate immune response. PMID:23509933

2013-01-01

92

Spirulina promotes stem cell genesis and protects against LPS induced declines in neural stem cell proliferation.  

PubMed

Adult stem cells are present in many tissues including, skin, muscle, adipose, bone marrow, and in the brain. Neuroinflammation has been shown to be a potent negative regulator of stem cell and progenitor cell proliferation in the neurogenic regions of the brain. Recently we demonstrated that decreasing a key neuroinflammatory cytokine IL-1beta in the hippocampus of aged rats reversed the age-related cognitive decline and increased neurogenesis in the age rats. We also have found that nutraceuticals have the potential to reduce neuroinflammation, and decrease oxidative stress. The objectives of this study were to determine if spirulina could protect the proliferative potential of hippocampal neural progenitor cells from an acute systemic inflammatory insult of lipopolysaccharide (LPS). To this end, young rats were fed for 30 days a control diet or a diet supplemented with 0.1% spirulina. On day 28 the rats were given a single i.p. injection of LPS (1 mg/kg). The following day the rats were injected with BrdU (50 mg/kg b.i.d. i.p.) and were sacrificed 24 hours after the first injection of BrdU. Quantification of the BrdU positive cells in the subgranular zone of the dentate gyrus demonstrated a decrease in proliferation of the stem/progenitor cells in the hippocampus as a result of the LPS insult. Furthermore, the diet supplemented with spirulina was able to negate the LPS induced decrease in stem/progenitor cell proliferation. In a second set of studies we examined the effects of spirulina either alone or in combination with a proprietary formulation (NT-020) of blueberry, green tea, vitamin D3 and carnosine on the function of bone marrow and CD34+ cells in vitro. Spirulina had small effects on its own and more than additive effects in combination with NT-020 to promote mitochondrial respiration and/or proliferation of these cells in culture. When examined on neural stem cells in culture spirulina increased proliferation at baseline and protected against the negative influence of TNFalpha to reduce neural stem cell proliferation. These results support the hypothesis that a diet enriched with spirulina and other nutraceuticals may help protect the stem/progenitor cells from insults. PMID:20463965

Bachstetter, Adam D; Jernberg, Jennifer; Schlunk, Andrea; Vila, Jennifer L; Hudson, Charles; Cole, Michael J; Shytle, R Douglas; Tan, Jun; Sanberg, Paul R; Sanberg, Cyndy D; Borlongan, Cesario; Kaneko, Yuji; Tajiri, Naoki; Gemma, Carmelina; Bickford, Paula C

2010-01-01

93

Cobalt protoporphyrin accelerates TFEB activation and lysosome reformation during LPS-induced septic insults in the rat heart.  

PubMed

Lipopolysaccharide (LPS)-induced myocardial dysfunction is caused, at least in part, by mitochondrial dysfunction. Mitochondrial dysfunction and the oxidative damage associated with it are scavenged through various cellular defense systems such as autophagy to prevent harmful effects. Our recent study has demonstrated that cobalt protoporphyrin IX (CoPPIX), a potent inducer of heme oxygenase-1 (HO-1), ameliorates septic liver injuries by enhancing mitochondrial autophagy in rats. In our current study, we show that CoPPIX (5 mg/kg s.c.) not only accelerates the autophagic response but also promotes lysosome reformation in the rat heart treated with LPS (15 mg/kg i.p.). Lysosomal membrane-associated protein-2 (LAMP2), which is essential to the maintenance of lysosomal functions in the heart, is depleted transiently but restored rapidly during LPS administration in the rat. Activation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, was also observed, indicating a hyper consumption and subsequent reformation of the lysosome to meet the increased demand for autophagosome cleaning. CoPPIX was found to promote these processes and tended to restore the LPS-induced suppression of cardiac performances whilst chloroquine (CQ; 20 mg/kg i.p.), an inhibitor of lysosomes and autophagic protein degradation, abrogates these beneficial effects. The cardioprotective effect of CoPPIX against LPS toxicity was also observed via decreased levels of cardiac releasing enzymes in the plasma. Taken together, our current data indicate that lysosome reformation mediated by TFEB may be involved in cardioprotection against LPS-induced septic insults, and serve as a novel mechanism by which CoPPIX protects the heart against oxidative stress. PMID:23457579

Unuma, Kana; Aki, Toshihiko; Funakoshi, Takeshi; Yoshida, Ken-ichi; Uemura, Koichi

2013-01-01

94

Heat Shock Protein 90 Inhibitors Prevent LPS-Induced Endothelial Barrier Dysfunction by Disrupting RhoA Signaling  

PubMed Central

Permeability of the endothelial monolayer is increased when exposed to the bacterial endotoxin LPS. Our previous studies have shown that heat shock protein (Hsp) 90 inhibitors protect and restore LPS-mediated hyperpermeability in bovine pulmonary arterial endothelial cells. In this study, we assessed the effect of Hsp90 inhibition against LPS-mediated hyperpermeability in cultured human lung microvascular endothelial cells (HLMVECs) and delineated the underlying molecular mechanisms. We demonstrate that Hsp90 inhibition is critical in the early phase, to prevent LPS-mediated hyperpermeability, and also in the later phase, to restore LPS-mediated hyperpermeability in HLMVECs. Because RhoA is a well known mediator of endothelial hyperpermeability, we investigated the effect of Hsp90 inhibition on LPS-mediated RhoA signaling. RhoA nitration and activity were increased by LPS in HLMVECs and suppressed when pretreated with the Hsp90 inhibitor, 17-allylamino-17 demethoxy-geldanamycin (17-AAG). In addition, inhibition of Rho kinase, a downstream effector of RhoA, protected HLMVECs from LPS-mediated hyperpermeability and abolished LPS-induced myosin light chain (MLC) phosphorylation, a target of Rho kinase. In agreement with these findings, 17-AAG or dominant-negative RhoA attenuated LPS-induced MLC phosphorylation. MLC phosphorylation induced by constitutively active RhoA was also suppressed by 17-AAG, suggesting a role for Hsp90 downstream of RhoA. Inhibition of Src family kinases also suppressed RhoA activity and MLC phosphorylation. Together, these data indicate that Hsp90 inhibition prevents and repairs LPS-induced lung endothelial barrier dysfunction by suppressing Src-mediated RhoA activity and signaling. PMID:23972231

Joshi, Atul D.; Dimitropoulou, Christiana; Thangjam, Gagan; Snead, Connie; Feldman, Sara; Barabutis, Nektarios; Fulton, David; Hou, Yali; Kumar, Sanjiv; Patel, Vijay; Gorshkov, Boris; Verin, Alexander D.; Black, Stephen M.

2014-01-01

95

Salidroside Reduces Cell Mobility via NF-?B and MAPK Signaling in LPS-Induced BV2 Microglial Cells  

PubMed Central

The unregulated activation of microglia following stroke results in the production of toxic factors that propagate secondary neuronal injury. Salidroside has been shown to exhibit protective effects against neuronal death induced by different insults. However, the molecular mechanisms responsible for the anti-inflammatory activity of salidroside have not been elucidated clearly in microglia. In the present study, we investigated the molecular mechanism underlying inhibiting LPS-stimulated BV2 microglial cell mobility of salidroside. The protective effect of salidroside was investigated in microglial BV2 cell, subjected to stretch injury. Moreover, transwell migration assay demonstrated that salidroside significantly reduced cell motility. Our results also indicated that salidroside suppressed LPS-induced chemokines production in a dose-dependent manner, without causing cytotoxicity in BV2 microglial cells. Moreover, salidroside suppressed LPS-induced activation of nuclear factor kappa B (NF-?B) by blocking degradation of I?B? and phosphorylation of MAPK (p38, JNK, ERK1/2), which resulted in inhibition of chemokine expression. These results suggest that salidroside possesses a potent suppressive effect on cell migration of BV2 microglia and this compound may offer substantial therapeutic potential for treatment of ischemic strokes that are accompanied by microglial activation. PMID:24864151

Hu, Haixia; Li, Zuanfang; Zhu, Xiaoqin; Lin, Ruhui; Chen, Lidian

2014-01-01

96

Lipid emulsions differentially affect LPS-induced acute monocytes inflammation: in vitro effects on membrane remodeling and cell viability.  

PubMed

The aim of this study was to assess how lipid emulsions for parenteral nutrition affect lipopolysaccharide (LPS)-induced acute monocyte inflammation in vitro. An 18 h long LPS induced human monocyte leukemia cell stimulation was performed and the cell-growth medium was supplemented with three different industrial lipid emulsions: Intralipid(®), containing long-chain triglycerides (LCT--soybean oil); Medialipid(®), containing LCT (soybean oil) and medium-chain triglycerides (MCT--coconut oil); and SMOFlipid(®), containing LCT, MCT, omega-9 and -3 (soybean, coconut, olive and fish oils). Cell viability and apoptosis were assessed by Trypan blue exclusion and flow cytometry respectively. Monocyte composition and membrane remodeling were studied using gas chromatography and NR12S staining. Microparticles released in supernatant were measured by prothrombinase assay. After LPS challenge, both cellular necrosis and apoptosis were increased (threefold and twofold respectively) and microparticle release was enhanced (sevenfold) after supplementation with Medialipid(®) compared to Intralipid(®), SMOFlipid(®) and monocytes in the standard medium. The monocytes differentially incorporated fatty acids after lipid emulsion challenge. Finally, lipid-treated cells displayed microparticles characterized by disrupted membrane lipid order, reflecting lipid remodeling of the parental cell plasma membrane. Our data suggest that lipid emulsions differentially alter cell viability, monocyte composition and thereby microparticle release. While MCT have deleterious effects, we have shown that parenteral nutrition emulsion containing LCT or LCT and MCT associated to n-3 and n-9 fatty acids have no effect on endotoxin-induced cell death and inflammation. PMID:25038627

Boisramé-Helms, Julie; Delabranche, Xavier; Klymchenko, Andrey; Drai, Jocelyne; Blond, Emilie; Zobairi, Fatiha; Mely, Yves; Hasselmann, Michel; Toti, Florence; Meziani, Ferhat

2014-11-01

97

Apigenin-7-Glycoside Prevents LPS-Induced Acute Lung Injury via Downregulation of Oxidative Enzyme Expression and Protein Activation through Inhibition of MAPK Phosphorylation  

PubMed Central

Apigenin-7-glycoside (AP7Glu) with multiple biological activities is a flavonoid that is currently prescribed to treat inflammatory diseases such as upper respiratory infections. Recently, several studies have shown that its anti-inflammatory activities have been strongly linked to the inhibition of secretion of pro-inflammatory proteins, such as inducible nitric oxide synthase (iNOs) and cyclooxygenase-2 (COX-2) induced through phosphorylation nuclear factor-?B (NF-?B) and mitogen-activated protein kinases (MAPK) pathways. Additionally, inflammation, which can decrease the activities of antioxidative enzymes (AOEs) is also observed in these studies. At the same time, flavonoids are reported to promote the activities of heme oxygenase-1 (HO-1) decreased by LPS. The purpose of this study was to assess these theories in a series of experiments on the suppressive effects of AP7Glu based on LPS-induced nitric oxide production in RAW264.7 macrophages in vitro and acute lung injury in mice in vivo. After six hours of lipopolysaccharide (LPS) stimulation, pulmonary pathological, myeloperoxidase (MPO) activity, total polymorphonuclear leukocytes (PMN) cells, cytokines in bronchoalveolar lavage fluid (BALF) and AOEs, are all affected and changed. Meanwhile, our data revealed that AP7Glu not only did significantly inhibit the LPS-enhanced inflammatory activity in lung, but also exhibited anti-inflammatory effect through the MAPK and inhibitor NF-?B (I?B) pathways. PMID:25590301

Li, Kun-Cheng; Ho, Yu-Ling; Hsieh, Wen-Tsong; Huang, Shyh-Shyun; Chang, Yuan-Shiun; Huang, Guan-Jhong

2015-01-01

98

Antinociceptive effect of tetrandrine on LPS-induced hyperalgesia via the inhibition of IKK? phosphorylation and the COX-2/PGE? pathway in mice.  

PubMed

Tetrandrine (TET) is a bisbenzylisoquinoline alkaloid that is isolated from the Stephania Tetrandra. It is known to possess anti-inflammatory and immunomodulatory effects. We have shown that TET can effectively suppress the production of bacterial lipopolysaccharide (LPS)-induced inflammatory mediators, including cyclooxygenases (COXs), in macrophages. However, whether TET has an antinociceptive effect on LPS-induced hyperalgesia is unknown. In the present study, we investigated the potential antinociceptive effects of TET and the mechanisms by which it elicits its effects on LPS-induced hyperalgesia. LPS effectively evoked hyperalgesia and induced the production of PGE2 in the sera, brain tissues, and cultured astroglia. TET pretreatment attenuated all of these effects. LPS also activated inhibitor of ?B (I?B) kinase ? (IKK?) and its downstream components in the I?B/nuclear factor (NF)-?B signaling pathway, including COX-2; the increase in expression levels of these components was significantly abolished by TET. Furthermore, in primary astroglia, knockdown of IKK?, but not IKK?, reversed the effects of TET on the LPS-induced increase in I?B phosphorylation, P65 phosphorylation, and COX-2. Our results suggest that TET can effectively exert antinociceptive effects on LPS-induced hyperalgesia in mice by inhibiting IKK? phosphorylation, which leads to the reduction in the production of important pain mediators, such as PGE2 and COX-2, via the IKK?/I?B/NF-?B pathway. PMID:24722146

Zhao, Hengguang; Luo, Fuling; Li, Hongzhong; Zhang, Li; Yi, Yongfen; Wan, Jingyuan

2014-01-01

99

Saponarin from barley sprouts inhibits NF-?B and MAPK on LPS-induced RAW 264.7 cells.  

PubMed

Saponarin (SA), a natural flavonoid, is known for its antioxidant and hepatoprotective activities. SA is the predominant compound (1142.7 ± 0.9 mg per 100 g) in barley sprouts, constituting 72% of the total polyphenol content. We investigated, for the first time, the effects of SA from barley sprouts on cellular anti-inflammatory responses. In lipopolysaccharide (LPS)-induced RAW 264.7 macrophages, SA suppressed the activation of NF-?B, as evidenced by the inhibition of NF-?B DNA binding, nuclear translocation, I?B? phosphorylation, and reporter gene expression, and it downregulated the expression of the pro-inflammatory mediator IL-6. Furthermore, SA reduced the transcription of NF-?B target molecules COX2 and FLIP inhibited the phosphorylation of mitogen-activated protein kinases ERK and p38. These results suggest that SA isolated from barley sprouts exerts anti-inflammatory effects in LPS-induced RAW 264.7 macrophages via inhibition of NF-?B, ERK and p38 signaling. Thus, SA may be a promising natural anti-inflammatory agent. PMID:25238253

Seo, Kyung Hye; Park, Mi Jin; Ra, Ji-Eun; Han, Sang-Ik; Nam, Min-Hee; Kim, Jin Hyo; Lee, Jin Hwan; Seo, Woo Duck

2014-11-01

100

Loss of protein kinase C-? protects against LPS-induced osteolysis owing to an intrinsic defect in osteoclastic bone resorption.  

PubMed

Bone remodeling is intrinsically regulated by cell signaling molecules. The Protein Kinase C (PKC) family of serine/threonine kinases is involved in multiple signaling pathways including cell proliferation, differentiation, apoptosis and osteoclast biology. However, the precise involvement of individual PKC isoforms in the regulation of osteoclast formation and bone homeostasis remains unclear. Here, we identify PKC-? as the major PKC isoform expressed among all PKCs in osteoclasts; including classical PKCs (-?, -? and -?), novel PKCs (-?, -?, -? and -?) and atypical PKCs (-?/? and -?). Interestingly, pharmacological inhibition and genetic ablation of PKC-? impairs osteoclastic bone resorption in vitro. Moreover, disruption of PKC-? activity protects against LPS-induced osteolysis in mice, with osteoclasts accumulating on the bone surface failing to resorb bone. Treatment with the PKC-? inhibitor Rottlerin, blocks LPS-induced bone resorption in mice. Consistently, PKC-? deficient mice exhibit increased trabeculae bone containing residual cartilage matrix, indicative of an osteoclast-rich osteopetrosis phenotype. Cultured ex vivo osteoclasts derived from PKC-? null mice exhibit decreased CTX-1 levels and MARKS phosphorylation, with enhanced formation rates. This is accompanied by elevated gene expression levels of cathepsin K and PKC -?, -? and -?, as well as altered signaling of pERK and pcSrc416/527 upon RANKL-induction, possibly to compensate for the defects in bone resorption. Collectively, our data indicate that PKC-? is an intrinsic regulator of osteoclast formation and bone resorption and thus is a potential therapeutic target for pathological osteolysis. PMID:23951014

Khor, Ee Cheng; Abel, Tamara; Tickner, Jennifer; Chim, Shek Man; Wang, Cathy; Cheng, Taksum; Ng, Benjamin; Ng, Pei Ying; Teguh, Dian Astari; Kenny, Jacob; Yang, Xiaohong; Chen, Honghui; Nakayama, Keiichi I; Nakayama, Keiko; Pavlos, Nathan; Zheng, Ming H; Xu, Jiake

2013-01-01

101

Resveratrol Inhibits LPS-Induced MAPKs Activation via Activation of the Phosphatidylinositol 3-Kinase Pathway in Murine RAW 264.7 Macrophage Cells  

PubMed Central

Background Resveratrol is a natural polyphenolic compound that has cardioprotective, anticancer and anti-inflammatory properties. We investigated the capacity of resveratrol to protect RAW 264.7 cells from inflammatory insults and explored mechanisms underlying inhibitory effects of resveratrol on RAW 264.7 cells. Methodology/Principal Findings Murine RAW 264.7 cells were treated with resveratrol (1, 5, and 10 µM) and/or LPS (5 µg/ml). Nitric oxide (NO) and prostaglandin E2 (PGE2) were measured by Griess reagent and ELISA. The mRNA and protein levels of proinflammatory proteins and cytokines were analysed by ELISA, RT-PCR and double immunofluorescence labeling, respectively. Phosphorylation levels of Akt, cyclic AMP-responsive element-binding protein (CREB), mitogen-activated protein kinases (MAPKs) cascades, AMP-activated protein kinase (AMPK) and expression of SIRT1(Silent information regulator T1) were measured by western blot. Wortmannin (1 µM), a specific phosphatidylinositol 3-kinase (PI3-K) inhibitor, was used to determine if PI3-K/Akt signaling pathway might be involved in resveratrol’s action on RAW 264.7 cells. Resveratrol significantly attenuated the LPS-induced expression of nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-? (TNF-?) and interleukin-1? (IL-1?) in RAW 264.7 cells. Resveratrol increased Akt phosphorylation in a time-dependent manner. Wortmannin, a specific phosphatidylinositol 3-kinase (PI3-K) inhibitor, blocked the effects of resveratrol on LPS-induced RAW 264.7 cells activation. In addition, PI3-K inhibition partially abolished the inhibitory effect of resveratrol on the phosphorylation of cyclic AMP-responsive element-binding protein (CREB) and mitogen-activated protein kinases (MAPKs) cascades. Meanwhile, PI3-K is essential for resveratrol-mediated phosphorylation of AMPK and expression of SIRT1. Conclusion and Implications This investigation demonstrates that PI3-K/Akt activation is an important signaling in resveratrol-mediated activation of AMPK phosphorylation and SIRT1 expression, and inhibition of phosphorylation of CREB and MAPKs activation, proinflammatory mediators and cytokines production in response to LPS in RAW 264.7 cells. PMID:22952890

Liu, Bin; Deng, Yi-Shu; Zhan, Dong; Chen, Yuan-Li; He, Ying; Liu, Jing; Zhang, Zong-Ji; Sun, Jun; Lu, Di

2012-01-01

102

Anti-Inflammatory Effect of Procyanidins from Wild Grape (Vitis amurensis) Seeds in LPS-Induced RAW 264.7 Cells  

PubMed Central

In the present study, the anti-inflammatory effect and underlying mechanisms of wild grape seeds procyanidins (WGP) were examined using lipopolysaccharide- (LPS-) stimulated RAW 264.7 cells. We used nitric oxide (NO) and prostaglandin E2 (PGE2) and reactive oxygen species (ROS) assays to examine inhibitory effect of WGP and further investigated the mechanisms of WGP suppressed LPS-mediated genes and upstream expression by Western blot and confocal microscopy analysis. Our data indicate that WGP significantly reduced NO, PGE2, and ROS production and also inhibited the expression of proinflammatory mediators such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expressions. Consistently, WGP significantly reduced LPS-stimulated expression of proinflammatory cytokines such as tumor necrosis factor ? (TNF-?) and interleukin- (IL-) 1?. Moreover, WGP prevented nuclear translocation of nuclear factor-?B (NF?B) p65 subunit by reducing inhibitory ?B-? (I?B?) and NF?B phosphorylation. Furthermore, we found that WGP inhibited LPS-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK). Taken together, our results demonstrated that WGP exerts potent anti-inflammatory activity through the inhibition of iNOS and COX-2 by regulating NF?B and p38 MAPK pathway. PMID:24260615

Bak, Min-Ji; Truong, Van Long; Kang, Hey-Sook; Jun, Mira; Jeong, Woo-Sik

2013-01-01

103

LPS induces pp60c-src-mediated tyrosine phosphorylation of Hsp90 in lung vascular endothelial cells and mouse lung  

PubMed Central

Heat shock protein 90 (Hsp90) inhibitors were initially developed as anticancer agents; however, it is becoming increasing clear that they also possess potent anti-inflammatory properties. Posttranslational modifications of Hsp90 have been reported in tumors and have been hypothesized to affect client protein- and inhibitor-binding activities. In the present study we investigated the posttranslational modification of Hsp90 in inflammation. LPS, a prototypical inflammatory agent, induced concentration- and time-dependent tyrosine (Y) phosphorylation of Hsp90? and Hsp90? in bovine pulmonary arterial and human lung microvascular endothelial cells (HLMVEC). Mass spectrometry identified Y309 as a major site of Y phosphorylation on Hsp90? (Y300 of Hsp90?). LPS-induced Hsp90 phosphorylation was prevented by the Hsp90 inhibitor 17-allyl-amino-demethoxy-geldanamycin (17-AAG) in vitro as well as in lungs from LPS-treated mice, in vivo. Furthermore, 17-AAG prevented LPS-induced pp60src activation. LPS-induced Hsp90 phosphorylation was also prevented by the pp60src inhibitor PP2. Additionally, Hsp90 phosphorylation was induced by infecting cells with a constitutively active pp60src adenovirus, whereas either a dominant-negative pp60src adenovirus or reduced expression of pp60src by a specific siRNA prevented the LPS-induced Y phosphorylation of Hsp90. Transfection of HLMVEC with the nonphosphorylatable Hsp90? Y300F mutant prevented LPS-induced Hsp90? tyrosine phosphorylation but not pp60src activation. Furthermore, the Hsp90? Y300F mutant showed a reduced ability to bind the Hsp90 client proteins eNOS and pp60src and HLMVEC transfected with the mutant exhibited reduced LPS-induced barrier dysfunction. We conclude that inflammatory stimuli cause posttranslational modifications of Hsp90 that are Hsp90-inhibitor sensitive and may be important to the proinflammatory actions of Hsp90. PMID:23585225

Barabutis, Nektarios; Handa, Vaishali; Dimitropoulou, Christiana; Rafikov, Ruslan; Snead, Connie; Kumar, Sanjiv; Joshi, Atul; Thangjam, Gagan; Fulton, David; Black, Stephen M.; Patel, Vijay

2013-01-01

104

Protective effect of rutin on LPS-induced acute lung injury via down-regulation of MIP-2 expression and MMP-9 activation through inhibition of Akt phosphorylation.  

PubMed

Lipopolysaccharide (LPS), also called endotoxin, is the important pathogen of acute lung injury (ALI), which is a clinical syndrome that still lacks effective therapeutic medicine. Rutin belongs to vitamin P and possesses various beneficial effects. In this study, we investigate the potential protective effects and the mechanisms of rutin on LPS-induced ALI. Pre-administration with rutin inhibited LPS-induced arterial blood gas exchange and neutrophils infiltration in the lungs. LPS-induced expression of macrophage inflammatory protein (MIP)-2 and activation of matrix metalloproteinase (MMP)-9 were suppressed by rutin. In addition, the inhibitory concentration of rutin on phosphorylation of Akt was similar as MIP-2 expression and MMP-9 activation. In conclusion, rutin is a potential protective agent for ALI via suppressing the blood gas exchange and neutrophil infiltration. The mechanism of rutin is down-regulation of MIP-2 expression and MMP-9 activation through inhibition of Akt phosphorylation. PMID:25091621

Chen, Wen-Ying; Huang, Yi-Chun; Yang, Ming-Ling; Lee, Chien-Ying; Chen, Chun-Jung; Yeh, Chung-Hsin; Pan, Pin-Ho; Horng, Chi-Ting; Kuo, Wu-Hsien; Kuan, Yu-Hsiang

2014-10-01

105

Salvia miltiorrhiza water-soluble extract, but not its constituent salvianolic acid B, abrogates LPS-induced NF-?B signalling in intestinal epithelial cells  

PubMed Central

Herbal medicine has become an increasing popular therapeutic alternative among patients suffering from various inflammatory disorders. The Salvia miltiorrhizae water-soluble extract (SME) have been shown to possess antioxidant and anti-inflammatory properties in vitro. However, the mechanism of action and impact of SME on LPS-induced gene expression is still unknown. We report that SME significantly abrogated LPS-induced I?B phosphorylation/degradation, NF-?B transcriptional activity and ICAM-1 gene expression in rat IEC-18 cells. Chromatin immunoprecipitation assay demonstrated that LPS-induced RelA recruitment to the ICAM-1 gene promoter was inhibited by SME. Moreover, in vitro kinase assay showed that SME directly inhibits LPS induced I?B kinase (IKK) activity in IEC-18 cells. To investigate the physiological relevance of SME inhibitory activity on NF-?B signalling, we used small intestinal explants and primary intestinal epithelial cells derived from a transgenic mouse expressing the enhanced green fluorescent protein (EGFP) under the transcriptional control of NF-?B cis-elements (cis-NF-?BEGFP). SME significantly blocked LPS-induced EGFP expression and I?B? phosphorylation in intestinal explants and primary IECs, respectively. However, salvianolic acid B, an activate component of SME did not inhibit NF-?B transcriptional activity and I?B phosphorylation/degradation in IEC-18 cells. These results indicate that SME blocks LPS-induced NF-?B signalling pathway by targeting the IKK complex in intestinal epithelial cells. Modulation of bacterial product-mediated NF-?B signalling by natural plant extracts may represent an attractive strategy towards the prevention and treatment of intestinal inflammation. PMID:15996193

Kim, J S; Narula, A S; Jobin, C

2005-01-01

106

Plasminogen Activator Inhibitor-1 Regulates LPS-Induced TLR4/MD-2 Pathway Activation and Inflammation in Alveolar Macrophages.  

PubMed

Toll-like receptor 4 (TLR4) and myeloid differentiation protein 2 (MD-2) are the main lipopolysaccharide (LPS) binding receptors that respond to inflammatory stimuli and mediate NF-kappa B (NF-?B) signaling pathway in macrophages. We have previously shown that plasminogen activator inhibitor-1 (PAI-1) deletion increased lung injury induced by intratracheal instillation of LPS through downregulation of TLR4 negative regulators. However, the mechanisms by which PAI-1 regulates lung inflammation are largely unknown. The aim of this study is to assess the relationship between PAI-1 and TLR4 signaling pathways in LPS-induced NR8383 cells inflammatory reaction. The results showed that the levels of PAI-1, TNF-?, and IL-1? protein were increased remarkably in NR8383 cell supernatants after LPS stimulation. PAI-1 gene knockdown reduced TNF-? and IL-1? levels in cell supernatants and inhibited the NF-?B p65 protein expression in NR8383 cells. The upregulated mRNA and protein expressions of TLR4, MD-2, and myeloid differentiation protein (MyD88) induced by LPS were attenuated after PAI-1 gene knockdown. Conversely, overexpression of PAI-1 in NR8383 cells not only resulted in additional mRNA and protein production of PAI-1, TLR4, MD-2, and MyD88, it also aggravated the inflammatory response induced by LPS. In conclusion, PAI-1 contributes to the regulation of LPS-induced inflammatory response in NR8383 cells, likely by affecting the TLR4-MD-2/NF-?B signaling transduction pathway. PMID:25342286

Ren, Weiying; Wang, Zhonghui; Hua, Feng; Zhu, Lei

2015-02-01

107

Glucosamine Inhibits Inducible Nitric Oxide Synthesis  

Microsoft Academic Search

Glucosamine is widely used in Europe for treatment of arthritis in humans. Based on recent findings that excess production of nitric oxide (NO) by inducible NO synthase (iNOS) mediates the pathogenesis of arthritis, we hypothesized that glucosamine may inhibit NO synthesis. To test this hypothesis, we used an in vivo rat model of lipopolysaccharide (LPS)-induced inflammation. Intravenous administration of d-glucosamine

Cynthia J. Meininger; Katherine A. Kelly; Hui Li; Tony E. Haynes; Guoyao Wu

2000-01-01

108

Selective inhibition of sphingosine kinase-1 protects adipose tissue against LPS-induced inflammatory response in Zucker diabetic fatty rats.  

PubMed

Obesity is associated with a state of chronic inflammation. The chemokine (C-C motif) ligand 5 (CCL5) has been proposed to modulate the inflammatory response in adipose tissue (AT). However, the mechanisms underlying CCL5 upregulation in AT remain undefined. The objective of the present study was to evaluate whether the enzyme sphingosine kinase-1 (SK1) would modulate the expression of CCL5 and other inflammatory biomarkers in primary adipocytes and its potential role in lipopolysaccharide (LPS)-induced AT inflammation in a rat model of diabetes. To address this, LPS-stimulated primary adipocytes and 3T3-L1 cells were treated with a SK inhibitor, and the expression of Ccl5 and other CC chemokines were studied. Moreover, the effect of SK1 knockdown on cytokine production was analyzed in 3T3-L1 cells by transfection of SK1-specific small-interfering RNA (siRNA). The anti-inflammatory effects of SK inhibitor in AT were also investigated in vivo using the Zucker lean normoglycemic control (ZLC) rats. LPS treatment stimulated Ccl5, IL-6, pentraxin 3 (Ptx3), and Tnf? mRNA expression in primary adipocytes and 3T3-L1 cells, whereas pharmacologically and siRNA-mediated SK1 inhibition strongly reduced mRNA levels of proinflammatory cytokines in these cells. Similarly, administration of SK inhibitor to ZLC rats prevented the LPS-induced inflammatory response in AT. Our data demonstrate a role for SK1 in endotoxin-induced cytokine expression in adipocytes and suggest that inhibition of SK1 may be a potential therapeutic tool in the prevention and treatment of chronic and common metabolic disorders, including obesity, insulin-resistance, and type 2 diabetes. PMID:25053402

Tous, Monica; Ferrer-Lorente, Raquel; Badimon, Lina

2014-09-01

109

Noninvasive molecular imaging reveals role of PAF in leukocyte-endothelial interaction in LPS-induced ocular vascular injury  

PubMed Central

Uveitis is a systemic immune disease and a common cause of blindness. The eye is an ideal organ for light-based imaging of molecular events underlying vascular and immune diseases. The phospholipid platelet-activating factor (PAF) is an important mediator of inflammation, the action of which in endothelial and immune cells in vivo is not well understood. The purpose of this study was to investigate the role of PAF in endothelial injury in uveitis. Here, we use our recently introduced in vivo molecular imaging approach in combination with the PAF inhibitors WEB 2086 (WEB) and ginkgolide B (GB). The differential inhibitory effects of WEB and GB in reducing LPS-induced endothelial injury in the choroid indicate an important role for PAF-like lipids, which might not require the PAF receptor for their signaling. P-selectin glycoprotein ligand-1-mediated rolling of mouse leukocytes on immobilized P-selectin in our autoperfused microflow chamber assay revealed a significant reduction in rolling velocity on the cells' contact with PAF. Rolling cells that came in contact with PAF rapidly assumed morphological signs of cell activation, indicating that activation during rolling does not require integrins. Our results show a key role for PAF in mediating endothelial and leukocyte activation in acute ocular inflammation. Our in vivo molecular imaging provides a detailed view of cellular and molecular events in the complex physiological setting.—Garland, R. C., Sun, D., Zandi, S., Xie, F., Faez, S., Tayyari, F., Frimmel, S. A. F., Schering, A., Nakao, S., Hafezi-Moghadam, A. Noninvasive molecular imaging reveals role of PAF in leukocyte-endothelial interaction in LPS-induced ocular vascular injury. PMID:21257713

Garland, Rebecca C.; Sun, Dawei; Zandi, Souska; Xie, Fang; Faez, Sepideh; Tayyari, Faryan; Frimmel, Sonja A. F.; Schering, Alexander; Nakao, Shintaro; Hafezi-Moghadam, Ali

2011-01-01

110

Effect of indomethacin on LPS-induced fever and on hyperthermia induced by physical restraint in the silver fox ( Vulpes vulpes)  

Microsoft Academic Search

1.1. The effects of indomethacin on LPS-induced fever, and on hyperthermia induced by physical restraint, were investigated in the silver fox (Vulpes vulpes).2.2. Base levels of deep body temperature (Tb) in undisturbed silver foxes measured with surgically implanted transmitters was 38.6°C (±0.1).3.3. Rectal temperature (Tre) five hours after treatment with LPS was 40.1°C (±0.1), indicating a febrile response.4.4. Tre in

Randi Oppermann Moe; Morten Bakken

1997-01-01

111

LPS-Induced Murine Systemic Inflammation Is Driven by Parenchymal Cell Activation and Exclusively Predicted by Early MCP-1 Plasma Levels  

PubMed Central

Systemic inflammation remains a major cause of morbidity and mortality in the United States, across many disease processes. One classic murine model to study this syndrome is lipopolysaccharide (LPS)–induced Toll-like receptor 4 (TLR4)–dependent systemic inflammation. Although most studies have focused on inflammatory cell TLR4 responses, parenchymal cells also express TLR4. Our objective was to define the in vivo role of parenchymal- versus marrow-derived cell activation via TLR4 during LPS-induced inflammation. Mice bearing TLR4 on parenchymal cells only, marrow-derived cells only, both, or neither were generated using bone marrow transplantation. Mortality occurred only in mice that had TLR4 expression on their parenchymal cells. Before onset, virtually all major plasma cytokines and blood neutrophil responses were related to marrow-derived cell activation via TLR4. The only cytokine predictive of oncoming systemic inflammation was the chemokine monocyte chemoattractant protein-1. Late blood neutrophil responses were related to the presence of TLR4 on either parenchymal or marrow cells, whereas plasma cytokine elevations late in LPS-induced systemic inflammation were dependent on mice having TLR4 in both cell compartments. Parenchymal cell activation via TLR4 is a key component of LPS-induced systemic inflammation and mortality, although most plasma cytokine levels and blood neutrophil responses were not key components. Given its unique role, future studies into monocyte chemoattractant protein-1's exact role during systemic inflammation are warranted. PMID:22067909

Juskewitch, Justin E.; Knudsen, Bruce E.; Platt, Jeffrey L.; Nath, Karl A.; Knutson, Keith L.; Brunn, Gregory J.; Grande, Joseph P.

2012-01-01

112

Pharmacological inhibition of GSK-3 in a guinea pig model of LPS-induced pulmonary inflammation: I. Effects on lung remodeling and pathology  

PubMed Central

Background Glycogen synthase kinase-3 (GSK-3) is a constitutively active kinase that regulates multiple signalling proteins and transcription factors involved in a myriad of cellular processes. The kinase acts as a negative regulator in ?-catenin signalling and is critically involved in the smad pathway. Activation of both pathways may contribute to pulmonary features of chronic obstructive pulmonary disease (COPD). Methods In the present study, we investigated the effect of the selective GSK-3 inhibitor SB216763 on pulmonary pathology in a guinea pig model of lipopolysaccharide (LPS)-induced COPD. Guinea pigs were instilled intranasally with LPS or saline twice weekly for 12 weeks and pre-treated with either intranasally instilled SB216763 or corresponding vehicle 30 min prior to each LPS/saline challenge. Results Repeated LPS exposures activated ?-catenin signalling, primarily in the airway epithelium and submucosa. LPS also induced pulmonary inflammation and tissue remodelling as indicated by inflammatory cell influx, increased pulmonary fibronectin expression and enhanced small airway collagen content. Inhibition of GSK-3 by SB216763 did not affect LPS-induced inflammatory cell influx, but prevented the small airway remodelling and, unexpectedly, inhibited the activation of ?-catenin in vivo. LPS or SB216763 treatment had no effect on the airway smooth muscle content and alveolar airspace size. However, GSK-3 inhibition prevented LPS-induced right ventricle hypertrophy. Conclusions Our findings indicate that GSK-3 inhibition prevents LPS-induced pulmonary pathology in guinea pigs, and that locally reduced LPS-induced ?-catenin activation appears in part to underlie this effect. PMID:24152196

2013-01-01

113

SIGNR1-mediated phagocytosis, but not SIGNR1-mediated endocytosis or cell adhesion, suppresses LPS-induced secretion of IL-6 from murine macrophages.  

PubMed

C-type lectin receptors (CLRs) serve as phagocytosis receptors for pathogens and also function as adhesion molecules and in the recognition and endocytosis of glycosylated self-antigens. In the present study, we demonstrated that phagocytosis mediated by a mouse mannose-binding CLR, SIGNR1 significantly suppressed the LPS-induced secretion of the specific pro-inflammatory cytokines from the resident peritoneal macrophages and the mouse macrophage-like cells that express SIGNR1 (RAW-SIGNR1). LPS-induced secretion of IL-6 from peritoneal macrophages suppressed in response to uptake of oligomannose-coated liposomes (OMLs), and the suppression was partly inhibited by treatment with an anti-SIGNR1 antibody. LPS-induced secretion of IL-6 from RAW-SIGNR1 cells was also clearly inhibited by treatment of the cells with OMLs >0.4?m in diameter, but treatment with OMLs <0.4?m in diameter did not affect the IL-6 secretion. In contrast, LPS-induced TNF-? secretion from the cells was not affected on treatment of the cells with OMLs. Suppression of the IL-6 secretion was not observed following treatment with oligomannose-containing soluble polymers or when cells were bound to an oligomannose-coated solid phase. Phagocytosis of oligomannose-coated liposomes did not interfere with the transcription of IL-6 mRNA, but did affect IL-6 mRNA stability, leading to suppression of IL-6 secretion. Interestingly, treatment of the cells with Ly290042, a PI3 kinase inhibitor, partly blocked the suppression of LPS-induced secretion of IL-6 by OML. Thus, we conclude that SIGNR1-mediated phagocytosis but not SIGNR1-mediated endocytosis and cell adhesion, suppresses the TLR4-mediated production of specific proinflammatory cytokines via PI3 kinase signaling. PMID:25226443

Kawauchi, Yoko; Takagi, Hideaki; Hanafusa, Kei; Kono, Mirei; Yamatani, Minami; Kojima, Naoya

2015-01-01

114

Neolignans from the fruits of Magnolia obovata and their inhibition effect on NO production in LPS-induced RAW 264.7 cells.  

PubMed

Three new neolignans, named 9-methoxyobovatol (6), magnobovatol (7), and 2-hydroxyobovaaldehyde (9), along with six known ones, magnolol (1), honokiol (2), isomagnolol (3), obovatol (4), obovatal (5), and obovaaldehyde (8), were isolated from the fruits of Magnolia obovata using silica gel and ODS column chromatography. From the results of spectroscopic data including EIMS, IR, 1H- and 13C-NMR, DEPT, and 2D-NMR (gCOSY, gHSQC, gHMBC), the chemical structures were determined. All isolated compounds were evaluated for inhibition activity on nitric oxide production in LPS-induced RAW 264.7 cells, and compounds 1-4, 6, 7, and 9 showed significant activity with IC50 values of 15.8 ± 0.3, 3.3 ± 1.2, 14.1 ± 0.9, 6.2 ± 1.2, 14.8 ± 2.3, 14.2 ± 1.2, and 14.8 ± 3.2 µM, respectively, without any visible toxic effect. PMID:23970426

Seo, Kyeong-Hwa; Lee, Dae-Young; Lee, Dong-Sung; Park, Ji-Hae; Jeong, Rak-Hun; Jung, Ye-Jin; Shrestha, Sabina; Chung, In-Sik; Kim, Geum-Soog; Kim, Youn-Chul; Baek, Nam-In

2013-09-01

115

EP2 and EP4 receptors on muscularis resident macrophages mediate LPS-induced intestinal dysmotility via iNOS upregulation through cAMP/ERK signals  

PubMed Central

Intestinal resident macrophages play an important role in gastrointestinal dysmotility by producing prostaglandins (PGs) and nitric oxide (NO) in inflammatory conditions. The causal correlation between PGs and NO in gastrointestinal inflammation has not been elucidated. In this study, we examined the possible role of PGE2 in the LPS-inducible inducible NO synthase (iNOS) gene expression in murine distal ileal tissue and macrophages. Treatment of ileal tissue with LPS increased the iNOS and cyclooxygenase (COX)-2 gene expression, which lead to intestinal dysmotility. However, LPS did not induce the expression of iNOS and COX-2 in tissue from macrophage colony-stimulating factor-deficient op/op mice, indicating that these genes are expressed in intestinal resident macrophages. iNOS and COX-2 protein were also expressed in dextran-phagocytized macrophages in the muscle layer. CAY10404, a COX-2 inhibitor, diminished LPS-dependent iNOS gene upregulation in wild-type mouse ileal tissue and also in RAW264.7 macrophages, indicating that PGs upregulate iNOS gene expression. EP2 and EP4 agonists upregulated iNOS gene expression in ileal tissue and isolated resident macrophages. iNOS mRNA induction mediated by LPS was decreased in the ileum isolated from EP2 or EP4 knockout mice. In addition, LPS failed to decrease the motility of EP2 and EP4 knockout mice ileum. EP2- or EP4-mediated iNOS expression was attenuated by KT-5720, a PKA inhibitor and PD-98059, an ERK inhibitor. Forskolin or dibutyryl-cAMP mimics upregulation of iNOS gene expression in macrophages. In conclusion, COX-2-derived PGE2 induces iNOS expression through cAMP/ERK pathways by activating EP2 and EP4 receptors in muscularis macrophages. NO produced in muscularis macrophages induces dysmotility during gastrointestinal inflammation. PMID:22159280

Tajima, Tsuyoshi; Murata, Takahisa; Aritake, Kosuke; Urade, Yoshihiro; Michishita, Masaki; Matsuoka, Toshiyuki; Narumiya, Shuh; Ozaki, Hiroshi

2012-01-01

116

A novel MyD-1 (SIRP-1alpha) signaling pathway that inhibits LPS-induced TNFalpha production by monocytes.  

PubMed

MyD-1 (CD172) is a member of the family of signal regulatory phosphatase (SIRP) binding proteins, which is expressed on human CD14+ monocytes and dendritic cells. We now show a novel role for MyD-1 in the regulation of the innate immune system by pathogen products such as lipopolysaccharide (LPS), purified protein derivative (PPD), and Zymosan. Specifically, we demonstrate that ligation of MyD-1 on peripheral blood mononuclear cells (PBMCs) inhibits tumor necrosis factor alpha (TNFalpha) secretion but has no effect on other cytokines induced in response to each of these products. In an attempt to understand the molecular mechanisms underlying this surprisingly selective effect we investigated signal transduction pathways coupled to MyD-1. Ligation of the SIRP was found to recruit the tyrosine phosphatase SHP-2 and promote sequential activation of phosphatidylinositol (PI) 3-kinase, phospholipase D, and sphingosine kinase. Inhibition of LPS-induced TNFalpha secretion by MyD-1 appears to be mediated by this pathway, as the PI 3-kinase inhibitor wortmannin restores normal LPS-driven TNFalpha secretion. MyD-1-coupling to this PI 3-kinase-dependent signaling pathway may therefore present a novel target for the development of therapeutic strategies for combating TNFalpha production and consequent inflammatory disease. PMID:12805067

Smith, Rosemary E; Patel, Vanshree; Seatter, Sandra D; Deehan, Maureen R; Brown, Marion H; Brooke, Gareth P; Goodridge, Helen S; Howard, Christopher J; Rigley, Kevin P; Harnett, William; Harnett, Margaret M

2003-10-01

117

LPS-induced indoleamine 2,3-dioxygenase is regulated in an interferon-c- 3 independent manner by a JNK signaling pathway in primary murine microglia  

PubMed Central

Inflammation-induced activation of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) causes depressive-like behavior in mice following acute activation of the innate immune system by lipopolysaccharide (LPS). Here we investigated the mechanism of IDO expression induced by LPS in primary cultures of microglia derived from neonatal C57BL/6J mice. LPS (10 ng/ml) induced IDO transcripts that peaked at 8 h and enzymatic activity at 24 h, resulting in an increase in extracellular kynurenine, the catabolic product of IDO-induced tryptophan catabolism. This IDO induction by LPS was accompanied by synthesis and secretion of the proinflammatory cytokines TNF? and IL-6, but without detectable IFN? expression. To explore the mechanism of LPS-induced IDO expression, microglia were pretreated with the c-Jun-N-terminal kinase (JNK) inhibitor SP600125 for 30 min before LPS treatment. We found that SP600125 blocked JNK phosphorylation and significantly decreased IDO expression induced by LPS, which was accompanied by a reduction of LPS-induced expression of TNF? and IL-6. Collectively, these data extend to microglia the property that LPS induces IDO expression via an IFN?-independent mechanism that depends upon activation of JNK. Inhibition of the JNK pathway may provide a new therapy for inflammatory depression. PMID:19577630

Wang, Yunxia; Lawson, Marcus A.; Dantzer, Robert; Kelley, Keith W.

2009-01-01

118

S-Form Lipopolysaccharide (LPS), but Not Lipid A or R-Chemo-type LPS, Induces Interleukin6 Production in Vitamin D 3-Differentiated THP1 Cells  

Microsoft Academic Search

Bacterial lipopolysaccharide (LPS) induces the production of various inflammatory cytokines and the inducibility is considered attributable to the glycolipid part of LPS called lipid A. We report anin vitromodel in which lipid A is not necessarily a minimal structure for the LPS activity. Vitamin D3-differentiated THP-1 cells, cultured human monocytic leukemia cells, produced a high level of interleukin-6 (IL-6) by

Yasuo Suda; Kazue Aoyama; Kazumi Arimoto; Toshihide Tamura; Shoichi Kusumoto

1999-01-01

119

Microbial transformation of acetyl-11-keto-?-boswellic acid and their inhibitory activity on LPS-induced NO production.  

PubMed

The capabilities of 20 strains of fungi to transform acetyl-11-keto-?-boswellic (AKBA) were screened. And biotransformation of AKBA by Cunninghamella blakesleana AS 3.970 afforded five metabolites (1-5), while two metabolites (6, 7) were isolated from biotransformation of Cunninghamella elegans AS 3.1207. The chemical structures of these metabolites were identified by spectral methods including 2D NMR and their structures were elucidated as 7?-hydroxy-3-acety-11-keto-?-boswellic acid (1), 21?-dihydroxy-3-acety-11-keto-?-boswellic acid (2), 7?,22?-dihydroxy-3-acety-11-keto-?-boswellic acid (3), 7?,16?-dihydroxy-3-acety-11-keto-?-boswellic acid (4), 7?,15?-dihydroxy-3-acety-11-keto-?-boswellic acid (5); 7?,15?,21?-trihydroxy-3-acety-11-keto-?-boswellic acid (6) and 15?,21?-dihydroxy-3-acety-11-keto-?-boswellic acid (7). All these products are previously unknown. Their primary structure-activity relationships (SAR) of inhibition activity on LPS-induced NO production in RAW 264.7 macrophage cells were evaluated. PMID:23391590

Sun, Yan; Liu, Dan; Xi, Ronggang; Wang, Xiaobo; Wang, Yan; Hou, Jie; Zhang, Baojing; Wang, Changyuan; Liu, Kexin; Ma, Xiaochi

2013-03-01

120

MRTF-A mediates LPS-induced pro-inflammatory transcription by interacting with the COMPASS complex.  

PubMed

Chronic inflammation underscores the pathogenesis of a range of human diseases. Lipopolysaccharide (LPS) elicits strong pro-inflammatory responses in macrophages through the transcription factor NF-?B. The epigenetic mechanism underlying LPS-induced pro-inflammatory transcription is not fully understood. Herein, we describe a role for myocardin-related transcription factor A (MRTF-A, also known as MKL1) in this process. MRTF-A overexpression enhanced NF-?B-dependent pro-inflammatory transcription, whereas MRTF-A silencing inhibited this process. MRTF-A deficiency also reduced the synthesis of pro-inflammatory mediators in a mouse model of colitis. LPS promoted the recruitment of MRTF-A to the promoters of pro-inflammatory genes in an NF-?B-dependent manner. Reciprocally, MRTF-A influenced the nuclear enrichment and target binding of NF-?B. Mechanistically, MRTF-A was necessary for the accumulation of active histone modifications on NF-?B target promoters by communicating with the histone H3K4 methyltransferase complex (COMPASS). Silencing of individual members of COMPASS, including ASH2, WDR5 and SET1 (also known as SETD1A), downregulated the production of pro-inflammatory mediators and impaired the NF-?B kinetics. In summary, our work has uncovered a previously unknown function for MRTF-A and provided insights into the rationalized development of anti-inflammatory therapeutic strategies. PMID:25189621

Yu, Liming; Weng, Xinyu; Liang, Peng; Dai, Xin; Wu, Xiaoyan; Xu, Huihui; Fang, Mingming; Fang, Fei; Xu, Yong

2014-11-01

121

Nicotine exaggerates LPS-induced airway hyperreactivity via JNK-mediated up-regulation of Toll-like receptor 4.  

PubMed

Tobacco smokers often display increased airway hyperreactivity (AHR) when faced with bacterial infections. The present study uses a murine organ-culture model to dissect the mechanisms involved in this exaggerated smooth muscle response. Nicotine simulates the effects of smoking, and LPS represents bacterial infection. Contractile responses of isolated murine tracheal segments were analyzed in myographs after organ culture with increasing concentrations of LPS and/or nicotine for 4 days with or without specific MAPK inhibitors. Nicotine's effect on the expression of cell surface Toll-like receptors (TLRs), MCP-1, COX-2, and TNF-? were examined by real-time PCR. Increased protein expression was verified by immunohistochemistry. LPS concentration-dependently increased contractile responses to bradykinin and des-Arg(9)-bradykinin. A combination of nicotine and low-dose LPS caused powerful synergistic contractions along with increased kinin receptor expression. Specific kinin B1 and B2 receptor inhibitors blocked this reaction. Nicotine increased mRNA and protein expression of TLR4 and -6 in the epithelium and smooth muscle layer, with MCP-1 and COX-2 mRNA increasing in parallel. Specific inhibition of JNK attenuated nicotine's effects. In conclusion, long-term exposure to nicotine up-regulated the expression of TLR4 and -6 via a JNK-related pathway, causing an exaggeration of the LPS-induced local airway inflammation and increased AHR. This might offer a mechanistic explanation to the increased AHR seen in tobacco smokers confronted with bacterial infections. PMID:24669857

Xu, Yuan; Zhang, Yaping; Cardell, Lars-Olaf

2014-09-01

122

Alliin, a Garlic (Allium sativum) Compound, Prevents LPS-Induced Inflammation in 3T3-L1 Adipocytes  

PubMed Central

Garlic (Allium sativum L.) has been used to alleviate a variety of health problems due to its high content of organosulfur compounds and antioxidant activity. The main active component is alliin (S-allyl cysteine sulfoxide), a potent antioxidant with cardioprotective and neuroprotective actions. In addition, it helps to decrease serum levels of glucose, insulin, triglycerides, and uric acid, as well as insulin resistance, and reduces cytokine levels. However its potential anti-inflammatory effect is unknown. We examined the effects of alliin in lipopolysaccharide- (LPS-) stimulated 3T3-L1 adipocytes by RT-PCR, Western blot, and microarrays analysis of 22,000 genes. Incubation of cells for 24?h with 100??mol/L alliin prevented the increase in the expression of proinflammatory genes, IL-6, MCP-1, and Egr-1 in 3T3-L1 adipocytes exposed to 100?ng/mL LPS for 1?h. Interestingly, the phosphorylation of ERK1/2, which is involved in LPS-induced inflammation in adipocytes, was decreased following alliin treatment. Furthermore, the gene expression profile by microarrays evidentiate an upregulation of genes involved in immune response and downregulation of genes related with cancer. The present results have shown that alliin is able to suppress the LPS inflammatory signals by generating an anti-inflammatory gene expression profile and by modifying adipocyte metabolic profile. PMID:24453416

Quintero-Fabián, Saray; Ortuńo-Sahagún, Daniel; Vázquez-Carrera, Manuel; López-Roa, Rocío Ivette

2013-01-01

123

Alliin, a garlic (Allium sativum) compound, prevents LPS-induced inflammation in 3T3-L1 adipocytes.  

PubMed

Garlic (Allium sativum L.) has been used to alleviate a variety of health problems due to its high content of organosulfur compounds and antioxidant activity. The main active component is alliin (S-allyl cysteine sulfoxide), a potent antioxidant with cardioprotective and neuroprotective actions. In addition, it helps to decrease serum levels of glucose, insulin, triglycerides, and uric acid, as well as insulin resistance, and reduces cytokine levels. However its potential anti-inflammatory effect is unknown. We examined the effects of alliin in lipopolysaccharide- (LPS-) stimulated 3T3-L1 adipocytes by RT-PCR, Western blot, and microarrays analysis of 22,000 genes. Incubation of cells for 24 h with 100 ?mol/L alliin prevented the increase in the expression of proinflammatory genes, IL-6, MCP-1, and Egr-1 in 3T3-L1 adipocytes exposed to 100 ng/mL LPS for 1 h. Interestingly, the phosphorylation of ERK1/2, which is involved in LPS-induced inflammation in adipocytes, was decreased following alliin treatment. Furthermore, the gene expression profile by microarrays evidentiate an upregulation of genes involved in immune response and downregulation of genes related with cancer. The present results have shown that alliin is able to suppress the LPS inflammatory signals by generating an anti-inflammatory gene expression profile and by modifying adipocyte metabolic profile. PMID:24453416

Quintero-Fabián, Saray; Ortuńo-Sahagún, Daniel; Vázquez-Carrera, Manuel; López-Roa, Rocío Ivette

2013-01-01

124

FPR2/ALX activation reverses LPS-induced vascular hyporeactivity in aorta and increases survival in a pneumosepsis model.  

PubMed

The formylpeptide receptor 2 (FPR2/ALX) is a very promiscuous receptor, utilized by lipid and protein ligands that trigger pro- or anti-inflammatory responses. FPR2/ALX expression is increased in lung tissues of septic animals and its activation has a beneficial therapeutic effect by controlling exacerbated inflammation. Although FPR2/ALX expression was observed in vascular smooth muscle cells, its role in vascular reactivity in inflammatory conditions has not been studied. In this study, we report that LPS increases FPR2/ALX expression in vascular smooth muscle cells (A7r5 cells) and aorta tissue, and that the selective agonist WKYMVm reverses LPS-induced vascular hyporeactivity in mouse aorta rings. Mice bearing pneumosepsis by Klebsiella pneumoniae and treated with WKYMVm recovered the reactivity to vasoconstrictors and the survival improved by 40%. As for the mechanisms involved, FPR2/ALX activation decreases NO production in LPS-stimulated cells and aorta, but it does not seem involve the regulation of NOS-2 expression. The molecular mechanism by which the peptide inhibits NO production still needs to be elucidated, but our data suggests an important role for NO in the WKYMVm beneficial effect observed in LPS injury and sepsis. In conclusion, our data suggest, for the first time, that a receptor, primarily described as a mediator of immune responses, may have an important role in the vascular dysfunctions observed in sepsis and may be a possible target for new therapeutic interventions. PMID:25478948

Horewicz, Verônica Vargas; Crestani, Sandra; de Sordi, Regina; Rezende, Edir; Assreuy, Jamil

2015-01-01

125

IkappaBbeta is an essential co-activator for LPS-induced IL-1beta transcription in vivo.  

PubMed

Inhibitor of ?B (I?B) ? (I?B?) represents one of the major primary regulators of NF-?B in mammals. In contrast to the defined regulatory interplay between NF-?B and I?B?, much less is known about the biological function of I?B?. To elucidate the physiological role of I?B? in NF-?B signaling in vivo, we generated I?B?-deficient mice. These animals proved to be highly refractory to LPS-induced lethality, accompanied by a strong reduction in sepsis-associated cytokine production. In response to LPS, I?B? is recruited to the IL-1? promoter forming a complex with the NF-?B subunits RelA/c-Rel required for IL-1? transcription. Further transcriptome analysis of LPS-stimulated wild-type and I?B?-deficient BM-derived macrophages revealed several other genes with known regulatory functions in innate immunity arguing that a subset of NF-?B target genes is under control of I?B?. Collectively, these findings provide an essential proinflammatory role for I?B? in vivo, and establish a critical function for I?B? as a transcriptional coactivator under inflammatory conditions. PMID:20975042

Scheibel, Melanie; Klein, Bettina; Merkle, Heidrun; Schulz, Manon; Fritsch, Ralph; Greten, Florian R; Arkan, Melek C; Schneider, Günter; Schmid, Roland M

2010-11-22

126

LPS-induced down-regulation of signal regulatory protein {alpha} contributes to innate immune activation in macrophages.  

PubMed

Activation of the mitogen-activated protein kinases (MAPKs) and nuclear factor kappaB (NF-kappaB) cascades after Toll-like receptor (TLR) stimulation contributes to innate immune responses. Signal regulatory protein (SIRP) alpha, a member of the SIRP family that is abundantly expressed in macrophages, has been implicated in regulating MAPK and NF-kappaB signaling pathways. In addition, SIRPalpha can negatively regulate the phagocytosis of host cells by macrophages, indicating an inhibitory role of SIRPalpha in innate immunity. We provide evidences that SIRPalpha is an essential endogenous regulator of the innate immune activation upon lipopolysaccharide (LPS) exposure. SIRPalpha expression was promptly reduced in macrophages after LPS stimulation. The decrease in SIRPalpha expression levels was required for initiation of LPS-induced innate immune responses because overexpression of SIRPalpha reduced macrophage responses to LPS. Knockdown of SIRPalpha caused prolonged activation of MAPKs and NF-kappaB pathways and augmented production of proinflammatory cytokines and type I interferon (IFN). Mice transferred with SIRPalpha-depleted macrophages were highly susceptible to endotoxic shock, developing multiple organ failure and exhibiting a remarkable increase in mortality. SIRPalpha may accomplish this mainly through its association and sequestration of the LPS signal transducer SHP-2. Thus, SIRPalpha functions as a biologically important modulator of TLR signaling and innate immunity. PMID:17954568

Kong, Xiao-Ni; Yan, He-Xin; Chen, Lei; Dong, Li-Wei; Yang, Wen; Liu, Qiong; Yu, Le-Xing; Huang, Dan-Dan; Liu, Shu-Qin; Liu, Hui; Wu, Meng-Chao; Wang, Hong-Yang

2007-10-29

127

LPS-induced 111In-eosinophil accumulation in guinea-pig skin: evidence for a role for TNF-alpha.  

PubMed Central

Lipopolysaccharide (LPS) is a major component of the cell wall of Gram-negative bacteria with powerful pro-inflammatory activities. Although the mechanisms involved in LPS-induced neutrophil accumulation have been studied extensively, few reports have focused on the effects of LPS on eosinophil infiltration. In this study we have used an in vivo model of local 111In-eosinophil accumulation in the guinea-pig to investigate the mechanisms of LPS-induced eosinophilia. Using a 4-hr in vivo test period, the intradermal injection of LPS (50-1000 ng/site) led to a marked and dose-dependent accumulation of 111In-eosinophils into guinea-pig skin sites. Time-course experiments revealed that this cell infiltration was delayed in onset, becoming significant 1 hr after the intradermal administration of LPS. The slow development of the response and its sensitivity to the locally administered protein synthesis inhibitor, actinomycin D, suggested that the LPS-induced 111In-eosinophil accumulation in vivo is mediated by the generation of de novo proteins. The intravenous pretreatment of guinea-pigs with a soluble tumour necrosis factor-alpha (TNF-alpha) receptor fusion protein (TNFR-IgG, 1 mg/kg), potently inhibited the 111In-eosinophil accumulation induced by LPS. Our results demonstrate that LPS can induce 111In-eosinophil accumulation in vivo in guinea-pig skin, and that this process is mediated by TNF-alpha. PMID:7890304

Weg, V B; Walsh, D T; Faccioli, L H; Williams, T J; Feldmann, M; Nourshargh, S

1995-01-01

128

Therapeutic Effect of Intravenous Infusion of Perfluorocarbon Emulsion on LPS-Induced Acute Lung Injury in Rats  

PubMed Central

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) are the leading causes of death in critical care. Despite extensive efforts in research and clinical medicine, mortality remains high in these diseases. Perfluorocarbon (PFC), a chemical compound known as liquid ventilation medium, is capable of dissolving large amounts of physiologically important gases (mainly oxygen and carbon dioxide). In this study we aimed to investigate the effect of intravenous infusion of PFC emulsion on lipopolysaccharide (LPS) induced ALI in rats and elucidate its mechanism of action. Forty two Wistar rats were randomly divided into three groups: 6 rats were treated with saline solution by intratracheal instillation (control group), 18 rats were treated with LPS by intratracheal instillation (LPS group) and the other 18 rats received PFC through femoral vein prior to LPS instillation (LPS+PFC group). The rats in the control group were sacrificed 6 hours later after saline instillation. At 2, 4 and 6 hours of exposure to LPS, 6 rats in the LPS group and 6 rats in LPS+PFC group were sacrificed at each time point. By analyzing pulmonary pathology, partial pressure of oxygen in the blood (PaO2) and lung wet-dry weight ratio (W/D) of each rat, we found that intravenous infusion of PFC significantly alleviated acute lung injury induced by LPS. Moreover, we showed that the expression of pulmonary myeloperoxidase (MPO), intercellular adhesion molecule-1 (ICAM-1) of endothelial cells and CD11b of polymorphonuclear neutrophils (PMN) induced by LPS were significantly decreased by PFC treatment in vivo. Our results indicate that intravenous infusion of PFC inhibits the infiltration of PMNs into lung tissue, which has been shown as the core pathogenesis of ALI/ARDS. Thus, our study provides a theoretical foundation for using intravenous infusion of PFC to prevent and treat ALI/ARDS in clinical practice. PMID:24489970

Lv, Qi; Yin, Xiaofeng; Song, Jianqi; Landén, Ning Xu; Fan, Haojun

2014-01-01

129

Pretreatment of lipopolysaccharide (LPS) ameliorates D-GalN/LPS induced acute liver failure through TLR4 signaling pathway  

PubMed Central

Endotoxin tolerance (ET) is an important phenomenon, which affects inflammation and phagocytosis. Pretreatment with low dose of lipopolysaccharide (LPS) can protect liver injury from various hepatotoxicants such as acetaminophen and pseudomonas aeruginosa exotoxin A. The current study aimed to investigate the protecting mechanisms of endotoxin tolerance in acute liver failure induced by D-galactosamine (D-GalN)/LPS and possible role of toll-like receptors 4 (TLR4) signaling pathway in this phenomenon. Acute liver failure was induced by Injection of D-GalN/LPS. To mimic endotoxin tolerance, male Sprague-Dawley rats were treated with low dose of LPS (0.1 mg/kg once a day intraperitoneally for consecutive five days) before subsequent injection of D-GalN/LPS. Rat survival was determined by survival rate. Liver injury was confirmed by serum biochemical and liver histopathological examination. Inflammatory cytokines were determined by ELISA and nuclear factor-kappa B (NF-?B) (P65), toll-like receptors 4 (TLR4) and Interleukin-1 receptor-associated kinase-1 (IRAK-1) were measured by reverse transcriptase polymerase chain reaction and western blot respectively. Pretreatment of LPS significantly improved rat survival. Moreover, rats pretreated with LPS exhibited lower serum enzyme (ALT, AST and TBiL) level, lower production of inflammatory cytokines and more minor liver histopathological damage than rats without pretreatment of LPS. LPS pretreatment suppressed production of TLR4 and IRAK-1. LPS pretreatment also inhibited activation of hepatic NF-?B. These results indicated that endotoxin tolerance contributed to liver protection against D-GalN/LPS induced acute liver failure through down-regulation of TLR4 and NF-?B pathway. PMID:25400741

Zhang, Sainan; Yang, Naibin; Ni, Shunlan; Li, Wenyuan; Xu, Lanman; Dong, Peihong; Lu, Mingqin

2014-01-01

130

The Probiotic Mixture VSL#3 Dampens LPS-Induced Chemokine Expression in Human Dendritic Cells by Inhibition of STAT-1 Phosphorylation  

PubMed Central

VSL#3, a mixture of 8 different probiotic bacteria, has successfully been used in the clinic to treat Ulcerative Colitis. We previously identified the modulation of chemokines as a major mechanism in the protective effect of the VSL#3 in a mouse model of colitis. This was supported by in vitro studies that implicated a role for VSL#3 in the suppression of LPS-induced chemokine production by mouse bone marrow-derived dendritic cells (DC). Herein, we validated these findings employing human monocyte-derived DC. Stimulation of human DC with LPS, VSL#3, or a combination of both resulted in their maturation, evident from enhanced expression of activation markers on the cell-surface, as well as the induction of various chemokines and cytokines. Interestingly, a set of LPS-induced chemokines was identified that were suppressed by VSL#3. These included CXCL9, CXCL10, CCL2, CCL7, and CCL8. In silico approaches identified STAT-1 as a dominant regulator of these chemokines, and this was confirmed by demonstrating that LPS-induced phosphorylation of this transcription factor was inhibited by VSL#3. This indicates that VSL#3 may contribute to the control of inflammation by selective suppression of STAT-1 induced chemokines. PMID:25546330

Mariman, Rob; Tielen, Frans; Koning, Frits; Nagelkerken, Lex

2014-01-01

131

Suppressive Effect of CORM-2 on LPS-Induced Platelet Activation by Glycoprotein Mediated HS1 Phosphorylation Interference  

PubMed Central

In recent years, it has been discovered that septic patients display coagulation abnormalities. Platelets play a major role in the coagulation system. Studies have confirmed that carbon monoxide (CO) has important cytoprotective and anti-inflammatory function. However, whether CO could alter abnormal activation of platelets and coagulation and thereby reduce the incidence of mortality during sepsis has not been defined. In this report, we have used CO-releasing molecules (CORM-2) to determine whether CO inhibits LPS-induced abnormal activation of platelets and have explored the potential mechanisms. LPS was used to induce activation of platelets in vitro, which were purified from the peripheral venous blood of healthy adult donors. CORM-2 was applied as a potential therapeutic agent. CORM-2 preconditioning and delayed treatment were also studied. We found that in the LPS groups, the function of platelets such as spreading, aggregation, and release were enhanced abnormally. By contrast, the platelets in the CORM-2 group were gently activated. Further studies showed that the expression of platelet membrane glycoproteins increased in the LPS group. Coincidently, both hematopoietic lineage cell-specific protein 1 and its phosphorylated form also increased dramatically. These phenomena were less dramatically seen in the CORM-2 groups. Taken together, we conclude that during LPS stimulation, platelets were abnormally activated, and this functional state may be associated with the signal that is transmitted between membrane glycoproteins and HS1. CORM-released CO suppresses the abnormal activation of platelets by interfering with glycoprotein-mediated HS1 phosphorylation. PMID:24376647

Liu, Dadong; Liang, Feng; Wang, Xu; Cao, Jie; Qin, Weiting; Sun, Bingwei

2013-01-01

132

LPS-induced release of IL-6 from glia modulates production of IL-1? in a JAK2-dependent manner  

PubMed Central

Background Compelling evidence has implicated neuroinflammation in the pathogenesis of a number of neurodegenerative conditions. Chronic activation of both astrocytes and microglia leads to excessive secretion of proinflammatory molecules such as TNF?, IL-6 and IL-1? with potentially deleterious consequences for neuronal viability. Many signaling pathways involving the mitogen-activated protein kinases (MAPKs), nuclear factor ?B (NF?B) complex and the Janus kinases (JAKs)/signal transducers and activators of transcription (STAT)-1 have been implicated in the secretion of proinflammatory cytokines from glia. We sought to identify signaling kinases responsible for cytokine production and to delineate the complex interactions which govern time-related responses to lipopolysaccharide (LPS). Methods We examined the time-related changes in certain signaling events and the release of proinflammatory cytokines from LPS-stimulated co-cultures of astrocytes and microglia isolated from neonatal rats. Results TNF? was detected in the supernatant approximately 1 to 2 hours after LPS treatment while IL-1? and IL-6 were detected after 2 to 3 and 4 to 6 hours, respectively. Interestingly, activation of NF?B signaling preceded release of all cytokines while phosphorylation of STAT1 was evident only after 2 hours, indicating that activation of JAK/STAT may be important in the up-regulation of IL-6 production. Additionally, incubation of glia with TNF? induced both phosphorylation of JAK2 and STAT1 and the interaction of JAK2 with the TNF? receptor (TNFR1). Co-treatment of glia with LPS and recombinant IL-6 protein attenuated the LPS-induced release of both TNF? and IL-1? while potentiating the effect of LPS on suppressor of cytokine signaling (SOCS)3 expression and IL-10 release. Conclusions These data indicate that TNF? may regulate IL-6 production through activation of JAK/STAT signaling and that the subsequent production of IL-6 may impact on the release of TNF?, IL-1? and IL-10. PMID:22697788

2012-01-01

133

Regulatory role of C5a in LPS-induced IL-6 production by neutrophils during sepsis.  

PubMed

Experimental sepsis in rodents occurring after cecal ligation/puncture (CLP) is associated with excessive complement activation and a systemic inflammatory response. The proinflammatory mediator IL-6 has recently been shown to be an important inducer of the C5a receptor (C5aR) during sepsis. We now provide evidence that serum IL-6 production during sepsis in rats was reduced in neutrophil-depleted animals and that absence of C5aR in mice as well as antibody-blockade of C5a in rats significantly reduced serum levels of IL-6 during sepsis. Lipopolysaccharide (LPS)-induced production in vitro of IL-6 by neutrophils was significantly enhanced in the co-presence of C5a, likely due to transcriptional up-regulation of IL-6. Production of IL-6 in neutrophils by LPS was NF-kappaB dependent (but not on the presence of p50) and dependent on phosphorylation of p38-mitogen activated protein kinase (MAPK) as well as p44/p42 MAPK (ERK1/2) but not on phosphorylation of c-Jun N-terminal kinases (JNK1/2). C5a stimulation of neutrophils elicited a rapid phosphorylation of ERK1/2 and p38 MAPK. Accordingly, we suggest that induction of IL-6 after CLP is neutrophil and C5a/C5aR dependent, likely due to the ability of C5a to cause activation of ERK1/2 and p38 MAPK signaling pathways. PMID:14688199

Riedemann, Niels C; Guo, Ren-Feng; Hollmann, Travis J; Gao, Hongwei; Neff, Thomas A; Reuben, Jayne S; Speyer, Cecilia L; Sarma, J Vidya; Wetsel, Rick A; Zetoune, Firas S; Ward, Peter A

2004-02-01

134

BQ-123 prevents LPS-induced preterm birth in mice via the induction of uterine and placental IL-10.  

PubMed

Preterm birth (PTB), defined as any delivery occurring prior to the completion of 37weeks' gestation, currently accounts for 11-12% of all births in the United States. Maternal genito-urinary infections account for up to 40% of all PTBS and induce a pro-inflammatory state in the host. The potent vasoconstrictor Endothelin-1 (ET-1) is known to be upregulated in the setting of infection, and elicits its effect by binding to the ETA receptor. We have previously shown that antagonism of the ETA receptor with BQ-123 is capable of preventing LPS-induced PTB in mice. We hypothesize that the administration of BQ-123 post LPS exposure will dismantle a positive feedback loop observed with pro-inflammatory cytokines upstream of ET-1. On GD 15.5, pregnant C57BL/6 mice were injected with PBS, LPS, BQ-123, or LPS+BQ-123. Changes at both the level of transcription and translation were observed in uterus and placenta in the ET-1 axis and in pro- and anti-inflammatory cytokines over the course of 12h. We discovered that BQ-123, when administered 10h post LPS, is capable of increasing production of uterine and placental Interleukin-10, causing a shift away from the pro-inflammatory state. We also observed that antagonism of the ETA receptor decreased IL-1? and TNF? in the placenta while also decreasing transcription of ET-1 in the uterus. Our results reinforce the role of ET-1 at the maternal fetal interface and highlight the potential benefit of ETA receptor blockade via the suppression of ET-1, and induction of a Th2 cytokine dominant state. PMID:25230003

Olgun, Nicole S; Hanna, Nazeeh; Reznik, Sandra E

2015-02-01

135

Niacin attenuates the production of pro-inflammatory cytokines in LPS-induced mouse alveolar macrophages by HCA2 dependent mechanisms.  

PubMed

Niacin has been reported to have potent anti-inflammatory effects in LPS-induced acute lung injury. However, the molecular mechanism of niacin has not been fully understood. The aim of the present study was to investigate the effects of niacin on the production of pro-inflammatory cytokines TNF-?, IL-6 and IL-1? in LPS-induced mouse alveolar macrophages and explore its underlying mechanism. Mouse alveolar macrophages were incubated in the presence or absence of various concentrations of niacin (1, 10, 100?mol/l) 1h before LPS (1?g/ml) challenge. The results showed that niacin reduced the levels of TNF-?, IL-6 and IL-1? in LPS-challenged alveolar macrophages. Furthermore, NF-?B activation was inhibited by niacin through blocking the phosphorylation of NF-?B p65 and I?B?. In addition, silencing HCA2 abrogated the effect of niacin on the production of pro-inflammatory cytokines. These findings suggested that niacin attenuated the LPS-induced pro-inflammatory cytokines possibly mediated by HCA2 in LPS-challenged alveolar macrophages. PMID:25038318

Zhou, Ershun; Li, Yimeng; Yao, Minjun; Wei, Zhengkai; Fu, Yunhe; Yang, Zhengtao

2014-07-16

136

Toona sinensis Inhibits LPS-Induced Inflammation and Migration in Vascular Smooth Muscle Cells via Suppression of Reactive Oxygen Species and NF-?B Signaling Pathway  

PubMed Central

Toona sinensis is one of the most popular vegetarian cuisines in Taiwan and it has been shown to possess antioxidant, antiangiogenic, and anticancer properties. In this study, we investigated the antiatherosclerotic potential of aqueous leaf extracts from Toona sinensis (TS; 25–100??g/mL) and its major bioactive compound, gallic acid (GA; 5??g/mL), in LPS-treated rat aortic smooth muscle (A7r5) cells. We found that pretreatment with noncytotoxic concentrations of TS and GA significantly inhibited inflammatory NO and PGE2 production by downregulating their precursors, iNOS and COX-2, respectively, in LPS-treated A7r5 cells. Furthermore, TS and GA inhibited LPS-induced intracellular ROS and their corresponding mediator, p47phox. Notably, TS and GA pretreatment significantly inhibited LPS-induced migration in transwell assays. Gelatin zymography and western blotting demonstrated that treatment with TS and GA suppressed the activity or expression of MMP-9, MMP-2, and t-PA. Additionally, TS and GA significantly inhibited LPS-induced VEGF, PDGF, and VCAM-1 expression. Further investigation revealed that the inhibition of iNOS/COX-2, MMPs, growth factors, and adhesion molecules was associated with the suppression of NF-?B activation and MAPK (ERK1/2, JNK1/2, and p38) phosphorylation. Thus, Toona sinensis may be useful for the prevention of atherosclerosis. PMID:24723997

Yang, Hsin-Ling; Huang, Pei-Jane; Liu, Yi-Ru; Kumar, K. J. Senthil; Hsu, Li-Sung; Lu, Te-Ling; Chia, Yi-Chen; Takajo, Tokuko; Kazunori, Anzai; Hseu, You-Cheng

2014-01-01

137

Genistein Suppresses LPS-Induced Inflammatory Response through Inhibiting NF-?B following AMP Kinase Activation in RAW 264.7 Macrophages  

PubMed Central

Genistein, the major isoflavone in soybean, was recently reported to exert beneficial effects in metabolic disorders and inflammatory diseases. In the present study, we investigated the effects and mechanisms of a dietary concentration of genistein on the inflammatory response in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. Our results demonstrated that genistein effectively inhibited the LPS-induced overproduction of tumor necrosis factor-alpha (TNF-?) and interleukin 6 (IL-6), as well as LPS-induced nuclear factor kappa B (NF-?B) activation. In addition, the data also showed that genistein prevented LPS-induced decrease in adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. These effects were obviously attenuated by an AMPK inhibitor. Taken together, our results suggest that the dietary concentration of genistein is able to attenuate inflammatory responses via inhibition of NF-?B activation following AMPK stimulation. The data provide direct evidence for the potential application of low concentrations of genistein in the prevention and treatment of inflammatory diseases. PMID:23300870

Ji, Guiyuan; Zhang, Yupei; Yang, Qinhe; Cheng, Shaobin; Hao, Jing; Zhao, Xihong; Jiang, Zhuoqin

2012-01-01

138

Characterization of LPS-induced TNF? factor (LITAF) from orange-spotted grouper, Epinephelus coioides.  

PubMed

Lipopolysaccharide-induced TNF? factor (LITAF) is an important transcription factor that mediates cell apoptosis and inflammatory response. In the present study, we cloned and characterized a LITAF gene from orange-spotted grouper (Epinephelus coioides) (Ec-LITAF). Ec-LITAF encoded a predicted 142 amino acid protein which shared 74% identity to sablefish (Anoplopoma fimbria) LITAF homolog. Multiple amino acid alignment showed that Ec-LITAF contained a typical LITAF domain with two CXXC motifs. Phylogenetic analysis indicated that Ec-LITAF was closely related to that of sablefish. Ec-LITAF mRNA was widely expressed in different tissues and its expression level in spleen was up-regulated after Singapore grouper iridovirus (SGIV) infection. Subcellular localization analysis revealed that the distribution of Ec-LITAF showed diffuse and aggregated patterns in cytoplasm. Interestingly, the distribution of Ec-LITAF overlayed with a viral LITAF homolog (vLITAF) encoded by SGIV. Overexpression of Ec-LITAF in vitro up-regulated the expression of tumor necrosis factors (TNF1 and TNF2) and TNF receptors (TNFR1 and TNFR2), and the expression of itself initiated apoptosis in fish cells. In addition, overexpression of Ec-LITAF not only accelerated SGIV infection induced CPE and cell death, but also increased viral gene transcription. Taken together, our data suggested that Ec-LITAF might play crucial roles during SGIV replication. PMID:24091064

Cai, Jia; Huang, Youhua; Wei, Shina; Ouyang, Zhengliang; Huang, Xiaohong; Qin, Qiwei

2013-12-01

139

Preferential macrophage recruitment and polarization in LPS-induced animal model for COPD: noninvasive tracking using MRI.  

PubMed

Noninvasive imaging of macrophages activity has raised increasing interest for diagnosis of chronic obstructive respiratory diseases (COPD), which make them attractive vehicles to deliver contrast agents for diagnostic or drugs for therapeutic purposes. This study was designed to monitor and evaluate the migration of differently polarized M1 and M2 iron labeled macrophage subsets to the lung of a LPS-induced COPD animal model and to assess their polarization state once they have reached the inflammatory sites in the lung after intravenous injection. Ex vivo polarized bone marrow derived M1 or M2 macrophages were first efficiently and safely labeled with amine-modified PEGylated dextran-coated SPIO nanoparticles and without altering their polarization profile. Their biodistribution in abdominal organs and their homing to the site of inflammation in the lung was tracked for the first time using a free-breathing non-invasive MR imaging protocol on a 4.7T magnet after their intravenous administration. This imaging protocol was optimized to allow both detection of iron labeled macrophages and visualization of inflammation in the lung. M1 and M2 macrophages were successfully detected in the lung starting from 2 hours post injection with no variation in their migration profile. Quantification of cytokines release, analysis of surface membrane expression using flow cytometry and immunohistochemistry investigations confirmed the successful recruitment of injected iron labeled macrophages in the lung of COPD mice and revealed that even with a continuum switch in the polarization profile of M1 and M2 macrophages during the time course of inflammation a balanced number of macrophage subsets predominate. PMID:24598763

Al Faraj, Achraf; Sultana Shaik, Asma; Pureza, Mary Angeline; Alnafea, Mohammad; Halwani, Rabih

2014-01-01

140

Preferential Macrophage Recruitment and Polarization in LPS-Induced Animal Model for COPD: Noninvasive Tracking Using MRI  

PubMed Central

Noninvasive imaging of macrophages activity has raised increasing interest for diagnosis of chronic obstructive respiratory diseases (COPD), which make them attractive vehicles to deliver contrast agents for diagnostic or drugs for therapeutic purposes. This study was designed to monitor and evaluate the migration of differently polarized M1 and M2 iron labeled macrophage subsets to the lung of a LPS-induced COPD animal model and to assess their polarization state once they have reached the inflammatory sites in the lung after intravenous injection. Ex vivo polarized bone marrow derived M1 or M2 macrophages were first efficiently and safely labeled with amine-modified PEGylated dextran-coated SPIO nanoparticles and without altering their polarization profile. Their biodistribution in abdominal organs and their homing to the site of inflammation in the lung was tracked for the first time using a free-breathing non-invasive MR imaging protocol on a 4.7T magnet after their intravenous administration. This imaging protocol was optimized to allow both detection of iron labeled macrophages and visualization of inflammation in the lung. M1 and M2 macrophages were successfully detected in the lung starting from 2 hours post injection with no variation in their migration profile. Quantification of cytokines release, analysis of surface membrane expression using flow cytometry and immunohistochemistry investigations confirmed the successful recruitment of injected iron labeled macrophages in the lung of COPD mice and revealed that even with a continuum switch in the polarization profile of M1 and M2 macrophages during the time course of inflammation a balanced number of macrophage subsets predominate. PMID:24598763

Al Faraj, Achraf; Sultana Shaik, Asma; Pureza, Mary Angeline; Alnafea, Mohammad; Halwani, Rabih

2014-01-01

141

LPS-inducible factor(s) from activated macrophages mediates cytolysis of Naegleria fowleri amoebae  

SciTech Connect

Soluble cytolytic factors of macrophage origin have previously been described with respect to their tumoricidal activity. The purpose of this study was to investigate the mechanism and possible factor(s) responsible for cytolysis of the amoeba Naegleria fowleri by activated peritoneal macrophages from B6C3F1 mice. Macrophages or conditioned medium (CM) from macrophage cultures were incubated with /sup 3/H-Uridine labeled amoebae. Percent specific release of label served as an index of cytolysis. Bacille Calmette-Guerin (BCG) and Corynebacterium parvum macrophages demonstrated significant cytolysis of amoebae at 24 h with an effector to target ratio of 10:1. Treatment of macrophages with inhibitors of RNA or protein synthesis blocked amoebicidal activity. Interposition of a 1 ..mu..m pore membrane between macrophages and amoebae inhibited killing. Inhibition in the presence of the membrane was overcome by stimulating the macrophages with LPS. CM from SPS-stimulated, but not unstimulated, cultures of activated macrophages was cytotoxic for amoebae. The activity was heat sensitive and was recovered from ammonium sulfate precipitation of the CM. Results indicate that amoebicidal activity is mediated by a protein(s) of macrophage origin induced by target cell contact or stimulation with LPS.

Cleary, S.F.; Marciano-Cabral, F.

1986-03-01

142

LPS-Induced Galectin-3 Oligomerization Results in Enhancement of Neutrophil Activation  

PubMed Central

Galectin-3 (Gal 3) is a glycan-binding protein that can be secreted by activated macrophages and mast cells at inflammation sites and plays an important role in inflammatory diseases caused by Bacteria and their products, such as lipopolysaccharides (LPS). Although it is well established that Gal 3 can interact with LPS, the pathophysiological importance of LPS/Gal 3 interactions is not fully understood. Data presented herein demonstrate for the first time that the interaction of Gal 3, either via its carbohydrate binding C-terminal domain or via its N-terminal part, with LPS from different bacterial strains, enhances the LPS-mediated neutrophil activation in vitro. Gal 3 allowed low LPS concentrations (1 µg/mL without serum, 1 ng/mL with serum) to upregulate CD11b expression and reactive oxygen species (ROS) generation on human neutrophils in vitro and drastically enhanced the binding efficiency of LPS to the neutrophil surface. These effects required LPS preincubation with Gal 3, before neutrophil stimulation and involved specific Gal 3/LPS interaction. A C-terminal Gal-3 fragment, which retains the lectin domain but lacks the N-terminal part, was still able to bind both to Escherichia coli LPS and to neutrophils, but had lost the ability to enhance neutrophil response to LPS. This result emphasizes the importance of an N-terminus-mediated Gal 3 oligomerization induced by its interaction with LPS. Finally we demonstrated that Balb/C mice were more susceptible to LPS-mediated shock when LPS was pretreated with Gal 3. Altogether, these results suggest that multimeric interactions between Gal 3 oligomers and LPS potentiate its pro-inflammatory effects on neutrophils. PMID:22031821

Fermino, Marise Lopes; Polli, Claudia Danella; Toledo, Karina Alves; Liu, Fu-Tong; Hsu, Dan K.; Roque-Barreira, Maria Cristina; Pereira-da-Silva, Gabriela

2011-01-01

143

Gypenoside XLIX, a naturally occurring gynosaponin, PPAR-alpha dependently inhibits LPS-induced tissue factor expression and activity in human THP-1 monocytic cells  

SciTech Connect

Tissue factor (TF) is involved not only in the progression of atherosclerosis and other cardiovascular diseases, but is also associated with tumor growth, metastasis, and angiogenesis and hence may be an attractive target for directed cancer therapeutics. Gynostemma pentaphyllum (GP) is widely used in the treatment of various cardiovascular diseases including atherosclerosis, as well as cancers. Gypenoside (Gyp) XLIX, a dammarane-type glycoside, is one of the prominent components in GP. We have recently reported Gyp XLIX to be a potent peroxisome proliferator-activated receptor (PPAR)-alpha activator. Here we demonstrate that Gyp XLIX (0-300 {mu}M) concentration dependently inhibited TF promoter activity after induction by the inflammatory stimulus lipopolysaccharide (LPS) in human monocytic THP-1 cells transfected with promoter reporter constructs pTF-LUC. Furthermore, Gyp XLIX inhibited LPS-induced TF mRNA and protein overexpression in THP-1 monocyte cells. Its inhibition of LPS-induced TF hyperactivity was further confirmed by chromogenic enzyme activity assay. The activities of Gyp XLIX reported in this study were similar to those of Wy-14643, a potent synthetic PPAR-alpha activator. Furthermore, the Gyp XLIX-induced inhibitory effect on TF luciferase activity was completely abolished in the presence of the PPAR-alpha selective antagonist MK-886. The present findings suggest that Gyp XLIX inhibits LPS-induced TF overexpression and enhancement of its activity in human THP-1 monocytic cells via PPAR-alpha-dependent pathways. The data provide new insights into the basis of the use of the traditional Chinese herbal medicine G. pentaphyllum for the treatment of cardiovascular and inflammatory diseases, as well as cancers.

Huang, Tom Hsun-Wei [Faculty of Pharmacy, University of Sydney, NSW 2006 (Australia); Van Hoan Tran [Faculty of Pharmacy, University of Sydney, NSW 2006 (Australia); Roufogalis, Basil D. [Faculty of Pharmacy, University of Sydney, NSW 2006 (Australia); Li Yuhao [Faculty of Pharmacy, University of Sydney, NSW 2006 (Australia)]. E-mail: yuhao@pharm.usyd.edu.au

2007-01-01

144

Bergenin Plays an Anti-Inflammatory Role via the Modulation of MAPK and NF-?B Signaling Pathways in a Mouse Model of LPS-Induced Mastitis.  

PubMed

Mastitis is a major disease in humans and other animals and is characterized by mammary gland inflammation. It is a major disease of the dairy industry. Bergenin is an active constituent of the plants of genus Bergenia. Research indicates that bergenin has multiple biological activities, including anti-inflammatory and immunomodulatory properties. The objective of this study was to evaluate the protective effects and mechanism of bergenin on the mammary glands during lipopolysaccharide (LPS)-induced mastitis. In this study, mice were treated with LPS to induce mammary gland mastitis as a model for the disease. Bergenin treatment was initiated after LPS stimulation for 24 h. The results indicated that bergenin attenuated inflammatory cell infiltration and decreased the concentration of NO, TNF-?, IL-1?, and IL-6, which were increased in LPS-induced mouse mastitis. Furthermore, bergenin downregulated the phosphorylation of nuclear factor-kappaB (NF-?B) and mitogen-activated protein kinases (MAPK) signaling pathway proteins in mammary glands with mastitis. In conclusion, bergenin reduced the expression of NO, TNF-?, IL-1?, and IL-6 proinflammatory cytokines by inhibiting the activation of the NF-?B and MAPKs signaling pathways, and it may represent a novel treatment strategy for mastitis. PMID:25487780

Gao, Xue-Jiao; Guo, Meng-Yao; Zhang, Ze-Cai; Wang, Tian-Cheng; Cao, Yong-Guo; Zhang, Nai-Sheng

2014-12-01

145

Unfractionated heparin attenuates LPS-induced IL-8 secretion via PI3K/Akt/NF-?B signaling pathway in human endothelial cells.  

PubMed

Unfractionated heparin (UFH) is largely used as anti-thrombotic drug. While UFH has been shown to suppress lipopolysaccharide (LPS)-induced nuclear factor-?B (NF-?B) activation, intracellular upstream events that cause NF-?B down-regulation in response to UFH remain unclear. Thus, we investigated the involvement of phosphoinositide-3-OH kinase (PI3K)/Akt in the inhibition of LPS-activated NF-?B pathway by UFH in human pulmonary microvascular endothelial cells (HPMECs). Pretreatment with UFH (0.1-1U/ml) significantly inhibited LPS (10?g/ml)-stimulated interleukin (IL)-6 and IL-8 production in HPMECs. LPS activated Akt and NF-?B, whereas UFH suppresses LPS-induced Akt phosphorylation and NF-?B nuclear translocation, which were required for IL-6 and IL-8 gene transcription. Inhibition studies by using wortmannin abrogated NF-?B-mediated IL-6 and IL-8 expression, suggesting the requirement of PI3K/Akt pathway. Our data provided the first evidence that UFH might repress LPS-activated PI3K/Akt pathway, leading to inhibitory effect of NF-?B activation with diminished IL-6 and IL-8 expression in HPMECs. PMID:25454806

Li, Xu; Liu, Yina; Wang, Liang; Li, Zhiliang; Ma, Xiaochun

2014-10-23

146

Quince (Cydonia oblonga Miller) peel polyphenols modulate LPS-induced inflammation in human THP-1-derived macrophages through NF-{kappa}B, p38MAPK and Akt inhibition  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer Quince peel polyphenols inhibit LPS-induced secretion of TNF-{alpha} and IL-8. Black-Right-Pointing-Pointer Quince peel polyphenols augment LPS-induced secretion of IL-10 and IL-6. Black-Right-Pointing-Pointer Quince peel polyphenols-mediated inhibition of LPS-induced secretion of TNF-{alpha} is partially mediated by IL-6. Black-Right-Pointing-Pointer The anti-inflammatory effects of quince polyphenols pass through NF-{kappa}B, p38MAPK and Akt inhibition. -- Abstract: Chronic inflammation is a hallmark of several pathologies, such as rheumatoid arthritis, gastritis, inflammatory bowel disease, atherosclerosis and cancer. A wide range of anti-inflammatory chemicals have been used to treat such diseases while presenting high toxicity and numerous side effects. Here, we report the anti-inflammatory effect of a non-toxic, cost-effective natural agent, polyphenolic extract from the Tunisian quince Cydonia oblonga Miller. Lipopolysaccharide (LPS) treatment of human THP-1-derived macrophages induced the secretion of high levels of the pro-inflammatory cytokine TNF-{alpha} and the chemokine IL-8, which was inhibited by quince peel polyphenolic extract in a dose-dependent manner. Concomitantly, quince polyphenols enhanced the level of the anti-inflammatory cytokine IL-10 secreted by LPS-treated macrophages. We further demonstrated that the unexpected increase in IL-6 secretion that occurred when quince polyphenols were associated with LPS treatment was partially responsible for the polyphenols-mediated inhibition of TNF-{alpha} secretion. Biochemical analysis showed that quince polyphenols extract inhibited the LPS-mediated activation of three major cellular pro-inflammatory effectors, nuclear factor-kappa B (NF-{kappa}B), p38MAPK and Akt. Overall, our data indicate that quince peel polyphenolic extract induces a potent anti-inflammatory effect that may prove useful for the treatment of inflammatory diseases and that a quince-rich regimen may help to prevent and improve the treatment of such diseases.

Essafi-Benkhadir, Khadija [Laboratoire d'epidemiologie Moleculaire et Pathologie Experimentale Appliquee Aux Maladies Infectieuses, Institut Pasteur de Tunis (Tunisia)] [Laboratoire d'epidemiologie Moleculaire et Pathologie Experimentale Appliquee Aux Maladies Infectieuses, Institut Pasteur de Tunis (Tunisia); Refai, Amira [Laboratoire de Recherche sur la Transmission, le Controle et l'immunobiologie des Infections, Institut Pasteur de Tunis (Tunisia)] [Laboratoire de Recherche sur la Transmission, le Controle et l'immunobiologie des Infections, Institut Pasteur de Tunis (Tunisia); Riahi, Ichrak [Laboratoire d'epidemiologie Moleculaire et Pathologie Experimentale Appliquee Aux Maladies Infectieuses, Institut Pasteur de Tunis (Tunisia)] [Laboratoire d'epidemiologie Moleculaire et Pathologie Experimentale Appliquee Aux Maladies Infectieuses, Institut Pasteur de Tunis (Tunisia); Fattouch, Sami [Laboratory LIP-MB National Institute of Applied Sciences and Technology, Tunis (Tunisia)] [Laboratory LIP-MB National Institute of Applied Sciences and Technology, Tunis (Tunisia); Karoui, Habib [Laboratoire d'epidemiologie Moleculaire et Pathologie Experimentale Appliquee Aux Maladies Infectieuses, Institut Pasteur de Tunis (Tunisia)] [Laboratoire d'epidemiologie Moleculaire et Pathologie Experimentale Appliquee Aux Maladies Infectieuses, Institut Pasteur de Tunis (Tunisia); Essafi, Makram, E-mail: makram.essafi@pasteur.rns.tn [Laboratoire de Recherche sur la Transmission, le Controle et l'immunobiologie des Infections, Institut Pasteur de Tunis (Tunisia)] [Laboratoire de Recherche sur la Transmission, le Controle et l'immunobiologie des Infections, Institut Pasteur de Tunis (Tunisia)

2012-02-03

147

ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-? and nitric oxide production and protects mice from lethal endotoxic shock  

Microsoft Academic Search

ONO 3403, a new synthetic serine protease inhibitor, is a derivative of camostat mesilate and has a higher protease-inhibitory activity. The effect of ONO 3403 on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-? and nitric oxide (NO) production in RAW 264.7 macrophage-like cells was examined. ONO 3403 significantly inhibited LPS-induced TNF-? production at a lower concentration than camostat mesilate. It also

Gantsetseg Tumurkhuu; Naoki Koide; Takaki Hiwasa; Motohiro Ookoshi; Jargalsaikhan Dagvadorj; Abu Shadat Mohammod Noman; Imtiaz Iftakhar-E-Khuda; Yoshikazu Naiki; Takayuki Komatsu; Tomoaki Yoshida; Takashi Yokochi

2011-01-01

148

Delphinidin Inhibits LPS-Induced MUC8 and MUC5B Expression Through Toll-like Receptor 4-Mediated ERK1/2 and p38 MAPK in Human Airway Epithelial Cells  

PubMed Central

Objectives Delphinidin is one of the anthocyanidins. It is believed to have anti-inflammatory property including antioxidant, antiangiogenic, and anti-cancer properties. However, the anti-inflammatory effect of delphinidin in mucin-producing human airway epithelial cells has not been determined. Therefore, this study was conducted in order to investigate the effect and the brief signaling pathway of delphinidin in lipopolysaccharide (LPS)-induced MUC8 and MUC5B expression in human airway epithelial cells. Methods In mucin-producing human NCI-H292 airway epithelial cells and primary cultures of normal nasal epithelial cells, the reverse transcriptase-polymerase chain reaction (RT-PCR), real-time PCR, enzyme immunoassay were used for investigating the expressions of MUC8, MUC5, and Toll-like receptor 4 (TLR4), after LPS treatment and delphinidin treatment. And the signaling pathway of delphinidin on LPS-induced MUC8 and MUC5B expression was investigated using the RT-PCR, and immunoblot analysis. To confirm the involvement of TLR4 in LPS-induced MUC8 and MU5B expression, the cells were transfected with TLR4 siRNA. Results In NCI-H292 airway epithelial cells, LPS (100 ng/mL) significantly induced TLR4, MUC8, and MUC5B expression. TLR4 siRNA significantly blocked LPS-induced MUC8 and MUC5B mRNA expression. LPS (100 ng/mL) significantly activated the phosphorylation of extracellular signal related kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK). Delphinidin (50 and 100 µM) inhibited LPS-induced TLR4, MUC8, and MUC5B expression and LPS-induced phosphorylation of ERK1/2 and p38 MAPK. In the primary cultures of normal nasal epithelial cells, delphinidin (50 and 100 µM) significantly inhibited LPS-induced TLR4, MUC8, and MUC5B gene expression. Conclusion These results suggest that delphinidin attenuates LPS-induced MUC8 and MUC5B expression through the TLR4-mediated ERK1/2 and p38 MAPK signaling pathway in human airway epithelial cells. These findings indicated that delphinidin may be a therapeutic agent for control of inflammatory airway diseases. PMID:25177436

Bae, Chang Hoon; Jeon, Bo Sung; Choi, Yoon Seok; Song, Si-Youn

2014-01-01

149

LPS-induced decrease in intracellular labile zinc, [Zn]i, contributes to apoptosis in cultured sheep pulmonary artery endothelial cells.  

PubMed

A role in signal transduction for a vanishingly small labile pool of intracellular zinc ([Zn](i)) has been inferred by the sensitivity of various physiological pathways to zinc chelators such as N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) and/or associations with changes in nonprotein-bound zinc-sensitive fluorophores. Although we (44) reported that LPS-induced apoptosis in cultured sheep pulmonary artery endothelial cells (SPAEC) was exacerbated by TPEN, 1) we did not detect acute (30 min) changes in [Zn](i), and 2) it is unclear from other reports whether LPS increases or decreases [Zn](i) and whether elevations or decreases in [Zn](i) are associated with cell death and/or apoptosis. In the present study, we used both chemical (FluoZin-3 via live cell epifluorescence microscopy and fluorescence-activated cell sorting) and genetic (luciferase activity of a chimeric reporter encoding zinc-sensitive metal-response element and changes in steady-state mRNA of zinc importer, SLC39A14 or ZIP14) techniques to show that LPS caused a delayed time-dependent (2-4 h) decrease in [Zn](i) in SPAEC. A contributory role of decreases in [Zn](i) in LPS-induced apoptosis (as determined by caspase-3/7 activation, annexin-V binding, and cytochrome c release) in SPAECs was revealed by mimicking the effect of LPS with the zinc chelator, TPEN, and inhibiting LPS- (or TPEN)-induced apoptosis with exogenous zinc. Collectively, these are the first data demonstrating a signaling role for decrease in [Zn](i) in pulmonary endothelial cells and suggest that endogenous levels of labile zinc may affect sensitivity of pulmonary endothelium to the important and complex proapoptotic stimulus of LPS. PMID:21239534

Thambiayya, Kalidasan; Wasserloos, Karla J; Huang, Zhentai; Kagan, Valerian E; St Croix, Claudette M; Pitt, Bruce R

2011-04-01

150

Caffeic acid regulates LPS-induced NF-?B activation through NIK/IKK and c-Src/ERK signaling pathways in endothelial cells.  

PubMed

The redox sensitive, proinflammatory nuclear transcription factor NF-?B plays a key role in inflammation. In a redox state disrupted by oxidative stress, pro-inflammatory genes are upregulated by the activation of NF-?B via diverse kinases. Thus, the search and characterization of new substances that modulate NF-?B are topics of considerable research interest. Caffeic acid is a component of garlic, some fruits, and coffee, and is widely used as a phenolic agent in beverages. In the present study, caffeic acid was examined with respect to the modulation of inflammatory NF-?B activation via the redox-related c-Src/ERK and NIK/IKK pathways via the reduction of oxidative stress. YPEN-1 cells (an endothelial cell line) were used to explore the molecular mechanism underlying the anti-inflammatory effect of caffeic acid by examining its modulation of NF-?B signaling pathway by LPS. Our results show that LPS-induced oxidative stress-related NF-?B activation upregulated pro-inflammatory COX-2, NF-?B targeting gene which were all inhibited effectively by caffeic acid. Our study shows that caffeic acid inhibits the activation of NF-?B via the c-Src/ERK and NIK/IKK signal transduction pathways. Our results indicate that antioxidative effect of caffeic acid and its restoration of redox balance are responsible for its anti-inflammatory action. Thus, the study provides new information regarding the anti-inflammatory properties of caffeic acid and the roles in the regulation of LPS-induced oxidative stress induces alterations in signal transduction pathways. PMID:23888332

Kim, So Ra; Jung, Yu Ri; Kim, Dae Hyun; An, Hye Jin; Kim, Mi Kyung; Kim, Nam Deuk; Chung, Hae Young

2014-04-01

151

Synthetic wogonin derivatives suppress lipopolysaccharide-induced nitric oxide production and hydrogen peroxide-induced cytotoxicity  

Microsoft Academic Search

Wogonin (5,7-dihydroxy-8-methoxyflavone) has been reported to exhibit a variety of biological properties including anti-inflammatory\\u000a and neuroprotective functions. In this study, biological activities of diverse synthetic wogonin derivatives have been evaluated\\u000a in two experimental cell culture models. Inhibitory activities of wogonin derivatives on lipopolysaccharide (LPS)-induced\\u000a nitric oxide (NO) production in BV2 microglial cells and on hydrogen peroxide (H202)-induced neuronal cell death

Wanjoo Chun; Hee Jae Lee; Pil-Jae Kong; Gun Hee Lee; ll-Young Cheongsu; Sung-Soo Kim

2005-01-01

152

Hericium erinaceus suppresses LPS-induced pro-inflammation gene activation in RAW264.7 macrophages.  

PubMed

The aim of this study was to investigate the anti-inflammatory properties of each fraction of Hericium erinaceus (HE). The ethanol extract from HE was partitioned with different solvents in the order of increasing polarity. The treatment with 10-100 ?g/mL of each fraction did not reduce RAW 264.7 cell viability except ethyl acetate fraction. Among the various extracts, the chloroform fraction showed the most potent activity against nitric oxide (NO), prostaglandin E(2) (PGE(2)) and reactive oxygen species (ROS). The western blotting and reverse transcriptase polymerase chain reaction (RT-PCR) analyses revealed that chloroform fraction from HE (CHE) significantly reduced the protein level of iNOS and cyclooxygenase-2 (COX-2) or mRNA levels of iNOS in lipopolysaccharide-induced macrophages. Furthermore, CHE inhibited the translocation of nuclear factor (NF)-?B p65 subunit, phsophorylation of I-?B, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) in a dose-dependent manner. Furthermore, the activation of both activator protein-1 (AP-1) and NF ?B in the nucleus were abrogated by CHE with luciferase assay. In conclusion, these results indicate that CHE may provide an anti-inflammatory effect by attenuating the generation of excessive NO, PGE(2), and ROS and by suppressing the expression of pro-inflammatory genes through the inhibition of NF-?B and JNK activity. PMID:22126451

Kim, Young-Ock; Lee, Sang-Won; Oh, Chung-Hun; Rhee, Yun-Hee

2012-06-01

153

CXC195 suppresses proliferation and inflammatory response in LPS-induced human hepatocellular carcinoma cells via regulating TLR4-MyD88-TAK1-mediated NF-?B and MAPK pathway.  

PubMed

CXC195 showed strong protective effects in neuronal apoptosis by exerting its antioxidant activity. However, the anti-cancer effects of CXC195 is still with limited acquaintance. Here, we investigated the role of CXC195 in lipopolysaccharide (LPS)-induced human hepatocellular carcinoma (HCC) cells lines (HepG2) and the possible signaling pathways. CXC195 exhibited significant anti-proliferative effect and induced cell cycle arrest in LPS-induced HepG2 cells. In addition, CXC195 suppressed the release of pro-inflammatory mediators in LPS-induced HepG2 cells, including TNF-?, iNOS, IL-1?, IL-6, CC chemokine ligand (CCL)-2, CCL-22 and epidermal growth factor receptor (EGFR). Moreover, CXC195 inhibited the expressions and interactions of TLR4, MyD88 and TAK1, NF-?B translocation to nucleus and its DNA binding activity, phosphorylation of ERK1/2, p38 and JNK. Our results suggested that treatment with CXC195 could attenuate the TLR4-mediated proliferation and inflammatory response in LPS-induced HepG2 cells, thus might be beneficial for the treatment of HCC. PMID:25475726

Wang, Yiting; Tu, Qunfei; Yan, Wei; Xiao, Dan; Zeng, Zhimin; Ouyang, Yuming; Huang, Long; Cai, Jing; Zeng, Xiaoli; Chen, Ya-Jie; Liu, Anwen

2015-01-01

154

Low dose of carbon monoxide intraperitoneal injection provides potent protection against GalN/LPS-induced acute liver injury in mice.  

PubMed

Carbon monoxide (CO) is an important effector-signaling molecule involved in various pathophysiological processes. Here we investigated the protective effects of exogenous CO in a murine model of acute liver damage induced by d-galactosamine (GalN) and lipopolysaccharide (LPS). Exogenous CO gas was administered to mice via intraperitoneal injection (first at a dose of 15?ml?kg(-1) and then, 6?h later, 8?ml?kg(-1)), which caused a significant elevation of blood carboxyhemoglobin levels of up to 12-14% for more than 12?h. GalN/LPS were given to induce acute liver damage in mice 30?min prior to CO exposure. This showed that GalN/LPS induced severe liver injury in mice, whereas CO injection remarkably improved the survival rate of mice and led to attenuated hepatocellular damage. CO exhibited anti-oxidative capabilities by inhibiting hepatic malondialdehyde contents and restoring superoxide dismutase and glutathione, as well as by reducing inducible NOS/NO production. The anti-apoptotic and anti-inflammatory effects of CO were substantial, characterized by a notable inhibition of hepatocyte apoptosis and a reduction of pro-inflammatory cytokines in mice. Our findings thus supported the hypothesis that exogenous CO provides protective effects against acute liver damage in mice, mainly dependent on its anti-oxidative, anti-inflammatory and anti-apoptotic properties. PMID:23015538

Wen, Zongmei; Liu, Yan; Li, Feng; Wen, Tao

2013-12-01

155

The fatty acid amide hydrolase (FAAH) inhibitor PF-3845 acts in the nervous system to reverse LPS-induced tactile allodynia in mice  

PubMed Central

BACKGROUND AND PURPOSE Inflammatory pain presents a problem of clinical relevance and often elicits allodynia, a condition in which non-noxious stimuli are perceived as painful. One potential target to treat inflammatory pain is the endogenous cannabinoid (endocannabinoid) system, which is comprised of CB1 and CB2 cannabinoid receptors and several endogenous ligands, including anandamide (AEA). Blockade of the catabolic enzyme fatty acid amide hydrolase (FAAH) elevates AEA levels and elicits antinociceptive effects, without the psychomimetic side effects associated with ?9-tetrahydrocannabinol (THC). EXPERIMENTAL APPROACH Allodynia was induced by intraplantar injection of LPS. Complementary genetic and pharmacological approaches were used to determine the strategy of blocking FAAH to reverse LPS-induced allodynia. Endocannabinoid levels were quantified using mass spectroscopy analyses. KEY RESULTS FAAH (?/?) mice or wild-type mice treated with FAAH inhibitors (URB597, OL-135 and PF-3845) displayed an anti-allodynic phenotype. Furthermore, i.p. PF-3845 increased AEA levels in the brain and spinal cord. Additionally, intraplantar PF-3845 produced a partial reduction in allodynia. However, the anti-allodynic phenotype was absent in mice expressing FAAH exclusively in the nervous system under a neural specific enolase promoter, implicating the involvement of neuronal fatty acid amides (FAAs). The anti-allodynic effects of FAAH-compromised mice required activation of both CB1 and CB2 receptors, but other potential targets of FAA substrates (i.e. µ-opioid, TRPV1 and PPAR? receptors) had no apparent role. CONCLUSIONS AND IMPLICATIONS AEA is the primary FAAH substrate reducing LPS-induced tactile allodynia. Blockade of neuronal FAAH reverses allodynia through the activation of both cannabinoid receptors and represents a promising target to treat inflammatory pain. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7 PMID:21506952

Booker, Lamont; Kinsey, Steven G; Abdullah, Rehab A; Blankman, Jacqueline L; Long, Jonathan Z; Ezzili, Cyrine; Boger, Dale L; Cravatt, Benjamin F; Lichtman, Aron H

2012-01-01

156

High glucose increases LPS-induced DC apoptosis through modulation of ERK1/2, AKT and Bax/Bcl-2  

PubMed Central

Background This study investigates the effect of glucose on the LPS-induced apoptosis of dendritic cells in the intestinal tract of mice and the dendritic cell line DC2.4. Methods Flow cytometry was used to detect dendritic cell apoptosis both in vivo and in vitro. Hoechst 33258 staining was used to detect the morphological changes characteristic of apoptotic nuclei. Expression of apoptosis related proteins was investigated by western blot analysis and immunohistochemistry. Results Pretreatment with a high concentration of glucose increased apoptosis of LPS-treated dendritic cells both in vivo and in vitro at 24 h. No effect was evident at the earlier time points of 15 min and 6 h in vitro. Furthermore, at 24 hours the expression of the survival proteins AKT, ERK and Bcl-2 was decreased, while the expression of the proapoptotic protein Bax was increased. AKT, ERK, Bcl-2 and Bax were mainly located in the cytoplasm by immunohistochemistry. Conclusions These results suggest that high glucose concentrations might prime dendritic cells for apoptosis induced by LPS in the intestinal tract through upregulating the expression of Bax and downregulating the expression of AKT, ERK and Bcl-2. Therefore, this study may give clues to understanding the immunological mechanism behind gastrointestinal complications in diabetes mellitus. PMID:24885625

2014-01-01

157

Perifosine inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-? production via regulation multiple signaling pathways: new implication for Kawasaki disease (KD) treatment.  

PubMed

Kawasaki disease (KD) is a multisystem vasculitis of unknown etiology, with coronary artery aneurysms occurring in majority of untreated cases. Tumor necrosis factor (TNF)-? is the pleiotropic inflammatory cytokine elevated during the acute phase of KD, which induces damage to vascular endothelial cells to cause systemic vasculitis. We here investigated the potential role of perifosine, a novel Akt inhibitor, on TNF? expression in LPS-stimulated macrophages and in ex-vivo cultured peripheral blood mononuclear cells (PBMCs) of acute KD patients. Here, we found that perifosine inhibited LPS-induced TNF? expression and production in mouse macrophages (RAW 264.7 cells and bone marrow-derived macrophages (BMDMs)). Meanwhile, perifosine administration down-regulated TNF? production in PBMCs isolated from acute KD patients. For the mechanism study, we found that perifosine significantly inhibited Akt and ERK/mitogen-activated protein kinases (MAPK) signaling, while activating AMP-activated protein kinase (AMPK) signaling in both patients' PBMCs and LPS-stimulated macrophages. Interestingly, although perifosine is generally known as an Akt inhibitor, our data suggested that ERK inhibition and AMPK activation, but not Akt inactivation were possibly involved in perifosine-mediated inhibition against TNF? production in monocytes. In conclusion, our data suggested that perifosine significantly inhibited TNF? production via regulation multiple signaling pathways. The results of this study should have significant translational relevance in managing this devastating disease. PMID:23806687

Shen, Jie; Liang, Li; Wang, Chunlin

2013-07-26

158

Flavonoid Fraction of Bergamot Juice Reduces LPS-Induced Inflammatory Response through SIRT1-Mediated NF-?B Inhibition in THP-1 Monocytes  

PubMed Central

Plant polyphenols exert anti-inflammatory activity through both anti-oxidant effects and modulation of pivotal pro-inflammatory genes. Recently, Citrus bergamia has been studied as a natural source of bioactive molecules with antioxidant activity, but few studies have focused on molecular mechanisms underlying their potential beneficial effects. Several findings have suggested that polyphenols could influence cellular function by acting as activators of SIRT1, a nuclear histone deacetylase, involved in the inhibition of NF-?B signaling. On the basis of these observations we studied the anti-inflammatory effects produced by the flavonoid fraction of the bergamot juice (BJe) in a model of LPS-stimulated THP-1 cell line, focusing on SIRT1-mediated NF-?B inhibition. We demonstrated that BJe inhibited both gene expression and secretion of LPS-induced pro-inflammatory cytokines (IL-6, IL-1?, TNF-?) by a mechanism involving the inhibition of NF-?B activation. In addition, we showed that BJe treatment reversed the LPS-enhanced acetylation of p65 in THP-1 cells. Interestingly, increasing concentrations of Sirtinol were able to suppress the inhibitory effect of BJe via p65 acetylation, underscoring that NF-?B–mediated inflammatory cytokine production may be directly linked to SIRT1 activity. These results suggest that BJe may be useful for the development of alternative pharmacological strategies aimed at reducing the inflammatory process. PMID:25260046

Risitano, Roberto; Currň, Monica; Cirmi, Santa; Ferlazzo, Nadia; Campiglia, Pietro; Caccamo, Daniela; Ientile, Riccardo; Navarra, Michele

2014-01-01

159

Chikusetsusaponin V inhibits inflammatory responses via NF-?B and MAPK signaling pathways in LPS-induced RAW 264.7 macrophages.  

PubMed

Excessive activation of macrophages is implicated in various inflammation resulted injuries. Saponins from Panax japonicus (SPJ) have been shown to possess anti-inflammatory activities. However, whether Chikusetsusaponin V (CsV), the most abundant component of SPJ, can exert anti-inflammatory activities is unknown. The present study was aimed to investigate the anti-inflammatory effects of CsV in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells and the underlying mechanisms. Our data showed that CsV dose-dependently inhibited NO, iNOS, TNF-? and IL-1? expressions in LPS-stimulated RAW264.7 cells. Increased protein levels of nuclear NF-?B and elevated phosphorylation levels of ERK and JNK in LPS-stimulated RAW 264.7 cells were also found downregulated by CsV treatment. Furthermore, the increase of CD14 and TLR4 mRNA expression due to LPS stimulation were significantly reversed by CsV treatment. These results suggested that CsV attenuated LPS-induced inflammatory responses partly via TLR4/CD14-mediated NF-?B and MAPK pathways. PMID:25228203

Wang, Ting; Dai, Yanwen; Dun, Yaoyan; Zhang, Changcheng; Wan, Jingzhi; Deng, Lili; Zhou, Zhiyong; Liu, Chaoqi; Yuan, Ding

2014-12-01

160

Anti-inflammatory effects of hydrophilic and lipophilic statins with hyaluronic acid against LPS-induced inflammation in porcine articular chondrocytes.  

PubMed

The objective of the study is to understand the therapeutic effects of lipophilic (simvastatin) and hydrophilic statins (pravastatin) combined with/without hyaluronic acid for osteoarthritis by an in vitro LPS-induced inflammatory model of articular chondrocytes. HA in combination with different doses of simvastatin or pravastatin were used. Beside cytotoxicity, the influence of statins on NO production, pro-inflammatory cytokine, inflammatory mediators, and NF-?B p50 protein were analyzed. Finally, TUNEL assay was performed to detect DNA strand breakage. Two statins were less able to lower NF-?B activity when they were administrated along without HA. The gene expression demonstrates that simvastatin and pravastatin had the ability to decrease pro-inflammatory and inflammatory mediator levels. High dose simvastatin with or without HA down regulated inflammatory cytokines, but resulted in higher cytotoxicity. TUNEL assay confirms the regulatory effect of statins with or without HA over the apoptosis of chondrocytes, especially in hydrophilic statins. The significant down-regulation of inflammatory mediators suggests that intra-articular injection of HA in combination with statins might feasibly slow the progress of osteoarthritis. Administration of simvastatin or pravastatin with hyaluronic acid may produce beneficial effects for OA treatment, but with better results when hydrophilic statin was used. PMID:24302463

Chang, Chih-Hung; Hsu, Yuan-Ming; Chen, Yu-Chun; Lin, Feng-Huei; Sadhasivam, Subramaniam; Loo, Siow-Tung; Savitha, Sivasubramanian

2014-04-01

161

Anethole, a Medicinal Plant Compound, Decreases the Production of Pro-Inflammatory TNF-? and IL-1? in a Rat Model of LPS-Induced Periodontitis  

PubMed Central

Periodontitis (PD) is known to be one of most prevalent worldwide chronic inflammatory diseases. There are several treatments including antibiotics for PD; however, since drug resistance is an increasing problem, new drugs particularly derived from plants with fewer side effects are required. The effects of trans-anethole on IL-1 ? and TNF-? level in a rat model of PD were investigated and compared to ketoprofen. Eschericia coli lipopolysaccharide (LPS, 30 µg) was injected bilaterally into the palatal gingiva (3 µL/site) between the upper first and second molars every two days for 10 days in anesthetized rats. Administration of either trans-anethole (10 or 50 mg/Kg, i.p.) or ketoprofen (10 mg/Kg, i.p.) was started 20 minute before LPS injection and continued for 10 days. Then, IL-1? and TNF-? levels were measured in blood samples by ELISA at day 0 (control) and at day 10. Anethole at both concentrations significantly suppressed IL-1? and TNF-? production when compared to LPS-treated rats. The suppressive effects of anethole on LPS-induced pro-inflammatory cytokines were almost similar as seen with ketoprofen. In conclusion, the present results suggest that anethole may have a potent inhibitory effect on PD through suppression of pro-inflammatory molecules; therefore it could be a novel therapeutic strategy for PD.

Moradi, Janet; Abbasipour, Fatemeh; Zaringhalam, Jalal; Maleki, Bita; Ziaee, Narges; Khodadoustan, Amin; Janahmadi, Mahyar

2014-01-01

162

Quantitative Proteomic Analysis of LPS-induced Differential Immune Response Associated with TLR4 Polymorphisms by Multiplex Amino Acid Coded Mass-tagging  

PubMed Central

Polymorphisms at Toll-like receptor 4 (TLR4) gene have been found to be associated with immune disorders. A murine macrophage cell line GG2EE derived from C3H/HeJ mice with a polymorphism site at TLR4 is hyposensitive to lipopolysacchride (LPS). To study the molecular base of diverse TLR4-mediated immune responses, the proteomic changes in both TLR4-deficient and –wild-type cell lines in response to the same LPS challenge were quantitatively compared by using multiplex amino acid coded mass-tagging (AACT)/SILAC-assisted mass spectrometry (MS). This strategy allows encoding of two distinct cell populations with different stable isotope-tagged lysine residues as the ‘in-spectra’ quantitative markers. In MS analysis of tryptic peptides derived from the equally mixed three cell populations, the lysine-containing peptides originated from two LPS stimulated cell populations can be clearly distinguished by their different mass shifts from the un-stimulated and unlabeled counterpart. The LPS-induced differential protein expression in TLR4 –deficient and –wild-type proteomes were obtained by comparing the intensities of isotopically encoded peptides. Among the more than 900 proteins identified, 35 were found to be deregulated at different levels in these two cell lines stimulated by LPS. This multiplex mass-tagging methodology can be readily extended to other comparative proteomic quantitation of different cell populations. PMID:18654986

Gu, Sheng; Wang, Tianyi; Chen, Xian

2013-01-01

163

Bacterial lipopolysaccharide (LPS)-induced type 2 iodothyronine deiodinase (D2) activation in the mediobasal hypothalamus (MBH) is independent of the LPS-induced fall in serum thyroid hormone levels  

Microsoft Academic Search

By administration of bacterial lipopolysaccharide (LPS) to intact and T4-replaced thyroidectomized rats, we demonstrate that in contrast to the cortex and anterior pituitary, there is a persistent increase in type 2 iodothyronine deiodinase (D2) activity in the mediobasal hypothalamus (MBH). We propose that endotoxin-induced D2 activation in the MBH is independent of circulating levels of thyroid hormone and that this

Csaba Fekete; Sumit Sarkar; Marcelo A. Christoffolete; Charles H. Emerson; Antonio C. Bianco; Ronald M. Lechan

2005-01-01

164

Inhibition of Glycogen Synthase Kinase 3? Ameliorates D-GalN/LPS-Induced Liver Injury by Reducing Endoplasmic Reticulum Stress-Triggered Apoptosis  

PubMed Central

Background Glycogen synthase kinase 3?(GSK3?) is a ubiquitous serine-threonine protein kinase that participates in numerous cellular processes and disease pathophysiology. We aimed to determine therapeutic potential of GSK3? inhibition and its mechanism in a well-characterized model of lipopolysaccharide (LPS)-induced model of acute liver failure (ALF). Methodology In a murine ALF model induced by D-GalN(700 mg/kg)/LPS(10 µg/kg), we analyzed GSK3? mechanisms using a specific chemical inhibitor, SB216763, and detected the role of endoplasmic reticulum stress (ERS). Mice were administered SB216763 at 2 h before or after D-GalN/LPS injection, respectively, and then sacrificed 6 h after D-GalN/LPS treatment to evaluate its prophylactic and therapeutic function. The lethality rate, liver damage, ERS, cytokine expression, MAP kinase, hepatocyte apoptosis and expression of TLR 4 were evaluated, respectively. Whether the inhibition of GSK3? activation protected hepatocyte from ERS-induced apoptosis was investigated in vitro. Principal Findings GSK3? became quickly activated (dephosphorylated) upon D-GalN/LPS exposure. Administration of SB216763 not only ameliorated liver injury, as evidenced by reduced transaminase levels, and well-preserved liver architecture, but also decreased lethality. Moreover, GSK3? inhibition resulted in down-regulation of pro-apoptotic proteins C/EBP–homologous protein(CHOP) and caspase-12, which are related to ERS. To further demonstrate the role of ERS, we found that GSK3? inhibition protected hepatocyte from ERS-induced cell death. GSK3? inhibition down-regulated the MAPK pathways, reduced expression of inflammatory cytokines and decreased expression of TLR4. Conclusions Our findings demonstrate the key function of GSK3? signaling in the pathophysiology of ALF, especially in regulating the ERS, and provide a rationale for targeting GSK3? as a potential therapeutic strategy to ameliorate ALF. PMID:23028846

Zhang, Haiyan; Wen, Tao; Piao, Zhengfu; Zhou, Li; Zheng, Sujun; Zhang, Jing; Chen, Yu; Han, Yuanping; Duan, Zhongping; Ma, Yingji

2012-01-01

165

Loss of lipopolysaccharide-induced nitric oxide production and inducible nitric oxide synthase expression in scrapie-infected N2a cells.  

PubMed

In scrapie-infected cells, the conversion of the cellular prion protein to the pathogenic prion has been shown to occur in lipid rafts, which are suggested to function as signal transduction platforms. Neuronal cells may respond to bacterial lipopolysaccharide (LPS) treatment with a sustained and elevated nitric oxide (NO) release. Because prions and the major LPS receptor CD14 are colocalized in lipid rafts, the LPS-induced NO production in scrapie-infected neuroblastoma cells was studied. This study shows that LPS induces a dose- and time-dependent increase in NO release in the murine neuroblastoma cell line N2a, with a 50-fold increase in NO production at 1 microg/ml LPS after 96 hr, as measured by nitrite in the medium. This massive NO release was not caused by activation of the neuronal NO synthase (nNOS), but by increased expression of the inducible NOS (iNOS) mRNA and protein. However, in scrapie-infected N2a cells (ScN2a), the LPS-induced NO production was completely abolished. The absence of LPS-induced NO production in ScN2a was due not to abolished enzymatic activity of iNOS but to a complete inhibition of the LPS-induced iNOS gene expression as measured by Western blot and RT-PCR. These results indicate that scrapie infection inhibits the LPS-mediated signal transduction upstream of the transcriptional step in the signaling cascade and may reflect the important molecular and cellular changes induced by scrapie infection. PMID:12503093

Lindegren, Heléne; Ostlund, Pernilla; Gyllberg, Hanna; Bedecs, Katarina

2003-01-15

166

INVOLVEMENT OF TOLL-LIKE RECEPTOR 4 AND MAPK PATHWAYS IN LPS-INDUCED CD40 EXPRESSION IN MONOCYTIC CELLS  

EPA Science Inventory

CD40 is a co-stimulatory surface molecule actively expressed on mature dendritic cells (DC). Recent studies suggest that endotoxin (LPS) inhalation induces DC maturation in the airways of healthy volunteers. To characterize the effect of LPS on CD40 expression and underlying mech...

167

Exploring LPS-induced sepsis in rats and mice as a model to study potential protective effects of the nociceptin/orphanin FQ system.  

PubMed

The nociceptin receptor (NOP) and its ligand nociceptin/orphanin FQ (N/OFQ) have been shown to exert a modulatory effect on immune cells during sepsis. We evaluated the suitability of an experimental lipopolysaccharide (LPS)-induced sepsis model for studying changes in the nociceptin system. C57BL/6 mice BALB/c mice and Wistar rats were inoculated with different doses of LPS with or without a nociceptin receptor antagonist (UFP-101 or SB-612111). In C57BL/6 mice LPS 0.85 mg/kg injection produced no septic response, whereas 1.2mg/kg produced a profound response within 5h. In BALB/c mice, LPS 4 mg/kg produced no response, whereas 7 mg/kg resulted in a profound response within 24h. In Wistar rats LPS 15 mg/kg caused no septic response in 6/10 animals, whereas 25mg/kg resulted in marked lethargy before 24h. Splenic interleukin-1? mRNA in BALB/c mice, and serum TNF-? concentrations in Wistar rats increased after LPS injection in a dose-dependent manner, but were undetectable in control animals, indicating that LPS had stimulated an inflammatory reaction. IL-1? and TNF-? concentrations in LPS-treated animals were unaffected by administration of a NOP antagonist. Similarly NOP antagonists had no effect on survival or expression of mRNA for NOP or ppN/OFQ (the N/OFQ precursor) in a variety of tissues. In these animal models, the dose-response curve for LPS was too steep to allow use in survival studies and no changes in the N/OFQ system occurred within 24h. We conclude that LPS-inoculation in rodents is an unsuitable model for studying possible changes in the NOP-N/OFQ system in sepsis. PMID:25161013

Thomas, Roisin C; Bath, Michael F; Stover, Cordula M; Lambert, David G; Thompson, Jonathan P

2014-11-01

168

Identification of a LPS-induced TNF-? factor (LITAF) from mollusk Solen grandis and its expression pattern towards PAMPs stimulation.  

PubMed

Lipopolysaccharide-induced TNF-? factor (LITAF) is one of the most important transcription factors mediating TNF-? transcription. In the present study, a LITAF gene (designated as SgLITAF) was identified from razor clams Solen grandis. The full-length cDNA of SgLITAF was of 1476 bp, encoding a polypeptide of 130 amino acids showed high similarity to other known LITAFs. SgLITAF encoded a LITAF domain and the Zn(2+)-binding motifs in the domain were well conserved. The mRNA transcripts of SgLITAF were detected in all tested tissues of healthy razor clams, including mantle, gill, gonad, hemocytes, muscle and hepatopancreas, and with the highest expression level in hepatopancreas. The expression level of SgLITAF in hemocytes was significantly up-regulated (P < 0.01) after razor clams were stimulated by LPS or ?-1, 3-glucan, but no obvious fluctuation of SgLITAF mRNA expression was observed after PGN stimulation. All the results indicated that there might be a LITAF-regulated TNF-? signaling pathway existing in S. grandis, which involved in the immune response not only against gram-negative bacteria but also towards fungi. PMID:23891855

Yang, Dinglong; Wei, Xiumei; Yang, Jianmin; Yang, Jialong; Xu, Jie; Fang, Jinghui; Wang, Sheng; Liu, Xiangquan

2013-10-01

169

Co-operation of TLR4 and raft proteins in LPS-induced pro-inflammatory signaling.  

PubMed

Toll-like receptor 4 (TLR4) is activated by lipopolysaccharide (LPS), a component of Gram-negative bacteria to induce production of pro-inflammatory mediators aiming at eradication of the bacteria. Dysregulation of the host responses to LPS can lead to a systemic inflammatory condition named sepsis. In a typical scenario, activation of TLR4 is preceded by binding of LPS to CD14 protein anchored in cholesterol- and sphingolipid-rich microdomains of the plasma membrane called rafts. CD14 then transfers the LPS to the TLR4/MD-2 complex which dimerizes and triggers MyD88- and TRIF-dependent production of pro-inflammatory cytokines and type I interferons. The TRIF-dependent signaling is linked with endocytosis of the activated TLR4, which is controlled by CD14. In addition to CD14, other raft proteins like Lyn tyrosine kinase of the Src family, acid sphingomyelinase, CD44, Hsp70, and CD36 participate in the TLR4 signaling triggered by LPS and non-microbial endogenous ligands. In this review, we summarize the current state of the knowledge on the involvement of rafts in TLR4 signaling, with an emphasis on how the raft proteins regulate the TLR4 signaling pathways. CD14-bearing rafts, and possibly CD36-rich rafts, are believed to be preferred sites of the assembly of a multimolecular complex which mediates the endocytosis of activated TLR4. PMID:25332099

P?óciennikowska, Agnieszka; Hromada-Judycka, Aneta; Borz?cka, Kinga; Kwiatkowska, Katarzyna

2015-02-01

170

Furanodien-6-one from Commiphora erythraea inhibits the NF-?B signalling and attenuates LPS-induced neuroinflammation.  

PubMed

We investigated the in vitro anti-inflammatory activity of 1(10),4-furanodien-6-one, one the most active compounds of the hexane extract of Commiphora erythraea (Ehrenb.) Engl., by exposing microglial BV-2 cells to lipopolysaccharide. We showed that furanodien-6-one pre-treatment restored cell viability and ROS to control levels while halving NO generation. Production of pro-inflammatory IL-6, IL-23, IL-17, TGF-?, and INF-?, significantly induced by LPS, was also markedly reduced by furanodien-6-one treatment. We further showed that furanodien-6-one protects primary neuronal cultures against the inflammatory/toxic insults of LPS-treated BV-2 conditioned media, indicating that furanodien-6-one exerts anti-inflammatory/cytoprotective effects in neuronal cells. We then investigated whether furanodien-6-one exerts anti-inflammatory properties in an in vivo model of microglial activation. In adult mice ip-injected with LPS we found that furanodien-6-one had strong cerebral anti-inflammatory properties by inhibiting liver and brain TNF? as well as IL-1? expression. Results were not unexpected since FTIR-metabolomic analyses showed that furanodien-6-one-treated mice had a reduced dissimilarity to control animals and that the response to LPS treatment was markedly modified by furanodien-6-one. In conclusion our data provide strong evidence of the anti-inflammatory properties of furanodien-6-one that could be exploited to counteract degenerative pathologies based on neuroinflammation. PMID:23357788

Bellezza, Ilaria; Mierla, Annalisa; Grottelli, Silvia; Marcotullio, Maria Carla; Messina, Federica; Roscini, Luca; Cardinali, Gianluigi; Curini, Massimo; Minelli, Alba

2013-07-01

171

p120 Modulates LPS-Induced NF-?B Activation Partially through RhoA in Bronchial Epithelial Cells  

PubMed Central

p120-Catenin (p120) is an adherens junction protein recognized to regulate cell-cell adhesion. Emerging evidence indicates that p120 may also play an important role in inflammatory responses, and the regulatory mechanisms are still unknown. In the present study, we showed that p120 was associated with airway inflammation. p120 downregulation induced nuclear factor-?B (NF-?B) activation, accompanied with I?B? degradation, p65 nuclear translocation, and increased expression of interleukin-8 (IL-8) in lipopolysaccharide (LPS)- treated C57BL mice and human bronchial epithelial cells (BECs). Moreover, we first found that p120 directly coprecipitated with RhoA in BECs. After LPS stimulation, although total RhoA and p120-bound RhoA were unchanged, RhoA activity was increased. Y27632, a ROCK inhibitor, could partially inhibit nuclear translocation of p65. Overexpression of p120 inactivated RhoA and NF-?B in BECs, whereas p120 loss significantly increased RhoA activity, p65 nuclear translocation, and IL-8 expression. Taken together, our study supports the regulatory role of p120 in airway inflammation and reveals that p120 may modulate NF-?B signaling partially through RhoA. PMID:24995336

Qin, Shenghui; Zhang, Yanli; Liu, Liwei; Wu, Renliang

2014-01-01

172

Dexamethasone attenuates LPS-induced changes in expression of urea transporter and aquaporin proteins, ameliorating brain endotoxemia in mice  

PubMed Central

Aim: AQP4 in the brain is involved in the occurrence and development of a variety of encephalopathy. AQPs family changes in kidney were accompanied by altered UTs family. The aim of this study was to observe AQP4 and UT-A3 expression in CNS and to explore their role in the pathogenesis of endotoxemia encephalopathy following peripheral LPS injection in mice. Methods: Endotoxemia was induced in C57Bl/6 mice by intraperitoneal injection of LPS. The expression of UT-A3 and AQP4 in brain were detected by Western blot and immunohistochemistry, the level of cytokines were detected by ELISA, and the content of LDH, AST/ALT, BUN and CREA were detected by colorimetric method. Results: As compared with the control group, in model group, the brain weight/ body weight ratio increased by 13%. Meanwhile, a 2.5 fold increase in LDH and a 1.2 fold increase in AST/ALT were found in peripheral serum (P < 0.05), and also, BUN and CREA increased 2.5 fold (P < 0.01). In addition to severe CNS injury in response to lipopolysaccharide, the contents of cytokines and the expression of AQP4 protein in hippocampal is increased (P < 0.05), while the expression of UT-A3 protein in the hippocampus and cortical astrocytes decreased (P < 0.05). And, in part, Dexa pretreatment attenuated those effects. Conclusions: In endotoxemia encephalopathy, AQPs and UTs which regulate the functions of cell membrane are both altered. We suggested that the molecular mechanisms of regulation in endotoxemia may provide a new strategy for clinical treatment of the disease and drug binding sites.

Du, Yanwei; Meng, Yan; Lv, Xuejiao; Guo, Lirong; Wang, Xiaoqin; Su, Zhenzhong; Li, Lu; Li, Na; Zhao, Shuhua; Zhao, Lijing; Zhao, Xuejian

2014-01-01

173

Role of TLR signaling in Francisella tularensis-LPS-induced, antibody-mediated protection against Francisella tularensis challenge  

PubMed Central

Immunization with Ft-LPS provokes an antigen-specific, B-1a cell-derived antibody response that protects WT mice against an otherwise lethal challenge with Ft LVS. However, this same regimen offers limited protection to TLR2?/? mice, despite production of WT levels of anti-Ft-LPS antibodies. As Ft-LPS exhibits no TLR2 agonist activity, and macrophage-induced cytokine production in response to Ft LVS is overwhelmingly TLR2-dependent, we hypothesized that treatment of TLR2?/? mice with an alternative, MyD88-dependent TLR agonist would compensate for reduced recognition of Ft LVS in TLR2?/? mice and thereby, restore Ft-LPS-mediated protection. Administration of the nontoxic TLR4 agonist, synthetic Escherichia coli MPL, at the time of Ft-LPS immunization or Ft LVS challenge, fully protected TLR2?/? mice, whereas treatment of WT or TLR2?/? mice with MPL alone conferred partial protection. The TLR5 agonist, flagellin, also synergized with Ft-LPS to protect TLR2?/? mice from lethal Ft LVS challenge. In contrast to Ft LVS, Ft-LPS pretreatment failed to protect mice against i.n. challenge with Ft Schu S4, whereas MPL, administered in the absence or presence of Ft-LPS, conferred significant, albeit partial, protection. MPL treatment of macrophages increased the uptake of Ft LVS and decreased intracellular bacterial survival while shifting the macrophage-differentiation phenotype from “alternatively activated” to “classically activated”. Collectively, our data suggest that optimal, Ft-LPS-mediated protection against Ft LVS infection requires two discrete events, i.e., production of Ft-LPS-specific antibody, as well as TLR-mediated macrophage activation, to fully control Francisella infection. PMID:21750122

Cole, Leah E.; Mann, Barbara J.; Shirey, Kari Ann; Richard, Katharina; Yang, Yang; Gearhart, Patricia J.; Chesko, Kirsty L.; Viscardi, Rose M.; Vogel, Stefanie N.

2011-01-01

174

LPS-induced NF-{kappa}B expression in THP-1Blue cells correlates with neopterin production and activity of indoleamine 2,3-dioxygenase  

SciTech Connect

Research highlights: {yields} LPS induces NF-{kappa}B, neopterin formation and tryptophan degradation in THP-1 cells. {yields} Close dose- and time-dependent correlations exist between these biochemical events. {yields} Data provides some evidence for a parallel induction of them upon TLR stimulation. {yields} Results can be of considerable relevance also in vivo. -- Abstract: Neopterin production is induced in human monocyte-derived macrophages and dendritic cells upon stimulation with Th1-type cytokine interferon-{gamma} (IFN-{gamma}). In parallel, IFN-{gamma} induces the tryptophan-(trp)-degrading enzyme indoleamine 2,3-dioxygenase (IDO) and triggers the formation of reactive oxygen species (ROS). Translocation of the signal transduction element nuclear factor-{kappa}B (NF-{kappa}B) is induced by ROS and accelerates the pro-inflammatory response by activation of other pro-inflammatory pathways. Therefore, a close relationship between NF-{kappa}B expression, the production of neopterin and the degradation of trp can be assumed, although this has not been demonstrated so far. In the present in vitro study we compared the influence of lipopolysaccharide (LPS) on NF-{kappa}B activation, neopterin formation and the degradation of trp in THP-1Blue cells, which represent the human myelomonocytic cell line THP-1 stably transfected with an NF-{kappa}B inducible reporter system. In cells stimulated with LPS, a significant induction of NF-{kappa}B was observed, and this was paralleled by an increase of kynureunine (kyn) and neopterin concentrations and a decline of trp. The increase of the kyn to trp quotient indicates accelerated IDO activity. Higher LPS concentrations and longer incubation of cells were associated with higher activities of all three biochemical pathways and significant correlations existed between NF-{kappa}B activation, neopterin release and trp degradation (all p < 0.001). We conclude that there is a parallel induction of NF-{kappa}B, neopterin formation and trp degradation in monocytic THP-1 cells, which is elicited by pro-inflammatory triggers like LPS during innate immune responses.

Schroecksnadel, Sebastian [Division of Biological Chemistry, Innsbruck Medical University, Innsbruck (Austria)] [Division of Biological Chemistry, Innsbruck Medical University, Innsbruck (Austria); Jenny, Marcel [Division of Biological Chemistry, Innsbruck Medical University, Innsbruck (Austria) [Division of Biological Chemistry, Innsbruck Medical University, Innsbruck (Austria); Division of Medical Biochemistry, Biocenter, Innsbruck Medical University, Innsbruck (Austria); Kurz, Katharina [Department of Internal Medicine, Innsbruck Medical University, Innsbruck (Austria)] [Department of Internal Medicine, Innsbruck Medical University, Innsbruck (Austria); Klein, Angela [Division of Medical Biochemistry, Biocenter, Innsbruck Medical University, Innsbruck (Austria)] [Division of Medical Biochemistry, Biocenter, Innsbruck Medical University, Innsbruck (Austria); Ledochowski, Maximilian [Department of Internal Medicine, Innsbruck Medical University, Innsbruck (Austria)] [Department of Internal Medicine, Innsbruck Medical University, Innsbruck (Austria); Uberall, Florian [Division of Medical Biochemistry, Biocenter, Innsbruck Medical University, Innsbruck (Austria)] [Division of Medical Biochemistry, Biocenter, Innsbruck Medical University, Innsbruck (Austria); Fuchs, Dietmar, E-mail: dietmar.fuchs@i-med.ac.at [Division of Biological Chemistry, Innsbruck Medical University, Innsbruck (Austria)] [Division of Biological Chemistry, Innsbruck Medical University, Innsbruck (Austria)

2010-09-03

175

Regulation of ENaC-mediated alveolar fluid clearance by insulin via PI3K/Akt pathway in LPS-induced acute lung injury  

PubMed Central

Background Stimulation of epithelial sodium channel (ENaC) increases Na+ transport, a driving force of alveolar fluid clearance (AFC) to keep alveolar spaces free of edema fluid that is beneficial for acute lung injury (ALI). It is well recognized that regulation of ENaC by insulin via PI3K pathway, but the mechanism of this signaling pathway to regulate AFC and ENaC in ALI remains unclear. The aim of this study was to investigate the effect of insulin on AFC in ALI and clarify the pathway in which insulin regulates the expression of ENaC in vitro and in vivo. Methods A model of ALI (LPS at a dose of 5.0 mg/kg) with non-hyperglycemia was established in Sprague-Dawley rats receiving continuous exogenous insulin by micro-osmotic pumps and wortmannin. The lungs were isolated for measurement of bronchoalveolar lavage fluid(BALF), total lung water content(TLW), and AFC after ALI for 8 hours. Alveolar epithelial type II cells were pre-incubated with LY294002, Akt inhibitor and SGK1 inhibitor 30 minutes before insulin treatment for 2 hours. The expressions of ?-,?-, and ?-ENaC were detected by immunocytochemistry, reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting. Results In vivo, insulin decreased TLW, enchanced AFC, increased the expressions of ?-,?-, and ?-ENaC and the level of phosphorylated Akt, attenuated lung injury and improved the survival rate in LPS-induced ALI, the effects of which were blocked by wortmannin. Amiloride, a sodium channel inhibitor, significantly reduced insulin-induced increase in AFC. In vitro, insulin increased the expressions of ?-,?-, and ?-ENaC as well as the level of phosphorylated Akt but LY294002 and Akt inhibitor significantly prevented insulin-induced increase in the expression of ENaC and the level of phosphorylated Akt respectively. Immunoprecipitation studies showed that levels of Nedd4-2 binding to ENaC were decreased by insulin via PI3K/Akt pathway. Conclusions Our study demonstrated that insulin alleviated pulmonary edema and enhanced AFC by increasing the expression of ENaC that dependent upon PI3K/Akt pathway by inhibition of Nedd4-2. PMID:22458687

2012-01-01

176

Synthesis and effects of new caffeic acid derivatives on nitric oxide production in lipopolysaccharide-induced RAW 264.7 macrophages  

PubMed Central

In this study, 20 new derivatives of caffeic acid esters were synthesized and their inhibitory activities against the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages were determined. Compounds 3l, 3r, 3s and 3t were found to decrease nitrite levels in a dose-dependent manner in LPS-induced cells and showed potent inhibitory activities against the NO production in RAW264.7 macrophages with IC50 values of 7.4, 5.9, 3.3 and 2.2 ?M, respectively. They could be selected as compromising compounds for the later pharmacological study. PMID:24955176

Zhang, Jie; Xu, Liu-Xin; Xu, Xu-Sheng; Li, Bo-Wei; Wang, Rui; Fu, Jian-Jun

2014-01-01

177

Synthesis and effects of new caffeic acid derivatives on nitric oxide production in lipopolysaccharide-induced RAW 264.7 macrophages.  

PubMed

In this study, 20 new derivatives of caffeic acid esters were synthesized and their inhibitory activities against the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages were determined. Compounds 3l, 3r, 3s and 3t were found to decrease nitrite levels in a dose-dependent manner in LPS-induced cells and showed potent inhibitory activities against the NO production in RAW264.7 macrophages with IC50 values of 7.4, 5.9, 3.3 and 2.2 ?M, respectively. They could be selected as compromising compounds for the later pharmacological study. PMID:24955176

Zhang, Jie; Xu, Liu-Xin; Xu, Xu-Sheng; Li, Bo-Wei; Wang, Rui; Fu, Jian-Jun

2014-01-01

178

Ethanol extract of Synurus deltoides (Aiton) Nakai suppresses in vitro LPS-induced cytokine production in RAW 264.7 macrophages and in vivo acute inflammatory symptoms  

PubMed Central

Synurus deltoides (Aiton) Nakai, belonging to the Compositae family, is an edible plant widely distributed in Northeast Asia. In this study, we examined the mechanisms underlying the immunomodulative effects of the ethanol extract of S. deltoides (SDE). The SDE extract strongly down-regulated the mRNA expression of the inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and tumour necrosis factor (TNF)-?, thereby inhibiting the production of nitric oxide (NO), prostaglandin E2 (PGE2), and TNF-? in the lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Furthermore, SDE also suppressed the nuclear translocation of the activation protein (AP)-1 and the nuclear factor-?B (NF-?B), and simultaneously decreased the phosphorylation of extracellular signal-regulated protein kinases (ERK), p38, and Akt. In agreement with the in vitro observations, the orally administered SDE ameliorated the acute inflammatory symptoms in the arachidonic acid-induced ear edema and the EtOH/HCl-induced gastritis in mice. Therefore, S. deltoides have a potential anti-inflammatory capacity in vitro and in vivo, suggesting the potential therapeutic use in the inflammation-associated disorders. PMID:24611100

Jiang, Yunyao

2014-01-01

179

Short-term heating reduces the anti-inflammatory effects of fresh raw garlic extracts on the LPS-induced production of NO and pro-inflammatory cytokines by downregulating allicin activity in RAW 264.7 macrophages.  

PubMed

Garlic has a variety of biologic activities, including anti-inflammatory properties. Although garlic has several biologic activities, some people dislike eating fresh raw garlic because of its strong taste and smell. Therefore, garlic formulations involving heating procedures have been developed. In this study, we investigated whether short-term heating affects the anti-inflammatory properties of garlic. Fresh and heated raw garlic extracts (FRGE and HRGE) were prepared with incubation at 25 °C and 95 °C, respectively, for 2 h. Treatment with FRGE and HRGE significantly reduced the LPS-induced increase in the pro-inflammatory cytokine concentration (TNF-?, IL-1?, and IL-6) and NO through HO-1 upregulation in RAW 264.7 macrophages. The anti-inflammatory effect was greater in FRGE than in HRGE. The allicin concentration was higher in FRGE than in HRGE. Allicin treatment showed reduced production of pro-inflammatory cytokines and NO and increased HO-1 activity. The results show that the decrease in LPS-induced NO and pro-inflammatory cytokines in RAW 264.7 macrophages through HO-1 induction was greater for FRGE compared with HRGE. Additionally, the results indicate that allicin is responsible for the anti-inflammatory effect of FRGE. Our results suggest a potential therapeutic use of allicin in the treatment of chronic inflammatory disease. PMID:23583806

Shin, Jung-Hye; Ryu, Ji Hyeon; Kang, Min Jung; Hwang, Cho Rong; Han, Jaehee; Kang, Dawon

2013-08-01

180

The Protein Kinase PKR is Critical for LPS-induced iNOS Production, but Dispensable for Inflammasome Activation in Macrophages  

PubMed Central

The inflammasomes are multi-protein platforms that drive the activation of caspase-1 leading to the processing and secretion of biologically active IL-1? and IL-18. Different inflammasomes including NLRP3, NLRC4 and AIM2 are activated and assembled in response to distinct microbial or endogenous stimuli. However, the mechanisms by which upstream stimuli trigger inflammasome activation remain poorly understood. PKR, a protein kinase activated by viral infection, has been recently shown to be required for activation of the inflammasomes. Using macrophages from two different mouse strains deficient in PKR, we found that PKR is important for the induction of the inducible nitric oxide synthase (iNOS). However, PKR was dispensable for caspase-1 activation, processing of pro-IL-1?/IL-18 and secretion of IL-1? induced by stimuli that trigger the activation of NLRP3, NLRC4 and AIM2. These results indicate that PKR is not required for inflammasome activation in macrophages. PMID:23401008

He, Yuan; Franchi, Luigi; Núńez, Gabriel

2013-01-01

181

Gomisin A decreases the LPS-induced expression of iNOS and COX-2 and activation of RIP2/NF-?B in mouse peritoneal macrophages.  

PubMed

Gomisin A (GA), a lignan component contained in the fruit of Schisandra chinensis Baillon, improves hepatic cell degeneration, vasodilatory activity and insulin sensitivity. These effects also impact the immune system, including various inflammatory mediators and cytokines. In this study, the anti-inflammatory effect of GA on lipopolysaccharide-stimulated mouse peritoneal macrophages was studied. Pretreatment with GA attenuated the expression of receptor-interacting protein 2 (RIP2) and I?B kinase-? (IKK-?) as well as IKK-? phosphorylation. The activation of nuclear factor-kappa B (NF-?B) in the nucleus, the phosphorylation of I?B? and degradation of I?B? in the cytosol were suppressed by GA. GA decreased the production and mRNA expression of the inflammatory cytokines tumor necrosis factor-alpha (TNF-?) and interleukin (IL)-6. In addition, expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and production of nitric oxide were decreased by pretreatment with GA. In conclusion, these results show that the anti-inflammatory properties of GA potentially result from the inhibition of COX-2, iNOS, IL-6, TNF-? and NO through the down-regulation of RIP2 and NF-?B activation. These results impact the development of potential health products for preventing and treating inflammatory diseases. PMID:24749675

Jeong, Hyun-Ja; Han, Na-Ra; Kim, Kyu-Yeob; Choi, Il-Sook; Kim, Hyung-Min

2014-06-01

182

Inhibition of LPS-induced TNF-? and NO production in mouse macrophage and inflammatory response in rat animal models by a novel Ayurvedic formulation, BV-9238.  

PubMed

Rheumatoid arthritis is a chronic crippling disease, where protein-based tumor necrosis factor-alpha (TNF-?) inhibitors show significant relief, but with potentially fatal side effects. A need for a safe, oral, cost-effective small molecule or phyto-pharmaceutical is warranted. BV-9238 is an Ayurvedic poly-herbal formulation containing specialized standardized extracts of Withania somnifera, Boswellia serrata, Zingiber officinale and Curcuma longa. The anti-inflammatory and anti-arthritic effects of BV-9238 were evaluated for inhibition of TNF-? and nitric oxide (NO) production, in lipopolysaccharide-stimulated, RAW 264.7, mouse macrophage cell line. BV-9238 reduced TNF-? and NO production, without any cytotoxic effects. Subsequently, the formulation was tested in adjuvant-induced arthritis (AIA) and carrageenan-induced paw edema (CPE) rat animal models. AIA was induced in rats by injecting Freund's complete adjuvant intra-dermally in the paw, and BV-9238 and controls were administered orally for 21?days. Arthritic scores in AIA study and inflamed paw volume in CPE study were significantly reduced upon treatment with BV-9238. These results suggest that the anti-inflammatory and anti-arthritic effects of BV-9238 are due to its inhibition of TNF-?, and NO, and this formulation shows promise as an alternate therapy for inflammatory disorders where TNF-? and NO play important roles. PMID:24706581

Dey, Debendranath; Chaskar, Sunetra; Athavale, Nitin; Chitre, Deepa

2014-10-01

183

Effects of Various Antioxidants on Endotoxin-Induced Lung Injury and Gene Expression mRNA Expressions of MnSOD, Interleukin1?  

Microsoft Academic Search

Antioxidants have been shown to be effective in attenuating acute lung injury. In this study, we determine the effects of various antioxidants by different mechanisms on the lipopolysaccharide (LPS)- induced changes. LPS was administered intravenously at a dose of 10 mg\\/kg to anesthetized rats. LPS induced a significant decrease in blood pressure (P < 0.01) and increased exhaled nitric oxide

Nan-Hsiung Feng; Shi-Jye Chu; David Wang; Kang Hsu; Chun-Hsiu Lin; Hen-I Lin

184

Anti-inflammatory effects of anthocyanins-rich extract from bilberry (Vaccinium myrtillus L.) on croton oil-induced ear edema and Propionibacterium acnes plus LPS-induced liver damage in mice.  

PubMed

Bilberry (Vaccinium myrtillus L.) has been known to play a protective role in human health due to its high anthocyanin content. This study investigated the anti-inflammatory effects of bilberry extract (BE, containing 42.04% anthocyanin) on Propionibacterium acnes (P. acnes) plus lipopolysaccharide (LPS) induced liver injury and croton oil-induced ear edema in mice. Results showed that BE could effectively inhibit croton oil-induced ear edema and liver inflammation provoked by P. acnes plus LPS, as reflected by the reduced plasma alanine aminotransferase and aspartate aminotransferase activities. These findings were confirmed by hepatic pathological examination. Moreover, BE administration markedly suppressed the increase of liver mRNA levels of iNOS, TNF-?, IL-1? and IL-6, and the protein levels of iNOS, TNF-? and NF-?B. In addition, liver malondialdehyde and NO contents were significantly reduced by BE treatment. These results indicated that BE has potent protective effects on acute and immunological inflammation, which might contribute to the study of the anti-inflammatory effects of natural products and healthy food. PMID:24548119

Luo, Hui; Lv, Xiao-Dan; Wang, Guo-En; Li, Yi-Fang; Kurihara, Hiroshi; He, Rong-Rong

2014-08-01

185

A role of cell apoptosis in lipopolysaccharide (LPS)-induced nonlethal liver injury in D-galactosamine (D-GalN)-sensitized rats.  

PubMed

Lipopolysaccharide (LPS) is implicated in the pathology of acute liver injury and can induce lethal liver failure when simultaneously administered with D-galactosamine (D-GalN). At the present time, nonlethal liver failure, the liver injury of clinical implication, is incompletely understood following challenge by low-dose LPS/D-GalN. We report here our investigation of the effects of liver injury following a nonlethal dose LPS/D-GalN and the role of apoptosis in this disorder. Blood biochemistry indexes, including those of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL), had risen by 6 h post-LPS/D-GalN injection, reached a peak at 24 h and sustained high levels at 48 h. An abnormal liver appearance was found at 24 and 48 h post-injection. Histopathological changes of hepatic injuries accompanied by hepatocellular death, inflammatory infiltration and hemorrhage began to appear at 6 h and were markedly aggravated at 24 and 48 h. Cell apoptosis was significantly induced by the nonlethal dose LPS/D-GalN challenge, and the apoptotic indexes (AIs) in 24 h- and 48 h-treated rats were approximately 70%, as estimated by the terminal transferase dUTP nick end labeling (TUNEL) assay. The mRNA levels of the inflammatory cytokine IL-1beta rose markedly at 6 h and maintained high levels at 24 and 48 h; however, TNF-alpha levels were normal in the liver tissues of 6-, 24- and 48-h-treated rats. mRNA expression of the damage gene nitric oxide synthase (NOS) was also induced early by the LPS/D-GalN challenge, reaching a peak at 6 h, then gradually decreasing in a stepwise manner; conversely, high expression levels of the apoptosis-inducing gene p53 mRNA were not found in the early post-injection period (6 h) but emerged in the crest-time of liver apoptosis (24 h) and were maintained at this level until the late stage (48 h). We also observed that in 24 h-treated rats, caspase-3, -8, -9 and -12 were markedly activated by LPS/D-GalN challenge. These results suggest that a challenge with low-dose LPS in conjunction with D-GalN can induce nonlethal but marked liver failure, the main morphological feature of which is hepatic apoptosis, which may be associated with a high expression of inducible (i)NOS (early post-injection period) and p53 genes (in the mid and late stages) and at least three apoptosis pathways participate in the pathogenesis. PMID:17934810

Liu, Liang-Ming; Zhang, Ji-Xiang; Luo, Jie; Guo, Hong-Xing; Deng, Huan; Chen, Jian-Yong; Sun, Sui-Lin

2008-05-01

186

ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-{alpha} and nitric oxide production and protects mice from lethal endotoxic shock.  

PubMed

ONO 3403, a new synthetic serine protease inhibitor, is a derivative of camostat mesilate and has a higher protease-inhibitory activity. The effect of ONO 3403 on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-? and nitric oxide (NO) production in RAW 264.7 macrophage-like cells was examined. ONO 3403 significantly inhibited LPS-induced TNF-? production at a lower concentration than camostat mesilate. It also inhibited LPS-induced NO production. Their inhibition was responsible for the reduced mRNA expression of TNF-? and inducible NO synthase. In LPS-stimulated cells, ONO 3403 prevented the augmentation of MyD88 expression and inhibited the phosphorylation of I?B-?, stress-activated protein kinase (SAPK) and IRF-3, and the production of interferon-?. ONO 3403 abolished the elevation of the extracellular serine protease activity in response to LPS. Further, it reduced the circulating TNF-? level, hepatic injury and mortality in mice receiving an injection of D-galactosamine and LPS. ONO 3403 was suggested to inhibit LPS-induced inflammatory responses via inactivation of MyD88-dependent and independent pathways. PMID:20023007

Tumurkhuu, Gantsetseg; Koide, Naoki; Hiwasa, Takaki; Ookoshi, Motohiro; Dagvadorj, Jargalsaikhan; Abu Shadat Mohammod Noman; Iftakhar-E-Khuda, Imtiaz; Naiki, Yoshikazu; Komatsu, Takayuki; Yoshida, Tomoaki; Yokochi, Takashi

2011-02-01

187

Enhancement of antinociception by coadminstration of minocycline and a non-steroidal anti-inflammatory drug indomethacin in naďve mice and murine models of LPS-induced thermal hyperalgesia and monoarthritis  

PubMed Central

Background Minocycline and a non-steroidal anti-inflammatory drug (NSAID) indomethacin, have anti-inflammatory activities and are both used in the management of rheumatoid arthritis. However, there are no reports on whether coadministration of these drugs could potentiate each other's activities in alleviating pain and weight bearing deficits during arthritis. Methods LPS was injected to BALB/c mice intraperitoneally (i.p.) to induce thermal hyperalgesia. The hot plate test was used to study thermal nociception in naďve BALB/c and C57BL/6 mice and BALB/c mice with LPS-induced thermal hyperalgesia and to evaluate antinociceptive effects of drugs administered i.p. Monoarthritis was induced by injection of LPS intra-articularly into the right hind (RH) limb ankle joint of C57BL/6 mice. Weight bearing changes and the effect of i.p. drug administration were analyzed in freely moving mice using the video-based CatWalk gait analysis system. Results In naďve mice indomethacin (5 to 50 mg/kg) had no significant activity, minocycline (25 to 100 mg/kg) produced hyperalgesia to thermal nociception, however, coadministration of minocycline 50 mg/kg with indomethacin 5 or 10 mg/kg produced significant antinociceptive effects in the hot plate test. A selective inhibitor of COX-1, FR122047 (10 mg/kg) and a selective COX-2 inhibitor, CAY10404 (10 mg/kg) had no significant antinociceptive activities to thermal nociception in naďve mice, however, coadministration of minocycline, with CAY10404 but not FR122047 produced significant antinociceptive effects. In mice with LPS-induced hyperalgesia vehicle, indomethacin (10 mg/kg) or minocycline (50 mg/kg) did not produce significant changes, however, coadministration of minocycline plus indomethacin resulted in antinociceptive activity. LPS-induced RH limb monoarthritis resulted in weight bearing (RH/left hind (LH) limb paw pressure ratios) and RH/LH print area ratios deficits. Treatment with indomethacin (1 mg/kg) or minocycline (50 mg/kg) had no effects on the weight bearing and print area ratios deficits of monoarthritic mice. However, combination of minocycline plus indomethacin restored weight bearing and paw print area ratios of monoarthritic mice similar to that observed in non-arthritic control mice. Conclusions Coadministration of indomethacin or a selective COX-2 inhibitor, CAY10404 with minocycline potentiates their effects and results in antinociception against thermal nociception, reduction of thermal hyperalgesia and alleviation of weight bearing deficits in monoarthritic mice at doses where either drug alone has no significant activity. Thus, the coadministration of lower doses of a NSAID or a selective COX-2 inhibitor plus minocycline could be useful in the management of inflammatory pain and arthritis. PMID:21122103

2010-01-01

188

HIF-1alpha protein is an essential factor for protection of myeloid cells against LPS-induced depletion of ATP and apoptosis that supports Toll-like receptor 4-mediated production of IL-6.  

PubMed

Sepsis is the leading cause of death in intensive care units, which reflects detrimental host response to infection where lipopolysaccharide (LPS) shared by Gram-negative bacteria acts as a potent activator of immune cells via Toll-like receptor 4 (TLR4). Recently it was found that TLR4 downstream signalling leads to the accumulation of hypoxia-inducible factor 1 alpha (HIF-1alpha), which is important for TLR4-dependent expression of pro-inflammatory cytokines, however, basic biochemical mechanisms of involvement of this protein in TLR4 downstream signalling remains unclear. Here we found that knockdown of the expression of HIF-1alpha protein by siRNA led to the depletion of ATP, which corresponded to the constant increase in the activity of apoptosis signal-regulating kinase 1 (ASK1) and therefore apoptosis as estimated based on the increase in the activity of caspase 3. On the other hand, LPS-dependent production of IL-6 was attenuated. Treatment of HIF-1alpha knockdown cells with extracellular ATP in combination with LPS preserved the IL-6 expression but not the activity of ASK1 on the level observed in LPS-stimulated control cells. We therefore suggested that HIF-1alpha protein supports LPS-dependent expression of IL-6 by preventing depletion of ATP. On the other hand HIF-1alpha protein is selectively required for down-regulation of ASK1 activated during LPS-induced TLR4 downstream signalling. PMID:18462799

Lall, Harjinder; Coughlan, Karen; Sumbayev, Vadim V

2008-06-01

189

Astrocytic TLR4 expression and LPS-induced nuclear translocation of STAT3 in the sensory circumventricular organs of adult mouse brain.  

PubMed

The sensory circumventricular organs (CVOs) comprise the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO), and area postrema (AP) and lack the blood-brain barrier. The expression of Toll-like receptor 4 (TLR4) was seen at astrocytes throughout the sensory CVOs and at microglia in the AP and solitary nucleus around the central canal. The peripheral and central administration of lipopolysaccharide induced a similar pattern of nuclear translocation of STAT3. A microglia inhibitor minocycline largely suppressed lipopolysaccharide-induced astrocytic nuclear translocation of STAT3 in the OVLT and AP, but its effect was less in the SFO. PMID:25595264

Nakano, Yousuke; Furube, Eriko; Morita, Shoko; Wanaka, Akio; Nakashima, Toshihiro; Miyata, Seiji

2015-01-15

190

Comparative analysis of the human hepatic and adipose tissue transcriptomes during LPS-induced inflammation leads to the identification of differential biological pathways and candidate biomarkers  

Microsoft Academic Search

Background: Insulin resistance (IR) is accompanied by chronic low grade systemic inflammation, obesity, and deregulation of total body energy homeostasis. We induced inflammation in adipose and liver tissues in vitro in order to mimic inflammation in vivo with the aim to identify tissue-specific processes implicated in IR and to find biomarkers indicative for tissue-specific IR. Methods: Human adipose and liver

E. Szalowska; M. Dijkstra; M. G. L. Elferink; D. Weening; Vries de M; M. Bruinenberg; A. Hoek; H. Roelofsen; G. M. M. Groothuis; R. J. Vonk

2011-01-01

191

Inhibitory effects of the beta-adrenergic receptor agonist zilpaterol on the LPS-induced production of TNF-alpha in vitro and in vivo.  

PubMed

In this study the anti-inflammatory properties of zilpaterol, a beta2-adrenergic receptor (AR) agonist specifically developed as a growth promoter in cattle were investigated. Although zilpaterol has a different structure compared with the beta2-AR agonists known to date, it was noted that it was able to bind to both the beta2-AR (Ki = 1.1 x 10(-6)) and the beta1-AR (Ki = 1.0 x 10(-5)). Using lipopolysaccharide (LPS)-exposed U937 macrophages, the production of cyclic adenosine-3',5'-cyclic monophosphate (cAMP) and tumor necrosis factor alpha (TNF-alpha) were investigated. Zilpaterol inhibited TNF-alpha release and induced intracellular cAMP levels in a dose-dependent manner. The inhibition of TNF-alpha release and induction of cAMP production was mainly mediated via the beta2-AR, as indicated by addition of beta1- and beta2-specific antagonists. The effects of zilpaterol were investigated in LPS-treated male Wistar rats after pretreatment with zilpaterol. Zilpaterol dosed at 500 microg/kg body weight reduced the TNF-alpha plasma levels. In conclusion, zilpaterol is a beta2-adrenergic agonist and an inhibitor of TNF-alpha production induced by LPS both in vivo and in vitro. PMID:16343285

Verhoeckx, K C M; Doornbos, R P; van der Greef, J; Witkamp, R F; Rodenburg, R J T

2005-12-01

192

Quince (Cydonia oblonga Miller) peel polyphenols modulate LPS-induced inflammation in human THP-1-derived macrophages through NF-?B, p38MAPK and Akt inhibition.  

PubMed

Chronic inflammation is a hallmark of several pathologies, such as rheumatoid arthritis, gastritis, inflammatory bowel disease, atherosclerosis and cancer. A wide range of anti-inflammatory chemicals have been used to treat such diseases while presenting high toxicity and numerous side effects. Here, we report the anti-inflammatory effect of a non-toxic, cost-effective natural agent, polyphenolic extract from the Tunisian quince Cydonia oblonga Miller. Lipopolysaccharide (LPS) treatment of human THP-1-derived macrophages induced the secretion of high levels of the pro-inflammatory cytokine TNF-? and the chemokine IL-8, which was inhibited by quince peel polyphenolic extract in a dose-dependent manner. Concomitantly, quince polyphenols enhanced the level of the anti-inflammatory cytokine IL-10 secreted by LPS-treated macrophages. We further demonstrated that the unexpected increase in IL-6 secretion that occurred when quince polyphenols were associated with LPS treatment was partially responsible for the polyphenols-mediated inhibition of TNF-? secretion. Biochemical analysis showed that quince polyphenols extract inhibited the LPS-mediated activation of three major cellular pro-inflammatory effectors, nuclear factor-kappa B (NF-?B), p38MAPK and Akt. Overall, our data indicate that quince peel polyphenolic extract induces a potent anti-inflammatory effect that may prove useful for the treatment of inflammatory diseases and that a quince-rich regimen may help to prevent and improve the treatment of such diseases. PMID:22252293

Essafi-Benkhadir, Khadija; Refai, Amira; Riahi, Ichrak; Fattouch, Sami; Karoui, Habib; Essafi, Makram

2012-02-01

193

MR imaging and targeting of a specific alveolar macrophage subpopulation in LPS-induced COPD animal model using antibody-conjugated magnetic nanoparticles  

PubMed Central

Purpose Targeting and noninvasive imaging of a specific alveolar macrophage subpopulation in the lung has revealed the importance for early and better diagnosis and therapy of chronic obstructive pulmonary disease (COPD). In this study, the in vivo effect of pulmonary administration of iron oxide nanoparticles on the polarization profile of macrophages was assessed, and a noninvasive free-breathing magnetic resonance imaging (MRI) protocol coupled with the use of biocompatible antibody-conjugated superparamagnetic iron oxide (SPIO) nanoparticles was developed to enable specific targeting and imaging of a particular macrophage subpopulation in lipopolysaccharide-induced COPD mice model. Materials and methods Enzyme-linked immunosorbent assay, Real-time polymerase chain reaction, and flow cytometry analysis were performed to assess the biocompatibility of PEGylated dextran-coated SPIO nanoparticles. Specific biomarkers for M1 and M2 macrophages subsets were selected for conjugation with magnetic nanoparticles. MRI protocol using ultra-short echo time sequence was optimized to enable simultaneous detection of inflammation progress in the lung and detection of macrophages subsets. Flow cytometry and immunohistochemistry analysis were finally performed to confirm MRI readouts and to characterize the polarization profile of targeted macrophages. Results The tested SPIO nanoparticles, under the current experimental conditions, were found to be biocompatible for lung administration in preclinical settings. Cluster of differentiation (CD)86- and CD206-conjugated magnetic nanoparticles enabled successful noninvasive detection of M1 and M2 macrophage subpopulations, respectively, and were found to co-localize with inflammatory regions induced by lipopolysaccharide challenge. No variation in the polarization profile of targeted macrophages was observed, even though a continuum switch in their polarization might occur. However, further confirmatory studies are required to conclusively establish this observation. Conclusion Coupling of magnetic iron oxide nanoparticles with a specific antibody targeted to a particular macrophage subpopulation could offer a promising strategy for an early and better diagnosis of pulmonary inflammatory diseases using noninvasive MRI. PMID:24711699

Al Faraj, Achraf; Shaik, Asma Sultana; Afzal, Sibtain; Al Sayed, Baraa; Halwani, Rabih

2014-01-01

194

Comparative analysis of the acute response of the trout, O. mykiss, head kidney to in vivo challenge with virulent and attenuated infectious hematopoietic necrosis virus and LPS-induced inflammation  

PubMed Central

Background The response of the trout, O. mykiss, head kidney to bacterial lipopolysaccharide (LPS) or active and attenuated infectious hematopoietic necrosis virus (IHNV and attINHV respectively) intraperitoneal challenge, 24 and 72 hours post-injection, was investigated using a salmonid-specific cDNA microarray. Results The head kidney response to i.p. LPS-induced inflammation in the first instance displays an initial stress reaction involving suppression of major cellular processes, including immune function, followed by a proliferative hematopoietic-type/biogenesis response 3 days after administration. The viral response at the early stage of infection highlights a suppression of hematopoietic and protein biosynthetic function and a stimulation of immune response. In fish infected with IHNV a loss of cellular function including signal transduction, cell cycle and transcriptional activity 72 hours after infection reflects the tissue-specific pathology of IHNV infection. attIHNV treatment on the other hand shows a similar pattern to native IHNV infection at 24 hours however at 72 hours a divergence from the viral response is seen and replace with a recovery response more similar to that observed for LPS is observed. Conclusion In conclusion we have been able to identify and characterise by transcriptomic analysis two different types of responses to two distinct immune agents, a virus, IHNV and a bacterial cell wall component, LPS and a 'mixed' response to an attenuated IHNV. This type of analysis will lead to a greater understanding of the physiological response and the development of effective immune responses in salmonid fish to different pathogenic and pro-inflammatory agents. PMID:18366750

MacKenzie, Simon; Balasch, Joan C; Novoa, Beatriz; Ribas, Laia; Roher, Nerea; Krasnov, Aleksei; Figueras, Antonio

2008-01-01

195

Melatonin modulates microsomal PGE synthase 1 and NF-E2-related factor-2-regulated antioxidant enzyme expression in LPS-induced murine peritoneal macrophages  

PubMed Central

BACKGROUND AND PURPOSE Increasing evidence demonstrates that melatonin regulates inflammatory and immune processes acting as both an activator and inhibitor of these responses. Nevertheless, the molecular mechanisms of its anti-inflammatory action remain unclear. Here we have characterized the cellular mechanisms underlying the redox modulation of LPS-stimulated inflammatory responses in murine peritoneal macrophages by melatonin to provide insight into its anti-inflammatory effects. EXPERIMENTAL APPROACH Murine peritoneal macrophages were isolated and treated with melatonin in the presence or absence of LPS (5 ?g·mL?1) for 18 h. Cell viability was determined using sulforhodamine B assay and NO production was measured using the Griess reaction. Pro-inflammatory enzymes and transcription factors were detected by Western blotting. KEY RESULTS Without affecting cell viability, melatonin (12.5, 25, 50 and 100 ?M) reduced the level of nitrites, inducible NOS (iNOS), COX-2 and microsomal PGE synthase-1 (mPGES1) protein, and p38 MAPK phosphorylation, and prevented NF-?B translocation. Furthermore, melatonin treatment significantly increased NF-E2-related factor 2 (Nrf2) and haem oxygenase 1 (HO1) protein levels in murine macrophages exposed to LPS. CONCLUSIONS AND IMPLICATIONS Melatonin reduced pro-inflammatory mediators and enhanced the expression of HO1 via NF-?B, p38 MAPK and Nrf2 cascade signalling pathways in murine macrophages. Thus, melatonin might be a promising target for diseases associated with overactivation of macrophages. PMID:24116971

Aparicio-Soto, M; Alarcón-de-la-Lastra, C; Cárdeno, A; Sánchez-Fidalgo, S; Sanchez-Hidalgo, M

2014-01-01

196

Microvascular and interstitial oxygen tension in the renal cortex and medulla studied in a 4-h rat model of LPS-induced endotoxemia.  

PubMed

The pathophysiology of sepsis-induced acute kidney injury remains poorly understood. As changes in renal perfusion and oxygenation have been shown, we aimed to study the short-term effects of endotoxemia on microvascular and interstitial oxygenation in the cortex and medulla, in conjunction with global and renal hemodynamics. In a 4-h rat model of endotoxemia, we simultaneously assessed renal artery blood flow and microvascular and interstitial oxygen tensions in the renal cortex and medulla using ultrasonic flowmetry, dual wavelength phosphorimetry, and tissue oxygen tension monitoring, respectively. Whereas medullary microvascular and interstitial oxygen tensions decreased promptly in line with macrovascular blood flow, changes in cortical oxygenation were only seen later on. During the entire experimental protocol, the gradient between microvascular PO? and tissue oxygen tension remained unchanged in both cortex and outer medulla. At study end, urine output was significantly decreased despite a maintained oxygen consumption rate. In this 4-h rat model of endotoxemia, total renal oxygen consumption and the gradient between microvascular PO? and tissue oxygen tension remained unaltered, despite falls in renal perfusion and oxygen delivery and urine output. Taken in conjunction with the decrease in urine output, our results could represent either a functional renal impairment or an adaptive response. PMID:21368713

Dyson, Alex; Bezemer, Rick; Legrand, Matthieu; Balestra, Gianmarco; Singer, Mervyn; Ince, Can

2011-07-01

197

Comparative analysis of the human hepatic and adipose tissue transcriptomes during LPS-induced inflammation leads to the identification of differential biological pathways and candidate biomarkers  

PubMed Central

Background Insulin resistance (IR) is accompanied by chronic low grade systemic inflammation, obesity, and deregulation of total body energy homeostasis. We induced inflammation in adipose and liver tissues in vitro in order to mimic inflammation in vivo with the aim to identify tissue-specific processes implicated in IR and to find biomarkers indicative for tissue-specific IR. Methods Human adipose and liver tissues were cultured in the absence or presence of LPS and DNA Microarray Technology was applied for their transcriptome analysis. Gene Ontology (GO), gene functional analysis, and prediction of genes encoding for secretome were performed using publicly available bioinformatics tools (DAVID, STRING, SecretomeP). The transcriptome data were validated by proteomics analysis of the inflamed adipose tissue secretome. Results LPS treatment significantly affected 667 and 483 genes in adipose and liver tissues respectively. The GO analysis revealed that during inflammation adipose tissue, compared to liver tissue, had more significantly upregulated genes, GO terms, and functional clusters related to inflammation and angiogenesis. The secretome prediction led to identification of 399 and 236 genes in adipose and liver tissue respectively. The secretomes of both tissues shared 66 genes and the remaining genes were the differential candidate biomarkers indicative for inflamed adipose or liver tissue. The transcriptome data of the inflamed adipose tissue secretome showed excellent correlation with the proteomics data. Conclusions The higher number of altered proinflammatory genes, GO processes, and genes encoding for secretome during inflammation in adipose tissue compared to liver tissue, suggests that adipose tissue is the major organ contributing to the development of systemic inflammation observed in IR. The identified tissue-specific functional clusters and biomarkers might be used in a strategy for the development of tissue-targeted treatment of insulin resistance in patients. PMID:21978410

2011-01-01

198

Microarray and pathway analysis reveal distinct mechanisms underlying cannabinoid-mediated modulation of LPS-induced activation of BV-2 microglial cells.  

PubMed

Cannabinoids are known to exert immunosuppressive activities. However, the mechanisms which contribute to these effects are unknown. Using lipopolysaccharide (LPS) to activate BV-2 microglial cells, we examined how ?(9)-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, and cannabidiol (CBD) the non-psychoactive component, modulate the inflammatory response. Microarray analysis of genome-wide mRNA levels was performed using Illumina platform and the resulting expression patterns analyzed using the Ingenuity Pathway Analysis to identify functional subsets of genes, and the Ingenuity System Database to denote the gene networks regulated by CBD and THC. From the 5338 transcripts that were differentially expressed across treatments, 400 transcripts were found to be upregulated by LPS, 502 by CBD+LPS and 424 by THC+LPS, while 145 were downregulated by LPS, 297 by CBD+LPS and 149 by THC+LPS, by 2-fold or more (p?0.005). Results clearly link the effects of CBD and THC to inflammatory signaling pathways and identify new cannabinoid targets in the MAPK pathway (Dusp1, Dusp8, Dusp2), cell cycle related (Cdkn2b, Gadd45a) as well as JAK/STAT regulatory molecules (Socs3, Cish, Stat1). The impact of CBD on LPS-stimulated gene expression was greater than that of THC. We attribute this difference to the fact that CBD highly upregulated several genes encoding negative regulators of both NF?B and AP-1 transcriptional activities, such as Trib3 and Dusp1 known to be modulated through Nrf2 activation. The CBD-specific expression profile reflected changes associated with oxidative stress and glutathione depletion via Trib3 and expression of ATF4 target genes. Furthermore, the CBD affected genes were shown to be controlled by nuclear factors usually involved in regulation of stress response and inflammation, mainly via Nrf2/Hmox1 axis and the Nrf2/ATF4-Trib3 pathway. These observations indicate that CBD, and less so THC, induce a cellular stress response and that this response underlies their high immunosuppressant activities. PMID:23637839

Juknat, Ana; Pietr, Maciej; Kozela, Ewa; Rimmerman, Neta; Levy, Rivka; Gao, Fuying; Coppola, Giovanni; Geschwind, Daniel; Vogel, Zvi

2013-01-01

199

Microarray and Pathway Analysis Reveal Distinct Mechanisms Underlying Cannabinoid-Mediated Modulation of LPS-Induced Activation of BV-2 Microglial Cells  

PubMed Central

Cannabinoids are known to exert immunosuppressive activities. However, the mechanisms which contribute to these effects are unknown. Using lipopolysaccharide (LPS) to activate BV-2 microglial cells, we examined how ?9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, and cannabidiol (CBD) the non-psychoactive component, modulate the inflammatory response. Microarray analysis of genome-wide mRNA levels was performed using Illumina platform and the resulting expression patterns analyzed using the Ingenuity Pathway Analysis to identify functional subsets of genes, and the Ingenuity System Database to denote the gene networks regulated by CBD and THC. From the 5338 transcripts that were differentially expressed across treatments, 400 transcripts were found to be upregulated by LPS, 502 by CBD+LPS and 424 by THC+LPS, while 145 were downregulated by LPS, 297 by CBD+LPS and 149 by THC+LPS, by 2-fold or more (p?0.005). Results clearly link the effects of CBD and THC to inflammatory signaling pathways and identify new cannabinoid targets in the MAPK pathway (Dusp1, Dusp8, Dusp2), cell cycle related (Cdkn2b, Gadd45a) as well as JAK/STAT regulatory molecules (Socs3, Cish, Stat1). The impact of CBD on LPS-stimulated gene expression was greater than that of THC. We attribute this difference to the fact that CBD highly upregulated several genes encoding negative regulators of both NF?B and AP-1 transcriptional activities, such as Trib3 and Dusp1 known to be modulated through Nrf2 activation. The CBD-specific expression profile reflected changes associated with oxidative stress and glutathione depletion via Trib3 and expression of ATF4 target genes. Furthermore, the CBD affected genes were shown to be controlled by nuclear factors usually involved in regulation of stress response and inflammation, mainly via Nrf2/Hmox1 axis and the Nrf2/ATF4-Trib3 pathway. These observations indicate that CBD, and less so THC, induce a cellular stress response and that this response underlies their high immunosuppressant activities. PMID:23637839

Juknat, Ana; Kozela, Ewa; Rimmerman, Neta; Levy, Rivka; Gao, Fuying; Coppola, Giovanni; Geschwind, Daniel; Vogel, Zvi

2013-01-01

200

Effects of phenylethanoid glycosides from Digitalis purpurea L. on the expression of inducible nitric oxide synthase.  

PubMed

We have isolated four different phenylethanoid glycosides (purpureaside A, desrhamnosyl acteoside, calceolarioside B and plantainoside D) from the leaves of Digitalis purpurea (foxglove). The effects of these glycosides on activator protein-1 (AP-1)-mediated inducible nitric oxide synthase (iNOS) gene expression in the Raw264.7 macrophage cell line have been studied. Of these four glycosides, purpureaside A potently inhibited iNOS induction by lipopolysaccharide (LPS). Increase in iNOS mRNA by LPS was completely suppressed by purpureaside A. Purpureaside A did not significantly affect LPS-inducible nuclear factor-kappaB (NF-kappaB) activation or the nuclear translocation of p65. Moreover, a reporter gene assay using AP-1 specific luciferase reporter revealed that the enhanced activity of AP-1 by LPS was completely abolished in cells treated with purpureaside A. These results demonstrated that purpureaside A inhibited LPS-inducible iNOS expression in macrophages through the suppression of AP-1, but not of NF-kappaB. PMID:15969951

Oh, Jae Wook; Lee, Jeong Yong; Han, Song Hee; Moon, Young Hee; Kim, Yoon Gyoon; Woo, Eun-Rhan; Kang, Keon Wook

2005-07-01

201

LPS-induced inflammation in the chicken is associated with CCAAT/enhancer binding protein beta-mediated fat mass and obesity associated gene down-regulation in the liver but not hypothalamus  

PubMed Central

Background The fat mass and obesity associated gene (FTO) is widely investigated in humans regarding its important roles in obesity and type 2 diabetes. Studies in mammals demonstrate that FTO is also associated with inflammation markers. However, the association of FTO with inflammation in chickens remains unclear. In this study, male chickens on day 28 posthatching were injected intraperitoneally with lipopolysaccharide (LPS) or saline to investigate whether the FTO gene is involved in LPS-induced inflammation. Results We detected significant down-regulation of FTO mRNA in the liver (P?

2013-01-01

202

SRC-FAMILY TYROSINE KINASE INHIBITOR (PP1) SUPPRESSES LPS-INDUCED EXPRESSION OF INDUCIBLE NITRIC OXIDE SYNTHASE MEDIATED THROUGH THE INHIBITION OF INTERFERON B EXPRESSION IN MACROPHAGES  

Technology Transfer Automated Retrieval System (TEKTRAN)

Bacterial lipopolysaccharide (LPS) activates Toll-like recptor (TLR4) leading to expression of inflammatory gene products. Non-receptor type Src-family tyrosine kinases are activated by LPS and associated with CD14, a co-receptor for LPS in monocytes and macrophages. Therefore, we determined the ro...

203

Recombinant tissue factor pathway inhibitor prevents lipopolysaccharide-induced systemic hypotension in rats by inhibiting excessive production of nitric oxide.  

PubMed

Excessive production of nitric oxide (NO) by the inducible form of NO synthase (iNOS) plays a key role in the development of endotoxin shock. Tumor necrosis factor-alpha (TNF-alpha) induces iNOS, thereby contributing to the development of shock. We recently reported that recombinant tissue factor pathway inhibitor (r-TFPI), an important inhibitor of the extrinsic pathway of the coagulation system, inhibits TNF-alpha production by monocytes. In this study, we investigated whether r-TFPI could ameliorate hypotension by inhibiting excessive production of NO in rats given lipopolysaccharide (LPS). Pretreatment of animals with r-TFPI prevented LPS-induced hypotension. Recombinant TFPI significantly inhibited the increases in both the plasma levels of NO2-/NO3- and lung iNOS activity 3 h after LPS administration. Expression of iNOS mRNA in the lung was also inhibited by intravenous administration of r-TFPI. However, neither DX-9065a, a selective inhibitor of factor Xa, nor an inactive derivative of factor VIIa (DEGR-F.Vlla) that selectively inhibits factor VIIa activity, had any effect on LPS-induced hypotension despite their potent anticoagulant effects. Moreover, neither the plasma levels of NO2-/NO3- nor lung iNOS activity were affected by administration of DX-9065a and DEGR-F.VIIa. These results suggested that r-TFPI ameliorates LPS-induced hypotension by reducing excessive production of NO in rats given LPS and this effect was not attributable to its anticoagulant effects, but to the inhibition of TNF-alpha production. PMID:11776329

Enkhbaatar, P; Okajima, K; Uchiba, M; Isobe, H; Okabe, H

2001-12-01

204

Inhibition of inducible nitric oxide synthase and interleukin-1? expression by tunicamycin in cultured glial cells exposed to lipopolysaccharide.  

PubMed

Endoplasmic reticulum (ER) stress has recently been implicated in human diseases such as Alzheimer?s disease (AD) and Parkinson?s disease (PD). However, the link between the immune system, ER stress, and the development of neurodegenerative diseases has not yet been clarified in detail. Mouse primary cultured astrocytes were treated with lipopolysaccharide (LPS) and/or tunicamycin (Tm), and inducible nitric oxide synthase (iNOS) and interleukin (IL)-1? levels were then measured using RT-PCR, ELISA, and Western blotting. Activation of the immune system by LPS triggered inflammatory responses in astrocytes, as measured by the induction of iNOS and IL-1?. Tm-induced ER stress inhibited the LPS-induced expression of IL-1? and iNOS at the protein level. On the other hand, ER stress alone did not induce the expression of IL-1? or iNOS. The inhibitory effect of ER stress on iNOS and IL-1? may not be mediated transcriptionally as we did not observe inhibition at the mRNA level. LPS-induced iNOS protein levels were attenuated by the Tm post-treatment in the absence of LPS. Overall, these results suggest that ER stress negatively regulates the expression of IL-1? and iNOS in LPS-activated astrocytes. PMID:24576488

Hosoi, Toru; Noguchi, Jun; Takakuwa, Misae; Honda, Miya; Okuma, Yasunobu; Nomura, Yasuyuki; Ozawa, Koichiro

2014-04-16

205

Alachlor and carbaryl suppress lipopolysaccharide-induced iNOS expression by differentially inhibiting NF-{kappa}B activation  

SciTech Connect

Nitric oxide (NO) produced by macrophages plays an important role in host defense and inflammation. We found that two agrochemicals, alachlor and carbaryl, inhibit lipopolysaccharide (LPS)-induced NO production by macrophages. In the present study, we investigated this inhibitory mechanism in RAW 264 cells. Both chemicals inhibited LPS-induced iNOS protein and mRNA expression as well as murine iNOS promoter activity. When treating these chemicals with reducing agents, the inhibition by carbaryl was reversed, but not the inhibition by alachlor. These chemicals also inhibited LPS-induced interferon-{beta} (IFN-{beta}) expression, an indispensable factor for LPS-induced iNOS expression. The inhibited iNOS expression, however, was not restored by exogenous IFN-{beta} supplementation. LPS-induced nuclear translocation of NF-{kappa}B, which is necessary for the expression of IFN-{beta} and iNOS, was inhibited by these chemicals: however, the LPS-induced degradation of I{kappa}B-{alpha} and I{kappa}B-{beta} was inhibited only by alachlor. These results indicate that alachlor and carbaryl differentially impair the LPS-induced NF-{kappa}B activation, leading to the inhibition of NO production.

Shimomura-Shimizu, Mifumi [Division of Microbiology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 (Japan); Sugiyama, Kei-ichi [Division of Microbiology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 (Japan); Muroi, Masashi [Division of Microbiology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 (Japan); Tanamoto, Ken-ichi [Division of Microbiology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 (Japan)]. E-mail: tanamoto@nihs.go.jp

2005-07-08

206

Enhancement of lipopolysaccharide-induced nitric oxide and interleukin-6 production by PEGylated gold nanoparticles in RAW264.7 cells  

NASA Astrophysics Data System (ADS)

While the immunogenicity and cytotoxicity of gold nanoparticles (AuNPs) are noted by many researchers, the mechanisms by which AuNPs exert these effects are poorly understood. In this study, we investigated the effects of polyethylene glycolylated AuNPs (PEG@AuNPs) on lipopolysaccharide (LPS)-induced nitric oxide (NO) and interleukin-6 (IL-6) production and the associated molecular mechanism in RAW264.7 cells. The results showed that PEG@AuNPs were internalized more quickly by LPS-activated RAW264.7 cells than unstimulated cells, and they reached saturation within 24 hours. PEG@AuNPs enhanced LPS-induced production of NO and IL-6 and inducible nitric oxide synthase (iNOS) expression in RAW264.7 cells, partially by activating p38 mitogen-activated protein kinases (p38 MAPK) and nuclear factor-kappaB pathways. In addition, the p38 MAPK inhibitor SB203580 attenuated PEG@AuNP-enhanced LPS-induced NO production and iNOS expression. Overproduction of NO and IL-6 is known to be closely correlated with the pathology of many diseases and inflammations. Thus, it is speculated that the highly biocompatible gold nanoparticles can induce immunotoxicity due to their potency to stimulate macrophages to release aberrant or excessive pro-inflammatory mediators.While the immunogenicity and cytotoxicity of gold nanoparticles (AuNPs) are noted by many researchers, the mechanisms by which AuNPs exert these effects are poorly understood. In this study, we investigated the effects of polyethylene glycolylated AuNPs (PEG@AuNPs) on lipopolysaccharide (LPS)-induced nitric oxide (NO) and interleukin-6 (IL-6) production and the associated molecular mechanism in RAW264.7 cells. The results showed that PEG@AuNPs were internalized more quickly by LPS-activated RAW264.7 cells than unstimulated cells, and they reached saturation within 24 hours. PEG@AuNPs enhanced LPS-induced production of NO and IL-6 and inducible nitric oxide synthase (iNOS) expression in RAW264.7 cells, partially by activating p38 mitogen-activated protein kinases (p38 MAPK) and nuclear factor-kappaB pathways. In addition, the p38 MAPK inhibitor SB203580 attenuated PEG@AuNP-enhanced LPS-induced NO production and iNOS expression. Overproduction of NO and IL-6 is known to be closely correlated with the pathology of many diseases and inflammations. Thus, it is speculated that the highly biocompatible gold nanoparticles can induce immunotoxicity due to their potency to stimulate macrophages to release aberrant or excessive pro-inflammatory mediators. Electronic supplementary information (ESI) available. See DOI: 10.1039/c2nr31355c

Liu, Zhimin; Li, Wenqing; Wang, Feng; Sun, Chunyang; Wang, Lu; Wang, Jun; Sun, Fei

2012-10-01

207

Serotonin 5HT2A receptor activation inhibits inducible nitric oxide synthase activity in C6 glioma cells.  

PubMed

C6-glioma cells endogenously express both 5HT2A receptors and inducible nitric oxide synthase (iNOS). iNOS can be induced by transcriptional activation to produce nitric oxide (NO) in response to a challenge with lipopolysaccharide (LPS). Experiments were conducted to determine whether 5HT2A receptor activation could modify the production of NO in response to LPS. Incubation of 10 microg/ml LPS with C6-glioma cells for a period of 24 hours resulted in a 2.6 fold increase in nitrite levels, as a measure of NO levels, over vehicle treated controls. Co-incubation with the selective 5HT2A receptor partial agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) produced a dose-dependent inhibition of the LPS-induced nitrite levels of 22% with an IC50 of 16 nM. The full agonists serotonin (5HT) and alpha-methyl-5HT produced an inhibition of approximately 30% at a concentration of 1 microM. The inhibitory effect of 1 microM DOI was blocked by the 5HT2A receptor antagonists spiperone and ritanserin (10 nM). Inhibition of protein kinase C (PKC) using 100 nM chelerythrine prevented the DOI-mediated decrease in LPS-induced nitrite levels. Addition of DOI to the cells after 1 hr following the LPS addition did not produce a decrease in nitrite levels indicating iNOS was not modified post-translationally. The data demonstrate that iNOS activity can be modulated by serotonin 5HT2A receptor activation, most likely at the initiation of the induction process, via PKC. We therefore suggest that there may be a link between the serotonergic system and NO-mediated immune responses in the brain. PMID:9365229

Miller, K J; Mariano, C L; Cruz, W R

1997-01-01

208

Isobutyrylshikonin inhibits lipopolysaccharide-induced nitric oxide and prostaglandin E2 production in BV2 microglial cells by suppressing the PI3K/Akt-mediated nuclear transcription factor-?B pathway.  

PubMed

Microglia are important macrophages to defend against pathogens in the central nervous system (CNS); however, persistent or acute inflammation of microglia lead to CNS disorders via neuronal cell death. Therefore, we theorized that a good strategy for the treatment of CNS disorders would be to target inflammatory mediators from microglia in disease. Consequently, we investigated whether isobutyrylshikonin (IBS) attenuates the production of proinflammatory mediators, such as nitric oxide (NO) and prostaglandin E2, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Treatment with IBS inhibited the secretion of NO and prostaglandin E2 (as well as the expression of their key regulatory genes), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2). Isobutyrylshikonin also suppressed LPS-induced DNA-binding activity of nuclear transcription factor-?B (NF-?B), by inhibiting the nuclear translocation of p50 and p65 in addition to blocking the phosphorylation and degradation of I?B?. Pretreatment with pyrrolidine dithiocarbamate, a specific NF-?B inhibitor, showed the down-regulation of LPS-induced iNOS and COX-2 messenger RNA by suppressing NF-?B activity. This indirectly suggests that IBS-mediated NF-?B inhibition is the main signaling pathway involved in the inhibition of iNOS and COX-2 expression. In addition, IBS attenuated LPS-induced phosphorylation of PI3K and Akt, which are upstream molecules of NF-?B, in LPS-stimulated BV2 microglial cells. The functional aspects of the PI3K/Akt signaling pathway were analyzed with LY294002, which is a specific PI3K/Akt inhibitor that attenuated LPS-induced iNOS and COX-2 expression by suppressing NF-?B activity. These data suggest that an IBS-mediated anti-inflammatory effect may be involved in suppressing the PI3K/Akt-mediated NF-?B signaling pathway. PMID:25454762

Jayasooriya, Rajapaksha Gedara Prasad Tharanga; Lee, Kyoung-Tae; Kang, Chang-Hee; Dilshara, Matharage Gayani; Lee, Hak-Ju; Choi, Yung Hyun; Choi, Il-Whan; Kim, Gi-Young

2014-12-01

209

The NADPH oxidase inhibitor apocynin induces nitric oxide synthesis via oxidative stress  

SciTech Connect

We have recently shown that apocynin elicits an oxidative stress in N11 mouse glial cells and other cell types. Here we report that apocynin increased the accumulation of nitrite, the stable derivative of nitric oxide (NO), in the extracellular medium of N11 cell cultures, and the NO synthase (NOS) activity in cell lysates. The increased synthesis of NO was associated with increased expression of inducible NOS (iNOS) mRNA, increased nuclear translocation of the redox-sensitive transcription factor NF-{kappa}B and decreased intracellular level of its inhibitor IkB{alpha}. These effects, accompanied by increased production of H{sub 2}O{sub 2}, were very similar to those observed after incubation with bacterial lipopolysaccharide (LPS) and were inhibited by catalase. These results suggest that apocynin, similarly to LPS, induces increased NO synthesis by eliciting a generation of reactive oxygen species (ROS), which in turn causes NF-{kappa}B activation and increased expression of iNOS. Therefore, the increased bioavailability of NO reported in the literature after in vivo or in vitro treatments with apocynin might depend, at least partly, on the drug-elicited induction of iNOS, and not only on the inhibition of NADPH oxidase and the subsequent decreased scavenging of NO by oxidase-derived ROS, as it is often supposed.

Riganti, Chiara [Dipartimento di Genetica, Biologia e Biochimica, Universita di Torino, Via Santena 5/bis, 10126 Torino (Italy)], E-mail: chiara.riganti@unito.it; Costamagna, Costanzo; Doublier, Sophie; Miraglia, Erica; Polimeni, Manuela; Bosia, Amalia; Ghigo, Dario [Dipartimento di Genetica, Biologia e Biochimica, Universita di Torino, Via Santena 5/bis, 10126 Torino (Italy)

2008-05-01

210

Anti-angiogenic and inhibitory activity on inducible nitric oxide production of the mushroom Ganoderma lucidum  

Microsoft Academic Search

Fresh fruit bodies of Ganoderma lucidum were extracted with 70% ethanol at room temperature. The extract (GL) showed significant anti-angiogenic activity, which was detected using a chick embryo chorioallantoic membrane assay. GL significantly inhibited LPS-induced NO production in RAW 264.7 macrophages. These results support the anti-tumor effect of Ganoderma lucidum.

Yun Seon Song; Sun-Hyoung Kim; Jae-Hoon Sa; Changbae Jin; Chang-Jin Lim; Eun-Hee Park

2004-01-01

211

Bauer Ketones 23 and 24 from Echinacea paradoxa var. paradoxa Inhibit Lipopolysaccharide-induced Nitric Oxide, Prostaglandin E2 and Cytokines in RAW 264.7 Mouse Macrophages  

PubMed Central

Among the nine Echinacea species, E. purpurea, E. angustifolia and E. pallida, have been widely used to treat the common cold, flu and other infections. In our study, ethanol extracts of these three Echinacea species and E. paradoxa, including its typical variety, E. paradoxa var. paradoxa, were screened in lipopolysaccharide (LPS)-stimulated macrophage cells to assess potential anti-inflammatory activity. Echinacea paradoxa var. paradoxa, rich in polyenes/polyacetylenes, was an especially efficient inhibitor of LPS-induced production of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-1 beta (IL-1?) and interleukin-6 (IL-6) by 46%, 32%, 53% and 26%, respectively, when tested at 20 ?g/ml in comparison to DMSO control. By bioactivity-guided fractionation, pentadeca-8Z-ene-11, 13-diyn-2-one (Bauer ketones 23, compound 1) and pentadeca-8Z, 13Z-dien-11-yn-2-one (Bauer ketone 24, compound 2) from E. paradoxa var. paradoxa were found primarily responsible for inhibitory effects on NO and PGE2 production. Moreover, Bauer ketone 24 (compound 2) was the major contributor to inhibition of inflammatory cytokine production in LPS-induced mouse macrophage cells. These results provide a rationale for exploring the medicinal effects of the Bauer ketone-rich taxon, E. paradoxa var. paradoxa, and confirm the anti-inflammatory properties of Bauer ketones 23 and 24. PMID:22133644

Zhang, Xiaozhu; Rizshsky, Ludmila; Hauck, Catherine; Qu, Luping; Widrlechner, Mark P.; Nikolau, Basil J.; Murphy, Patricia A.; Birt, Diane F.

2011-01-01

212

Fucosterol isolated from Undaria pinnatifida inhibits lipopolysaccharide-induced production of nitric oxide and pro-inflammatory cytokines via the inactivation of nuclear factor-?B and p38 mitogen-activated protein kinase in RAW264.7 macrophages.  

PubMed

It has been reported that fucosterol has anti-diabetic, anti-oxidant, and anti-osteoporotic effects. We investigated the anti-inflammatory effects and the underlying molecular mechanism of fucosterol in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Fucosterol suppressed the expressions of inducible nitric oxide synthase (iNOS), tumour necrosis factor-? (TNF-?), and interleukin-6 (IL-6) by downregulating their transcriptions, and subsequently inhibited the productions of nitric oxide, TNF-?, and IL-6. In addition, fucosterol attenuated LPS-induced DNA binding and the transcriptional activity of nuclear factor-?B (NF-?B). These reductions were accompanied by parallel reductions in the phosphorylation and nuclear translocation of NF-?B. Furthermore, fucosterol attenuated the phosphorylations of mitogen-activated protein kinase kinases 3/6 (MKK3/6) and mitogen-activated protein kinase-activated protein kinase 2 (MK2), which are both involved in the p38 MAPK pathway. These results suggest that the anti-inflammatory effects of fucosterol are associated with the suppression of the NF-?B and p38 MAPK pathways. PMID:22953812

Yoo, Min-Sang; Shin, Ji-Sun; Choi, Hye-Eun; Cho, Young-Wuk; Bang, Myun-Ho; Baek, Nam-In; Lee, Kyung-Tae

2012-12-01

213

Wogonin but not Nor-wogonin inhibits lipopolysaccharide and lipoteichoic acid-induced iNOS gene expression and NO production in macrophages  

Microsoft Academic Search

Wogonin (Wog; 5,7-dihydroxy-8-methoxy flavone) has been shown to effectively inhibit lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) gene expression and nitric oxide production in our previous study. In the present study, we found that Nor-wogonin (N-Wog; 5,7,8-trihydroxyl flavone), a structural analogue of Wog with an OH substitution at C8, performed different effect on LPS- or lipoteichoic acid (LTA)-induced iNOS gene

Guan-Cheng Huang; Jyh-Ming Chow; Shing-Chuan Shen; Liang-Yo Yang; Cheng-Wei Lin; Yen-Chou Chen

2007-01-01

214

Atypical “seizure-like” activity in cortical reverberating networks in vitro can be caused by LPS-induced inflammation: a multi-electrode array study from a hundred neurons  

PubMed Central

We show here that a mild sterile inflammation induced by the endotoxin lipopolysaccharide (LPS), in a neuron/astrocyte/microglial cortical network, modulates neuronal excitability and can initiate long-duration burst events resembling epileptiform seizures, a recognized feature of various central nervous neurodegenerative, neurological and acute systemic diseases associated with neuroinflammation. To study this action, we simultaneously analyzed the reverberating bursting activity of a hundred neurons by using in vitro multi-electrode array methods. ?5 h after LPS application, we observed a net increase in the average number of spikes elicited in engaged cells and within each burst, but no changes neither in spike waveforms nor in burst rate. This effect was characterized by a slow, twofold exponential increase of the burst duration and the appearance of rarely occurring long burst events that were never seen during control recordings. These changes and the time-course of microglia-released proinflammatory cytokine, tumor necrosis factor-alpha (TNF-?), were blocked by pre-treatment with 50 nM minocycline, an established anti-inflammatory agent which was inactive when applied alone. Assay experiments also revealed that application of 60 pM exogenous TNF-? after 12–15 h, produced non-washable changes of neuronal excitability, completely different from those induced by LPS, suggesting that TNF-? release alone was not responsible for our observed findings. Our results indicate that the link between neuroinflammation and hyperexcitability can be unveiled by studying the long-term activity of in vitro neuronal/astrocyte/microglial networks. PMID:25404893

Gullo, Francesca; Amadeo, Alida; Donvito, Giulia; Lecchi, Marzia; Costa, Barbara; Constanti, Andrew; Wanke, Enzo

2014-01-01

215

Selenium Attenuates Lipopolysaccharide-Induced Oxidative Stress Responses Through Modulation of p38 MAPK and NF-jB Signaling Pathways  

Microsoft Academic Search

Lipopolysaccharide (LPS) produces reactive oxygen species (ROS) and nitric oxide (NO) in macrophages. These molecules are involved in inflammation associated with endotoxic shock. Selenium (Se), a biologically essential trace element, modulates the functions of many regulatory proteins involved in signal transduction and affects a variety of cellular activities, including cell growth and survival. We demonstrate that Se attenuated LPS-induced ROS

SANG HYUN KIM; VICTOR J. JOHNSON; TAE-YONG SHIN; RAGHUBIR P. SHARMA

216

Endotoxin-induced nitric oxide production rescues airway growth and maturation in atrophic fetal rat lung explants  

SciTech Connect

Inflammation induces premature maturation of the fetal lung but the signals causing this effect remain unclear. We determined if nitric oxide (NO) synthesis, evoked by Escherichia coli lipopolysaccharide (LPS, 2 {mu}g ml{sup -1}), participated in this process. Fetal rat lung airway surface complexity rose 2.5-fold over 96 h in response to LPS and was associated with increased iNOS protein expression and activity. iNOS inhibition by N6-(1-iminoethyl)-L-lysine-2HCl (L-NIL) abolished this and induced airway atrophy similar to untreated explants. Surfactant protein-C (SP-C) expression was also induced by LPS and abolished by L-NIL. As TGF{beta} suppresses iNOS activity, we determined if feedback regulation modulated NO-dependent maturation. LPS induced TGF{beta}1 release and SMAD4 nuclear translocation 96 h after treatment. Treatment of explants with a blocking antibody against TGF{beta}1 sustained NO production and airway morphogenesis whereas recombinant TGF{beta}1 antagonized these effects. Feedback regulation of NO synthesis by TGF{beta} may, thus, modulate airway branching and maturation of the fetal lung.

Rae, C. [Division of Maternal and Child Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY Scotland (United Kingdom); Cherry, J.I. [Division of Maternal and Child Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY Scotland (United Kingdom); Land, F.M. [Division of Maternal and Child Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY Scotland (United Kingdom); Land, S.C. [Division of Maternal and Child Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY Scotland (United Kingdom)]. E-mail: s.c.land@dundee.ac.uk

2006-10-13

217

Nitric oxide inhibits tissue factor synthesis, expression and activity in human monocytes by prior formation of peroxynitrite  

Microsoft Academic Search

Objective: Nitric oxide (NO) has antithrombotic properties by regulating platelet function, whereas direct effects on plasmatic coagulation\\u000a are rarely described. In sepsis and inflammation, when synthesis of NO, oxygen radicals and toxic metabolites is crucial,\\u000a the expression of tissue factor (TF) on monocytes stimulated by lipopolysaccharides (LPS) induces intravascular coagulation.\\u000a This study was performed to examine the influence of NO

M. Gerlach; D. Keh; G. Bezold; S. Spielmann; I. Kürer; R. U. Peter; K. J. Falke; H. Gerlach

1998-01-01

218

Asymmetric dimethylarginine regulates the lipopolysaccharide-induced nitric oxide production in macrophages by suppressing the activation of NF-kappaB and iNOS expression.  

PubMed

Two major effector systems are frequently implicated in the immune and endothelial cell alternations associated with inflammation. They include the enhanced production of reactive oxygen species and diminished bioavailability of nitric oxide (NO). Importantly, these processes can be regulated by endogenously produced methylarginines, inhibitors for NO derived from macrophages and endothelial cells. Therefore, the aim of this study was to show the potential pharmacological intervention of methylarginines (N(G)-methyl-L-arginine, L-NMMA; N(G), N(G)'-dimethyl-L-arginine-symmetric dimethylarginine, SDMA; and N(G), N(G)-dimethyl-L-arginine-asymmetric dimethylarginine, ADMA) in activation of murine peritoneal (RAW 264.7) and alveolar (MHS) macrophages with lipopolysaccharide from Gram-negative bacteria (LPS). The data presented in this study clearly declare that L-NMMA (1-50?M) and ADMA (10-50 ?M) significantly inhibited the LPS-induced NO production from macrophages in a concentration-dependent manner. It was demonstrated, for the first time, that the ADMA- and L-NMMA-induced down regulation of NO production was accompanied by reduced expression of mRNA and protein for inducible NO synthase as well as decreased activation of nuclear factor-?B. Importantly, we found a negative correlation between the ADMA-dependent reduction of NO production and ADMA-increased superoxide formation, which indicates that ADMA can negatively affect the balance in LPS-induced macrophage-derived production of reactive mediators. The only effect of SDMA was observed for LPS-triggered superoxide production, which was significantly decreased in its highest concentration (50 ?M). In summary, L-NMMA and ADMA can mediate their effects on macrophage activation via regulation of intracellular signaling pathways, which can affect critical functions in activated macrophages. PMID:23665490

Pekarova, Michaela; Kubala, Lukas; Martiskova, Hana; Bino, Lucia; Twarogova, Michaela; Klinke, Anna; Rudolph, Tanja K; Kuchtova, Zdenka; Kolarova, Hana; Ambrozova, Gabriela; Kuchta, Radek; Kadlec, Jaroslav; Lojek, Antonin

2013-08-01

219

TGF-beta 1 inhibits both endotoxin-induced prostaglandin synthesis and expression of the TIS10/prostaglandin synthase 2 gene in murine macrophages.  

PubMed

Activated macrophages produce substantial quantities of paracrine mediators, including cytokines, nitric oxide, and prostaglandins. Transforming growth factor beta 1 (TGF-beta) is a potent modulator of immune function. TGF-beta inhibits the cytotoxic activity of endotoxin/lipopolysaccharide (LPS)-activated macrophage cell lines and primary macrophage cultures, reducing their expression of cytokines and nitric oxide. In this report we demonstrate that TGF-beta also attenuates the LPS-induced synthesis and secretion of prostaglandin E2 in murine RAW 264.7 macrophage cells. Macrophage activation also induces accumulation of the recently described ligand-responsive prostaglandin synthase (PGS) TIS10/PGS-2. While TGF-beta alone has no effect on expression from the TIS10/PGS-2 gene, this cytokine inhibits LPS-induced TIS10/PGS-2 protein accumulation and synthesis, as well as LPS-induced TIS10/PGS-2 message accumulation in RAW 264.7 cells. TGF-beta concentrations in the range of 0.1-1.0 ng/ml (4-40 pM) maximally inhibit LPS-induced TIS10/PGS-2 message accumulation. In contrast, neither LPS nor TGF-beta has any effect on the level of PGS-1 (EC 1.14.99.1) message. TGF-beta also attenuates LPS-induced accumulation of unspliced TIS10/PGS-2 transcripts in RAW 264.7 cells, suggesting that this cytokine exerts its effects on TIS10/PGS-2 expression at the transcriptional level. TGF-beta inhibits the LPS-induced accumulation of TIS10/PGS-2 protein and message in cultured murine peritoneal macrophages, as well as in macrophage cell lines. PMID:8301216

Reddy, S T; Gilbert, R S; Xie, W; Luner, S; Herschman, H R

1994-02-01

220

Preparation and biological evaluation of enzyme-assisted extracts from edible seaweed (Enteromorpha prolifera) as antioxidant, anti-acetylcholinesterase and inhibition of lipopolysaccharide-induced nitric oxide production in murine macrophages.  

PubMed

The multifunctional bioactive materials were prepared from Enteromorpha prolifera by enzyme-assisted extraction using four proteases and seven carbohydrases, and the biological activities of the enzyme-assisted extracts were evaluated as antioxidant, anti-acetylcholinesterase (AChE) and anti-inflammatory effect as the measures of inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells. The enzyme-assisted extracts were rich in polyphenols in the range 124 ± 4.2 to 844 ± 9.1 mg/100 g and flavonoids in the range 453 ± 6.0 to 675 ± 5.2 mg/100 g, and Protamex and Viscozyme extracts, which were rich in polyphenols and flavonoids, showed the highest 2,2-diphenyl-1-picrylhydrazyl scavenging, hydrogen peroxide scavenging, ferrous ion chelating and reducing power. Flavourzyme extract (89.92%) and Promozyme extract (93.64%) showed the highest AChE inhibitory activities at the concentration of 1.0 mg/ml. All enzyme-assisted extracts showed no cytotoxic effect on RAW264.7 cells at the tested concentration and significantly inhibited the LPS-induced NO production in RAW264.7 cells. PMID:21913802

Ahn, Chang-Bum; Park, Pyo-Jam; Je, Jae-Young

2012-03-01

221

Cytotoxicity and inhibition of nitric oxide in lipopolysaccharide induced mammalian cell lines by aqueous extracts of brown seaweed.  

PubMed

Aqueous extracts obtained from five Malaysian brown seaweeds, Sargassum duplicatum, Sargassum binderi, Sargassum fulvellum, Padina australis, and Turbinaria turbinata, were investigated for their abilities to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-induced macrophage RAW 264.7 cell lines as well as to determine their chemical composition. The percentage yield of extracts varied among species, with P. australis having the lowest yield and T. turbinata having the highest yield. The chemical compositions of the extracts showed that the percentage of sulfate ions as well as uronic acid and total sugar content varied significantly. All extracts contained high fucose and inhibited NO secretion in a dose-dependent manner. Extracts of P. australis and T. turbinata dosed at 200 ?g/mL were able to inhibit NO secretion by > 75%. Furthermore, cytotoxicity assays revealed that some extracts were moderately toxic, while others were not. Based on these results, brown seaweed of Malaysian origin should be investigated for the production of additional anti-inflammatory compounds. PMID:25007746

Jaswir, Irwandi; Monsur, Hammed Ademola; Simsek, Senay; Amid, Azura; Alam, Zahangir; bin Salleh, Mohammad Noor; Tawakalit, Asiyanbi-Hammed; Octavianti, Fitri

2014-01-01

222

Protective effects of agmatine against D-galactosamine and lipopolysaccharide-induced fulminant hepatic failure in mice.  

PubMed

Fulminant hepatic failure (FHF) is a life-threatening syndrome characterized by massive hepatic necrosis and high mortality. There is no effective therapy for the disease other than liver transplantation. This study aimed to investigate the effect of agmatine, inducible nitric oxide synthase (iNOS) inhibitor, on D-galactosamine and lipopolysaccharide (GalN/LPS)-induced FHF in mice and explore its possible mechanism(s). Male Swiss albino mice were injected with a single dose agmatine (14 mg/kg, IP) 8 h prior to challenge with a single intraperitoneal injection of both GalN (800 mg/kg) and LPS (50 ?g/kg). Agmatine significantly attenuated all GalN/LPS-induced biochemical and pathological changes in liver. It prevented the increase of serum transaminases and alkaline phosphatase (ALP). In addition, agmatine markedly attenuated GalN/LPS-induced necrosis and inflammation. Agmatine significantly reduced oxidative stress and enhanced antioxidant enzymes. Importantly, agmatine decreased total nitric oxide (NO) and pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-?). These findings reveal that agmatine has hepatoprotective effects against GalN/LPS-induced FHF in mice that may be related to its ability to suppress oxidative stress, NO synthesis and TNF-? production. Therefore, agmatine may serve as a novel therapeutic strategy for hepatic inflammatory diseases. PMID:23989863

El-Agamy, Dina S; Makled, Mirhan N; Gamil, Nareman M

2014-06-01

223

Rosmarinic acid in Prunella vulgaris ethanol extract inhibits lipopolysaccharide-induced prostaglandin E2 and nitric oxide in RAW 264.7 mouse macrophages.  

PubMed

Prunella vulgaris has been used therapeutically for inflammation-related conditions for centuries, but systematic studies of its anti-inflammatory activity are lacking and no specific active components have been identified. In this study, water and ethanol extracts of four P. vulgaris accessions were applied to RAW 264.7 mouse macrophages, and the ethanol extracts significantly inhibited lipopolysaccharide (LPS)-stimulated prostaglandin E2 (PGE2) and nitric oxide (NO) production at 30 microg/mL without affecting cell viability. Extracts from different accessions of P. vulgaris were screened for anti-inflammatory activity to identify accessions with the greatest activity. The inhibition of PGE2 and NO production by selected extracts was dose-dependent, with significant effects seen at concentrations as low as 10 microg/mL. Fractionation of ethanol extracts from the active accession, Ames 27664, suggested fractions 3 and 5 as possible major contributors to the overall activity. Rosmarinic acid (RA) content in P. vulgaris was found to independently inhibit inflammatory response, but it only partially explained the extracts' activity. LPS-induced cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS) protein expression were both attenuated by P. vulgaris ethanol extracts, whereas RA inhibited only COX-2 expression. PMID:19919113

Huang, Nan; Hauck, Cathy; Yum, Man-Yu; Rizshsky, Ludmila; Widrlechner, Mark P; McCoy, Joe-Ann; Murphy, Patricia A; Dixon, Philip M; Nikolau, Basil J; Birt, Diane F

2009-11-25

224

Catecholamines?? Enhancement of Inducible Nitric Oxide Synthase-Induced Nitric Oxide Biosynthesis Involves CAT1 and CAT2A  

Microsoft Academic Search

Catecholamines enhance inducible nitric oxide syn- thase (iNOS) expression that results in nitric oxide (NO) overproduction in lipopolysaccharide (LPS)- stimulated macrophages. L-arginine transport medi- ated by cationic amino acid transporters (including CAT-1, CAT-2, CAT-2A, and CAT-2B) is crucial in regulating iNOS activity. We sought to assess the ef- fects of catecholamines on L-arginine transport and CATisozymeexpressioninstimulatedmacrophages. Confluent RAW264.7 cells were

Wen-Chou Lin; Pei-Shan Tsai; Chun-Jen Huang

2005-01-01

225

Protective Effect of Naringenin Against Lipopolysaccharide-Induced Injury in Normal Human Bronchial Epithelium via Suppression of MAPK Signaling.  

PubMed

The present study aimed to evaluate the effect of naringenin on protection in lipopolysaccharide (LPS)-induced injury in normal human bronchial epithelium (NHBE) and to provide insights into the possible underlying mechanisms. NHBE were stimulated by LPS in the presence or absence of the narigenin. In vitro treatment with naringenin led to a significant attenuation in the LPS-induced NHBE secretion of tumor necrosis factor alpha (TNF-?), interleukin-6 (IL-6), superoxidase dismutase (SOD), nitricoxide synthase (NOS), myeloperoxidase (MPO), and nitric oxide (NO). RT-qPCR demonstrated that naringenin significantly reduced the LPS-induced upregulation of TNF-?, IL-6, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) p65 mRNA expression in a dose-dependent manner. Additionally, Western blot analysis revealed that naringenin effectively suppressed NF-?B activation by inhibiting the degradation of I?B-? and the translocation of p65. Naringenin also attenuated mitogen-activated protein kinase (MAPK) activation by inhibiting the phosphorylation of ERK1/2, c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK. Taken together, these demonstrate that naringenin reduces TNF-? and IL-6 secretion and mRNA expression, possibly by blocking the activation of the NF-?B and MAPK signaling pathways in LPS-treated NHBE. These results indicated that naringenin had a protective effect on LPS-induced injury in NHBE. PMID:25303878

Yu, Dan-Hong; Ma, Chun-Hua; Yue, Zhi-Qiang; Yao, Xin; Mao, Chen-Mei

2014-10-11

226

Subtilase cytotoxin enhances Escherichia coli survival in macrophages by suppression of nitric oxide production through the inhibition of NF-?B activation.  

PubMed

Subtilase cytotoxin (SubAB), which is produced by certain strains of Shiga-toxigenic Escherichia coli (STEC), cleaves an endoplasmic reticulum (ER) chaperone, BiP/Grp78, leading to induction of ER stress and caspase-dependent apoptosis. SubAB alters the innate immune response. SubAB pretreatment of macrophages inhibited lipopolysaccharide (LPS)-induced production of both monocyte chemoattractant protein 1 (MCP-1) and tumor necrosis factor ? (TNF-?). We investigated here the mechanism by which SubAB inhibits nitric oxide (NO) production by mouse macrophages. SubAB suppressed LPS-induced NO production through inhibition of inducible NO synthase (iNOS) mRNA and protein expression. Further, SubAB inhibited LPS-induced I?B-? phosphorylation and nuclear localization of the nuclear factor-?B (NF-?B) p65/p50 heterodimer. Reporter gene and chromatin immunoprecipitation (ChIP) assays revealed that SubAB reduced LPS-induced NF-?B p65/p50 heterodimer binding to an NF-?B binding site on the iNOS promoter. In contrast to the native toxin, a catalytically inactivated SubAB mutant slightly enhanced LPS-induced iNOS expression and binding of NF-?B subunits to the iNOS promoter. The SubAB effect on LPS-induced iNOS expression was significantly reduced in macrophages from NF-?B1 (p50)-deficient mice, which lacked a DNA-binding subunit of the p65/p50 heterodimer, suggesting that p50 was involved in SubAB-mediated inhibition of iNOS expression. Treatment of macrophages with an NOS inhibitor or expression of SubAB by E. coli increased E. coli survival in macrophages, suggesting that NO generated by macrophages resulted in efficient killing of the bacteria and SubAB contributed to E. coli survival in macrophages. Thus, we hypothesize that SubAB might represent a novel bacterial strategy to circumvent host defense during STEC infection. PMID:22949549

Tsutsuki, Hiroyasu; Yahiro, Kinnosuke; Suzuki, Kotaro; Suto, Akira; Ogura, Kohei; Nagasawa, Sayaka; Ihara, Hideshi; Shimizu, Takeshi; Nakajima, Hiroshi; Moss, Joel; Noda, Masatoshi

2012-11-01

227

Subtilase Cytotoxin Enhances Escherichia coli Survival in Macrophages by Suppression of Nitric Oxide Production through the Inhibition of NF-?B Activation  

PubMed Central

Subtilase cytotoxin (SubAB), which is produced by certain strains of Shiga-toxigenic Escherichia coli (STEC), cleaves an endoplasmic reticulum (ER) chaperone, BiP/Grp78, leading to induction of ER stress and caspase-dependent apoptosis. SubAB alters the innate immune response. SubAB pretreatment of macrophages inhibited lipopolysaccharide (LPS)-induced production of both monocyte chemoattractant protein 1 (MCP-1) and tumor necrosis factor ? (TNF-?). We investigated here the mechanism by which SubAB inhibits nitric oxide (NO) production by mouse macrophages. SubAB suppressed LPS-induced NO production through inhibition of inducible NO synthase (iNOS) mRNA and protein expression. Further, SubAB inhibited LPS-induced I?B-? phosphorylation and nuclear localization of the nuclear factor-?B (NF-?B) p65/p50 heterodimer. Reporter gene and chromatin immunoprecipitation (ChIP) assays revealed that SubAB reduced LPS-induced NF-?B p65/p50 heterodimer binding to an NF-?B binding site on the iNOS promoter. In contrast to the native toxin, a catalytically inactivated SubAB mutant slightly enhanced LPS-induced iNOS expression and binding of NF-?B subunits to the iNOS promoter. The SubAB effect on LPS-induced iNOS expression was significantly reduced in macrophages from NF-?B1 (p50)-deficient mice, which lacked a DNA-binding subunit of the p65/p50 heterodimer, suggesting that p50 was involved in SubAB-mediated inhibition of iNOS expression. Treatment of macrophages with an NOS inhibitor or expression of SubAB by E. coli increased E. coli survival in macrophages, suggesting that NO generated by macrophages resulted in efficient killing of the bacteria and SubAB contributed to E. coli survival in macrophages. Thus, we hypothesize that SubAB might represent a novel bacterial strategy to circumvent host defense during STEC infection. PMID:22949549

Tsutsuki, Hiroyasu; Suzuki, Kotaro; Suto, Akira; Ogura, Kohei; Nagasawa, Sayaka; Ihara, Hideshi; Shimizu, Takeshi; Nakajima, Hiroshi; Moss, Joel; Noda, Masatoshi

2012-01-01

228

Acanthopanax koreanum Fruit Waste Inhibits Lipopolysaccharide-Induced Production of Nitric Oxide and Prostaglandin E2 in RAW 264.7 Macrophages  

PubMed Central

The Acanthopanax koreanum fruit is a popular fruit in Jeju Island, but the byproducts of the alcoholic beverage prepared using this fruit are major agricultural wastes. The fermentability of this waste causes many economic and environmental problems. Therefore, we investigated the suitability of using A. koreanum fruit waste (AFW) as a source of antiinflammatory agents. AFWs were extracted with 80% EtOH. The ethanolic extract was then successively partitioned with hexane, CH2Cl2, EtOAc, BuOH, and water. The results indicate that the CH2Cl2 fraction (100 ?g/mL) of AFW inhibited the LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in RAW 264.7 cells by 79.6% and 39.7%, respectively. These inhibitory effects of the CH2Cl2 fraction of AFWs were accompanied by decreases in the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins and iNOS and COX-2 mRNA in a dose-dependent pattern. The CH2Cl2 fraction of AFWs also prevented degradation of I?B-? in a dose-dependent manner. Ursolic acid was identified as major compound present in AFW, and CH2Cl2 extracts by high performance liquid chromatography (HPLC). Furthermore using pure ursolic acid as standard and by HPLC, AFW and CH2Cl2 extracts was found to contain 1.58?mg/g and 1.75?mg/g, respectively. Moreover, we tested the potential application of AFW extracts as a cosmetic material by performing human skin primary irritation tests. In these tests, AFW extracts did not induce any adverse reactions. Based on these results, we suggest that AFW extracts be considered possible anti-inflammatory candidates for topical application. PMID:20368786

Yang, Eun-Jin; Moon, Ji-Young; Lee, Jung-Soon; Koh, Jaesook; Lee, Nam Ho; Hyun, Chang-Gu

2010-01-01

229

Melatonin ameliorates brain injury induced by systemic lipopolysaccharide in neonatal rats.  

PubMed

Our previous study showed that lipopolysaccharide (LPS)-induced brain injury in the neonatal rat is associated with nitrosative and oxidative stress. The present study was conducted to examine whether melatonin, an endogenous molecule with antioxidant properties, reduces systemic LPS-induced nitrosative and oxidative damage in the neonatal rat brain. Intraperitoneal (i.p.) injection of LPS (2mg/kg) was administered to Sprague-Dawley rat pups on postnatal day 5 (P5), and i.p. administration of melatonin (20mg/kg) or vehicle was performed 5min after LPS injection. Sensorimotor behavioral tests were performed 24h after LPS exposure, and brain injury was examined after these tests. The results show that systemic LPS exposure resulted in impaired sensorimotor behavioral performance, and acute brain injury, as indicated by the loss of oligodendrocyte immunoreactivity and a decrease in mitochondrial activity in the neonatal rat brain. Melatonin treatment significantly reduced LPS-induced neurobehavioral disturbances and brain damage in neonatal rats. The neuroprotective effect of melatonin was associated with attenuation of LPS-induced nitrosative and oxidative stress, as indicated by the decreased nitrotyrosine- and 4-hydroxynonenal-positive staining in the brain following melatonin and LPS exposure in neonatal rats. Further, melatonin significantly attenuated LPS-induced increases in the number of activated microglia in the neonatal rat brain. The protection provided by melatonin was also associated with a reduced number of inducible nitric oxide synthase (iNOS)+ cells, which were double-labeled with ED1 (microglia). Our results show that melatonin prevents the brain injury and neurobehavioral disturbances induced by systemic LPS exposure in neonatal rats, and its neuroprotective effects are associated with its impact on nitrosative and oxidative stress. PMID:24613717

Wong, C-S; Jow, G-M; Kaizaki, A; Fan, L-W; Tien, L-T

2014-05-16

230

UV Induced Oxidation of Nitric Oxide  

NASA Technical Reports Server (NTRS)

Nitric oxide in a gaseous stream is converted to nitrogen dioxide using oxidizing species generated at least in part using in situ UV radiation sources. The sources of the oxidizing species include oxygen and/or hydrogen peroxide. The oxygen may be a component of the gaseous stream or added to the gaseous stream, preferably near a UV radiation source, and is converted to ozone by the UV irradiation. The hydrogen peroxide is decomposed through a combination of vaporization and UV irradiation. The hydrogen peroxide is preferably stored at stable concentration levels, i.e., approximately 50% by volume and increased in concentration in a continuous process preceding vaporization within the flow channel of the gaseous stream and in the presence of the UV radiation sources.

Parrish, Clyde, F. (Inventor); Luecke, Dale E. (Inventor)

2007-01-01

231

Nitric Oxide Mediates Relative Airway Hyporesponsiveness to Lipopolysaccharide in Surfactant Protein A–Deficient Mice  

PubMed Central

Surfactant protein A (SP-A) mediates innate immune cell responses to LPS, a cell wall component of gram-negative bacteria that is found ubiquitously in the environment and is associated with adverse health effects. Inhaled LPS induces lung inflammation and increases airway responsiveness (AR). However, the role of SP-A in mediating LPS-induced AR is not well-defined. Nitric oxide (NO) is described as a potent bronchodilator, and previous studies showed that SP-A modulates the LPS-induced production of NO. Hence, we tested the hypothesis that increased AR, observed in response to aerosolized LPS exposure, would be significantly reduced in an SP-A–deficient condition. Wild-type (WT) and SP-A null (SP-A?/?) mice were challenged with aerosolized LPS. Results indicate that despite similar inflammatory indices, LPS-treated SP-A?/? mice had attenuated AR after methacholine challenge, compared with WT mice. The attenuated AR could not be attributed to inherent differences in SP-D concentrations or airway smooth muscle contractile and relaxation properties, because these measures were similar between WT and SP-A?/? mice. LPS-treated SP-A?/? mice, however, had elevated nitrite concentrations, inducible nitric oxide synthase (iNOS) expression, and NOS activity in their lungs. Moreover, the administration of the iNOS-specific inhibitor 1400W completely abrogated the attenuated AR. Thus, when exposed to aerosolized LPS, SP-A?/? mice demonstrate a relative airway hyporesponsiveness that appears to be mediated at least partly via an iNOS-dependent mechanism. These findings may have clinical significance, because recent studies reported associations between surfactant protein polymorphisms and a variety of lung diseases. PMID:20348208

Pastva, Amy M.; Walker, Julia K. L.; Maddox, Lee A.; Mukherjee, Sambuddho; Giamberardino, Charles; Hsia, Bethany; Potts, Erin; Zhu, Hongmei; Degan, Simone; Sunday, Mary E.; Lawson, Barbara L.; Korfhagen, Thomas R.; Schwartz, David A.; Eu, Jerry P.; Foster, William M.; McMahon, Timothy J.; Que, Loretta; Wright, Jo Rae

2011-01-01

232

Cellular/Molecular A Calcium-Induced Calcium Influx Factor, Nitric Oxide,  

E-print Network

Cellular/Molecular A Calcium-Induced Calcium Influx Factor, Nitric Oxide, Modulates the Refilling in astrocytes, we imaged the formation of nitric oxide in cultured murine cortical astrocytes using DAF-FM (4 concentrations of ATP induced a Ca2 -dependent production of nitric oxide. We then investigated the roles

Newman, Eric A.

233

Altered immune responses in mice lacking inducible nitric oxide synthase  

Microsoft Academic Search

NITRIC oxide (NO) is important in many biological functions1-5. It is generated from L-arginine by the enzyme NO synthase (NOS). The cytokine-inducible NOS (iNOS) is activated by several immunological stimuli, leading to the production of large quantities of NO which can be cytotoxic6. To define the biological role of iNOS further, we generated iNOS mutant mice. These are viable, fertile

Xiao-Qing Wei; I. G. Charles; Austin Smith; Jan Ure; Gui-Jie Feng; Fang-Ping Huang; Damo Xu; W. Muller; Salvador Moncada

1995-01-01

234

Anandamide rescues retinal barrier properties in Müller glia through nitric oxide regulation.  

PubMed

The blood retinal barrier (BRB) can mitigate deleterious immune response. Dysfunction at the BRB can affect disease progression. Under inflammatory conditions Müller glia produce increased pro-inflammatory factors, like nitric oxide (NO). In this study we describe molecular events at the Müller glia during inflammation which could affect inner BRB properties. Griess assay and 4,5-diaminofluorescein diacetate (DAF-2DA) time-lapse fluorescence were used to measure NO production. Western blot was used to analyze the expression of inducible nitric oxide synthase (iNOS) and mitogen-activated protein kinases (MAPK) components. Lucifer Yellow was used to measure permeability. Griess assay and DAF-2DA time-lapse fluorescence images revealed that lipopolysaccharide (LPS) induced inflammation and increased NO production. In parallel, changes were observed in tight junction proteins, zona occludens 1 (ZO-1), connexin 43 (Cx43), and permeability. This was mediated through activation of iNOS and mitogen-activated protein kinase phosphatase-1 (MKP-1), implicated in immune response. Endocannabinoids can exert a protective and anti-inflammatory effect. Exogenous arachidonoyl ethanolamide (AEA) inhibited NO generation and also abolished LPS-induced increase in permeability. Our work suggests that subtle changes in Müller glia function, which act as part of the BRB, could contribute to retinal health. AEA which can reduce inflammatory cytotoxicity has potential as treatment in several ocular manifestations where the integrity of the BRB is crucial. PMID:25453774

Krishnan, G; Chatterjee, N

2015-01-22

235

Inhibition of lipopolysaccharide-inducible nitric oxide synthase and IL-1beta through suppression of NF-kappaB activation by 3-(1'-1'-dimethyl-allyl)-6-hydroxy-7-methoxy-coumarin isolated from Ruta graveolens L.  

PubMed

The Ruta graveolens L. plant is used in traditional medicine to treat a large number of diseases. The methanol (50%) extract of the whole plant was observed to inhibit the expression of inducible nitric oxide synthase (iNOS) and the cycloxygenase-2 (COX-2) gene in lipopolysaccharide (LPS)-induced macrophage cells (J774A.1, [Raghav, S.K., Gupta, B., Agrawal, C., Goswami, K., Das, H.R., 2006b. Anti-inflammatory effect of Ruta graveolens L. in murine macrophage cells. J. Ethnopharmacol. 104, 234-239]). The effect of whole plant extract on the expression of other pro-inflammatory genes such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-12, interferon-gamma (IFN-gamma) and the activation of nuclear factor-kB (NF-kappaB) were investigated in LPS stimulated macrophage cells. An active compound was isolated from this methanol extract by further solvent fractionation and reverse phase high performance liquid chromatography (RP-HPLC). The purified compound was identified as 3-(1'-1'-dimethyl-allyl)-6-hydroxy-7-methoxy-coumarin having IUPAC nomenclature of 6-hydroxy-7-methoxy-3-(2-methyl but-3-en-2yl)-2H-chromen-2-one by ESI-MS, MALDI, FT-IR and NMR. Effect of this purified compound was assessed on iNOS, COX-2 and various pro-inflammatory cytokine genes and was observed to inhibit both the protein and mRNA expression of iNOS and IL-1beta in LPS challenged macrophages. Electrophoretic mobility shift assay (EMSA) and Western blot analyses indicated that the plant extract and the isolated active compound blocked the LPS-induced activation of NF-kappaB through the prevention of inhibitor-kB (IkB) degradation. The purified compound also showed the anti-oxidant activity. The active compound at a dose of 40 mg/kg body weight was observed to inhibit the iNOS and IL-1beta gene expression significantly in endotoxin-induced inflammatory model of BALB/c mice. The low level of nitric oxide production was also observed in the sera of compound treated mice. The normal behavioral condition in LPS challenged BALB/c mice was noticed when these were treated with active compound. PMID:17292351

Raghav, Sunil Kumar; Gupta, Bhawna; Shrivastava, Anju; Das, Hasi Rani

2007-03-29

236

Comparative study of the high molecular mass fraction and low molecular mass fraction of Sho-saiko-to in a murine immunologically induced liver injury model.  

PubMed

We compared the pharmacological actions of the high and low molecular mass fractions of Sho-saiko-to using a murine immunologically induced liver injury model to estimate the roles of these fractions in the expression of the pharmacological action. In a Bacillus Calmette-Guerin (BCG)/lipopolysaccharide (LPS)-induced liver injury model, Sho-saiko-to and both of its fractions significantly reduced the increases in the aminotranseferase levels in serum. They also reduced the increase in the nitric oxide (NOx) level in serum. On the other hand, Sho-saiko-to and its high molecular mass fraction suppressed the increase in plasma NOx level in an LPS-induced endotoxin shock model but its low molecular mass fraction did not. These results suggest the possibility that both fractions act hepatoprotectively in a different manner. We believe that these results can help to elucidate the mechanism of action of ingredients in Sho-saiko-to. PMID:11824559

Nose, Mitsuhiko; Terawaki, Kiyoshi; Iwahashi, Naomi; Oguri, Kanayo; Ogihara, Yukio

2002-01-01

237

Hsp90? inhibition modulates nitric oxide production and nitric oxide-induced apoptosis in human chondrocytes  

PubMed Central

Background Hsp90? is a member of the Hsp90 family of protein chaperones. This family plays essential roles in the folding, maturation and activity of many proteins that are involved in signal transduction and transcriptional regulation. The role of this protein in chondrocytes is not well understood, although its increase in osteoarthritic cells has been reported. The present study aimed to explore the role of Hsp90? in key aspects of OA pathogenesis. Methods Human OA chondrocytes were isolated from cartilage obtained from patients undergoing joint replacement surgery, and primary cultured. Cells were stimulated with proinflammatory cytokines (IL-1? or TNF-?) and nitric oxide donors (NOC-12 or SNP). For Hsp90? inhibition, two different chemical inhibitors (Geldanamycin and Novobiocin) were employed, or siRNA transfection procedures were carried out. Gene expression was determined by real-time PCR, apoptosis was quantified by flow cytometry and ELISA, and nitric oxide (NO) production was evaluated by the Griess method. Indirect immunofluorescence assays were performed to evaluate the presence of Hsp90? in stimulated cells. Results Hsp90? was found to be increased by proinflammatory cytokines. Inhibition of Hsp90? by the chemicals Geldanamycin (GA) and Novobiocin (NB) caused a dose-dependent decrease of the NO production induced by IL-1? in chondrocytes, up to basal levels. Immunofluorescence analyses demonstrate that the NO donors NOC-12 and SNP also increased Hsp90?. Chemical inhibition or specific gene silencing of this chaperone reduced the DNA condensation and fragmentation, typical of death by apoptosis, that is induced by NO donors in chondrocytes. Conclusions The present results show how Hsp90? modulates NO production and NO-mediated cellular death in human OA chondrocytes. PMID:22004293

2011-01-01

238

Nitric oxide mediates prostaglandins' deleterious effect on lipopolysaccharide-triggered murine fetal resorption  

PubMed Central

Genital tract bacterial infections could induce abortion and are some of the most common complications of pregnancy; however, the mechanisms remain unclear. We investigated the role of prostaglandins (PGs) in the mechanism of bacterial lipopolysaccharide (LPS)-induced pregnancy loss in a mouse model, and we hypothesized that PGs might play a central role in this action. LPS increased PG production in the uterus and decidua from early pregnant mice and stimulated cyclooxygenase (COX)-II mRNA and protein expression in the decidua but not in the uterus. We also observed that COX inhibitors prevented embryonic resorption (ER). To study the possible interaction between nitric oxide (NO) and PGs, we administered aminoguanidine, an inducible NO synthase inhibitor. NO inhibited basal PGE and PGF2? production in the decidua but activated their uterine synthesis and COX-II mRNA expression under septic conditions. A NO donor (S-nitroso-N-acetylpenicillamine) produced 100% ER and increased PG levels in the uterus and decidua. LPS-stimulated protein nitration was higher in the uterus than in the decidua. Quercetin, a peroxynitrite scavenger, did not reverse LPS-induced ER. Our results suggest that in a model of septic abortion characterized by increased PG levels, NO might nitrate and thus inhibit COX catalytic activity. ER prevention by COX inhibitors adds a possible clinical application to early pregnancy complications due to infections. PMID:17460035

Aisemberg, J.; Vercelli, C.; Billi, S.; Ribeiro, M. L.; Ogando, D.; Meiss, R.; McCann, S. M.; Rettori, V.; Franchi, A. M.

2007-01-01

239

Expression of Inducible Nitric Oxide Synthase in the Eye From Endotoxin-Induced Uveitis Rats  

Microsoft Academic Search

Purpose. Inducible nitric oxide (NO) synthase (iNOS) has been implicated in the pathogenesis of endotoxin-induced uveitis (EIU). This study was undertaken to localize the cells, in the eye, which express iNOS during EIU in the rat. Methods. EIU was induced in Lewis rats by a single foot pad injection of 150 \\/ig lipopolysaccha- ride (LPS) from Salmonella typhimurium. At different

Edith Jacquemin; Yvonne de Kozak; Brigitte Thillaye; Yves Courtois; Olivier Goureau

1996-01-01

240

Extracellular Signal-regulated Kinase Mediates Expression of Arginase II but Not Inducible Nitric-oxide Synthase in Lipopolysaccharide-stimulated Macrophages.  

PubMed

The mitogen-activated protein kinases (MAPK) have been shown to participate in iNOS induction following lipopolysaccharide (LPS) stimulation, while the role of MAPKs in the regulation of arginase remains unclear. We hypothesized that different MAPK family members are involved in iNOS and arginase expression following LPS stimulation. LPS-stimulated RAW 264.7 cells exhibited increased protein and mRNA levels for iNOS, arginase I, and arginase II; although the induction of arginase II was more robust than that for arginase I. A p38 inhibitor completely prevented iNOS expression while it only attenuated arginase II induction. In contrast, a MEK1/2 inhibitor (ERK pathway) completely abolished arginase II expression while actually enhancing iNOS induction in LPS-stimulated cells. Arginase II promoter activity was increased by ?4-fold following LPS-stimulation, which was prevented by the ERK pathway inhibitor. Arginase II promoter activity was unaffected by a p38 inhibitor or JNK pathway interference. Transfection with a construct expressing a constitutively active RAS mutant increased LPS-induced arginase II promoter activity, while transfection with a vector expressing a dominant negative ERK2 mutant or a vector expressing MKP-3 inhibited the arginase II promoter activity. LPS-stimulated nitric oxide (NO) production was increased following siRNA-mediated knockdown of arginase II and decreased when arginase II was overexpressed. Our results demonstrate that while both the ERK and p38 pathways regulate arginase II induction in LPS-stimulated macrophages, iNOS induction by LPS is dependent on p38 activation. These results suggest that differential inhibition of the MAPK pathway may be a potential therapeutic strategy to regulate macrophage phenotype. PMID:25451938

Jin, Yi; Liu, Yusen; Nelin, Leif D

2015-01-23

241

Potential chemoprevention of LPS-stimulated nitric oxide and prostaglandin E? production by ?-L-rhamnopyranosyl-(1?6)-?-D-glucopyranosyl-3-indolecarbonate in BV2 microglial cells through suppression of the ROS/PI3K/Akt/NF-?B pathway.  

PubMed

?-l-Rhamnopyranosyl-(1?6)-?-d-glucopyranosyl-3-indolecarbonate (RG3I) is a chemical constituent isolated from the commonly used Asian traditional medicinal plant, Clematis mandshurica; however, no studies have been reported on its anti-inflammatory properties. In the present study, we found that RG3I attenuates the lipopolysaccharide (LPS)-induced DNA-binding activity of nuclear factor-?B (NF-?B) via the dephosphorylation of PI3K/Akt in BV2 microglial cells, leading to a suppression of nitric oxide (NO) and prostaglandin E2 (PGE2) production, along with that of their regulatory genes, inducible NO synthase (iNOS) and cyclooxygenase-2 (Cox-2). Further, the PI3K/Akt inhibitor, LY294002 diminished the expression of LPS-stimulated iNOS and COX-2 genes by suppressing NF-?B activity. Moreover, RG3I significantly inhibited LPS-induced reactive oxygen species (ROS) generation similar to the ROS inhibitors, N-acetylcysteine (NAC) and glutathione (GSH). Notably, NAC and GSH abolished the LPS-induced expression of iNOS and Cox-2 in BV2 microglial cells by inhibiting NF-?B activity. Taken together, our data indicate that RG3I suppresses the production of proinflammatory mediators such as NO and PGE2 as well as their regulatory genes in LPS-stimulated BV2 microglial cells by inhibiting the PI3K/Akt- and ROS-dependent NF-?B signaling pathway, suggesting that RG3I may be a good candidate to regulate LPS-induced inflammatory response. PMID:24486459

Dilshara, Matharage Gayani; Lee, Kyoung-Tae; Choi, Yung Hyun; Moon, Dong-Oh; Lee, Hak-Ju; Yun, Sung Gyu; Kim, Gi-Young

2014-02-01

242

Nitric Oxide Signaling in Hypergravity-Induced Neuronal Plasticity  

NASA Technical Reports Server (NTRS)

The goal of this research project was to identify the neurons and circuits in the vestibular nuclei and nucleus prepositus hypoglossi that utilize nitric oxide (NO) for intercellular signaling during gravity-induced plasticity. This objective was pursued using histochemical and immunocytochemical approaches to localize NO-producing neurons and characterize the fine morphology of the cells in ground-based studies of normal rats, rats adapted to hypergravity, and rats adapted to hypergravity and then re-adapted to the 1G environment. NO-producing neurons were identified and studied using four methodologies: i) immunocytochemistry employing polyclonal antibodies directed against neuronal nitric oxide synthase (nNOS), to provide an indication of the capacity of a cell for NO production; ii) immunocytochemistry employing a monoclonal antibody directed against L-citrulline, to provide an indirect index of the enzyme's activity; iii) histochemistry based on the NADPH-diaphorase reaction, for fuI1 cytological visualization of neurons; and iv) double immunofluorescence to co-localize nNOS and L-citrulline in individual vestibular nuclei (VN) and neurons.

Holstein, Gay R.

2003-01-01

243

Prunella vulgaris extract and rosmarinic acid suppress lipopolysaccharide-induced alteration in human gingival fibroblasts.  

PubMed

Periodontitis is a chronic disease associated with inflammation of the tooth-supporting tissues. The inflammation is initiated by a group of gram-negative anaerobic bacteria. These express a number of irritating factors including a lipopolysaccharide (LPS), which plays a key role in periodontal disease development. Plant extracts with anti-inflammatory and anti-microbial properties have been shown to inhibit bacterial plaque formation and thus prevent chronic gingivitis. In this study we tested effects of Prunella vulgaris L. extract (PVE; 5, 10, 25microg/ml) and its component rosmarinic acid (RA; 1microg/ml) on LPS-induced oxidative damage and inflammation in human gingival fibroblasts. PVE and RA reduced reactive oxygen species (ROS) production, intracellular glutathione (GSH) depletion as well as lipid peroxidation in LPS-treated cells. Treatment with PVE and RA also inhibited LPS-induced up-regulation of interleukin 1beta (IL-1beta), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and suppressed expression of inducible nitric oxide synthase (iNOS). The results indicate that PVE and RA are able to suppress LPS-induced biological changes in gingival fibroblasts. The effects of PVE and RA are presumably linked to their anti-inflammatory activities and thus use of PVE and RA may be relevant in modulating the inflammation process, including periodontal disease. PMID:19159670

Zdarilová, A; Svobodová, A; Simánek, V; Ulrichová, J

2009-04-01

244

Dietary selenium deficiency exacerbates lipopolysaccharide-induced inflammatory response in mouse mastitis models.  

PubMed

Selenium (Se) is an essential micronutrient that plays a critical role in anti-inflammatory processes and antioxidant defense system. In this study, we investigated the effects of dietary selenium deficiency on lipopolysaccharide (LPS)-induced mastitis in mouse models. Se content in the liver was assessed by fluorescent atomic absorption spectrometry. Glutathione peroxidase (GPx) activity in the blood, myeloperoxidase (MPO) activity, tumor necrosis actor alpha (TNF-?), and interleukin (IL)-1? in the supernatant of the mammary tissue were determined according to the corresponding kits. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions were evaluated by Western blotting. The results showed that the Se-deficient mouse model was successfully replicated, and selenium deficiency exacerbated mammary gland histopathology, increased the expressions of TNF-? and IL-1?, and facilitated the activation of iNOS and COX-2 in LPS-induced mouse mastitis. In conclusion, our studies demonstrated that selenium deficiency resulted in more severe inflammatory response in LPS-induced mouse mastitis. PMID:24844733

Wei, Zhengkai; Yao, Minjun; Li, Yimeng; He, Xuexiu; Yang, Zhengtao

2014-12-01

245

MEMANTINE PROTECTS AGAINST LPS-INDUCED NEUROINFLAMMATION, RESTORES BEHAVIORALLY-INDUCED GENE  

E-print Network

, autism, Down syndrome, HIV de- mentia, and demyelinating diseases, such as multiple scle- rosis, and Aging, University of Arizona, Tucson, AZ 85724, USA b Cognitive Neuroscience Center and Department of neuroinflammation-influenced diseases may confer neural and cognitive protection. © 2006 IBRO. Pub- lished

Wenk, Gary

246

Lipopolysaccharide-Binding Protein Critically Regulates Lipopolysaccharide-Induced IFN Signaling Pathway in Human Monocytes1  

Microsoft Academic Search

LPS binding to Toll-like receptor 4 induces a large number of genes through activation of NF-B and IFN-regulatory factor-3 (IRF-3). However, no previous reports have tested the role of serum proteins in LPS-induced gene expression profiles. To inves- tigate how serum proteins affect LPS-induced signaling, we investigated LPS-inducible genes in PBMC using an oligonucleotide probe-array system. Approximately 120 genes up-regulated

Atsushi Kato; Takahisa Ogasawara; Toshiki Homma; Hirohisa Saito; Kenji Matsumoto

247

Suppression of lipopolysaccharide-induced of inducible nitric oxide synthase and cyclooxygenase-2 by Sanguis Draconis, a dragon's blood resin, in RAW 264.7 cells.  

PubMed

Sanguis Draconis (SD) is a kind of dragon's blood resin that is obtained from Daemomorops draco (Palmae). It is used in traditional medicine and has shown anti-inflammatory activity in some diseases. In this study, we examined the effects of Sanguis Dranonis ethanol extract (SDEE) on LPS-induced inflammation using RAW 264.7 cells. Our data indicated that SDEE inhibits LPS-stimulated NO, PGE2, IL-1 beta and TNF-alpha release, and iNOS and COX-2 expression. Furthermore, SDEE suppressed the LPS-induced p65 expression of NF-kappa B, which was associated with the inhibition of I kappa B-alpha degradation. We also found that the expression of HO-1 was significantly increased in RAW 264.7 cells by SDEE. These results suggest among possibilities of anti-inflammation that SDEE inhibits the production of NO and PGE2 by the down-regulation of iNOS and COX-2 gene expression via the suppression of NF-kappaB (p65) activation. SDEE can induce HO-1 over-expression in macrophage cells, which indicates that it may possess antioxidant properties. This result means that SEDD its anti-inflammatory effects in macrophages may be through a novel mechanism that involves the action of HO-1. Thus, SD could provide a potential therapeutic approach for inflammation-associated disorders. PMID:18060707

Choy, Cheuk-Sing; Hu, Chien-Ming; Chiu, Wen-Ta; Lam, Carlos-Shu Kei; Ting, Yih; Tsai, Shin-Han; Wang, Tzu-Chien

2008-02-12

248

Nitric oxide stress in sporadic inclusion body myositis muscle fibres: inhibition of inducible nitric oxide synthase prevents interleukin-1?-induced accumulation of ?-amyloid and cell death.  

PubMed

Sporadic inclusion body myositis is a severely disabling myopathy. The design of effective treatment strategies is hampered by insufficient understanding of the complex disease pathology. Particularly, the nature of interrelationships between inflammatory and degenerative pathomechanisms in sporadic inclusion body myositis has remained elusive. In Alzheimer's dementia, accumulation of ?-amyloid has been shown to be associated with upregulation of nitric oxide. Using quantitative polymerase chain reaction, an overexpression of inducible nitric oxide synthase was observed in five out of ten patients with sporadic inclusion body myositis, two of eleven with dermatomyositis, three of eight with polymyositis, two of nine with muscular dystrophy and two of ten non-myopathic controls. Immunohistochemistry confirmed protein expression of inducible nitric oxide synthase and demonstrated intracellular nitration of tyrosine, an indicator for intra-fibre production of nitric oxide, in sporadic inclusion body myositis muscle samples, but much less in dermatomyositis or polymyositis, hardly in dystrophic muscle and not in non-myopathic controls. Using fluorescent double-labelling immunohistochemistry, a significant co-localization was observed in sporadic inclusion body myositis muscle between ?-amyloid, thioflavine-S and nitrotyrosine. In primary cultures of human myotubes and in myoblasts, exposure to interleukin-1? in combination with interferon-? induced a robust upregulation of inducible nitric oxide synthase messenger RNA. Using fluorescent detectors of reactive oxygen species and nitric oxide, dichlorofluorescein and diaminofluorescein, respectively, flow cytometry revealed that interleukin-1? combined with interferon-? induced intracellular production of nitric oxide, which was associated with necrotic cell death in muscle cells. Intracellular nitration of tyrosine was noted, which partly co-localized with amyloid precursor protein, but not with desmin. Pharmacological inhibition of inducible nitric oxide synthase by 1400W reduced intracellular production of nitric oxide and prevented accumulation of ?-amyloid, nitration of tyrosine as well as cell death inflicted by interleukin-1? combined with interferon-?. Collectively, these data suggest that, in skeletal muscle, inducible nitric oxide synthase is a central component of interactions between interleukin-1? and ?-amyloid, two of the most relevant molecules in sporadic inclusion body myositis. The data further our understanding of the pathology of sporadic inclusion body myositis and may point to novel treatment strategies. PMID:22436237

Schmidt, Jens; Barthel, Konstanze; Zschüntzsch, Jana; Muth, Ingrid E; Swindle, Emily J; Hombach, Anja; Sehmisch, Stephan; Wrede, Arne; Lühder, Fred; Gold, Ralf; Dalakas, Marinos C

2012-04-01

249

Nitric oxide mediates elicitor-induced saponin synthesis in cell cultures of Panax ginseng  

Microsoft Academic Search

The elicitor oligogalacturonic acid (OGA) stimulated nitric oxide (NO) accumulation in the growth medium of ginseng suspension cultures and induced increased nitric oxide synthase (NOS) activity in ginseng cells. OGA also stimulated accumulation of saponin, transcription of genes encoding squalene synthase (sqs) and squalene epoxidase (sqe), two early enzymes of saponin synthesis, and the accumulation of ?-amyrin synthase protein (?-AS).

Xiangyang Hu; Steven J. Neill; Weiming Cai; Zhangcheng Tang

2003-01-01

250

The effect of inhaled nitric oxide on the carrageenan-induced paw edema.  

PubMed

Inhaled nitric oxide therapy reaches not only pulmonary vessels, but also other vasculatures, presenting anti-inflammatory effects. Therefore, this study investigated the effects of inhaled nitric oxide on a mice model of carrageenan-induced paw edema. Paw edema was induced in male Swiss mice (20-30 g) by subplantar injection of carrageenan (0.05 ml of a 1% suspension in 0.9% saline). The evaluation of time-course edema (mililiter) was measured by plethysmometry until 12 h following carrageenan administration. Thirty minutes after carrageenan injection, some groups received inhaled nitric oxide (300 ppm at variable doses and times) or Indometacin (INDO 5 mg/Kg, v.o), while others received sildenafil (1 mg/Kg, i.p) or rolipram (3 mg/Kg, i.p.) with or without inhaled nitric oxide. Paws were assessed for edema levels by plethysmometry, mieloperoxidase activity and histological analysis. Inhaled nitric oxide significantly reduced carrageenan-induced paw edema, mieloperoxidase activity and inflammatory infiltrate, although similar results were also observed in sildenafil and rolipram treated groups. In addition, significant effects between inhaled nitric oxide with pharmacological therapy was observed. Inhaled nitric oxide presents anti-inflammatory effects on carrageenan-induce paw edema, as observed through reduced edema, mieloperoxidase activity and neutrophil infiltration, indicating that inhaled nitric oxide therapy goes beyond lung vascular effects. PMID:25070733

Coelho, Carly Faria; Vieira, Rodolfo P; Lopes-Martins, Patrícia Sardinha Leonardo; Teixeira, Simone Aparecida; Borbely, Alexandre Urban; Gouvea, Irene Maria; Frigo, Lucio; Lopes-Martins, Rodrigo Álvaro Brandăo

2015-01-01

251

Mechanisms regulating macrophage-induced nitric oxide production by spontaneously transformed hamster fibroblasts.  

PubMed

Nitric oxide has been implicated as an important effector molecule involved in tumor cell growth and cytotoxicity. In these studies we examined mechanisms regulating nitric oxide production by hamster tumor cells. Cocultures of hamster alveolar macrophages (HAM) and spontaneously transformed hamster embryonic fibroblasts (STHE cells) produced significant quantities of nitric oxide in response to lipopolysaccharide (LPS). Culture supernatants from HAM treated with LPS also stimulated nitric oxide production by STHE cells, whereas tumor cell culture supernatants had no effect on HAM. These data, together with the findings that paraformaldehyde treatment of STHE cells, but not macrophages, completely abrogated nitric oxide production in the cocultures demonstrate that the tumor cells were the source of this mediator. In contrast to STHE cells, STHE-83/20 cells, a highly malignant variant, did not produce nitric oxide in response to HAM or HAM culture supernatants even in the presence of LPS. Both anti-tumor necrosis factor-alpha (TNF-alpha) and anti-interleukin-1alpha (IL-1alpha) antibodies inhibited HAM-induced nitric oxide production by STHE cells. However, the kinetics of their effects were different. Moreover, although the nitric oxide stimulating activity in HAM culture supernatants was abrogated by anti-TNF-alpha antibody, it was only minimally reduced by anti-IL-1alpha antibody. These data demonstrate that TNF-alpha and IL-1alpha play distinct roles in induction of nitric oxide synthesis in STHE cells. HAM were also found to suppress proliferation of STHE cells, an effect that was inhibited by anti-TNF-alpha antibody, but not NG-monomethyl-L-arginine, which blocks nitric oxide synthase. Abrogation of macrophage-induced cytostasis in STHE cells by anti-TNF-alpha antibody was associated with decreased nitric oxide production. Thus TNF-alpha released by macrophages may indirectly activate STHE cells for nitric oxide synthesis by suppressing tumor cell proliferation. PMID:8864131

Lavnikova, N; Prokhorova, S; Burdelia, L; Lakhotia, A; Laskin, D L

1996-10-01

252

Cytostasis is required for IL-1 induced nitric oxide production in transformed hamster fibroblasts.  

PubMed

Interleukin-1 (IL-1) is known to inhibit proliferation in some tumor cells. This proinflammatory cytokine also induces nitric oxide production in a variety of cell types. In the present studies we determined if nitric oxide is involved in IL-1 induced growth inhibition in spontaneously transformed hamster embryonic fibroblasts (STHE cells). Both IL-1 alpha and IL-1 beta were found to stimulate nitric oxide production and to reduce 3H-thymidine (TdR) incorporation in high density cultures of STHE cells. However, maximal cytostasis was observed at least 24 h before significant amounts of nitric oxide accumulated in the cultures. In addition, doses of IL-1 which were too low to stimulate nitric oxide synthesis were effective in inducing cytostasis. Furthermore, in low density cultures of STHE cells, IL-1 inhibited DNA synthesis without inducing nitric oxide production. The nitric oxide synthase inhibitor NG-monomethyl-1-arginine (L-NMMA) had no effect on proliferation of cells plated at low density. In contrast, L-NMMA treatment resulted in a 40-60% reduction in IL-1 induced cytostasis in high density cultures. Neutralizing antibodies to IL-1 were found to completely block IL-1 induced cytostasis and nitric oxide production in cells plated at both densities. Although anti-IL-1 alpha and anti-IL-1 beta antibodies were highly specific and did not cross react, anti-tumor necrosis factor-alpha (TNF-alpha) antibody was able to partially suppress activation of STHE cells by both IL-1 alpha and IL-1 beta. These data suggest a potential involvement of endogenous TNF-alpha in IL-1 induced cytostasis and nitric oxide production. Exponentially growing STHE cells produced six-times less nitric oxide than non-proliferating cells. A ten-fold excess of 1-arginine was found to stimulate nitric oxide synthesis, an action that was independent of the rate of cellular proliferation. Taken together these data suggest that nitric oxide is not a major mediator of IL-1 induced cytostasis in STHE cells. Moreover, cytostasis appears to be required for nitric oxide synthesis in these cells. PMID:8952702

Lavnikova, N; Lakhotia, A; Patel, N; Prokhorova, S; Laskin, D L

1996-12-01

253

Nitric oxide inhibits lipopolysaccharide-induced apoptosis in pulmonary artery endothelial cells  

E-print Network

YOUNG-MYEONG KIM,2,3 TIMOTHY R. BILLIAR,2 SIMON A. WATKINS,6 AND BRUCE R. PITT1,3 3Department. Billiar, Simon A. Watkins, and Bruce R. Pitt. Nitric oxide inhibits lipopolysaccharide- induced apoptosis

Engelhardt, John F.

254

Nitric oxide induces cell death in Taxus cells.  

PubMed

Sodium nitroprusside (SNP), a nitric oxide donor, or centrifugation at 150 times unit gravity, caused a nitric oxide burst in oocyte-derived Taxus brevifolia haploid cultures. This burst, visualized by the specific fluorescent probe 4,5-diaminofluorescein diacetate (DAF-2 DA), preceded a significant increase in nuclear DNA fragmentation and cell death. DNA fragmentation was detected in situ by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) of DNA 3'-OH groups. Nitric oxide formation and cell death were significantly decreased by N(G)-monomethyl-L-arginine (L-NMMA), a nitric oxide-synthase (NOS; EC 1.14.13.39) inhibitor. Our results show that nitric oxide leads to irreversible DNA fragmentation and cell death under stressful conditions, and that its effect can be prevented by L-NMMA. PMID:10960730

Pedroso; Magalhaes; Durzan

2000-08-22

255

Berberine hydrochloride attenuates lipopolysaccharide-induced endometritis in mice by suppressing activation of NF-?B signal pathway.  

PubMed

Endometritis is a common disease in animal production and influences breeding all over the world. Berberine is one of the main alkaloids isolated from Rhizoma coptidis. Previous reports showed that berberine has anti-inflammatory potential. However, there have been a limited number of published reports on the anti-inflammatory effect of berberine hydrochloride on LPS-induced endometritis. The purpose of the present study was to investigate the effects of berberine hydrochloride on LPS-induced mouse endometritis. Berberine hydrochloride was administered intraperitoneally at 1h before and 12h after LPS induction. Then, a biopsy was performed, and uterine myeloperoxidase (MPO) and nitric oxide (NO) concentrations were determined. Tumor necrosis factor-? (TNF-?) and interleukin-1? (IL-1?) levels in the uterus homogenate were measured by ELISA. The extent of I?B-? and P65 phosphorylation was detected by Western blot. The results showed that berberine hydrochloride significantly attenuated neutrophil infiltration, suppressed myeloperoxidase activity and decreased NO, TNF-?and IL-1?production. Furthermore, berberine hydrochloride inhibited the phosphorylation of the NF-?B p65 subunit and the degradation of its inhibitor, I?B?. These findings suggest that berberine hydrochloride exerts potent anti-inflammatory effects on LPS-induced mouse endometritis and might be a potential therapeutic agent for endometritis. PMID:25479718

Fu, Kaiqiang; Lv, Xiaopei; Li, Weishi; Wang, Yu; Li, Huatao; Tian, Wenru; Cao, Rongfeng

2015-01-01

256

Phosphorylation of Akt Mediates Anti-Inflammatory Activity of 1-p-Coumaroyl ?-D-Glucoside Against Lipopolysaccharide-Induced Inflammation in RAW264.7 Cells  

PubMed Central

Hydroxycinnamic acids have been reported to possess numerous pharmacological activities such as antioxidant, anti-inflammatory, and anti-tumor properties. However, the biological activity of 1-p-coumaroyl ?-D-glucoside (CG), a glucose ester derivative of p-coumaric acid, has not been clearly examined. The objective of this study is to elucidate the anti-inflammatory action of CG in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. In the present study, CG significantly suppressed LPS-induced excessive production of pro-inflammatory mediators such as nitric oxide (NO) and PGE2 and the protein expression of iNOS and COX-2. CG also inhibited LPS-induced secretion of pro-inflammatory cytokines, IL-1? and TNF-?. In addition, CG significantly suppressed LPS-induced degradation of I?B. To elucidate the underlying mechanism by which CG exerts its anti-inflammatory action, involvement of various signaling pathways were examined. CG exhibited significantly increased Akt phosphorylation in a concentration-dependent manner, although MAPKs such as Erk, JNK, and p38 appeared not to be involved. Furthermore, inhibition of Akt/PI3K signaling pathway with wortmannin significantly, albeit not completely, abolished CG-induced Akt phosphorylation and anti-inflammatory actions. Taken together, the present study demonstrates that Akt signaling pathway might play a major role in CG-mediated anti-inflammatory activity in LPS-stimulated RAW264.7 macrophage cells. PMID:24634601

Vo, Van Anh; Lee, Jae-Won; Kim, Ji-Young; Park, Jun-Ho; Lee, Hee Jae; Kim, Sung-Soo; Kwon, Yong-Soo

2014-01-01

257

In vivo Expression of Inducible Nitric Oxide Synthase in Experimentally Induced Neurologic Diseases  

NASA Astrophysics Data System (ADS)

The purpose of this study was to investigate the induction of inducible nitric oxide synthase (iNOS) mRNA in the brain tissue of rats and mice under the following experimental conditions: in rats infected with borna disease virus and rabies virus, in mice infected with herpes simplex virus, and in rats after the induction of experimental allergic encephalitis. The results showed that iNOS mRNA, normally nondetectable in the brain, was present in animals after viral infection or after induction of experimental allergic encephalitis. The induction of iNOS mRNA coincided with the severity of clinical signs and in some cases with the presence of inflammatory cells in the brain. The results indicate that nitric oxide produced by cells induced by iNOS may be the toxic factor accounting for cell damage and this may open the door to approaches to the study of the pathogenesis of neurological diseases.

Koprowski, Hilary; Zheng, Yong Mu; Heber-Katz, Ellen; Fraser, Nigel; Rorke, Lucy; Fu, Zhen Fang; Hanlon, Cathleen; Dietzschold, Bernhard

1993-04-01

258

Wogonin but not Nor-wogonin inhibits lipopolysaccharide and lipoteichoic acid-induced iNOS gene expression and NO production in macrophages.  

PubMed

Wogonin (Wog; 5,7-dihydroxy-8-methoxy flavone) has been shown to effectively inhibit lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) gene expression and nitric oxide production in our previous study. In the present study, we found that Nor-wogonin (N-Wog; 5,7,8-trihydroxyl flavone), a structural analogue of Wog with an OH substitution at C8, performed different effect on LPS- or lipoteichoic acid (LTA)-induced iNOS gene expression and nitric oxide (NO) production in macrophages. Wog, but not N-Wog, significantly inhibits LPS- or LTA-induced NO production through suppressing iNOS gene expression at both protein and mRNA without affecting NO donor sodium nitroprusside-induced NO production, NOS enzyme activity, and cells viability. Activation of JNKs (not ERKs) via phosphorylation induction, and an increase in c-Jun (not c-Fos) protein expression were involved in LPS- and LTA-treated RAW264.7 cells, and those events were blocked by Wog, but not N-Wog, addition. Furthermore, 5,7-diOH flavone, but not 5-OH flavone, 7-OH flavone, 5-OH-7-OCH(3) flavone, significantly inhibits LPS-induced iNOS protein expression and NO production, and 7,8-diOCH(3) flavone performs more effective inhibitory activity on LPS-induced NO production and iNOS protein expression than 7-OCH(3)-8-OH flavone. These data suggest that OHs at both C5 and C7 are essential for NO inhibition of flavonoids, and OCH(3) at C8 may contribute to this activity, and suppression of JNKs-c-Jun activation is involved. PMID:17570322

Huang, Guan-Cheng; Chow, Jyh-Ming; Shen, Shing-Chuan; Yang, Liang-Yo; Lin, Cheng-Wei; Chen, Yen-Chou

2007-08-01

259

Inducible Nitric Oxide Synthase Mediates Hypoxia-Induced Hypoxia-Inducible Factor1? Activation and Vascular Endothelial Growth Factor Expression in Oxygen-Induced Retinopathy  

Microsoft Academic Search

Objective: Previous studies provided evidence that many factors contribute to retinal angiogenesis, including inducible nitric oxide synthase (iNOS), hypoxia-inducible factor-1? (HIF-1?) and vascular endothelial growth factor (VEGF). But the role of nitric oxide generated by iNOS in the regulation of expression of hypoxia-inducible genes in retinopathy of prematurity remains unclear. So we sought to better define the molecular basis of

Tao He; Ming Ai; Xiao-Hui Zhao; Yi-Qiao Xing

2007-01-01

260

Plexin-A1 is required for Toll-like receptor-mediated microglial activation in the development of lipopolysaccharide-induced encephalopathy  

PubMed Central

Recent investigations have suggested that semaphorins, which are known repulsive axon guidance molecules, may play a crucial role in maintaining brain homeostasis by regulating microglial activity. Sema3A, secreted in higher amounts from injured neurons, is considered to suppress excessive inflammatory responses by inducing microglial apoptosis through its binding to Plexin-A1 receptors on activated microglia. To clarify the in vivo role of Plexin-A1-mediated signaling in lipopolysaccharide (LPS)-induced injury in mouse brain, we examined the neuroinflammatory changes initiated by LPS administration to the cerebral ventricles of wild-type (WT) and Plexin-A1-deficient (?/?) mice. WT mice administered LPS exhibited a significantly higher expression of COX-2, iNOS, IL-1? and TNF-? in the hippocampus, and a significantly greater ventricular enlargement and intracerebral infiltration of leukocytes, as compared with the saline-treated group. By contrast, Plexin-A1?/? mice administered LPS did not exhibit a significantly increased expression of COX-2, iNOS, IL-1? or TNF-? in the hippocampus as compared with the saline-treated group. Plexin-A1?/? mice administered LPS did not show significant increases in ventricle size or infiltration of leukocytes into the brain, as compared with the saline-treated group. In WT, but not in the Plexin-A1?/? primary microglia treated with LPS, Sema3A induced significantly more nitric oxide production than in the immunoglobulin G control. These results revealed the crucial role of the Sema3A-Plexin-A1 interaction in the Toll-like receptor 4-mediated signaling of the LPS-induced activation of microglia. Thus, results of the present study revealed the essential role of Plexin-A1 in the development of LPS-induced neuroinflammation in mice, suggesting the possible application of microglial control of the semaphorin-plexin signaling system to the treatment of LPS-induced encephalopathy and other psychiatric diseases associated with neuroinflammation. PMID:24604454

ITO, TAKUJI; YOSHIDA, KENJI; NEGISHI, TAKAYUKI; MIYAJIMA, MASAYASU; TAKAMATSU, HYOTA; KIKUTANI, HITOSHI; KUMANOGOH, ATSUSHI; YUKAWA, KAZUNORI

2014-01-01

261

Plexin-A1 is required for Toll-like receptor-mediated microglial activation in the development of lipopolysaccharide-induced encephalopathy.  

PubMed

Recent investigations have suggested that semaphorins, which are known repulsive axon guidance molecules, may play a crucial role in maintaining brain homeostasis by regulating microglial activity. Sema3A, secreted in higher amounts from injured neurons, is considered to suppress excessive inflammatory responses by inducing microglial apoptosis through its binding to Plexin-A1 receptors on activated microglia. To clarify the in vivo role of Plexin-A1-mediated signaling in lipopolysaccharide (LPS)-induced injury in mouse brain, we examined the neuroinflammatory changes initiated by LPS administration to the cerebral ventricles of wild-type (WT) and Plexin-A1-deficient (-/-) mice. WT mice administered LPS exhibited a significantly higher expression of COX-2, iNOS, IL-1? and TNF-? in the hippocampus, and a significantly greater ventricular enlargement and intracerebral infiltration of leukocytes, as compared with the saline-treated group. By contrast, Plexin-A1-/- mice administered LPS did not exhibit a significantly increased expression of COX-2, iNOS, IL-1? or TNF-? in the hippocampus as compared with the saline-treated group. Plexin-A1-/- mice administered LPS did not show significant increases in ventricle size or infiltration of leukocytes into the brain, as compared with the saline-treated group. In WT, but not in the Plexin-A1-/- primary microglia treated with LPS, Sema3A induced significantly more nitric oxide production than in the immunoglobulin G control. These results revealed the crucial role of the Sema3A-Plexin-A1 interaction in the Toll-like receptor 4-mediated signaling of the LPS-induced activation of microglia. Thus, results of the present study revealed the essential role of Plexin-A1 in the development of LPS-induced neuroinflammation in mice, suggesting the possible application of microglial control of the semaphorin-plexin signaling system to the treatment of LPS-induced encephalopathy and other psychiatric diseases associated with neuroinflammation. PMID:24604454

Ito, Takuji; Yoshida, Kenji; Negishi, Takayuki; Miyajima, Masayasu; Takamatsu, Hyota; Kikutani, Hitoshi; Kumanogoh, Atsushi; Yukawa, Kazunori

2014-05-01

262

GAPDH regulates cellular heme insertion into inducible nitric oxide synthase  

PubMed Central

Heme proteins play essential roles in biology, but little is known about heme transport inside mammalian cells or how heme is inserted into soluble proteins. We recently found that nitric oxide (NO) blocks cells from inserting heme into several proteins, including cytochrome P450s, hemoglobin, NO synthases, and catalase. This finding led us to explore the basis for NO inhibition and to identify cytosolic proteins that may be involved, using inducible NO synthase (iNOS) as a model target. Surprisingly, we found that GAPDH plays a key role. GAPDH was associated with iNOS in cells. Pure GAPDH bound tightly to heme or to iNOS in an NO-sensitive manner. GAPDH knockdown inhibited heme insertion into iNOS and a GAPDH mutant with defective heme binding acted as a dominant negative inhibitor of iNOS heme insertion. Exposing cells to NO either from a chemical donor or by iNOS induction caused GAPDH to become S-nitrosylated at Cys152. Expressing a GAPDH C152S mutant in cells or providing a drug to selectively block GAPDH S-nitrosylation both made heme insertion into iNOS resistant to the NO inhibition. We propose that GAPDH delivers heme to iNOS through a process that is regulated by its S-nitrosylation. Our findings may uncover a fundamental step in intracellular heme trafficking, and reveal a mechanism whereby NO can govern the process. PMID:20921417

Chakravarti, Ritu; Aulak, Kulwant S.; Fox, Paul L.; Stuehr, Dennis J.

2010-01-01

263

Regulation of Inducible Nitric Oxide Synthase Gene in Glial Cells  

PubMed Central

Elevated levels of NO produced within the central nervous system (CNS) are associated with the pathogenesis of neuroinflammatory and neurodegenerative human diseases such as multiple sclerosis, HIV dementia, brain ischemia, trauma, Parkinson's disease, and Alzheimer's disease. Resident glial cells in the CNS (astroglia and microglia) express inducible nitric oxide synthase (iNOS) and produce high levels of NO in response to a wide variety of proinflammatory and degenerative stimuli. Although pathways resulting in the expression of iNOS may vary in two different glial cells of different species, the intracellular signaling events required for the expression of iNOS in these cells are slowly becoming clear. Various signaling cascades converge to activate several transcription factors that control the transcription of iNOS in glial cells. The present review summarizes different results and discusses current understandings about signaling mechanisms for the induction of iNOS expression in activated glial cells. A complete understanding of the regulation of iNOS expression in glial cells is expected to identify novel targets for therapeutic intervention in NO-mediated neurological disorders. PMID:16771683

Saha, Ramendra N.; Pahan, Kalipada

2007-01-01

264

Regulation of prostaglandin production by nitric oxide; an in vivo analysis.  

PubMed Central

1. Endotoxin E. Coli lipopolysaccharide (LPS)-treatment in conscious, restrained rats increased plasma and urinary prostaglandin (PG) and nitric oxide (NO) production. Inducible cyclo-oxygenase (COX-2) and nitric oxide synthase (iNOS) expression accounted for the LPS-induced PG and NO release since the glucocorticoid, dexamethasone inhibited both effects. Thus, LPS (4 mg kg-1) increased the plasma levels of nitrite/nitrate from 14 +/- 1 to 84 +/- 7 microM within 3 h and this rise was inhibited to 35 +/- 1 microM by dexamethasone. Levels of 6-keto PGF1 alpha in the plasma were below the detection limit of the assay (< 0.2 ng ml-1). However, 3 h after the injection of LPS these levels rose to 2.6 +/- 0.2 ng ml-1 and to 0.7 +/- 0.01 ng ml-1 after LPS in rats that received dexamethasone. 2. The induced enzymes were inhibited in vivo with selective COX and NOS inhibitors. Furthermore, NOS inhibitors, that did not affect COX activity in vitro markedly suppressed PG production in the LPS-treated animals. For instance, the LPS-induced increased in plasma nitrite/nitrate and 6-keto PGF1 alpha at 3 h was decreased to 18 +/- 2 microM and 0.5 +/- 0.02 ng ml-1, 23 +/- 1 microM and 0.7 +/- 0.01 ng ml-1, 29 +/- 2 microM and 1 +/- 0.01 ng ml-1 in rats treated with LPS in the presence of the NOS inhibitors NG-monomethyl-L-arginine, NG-nitro arginine methyl ester and aminoguanidine, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7542531

Salvemini, D; Settle, S L; Masferrer, J L; Seibert, K; Currie, M G; Needleman, P

1995-01-01

265

Nilotinib ameliorates lipopolysaccharide-induced acute lung injury in rats  

SciTech Connect

The present study aimed to investigate the effect of the new tyrosine kinase inhibitor, nilotinib on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats and explore its possible mechanisms. Male Sprague-Dawley rats were given nilotinib (10 mg/kg) by oral gavage twice daily for 1 week prior to exposure to aerosolized LPS. At 24 h after LPS exposure, bronchoalveolar lavage fluid (BALF) samples and lung tissue were collected. The lung wet/dry weight (W/D) ratio, protein level and the number of inflammatory cells in the BALF were determined. Optical microscopy was performed to examine the pathological changes in lungs. Malondialdehyde (MDA) content, superoxidase dismutase (SOD) and reduced glutathione (GSH) activities as well as nitrite/nitrate (NO{sub 2}{sup -}/NO{sub 3}{sup -}) levels were measured in lung tissues. The expression of inflammatory cytokines, tumor necrosis factor-{alpha} (TNF-{alpha}), transforming growth factor-{beta}{sub 1} (TGF-{beta}{sub 1}) and inducible nitric oxide synthase (iNOS) were determined in lung tissues. Treatment with nilotinib prior to LPS exposure significantly attenuated the LPS-induced pulmonary edema, as it significantly decreased lung W/D ratio, protein concentration and the accumulation of the inflammatory cells in the BALF. This was supported by the histopathological examination which revealed marked attenuation of LPS-induced ALI in nilotinib treated rats. In addition, nilotinib significantly increased SOD and GSH activities with significant decrease in MDA content in the lung. Nilotinib also reduced LPS mediated overproduction of pulmonary NO{sub 2}{sup -}/NO{sub 3}{sup -} levels. Importantly, nilotinib caused down-regulation of the inflammatory cytokines TNF-{alpha}, TGF-{beta}{sub 1} and iNOS levels in the lung. Taken together, these results demonstrate the protective effects of nilotinib against the LPS-induced ALI. This effect can be attributed to nilotinib ability to counteract the inflammatory cells infiltration and hence ROS generation and regulate cytokine effects. - Research highlights: > The protective effects of nilotinib against LPS-induced ALI in rats were studied. > Nilotinib showed potent anti-inflammatory activity as it attenuated PMN infiltration and hence ROS generation. > In addition, nilotinib caused down-regulation of proinflammatory cytokine production.

El-Agamy, Dina S., E-mail: dinaagamy1@yahoo.com

2011-06-01

266

Isobavachalcone suppresses expression of inducible nitric oxide synthase induced by Toll-like receptor agonists.  

PubMed

Toll-like receptors (TLRs) play an important role by recognizing many pathogen-associated molecular patterns and inducing innate immunity. Dysregulated activation of TLR signaling pathways induces the activation of various transcription factors such as nuclear factor-?B, leading to the induction of pro-inflammatory gene products such as inducible nitric oxide synthase (iNOS). The present study investigated the effect of isobavachalcone (IBC), a natural chalcone component of Angelica keiskei, on inflammation by modulating iNOS expression induced by TLR agonists in murine macrophages. IBC suppressed iNOS expression induced by macrophage-activating lipopeptide 2-kDa, polyriboinosinic polyribocytidylic acid, or lipopolysaccharide. These results indicate the potential of IBC as a potent anti-inflammatory drug. PMID:23164691

Shin, Hwa-Jeong; Shon, Dong-Hwa; Youn, Hyung-Sun

2013-01-01

267

Statin decreases IL1 and LPS-induced inflammatory cytokines production in oral epithelial cells  

Microsoft Academic Search

Periodontitis is a choronic inflammatory disease associated with degradation of periodontal tissues. This disease is considered\\u000a to result of production of proinflammatory cytokines and tissue degradative enzymes which are initiated and advanced by lipopolysaccharide\\u000a (LPS) of oral bacteria.\\u000a \\u000a Statin, 3-hydroxy-3-mrthylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is known as a drug lowering serum cholesterol.\\u000a In hyperlipidemia, the increase of cholesterol develops

Michihiko Usuit; Reiko Sudat; Yasushi Miyazawat; Makoto Kobayashit; Yoshimasa Okamatsu; Hisashi Takiguchi; Motoyuki Suzuki; Matsuo Yamamoto

268

Skeletal Muscle PGC-1? Is Required for Maintaining an Acute LPS-Induced TNF? Response  

PubMed Central

Many lifestyle-related diseases are associated with low-grade inflammation and peroxisome proliferator activated receptor ? coactivator (PGC)-1? has been suggested to be protective against low-grade inflammation. However, whether these anti-inflammatory properties affect acute inflammation is not known. The aim of the present study was therefore to investigate the role of muscle PGC-1? in acute inflammation. Quadriceps muscles were removed from 10-week old whole body PGC-1? knockout (KO), muscle specific PGC-1? KO (MKO) and muscle-specific PGC-1? overexpression mice (TG), 2 hours after an intraperitoneal injection of either 0.8 µg LPS/g body weight or saline. Basal TNF? mRNA content was lower in skeletal muscle of whole body PGC-1? KO mice and in accordance TG mice showed increased TNF? mRNA and protein level relative to WT, indicating a possible PGC-1? mediated regulation of TNF?. Basal p65 phosphorylation was increased in TG mice possibly explaining the elevated TNF? expression in these mice. Systemically, TG mice had reduced basal plasma TNF? levels compared with WT suggesting a protective effect against systemic low-grade inflammation in these animals. While TG mice reached similar TNF? levels as WT and showed more marked induction in plasma TNF? than WT after LPS injection, MKO PGC-1? mice had a reduced plasma TNF? and skeletal muscle TNF? mRNA response to LPS. In conclusion, the present findings suggest that PGC-1? enhances basal TNF? expression in skeletal muscle and indicate that PGC-1? does not exert anti-inflammatory effects during acute inflammation. Lack of skeletal muscle PGC-1? seems however to impair the acute TNF? response, which may reflect a phenotype more susceptible to infections as also observed in type 2 diabetes patients. PMID:22384185

Olesen, Jesper; Larsson, Signe; Iversen, Ninna; Yousafzai, Simi; Hellsten, Ylva; Pilegaard, Henriette

2012-01-01

269

Regulation of LPS-induced tissue factor expression in human monocytic THP-1 cells by curcumin  

Technology Transfer Automated Retrieval System (TEKTRAN)

Tissue factor (TF) is a transmembrane receptor, which initiates thrombotic episodes associated with various diseases. In addition to membrane-bound TF, we have discovered an alternatively spliced form of human TF mRNA. It was later confirmed that this form of TF mRNA expresses a soluble protein circ...

270

AURANOFIN, AS AN ANTI-RHEUMATIC GOLD COMPOUND SUPPRESSES LPS-INDUCED HOMODIMERIZATION OF TLR4  

Technology Transfer Automated Retrieval System (TEKTRAN)

Toll-like receptors (TLRs), which are activated by invading microorganisms or endogenous molecules, evoke immune and inflammatory responses. TLR activation is closely linked to the development of many chronic inflammatory diseases including rheumatoid arthritis. Auranofin, an Au(I) compound, is a we...

271

?2Adrenergic receptor stimulation inhibits LPS-induced IL18 and IL12 production in monocytes  

Microsoft Academic Search

We examined the effects of ?2-adrenergic receptor (?2-AR) agonists on monocyte-derived cytokines, interleukin (IL)-18 and IL-12 production in lipopolysaccharide (LPS)-stimulated monocytes derived from human peripheral blood mononuclear cells (PBMCs), as in vitro model of sepsis. The study found that ?2-AR agonists inhibited IL-18 and IL-12 production in monocytes, and that AR agonist activity was antagonized by the selective ?2-AR antagonist,

Kenji Mizuno; Hideo Kohka Takahashi; Hiromi Iwagaki; Goutaro Katsuno; Huda A. S. M. Kamurul; Satoru Ohtani; Shuji Mori; Tadashi Yoshino; Masahiro Nishibori; Noriaki Tanaka

2005-01-01

272

ROLE OF CELL SIGNALING IN PROTECTION FROM DIESEL AND LPS INDUCED ACUTE LUNG INJURY  

EPA Science Inventory

We have previously demonstrated in CD-1 mice that pre-administration of N-acetyl cysteine (NAC) or the p38 MAP kinase inhibitor (SB203580) reduces acute lung injury and inflammation following pulmonary exposures to diesel exhaust particles (DEP) or lipopolysaccharide (LPS). Here ...

273

LPS-Induced Genes in Intestinal Tissue of the Sea Cucumber Holothuria glaberrima  

PubMed Central

Metazoan immunity is mainly associated with specialized cells that are directly involved with the immune response. Nevertheless, both in vertebrates and invertebrates other organs might respond to immune activation and participate either directly or indirectly in the ongoing immune process. However, most of what is known about invertebrate immunity has been restricted to immune effector cells and little information is available on the immune responses of other tissues or organs. We now focus on the immune reactions of the intestinal tissue of an echinoderm. Our study employs a non-conventional model, the echinoderm Holothuria glaberrima, to identify intestinal molecules expressed after an immune challenge presented by an intra-coelomic injection of lipopolysaccharides (LPS). The expression profiles of intestinal genes expressed differentially between LPS-injected animals and control sea water-injected animals were determined using a custom-made Agilent microarray with 7209 sea cucumber intestinal ESTs. Fifty (50) unique sequences were found to be differentially expressed in the intestine of LPS-treated sea cucumbers. Seven (7) of these sequences represented homologues of known proteins, while the remaining (43) had no significant similarity with any protein, EST or RNA database. The known sequences corresponded to cytoskeletal proteins (Actin and alpha-actinin), metabolic enzymes (GAPDH, Ahcy and Gnmt), metal ion transport/metabolism (major yolk protein) and defense/recognition (fibrinogen-like protein). The expression pattern of 11 genes was validated using semi-quantitative RT-PCR. Nine of these corroborated the microarray results and the remaining two showed a similar trend but without statistical significance. Our results show some of the molecular events by which the holothurian intestine responds to an immune challenge and provide important information to the study of the evolution of the immune response. PMID:19584914

Ramírez-Gómez, Francisco; Ortiz-Pineda, Pablo A.; Rivera-Cardona, Gabriela; García-Arrarás, José E.

2009-01-01

274

Evidence for the role of nitric oxide in caffeine-induced locomotor activity in mice  

Microsoft Academic Search

Rationale Nitric oxide (NO) is implicated in the acute locomotor activating effects of some addictive drugs such as amphetamine and cocaine, but has not been investigated in the case of caffeine. Objectives We investigated the effects of a nitric oxide synthase (NOS) inhibitor N?-Nitro-l-arginine methyl ester (l-NAME) and a combination of l-arginine, a NO precursor, and l-NAME on caffeine induced

Hakan Kayir; I. Tayfun Uzbay

2004-01-01

275

Inhibitory constituents of Sophora tonkinensis on nitric oxide production in RAW 264.7 macrophages.  

PubMed

Bioactivity-guided fractionation of the MeOH extract from the roots of Sophora tonkinensis resulted in the isolation of a new pterocarpan glycoside (1) together with nine known compounds, maackiain (2), sophoranone (3), sophoranochromene (4), pinoresinol (5), syringaresinol (6), medioresinol (7), 4',7-dihydroxyflavone (8), calycosin (9), and genistein (10). The structure of the new compound was determined on the basis of spectroscopic analysis including NMR and CD data in combination with acid hydrolysis. Compounds 1-4 exhibited the inhibitory effects on LPS-induced nitric oxide production with IC50 values ranging from 13.6 to 33.0?M in RAW 264.7 macrophages. PMID:25592708

Lee, Jin Woo; Lee, Ji Hoon; Lee, Chul; Jin, Qinghao; Lee, Dongho; Kim, Youngsoo; Hong, Jin Tae; Lee, Mi Kyeong; Hwang, Bang Yeon

2015-02-15

276

Indole alkaloids from the roots of Isatis indigotica and their inhibitory effects on nitric oxide production.  

PubMed

Three rare indole-2-S-glycosides, indole-3-acetonitrile-2-S-?-D-glucopyranoside (1), indole-3-acetonitrile-4-methoxy-2-S-?-D-glucopyranoside (2) and N-methoxy-indole-3-acetonitrile-2-S-?-D-glucopyranoside (3), together with 11 known indole alkaloids were isolated from the roots of Isatis indigotica Fort. (Cruciferae). The structures of 1-3 were elucidated on the basis of mass spectrometry and extensive 1D and 2D NMR spectroscopy. All of the isolated compounds were tested for inhibitory activity against LPS-induced nitric oxide production in RAW 264.7 macrophages. A plausible biosynthesis pathway of 1-3 is also proposed. PMID:24685504

Yang, Liguo; Wang, Guan; Wang, Meng; Jiang, Hongmei; Chen, Lixia; Zhao, Feng; Qiu, Feng

2014-06-01

277

Nitric oxide enhancement of melphalan-induced cytotoxicity.  

PubMed Central

The effects of the diatomic radical, nitric oxide (NO), on melphalan-induced cytotoxicity in Chinese hamster V79 and human MCF-7 breast cancer cells were studied using clonogenic assays. NO delivered by the NO-releasing agent (C2H5)2N[N(O)NO]- Na+ (DEA/NO; 1 mM) resulted in enhancement of melphalan-mediated toxicity in Chinese hamster V79 lung fibroblasts and human breast cancer (MCF-7) cells by 3.6- and 4.3-fold, respectively, at the IC50 level. Nitrite/nitrate and diethylamine, the ultimate end products of DEA/NO decomposition, had little effect on melphalan cytotoxicity, which suggests that NO was responsible for the sensitization. Whereas maximal sensitization of melphalan cytotoxicity by DEA/NO was observed for simultaneous exposure of DEA/NO and melphalan, cells pretreated with DEA/NO were sensitized to melphalan for several hours after NO exposure. Reversing the order of treatment also resulted in a time-dependent enhancement in melphalan cytotoxicity. To explore possible mechanisms of NO enhancement of melphalan cytotoxicity, the effects of DEA/NO on three factors that might influence melphalan toxicity were examined, namely NO-mediated cell cycle perturbations, intracellular glutathione (GSH) levels and melphalan uptake. NO pretreatment resulted in a delayed entry into S phase and a G2/M block for both V79 and MCF-7 cells; however, cell cycle redistribution for V79 cells occurred after the cells returned to a level of cell survival, consistent with treatment with melphalan alone. After 15 min exposure of V79 cells to DEA/NO (1 mM), GSH levels were reduced to 40% of control values; however, GSH levels recovered fully after 1 h and were elevated 2 h after DEA/NO incubation. In contrast, DEA/NO (1 mM) incubation did not reduce GSH levels significantly in MCF-7 cells (approximately 10%). Melphalan uptake was increased by 33% after DEA/NO exposure in V79 cells. From these results enhancement of melphalan cytotoxicity mediated by NO appears to be complex and may involve several pathways, including possibly alteration of the repair of melphalan-induced lesions. Our observations may give insights for improving tumour kill with melphalan using either exogenous or possibly endogenous sources of NO. PMID:9252199

Cook, J. A.; Krishna, M. C.; Pacelli, R.; DeGraff, W.; Liebmann, J.; Mitchell, J. B.; Russo, A.; Wink, D. A.

1997-01-01

278

Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death.  

PubMed Central

Nitric oxide produced by cytokine-inducible nitric oxide synthase (iNOS) is thought to be important in the pathogenesis of septic shock. To further our understanding of the role of iNOS in normal biology and in a variety of inflammatory disorders, including septic shock, we have used gene targeting to generate a mouse strain that lacks iNOS. Mice lacking iNOS were indistinguishable from wild-type mice in appearance and histology. Upon treatment with lipopolysaccharide and interferon gamma, peritoneal macrophages from the mutant mice did not produce nitric oxide measured as nitrite in the culture medium. In addition, lysates of these cells did not contain iNOS protein by immunoblot analysis or iNOS enzyme activity. In a Northern analysis of total RNA, no iNOS transcript of the correct size was detected. No increases in serum nitrite plus nitrate levels were observed in homozygous mutant mice treated with a lethal dose of lipopolysaccharide, but the mutant mice exhibited no significant survival advantage over wild-type mice. These results show that lack of iNOS activity does not prevent mortality in this murine model for septic shock. Images Fig. 2 Fig. 3 PMID:7479866

Laubach, V E; Shesely, E G; Smithies, O; Sherman, P A

1995-01-01

279

Energetic particle-induced enhancements of stratospheric nitric acid  

NASA Technical Reports Server (NTRS)

Inclusion of complete ion chemistry in the calculation of minor species production during energetic particle deposition events leads to significant enhancement in the calculated nitric acid concentration during precipitation. An ionization rate of 1.2 x 10(exp 3)/cu cm/s imposed for 1 day increases HNO3 from 3 x 10(exp 5) to 6 x 10(exp 7)/cu cm at 50 km. With an ionization rate of 600 cu cm/s, the maximum HNO3 is 3 x 10(exp 7)/cu cm. Calculations which neglect negative ions predict the nitric acid will fall during precipitation events. The decay time for converting HNO3 into odd nitrogen and hydrogen is more than 1 day for equinoctial periods at 70 deg latitude. Examination of nitric acid data should yield important information on the magnitude and frequency of charged particle events.

Aikin, Arthur C.

1994-01-01

280

Time course and cellular localization of inducible nitric oxide synthases expression during cardiac allograft rejection  

Microsoft Academic Search

Background. We have demonstrated that inhibition of inducible nitric oxide synthase (NOS) ameliorated acute cardiac allograft rejection. This study determined the time course and cellular localization of inducible NOS expression during the histologic progression of unmodified acute rat cardiac allograft rejection.Methods. Tissue from syngeneic (ACI to ACI) and allogeneic (Lewis to ACI) transplants were harvested on postoperative days 3 through

Neil K Worrall; Thomas P Misko; Mitchell D Botney; Patrick M Sullivan; Jia-J Hui; Gloria M Suau; Pamela T Manning; T. Bruce Ferguson

1999-01-01

281

Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models  

PubMed Central

Background Neuroinflammation is important in the pathogenesis and progression of Alzheimer disease (AD). Previously, we demonstrated that lipopolysaccharide (LPS)-induced neuroinflammation caused memory impairments. In the present study, we investigated the possible preventive effects of 4-O-methylhonokiol, a constituent of Magnolia officinalis, on memory deficiency caused by LPS, along with the underlying mechanisms. Methods We investigated whether 4-O-methylhonokiol (0.5 and 1 mg/kg in 0.05% ethanol) prevents memory dysfunction and amyloidogenesis on AD model mice by intraperitoneal LPS (250 ?g/kg daily 7 times) injection. In addition, LPS-treated cultured astrocytes and microglial BV-2 cells were investigated for anti-neuroinflammatory and anti-amyloidogenic effect of 4-O-methylhonkiol (0.5, 1 and 2 ?M). Results Oral administration of 4-O-methylhonokiol ameliorated LPS-induced memory impairment in a dose-dependent manner. In addition, 4-O-methylhonokiol prevented the LPS-induced expression of inflammatory proteins; inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as activation of astrocytes (expression of glial fibrillary acidic protein; GFAP) in the brain. In in vitro study, we also found that 4-O-methylhonokiol suppressed the expression of iNOS and COX-2 as well as the production of reactive oxygen species, nitric oxide, prostaglandin E2, tumor necrosis factor-?, and interleukin-1? in the LPS-stimulated cultured astrocytes. 4-O-methylhonokiol also inhibited transcriptional and DNA binding activity of NF-?B via inhibition of I?B degradation as well as p50 and p65 translocation into nucleus of the brain and cultured astrocytes. Consistent with the inhibitory effect on neuroinflammation, 4-O-methylhonokiol inhibited LPS-induced A?1-42 generation, ?- and ?-secretase activities, and expression of amyloid precursor protein (APP), BACE1 and C99 as well as activation of astrocytes and neuronal cell death in the brain, in cultured astrocytes and in microglial BV-2 cells. Conclusion These results suggest that 4-O-methylhonokiol inhibits LPS-induced amyloidogenesis via anti-inflammatory mechanisms. Thus, 4-O-methylhonokiol can be a useful agent against neuroinflammation-associated development or the progression of AD. PMID:22339795

2012-01-01

282

Fertilizer-induced nitric oxide emissions from agricultural soils  

Microsoft Academic Search

We summarize and evaluate 23 studies of the effect of fertilizer use on nitric oxide (NO) emission from agricultural soils. To quantify this effect we selected only field-scale studies with duration of at least one complete growing season and excluded studies with a legume as the principle crop. Only 6 studies met the established criteria, resulting in a total of

Edzo Veldkamp; Michael Keller

1997-01-01

283

Flavonoid combinations cause synergistic inhibition of proinflammatory mediator secretion from lipopolysaccharide-induced RAW 264.7 cells  

Microsoft Academic Search

Objectives  We evaluated several flavonoid combinations for synergy in the inhibition of proinflammatory mediator synthesis in the RAW\\u000a 264.7 cellular model of inflammation.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  The inhibitory effect of chrysin, kaempferol, morin, silibinin, quercetin, diosmin and hesperidin upon nitric oxide (NO),\\u000a prostaglandin E2 (PGE2) and tumour necrosis factor-? (TNF-?) secretion from the LPS-induced RAW 264.7 monocytic macrophage was assessed and IC50 values obtained.

Omar A. Harasstani; Saidi Moin; Chau Ling Tham; Choi Yi Liew; Norazren Ismail; Revathee Rajajendram; Hanis H. Harith; Zainul A. Zakaria; Azam S. Mohamad; Mohamad R. Sulaiman; Daud A. Israf

2010-01-01

284

Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced release of nitric oxide  

Microsoft Academic Search

Administration of bacterial lipopolysaccharide (LPS) to laboratory animals and cultured macrophages is known to induce the production of nitric oxide (NO) from inducible nitric oxide synthase (iNOS). Here we show that pre-treatment with Ginkgo biloba extract (EGb 761) suppresses the in vivo production of NO (measured by the Griess reaction) after challenge with LPS. In order to begin to understand

Teri L Wadsworth; Dennis R Koop

2001-01-01

285

Intermittent fasting attenuates lipopolysaccharide-induced neuroinflammation and memory impairment  

PubMed Central

Background Systemic bacterial infections often result in enduring cognitive impairment and are a risk factor for dementia. There are currently no effective treatments for infection-induced cognitive impairment. Previous studies have shown that intermittent fasting (IF) can increase the resistance of neurons to injury and disease by stimulating adaptive cellular stress responses. However, the impact of IF on the cognitive sequelae of systemic and brain inflammation is unknown. Methods Rats on IF for 30 days received 1 mg/kg of lipopolysaccharide (LPS) or saline intravenously. Half of the rats were subjected to behavioral tests and the other half were euthanized two hours after LPS administration and the hippocampus was dissected and frozen for analyses. Results Here, we report that IF ameliorates cognitive deficits in a rat model of sepsis by a mechanism involving NF-?B activation, suppression of the expression of pro-inflammatory cytokines, and enhancement of neurotrophic support. Treatment of rats with LPS resulted in deficits in cognitive performance in the Barnes maze and inhibitory avoidance tests, without changing locomotor activity, that were ameliorated in rats that had been maintained on the IF diet. IF also resulted in reduced levels of mRNAs encoding the LPS receptor TLR4 and inducible nitric oxide synthase (iNOS) in the hippocampus. Moreover, IF prevented LPS-induced elevation of IL-1?, IL-1? and TNF-? levels, and prevented the LPS-induced reduction of BDNF levels in the hippocampus. IF also significantly attenuated LPS-induced elevations of serum IL-1?, IFN-?, RANTES, TNF-? and IL-6 levels. Conclusions Taken together, our results suggest that IF induces adaptive responses in the brain and periphery that can suppress inflammation and preserve cognitive function in an animal model of systemic bacterial infection. PMID:24886300

2014-01-01

286

Isolation of benzoic and cinnamic acid derivatives from the grains of Sorghum bicolor and their inhibition of lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells.  

PubMed

Two new caffeoylglycerols, (hwanggeumchal A-B, 9-10), together with eight known derivatives (1-8) were isolated from the grains of Sorghum bicolor (L.) Moench var. hwanggeumchal. Their chemical structures were established mainly by 1D and 2D NMR techniques and MS data analysis. Amongst those, methyl 3,4-dihydroxybenzoate (2), 3,4,5-trihydroxycinnamate (3), methyl 3,4-dihydroxycinnamate (5), caffeoylglycolic acid methyl ester (7) and 1-O-caffeoylglycerol (8) displayed potential inhibitory effects against LPS-induced NO production in macrophage RAW264.7 cells with IC50 values of 11.9, 2.9, 27.1, 29.0 and 18.5?M, respectively. Furthermore, these compounds dose-dependently reduced the LPS-induced iNOS expression. In addition, pre-incubation of cells with compounds 2, 3 and 5 significantly suppressed LPS-induced COX-2 protein expression. SAR investigation revealed that compounds with a methyl ester (COOCH3) group possessed stronger activity. Our obtained data suggest that S. bicolor and its caffeoylglyceride-enrich extracts may be applied as supplemental and/or functional foods having a beneficial effect against inflammation. PMID:25172742

Nguyen, Phi-Hung; Zhao, Bing Tian; Lee, Jeong Hyung; Kim, Young Ho; Min, Byung Sun; Woo, Mi Hee

2015-02-01

287

Leukaemia Inhibitory Factor Stimulates Proliferation of Olfactory Neuronal Progenitors via Inducible Nitric Oxide Synthase  

PubMed Central

Neurogenesis continues in the adult brain and in the adult olfactory epithelium. The cytokine, leukaemia inhibitory factor and nitric oxide are both known to stimulate neuronal progenitor cell proliferation in the olfactory epithelium after injury. Our aim here was to determine whether these observations are independent, specifically, whether leukaemia inhibitory factor triggers neural precursor proliferation via the inducible nitric oxide synthase pathway. We evaluated the effects of leukaemia inhibitory factor on inducible form of nitric oxide synthase (iNOS) expression, and cell proliferation in olfactory epithelial cell cultures and olfactory neurosphere-derived cells. Leukaemia inhibitory factor induced expression of iNOS and increased cell proliferation. An iNOS inhibitor and an anti-leukaemia inhibitory factor receptor blocking antibody inhibited leukaemia inhibitory factor-induced cell proliferation, an effect that was reversed by a NO donor. Altogether, the results strongly suggest that leukaemia inhibitory factor induces iNOS expression, increasing nitric oxide levels, to stimulate proliferation of olfactory neural precursor cells. This finding sheds light on neuronal regeneration occurring after injury of the olfactory epithelium. PMID:23024784

Lopez-Arenas, Estefania; Mackay-Sim, Alan; Bacigalupo, Juan; Sulz, Lorena

2012-01-01

288

A novel mechanism for inhibition of lipopolysaccharide-induced proinflammatory cytokine production by valproic acid.  

PubMed

The inhibitory effect of valproic acid (VPA) on lipopolysaccharide (LPS)-induced inflammatory response was studied by using mouse RAW 264.7 macrophage-like cells. VPA pretreatment attenuated LPS-induced phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt, but not nuclear factor (NF)-?B and mitogen-activated protein kinases. VPA reduced phosphorylation of MDM2, an ubiquitin ligase and then prevented LPS-induced p53 degradation, followed by enhanced p53 expression. Moreover, p53 small interfering RNA (siRNA) abolished the inhibitory action of VPA on LPS-induced NF-?B p65 transcriptional activation and further LPS-induced tumor necrosis factor (TNF)-? and interleukin (IL)-6 production. VPA prevented LPS-induced degradation of phosphatase and tensin homologue deleted on chromosome ten (PTEN) and up-regulated the PTEN expression. Taken together, VPA was suggested to down-regulate LPS-induced NF-?B-dependent transcriptional activity via impaired PI3K/Akt/MDM2 activation and enhanced p53 expression. A detailed mechanism for inhibition of LPS-induced inflammatory response by VPA is discussed. PMID:24631367

Jambalganiin, Ulziisaikhan; Tsolmongyn, Bilegtsaikhan; Koide, Naoki; Odkhuu, Erdenezaya; Naiki, Yoshikazu; Komatsu, Takayuki; Yoshida, Tomoaki; Yokochi, Takashi

2014-05-01

289

The role of nitric oxide in digoxin-induced arrhythmias in guinea-pigs.  

PubMed

We have investigated the effects of nitric oxide synthase inhibitor (L-NAME), nitric oxide precursor (L-arginine) and nitric oxide donor (sodium nitroprusside) on digoxin-induced arrhythmias both in guinea-pig isolated hearts and in anaesthetised animals. Sodium nitroprusside (0.1 mumol kg-1 min.-1 for 70 min.) caused a marked inhibition in mortality and arrhythmia score but L-NAME (10 mg kg-1) and L-arginine (30 mg kg-1 intravenous bolus followed by 10 mg kg-1 min.-1 for 60 min.) treatments were ineffective in anaesthetised guinea-pigs. None of the drugs markedly affected the time of onset of first arrhythmias or ventricular fibrillation incidence. In isolated heart experiments, nitric oxide generated by either L-arginine (1 mM) or sodium nitroprusside (1 mM) significantly reduced the arrhythmia score whereas L-NAME (1 mM) had no effect. Ventricular fibrillation incidence was totally abolished by sodium nitroprusside and none of the hearts treated with L-arginine had an irreversible ventricular fibrillation. L-NAME decreased ventricular tachycardia duration but increased ventricular fibrillation duration. There were no marked changes in the time of onset of first arrhythmias with these drugs in in vitro experiments. These results suggest that nitric oxide may play a modulatory role in the digoxin-induced arrhythmias in guinea-pigs. PMID:9974183

Altu?, S; Uzun, O; Demiryürek, A T; Cakici, I; Abacio?lu, N; Kanzik, I

1999-01-01

290

Five withanolides from the leaves of Datura metel L. and their inhibitory effects on nitric oxide production.  

PubMed

Four new withanolides named dmetelins A-D (compounds 1-4), along with the known compound 7?,27-dihydroxy-1-oxo-witha-2,5,24-trienolide (5) were isolated from the leaves of Datura metel L. (Solanaceae). Their structures were elucidated on the basis of detailed analysis of 1D and 2D NMR and mass spectrometry data. All the compounds were evaluated for their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells. Compounds 1, 4 and 5 showed significant inhibitory activities, and compounds 2 and 3 showed moderate inhibitory activities with IC50 values of 17.8, 11.6, 14.9, 33.3 and 28.6 ?M, respectively. PMID:24731984

Yang, Bing-You; Guo, Rui; Li, Ting; Liu, Yan; Wang, Chang-Fu; Shu, Zun-Peng; Wang, Zhi-Bin; Zhang, Jing; Xia, Yong-Gang; Jiang, Hai; Wang, Qiu-Hong; Kuang, Hai-Xue

2014-01-01

291

Endotoxin-Induced Uveitis in the Rat Is Attenuated by Inhibition of Nitric Oxide Production  

Microsoft Academic Search

Purpose. These experiments were undertaken to assess the role of increased nitric oxide pro- duction in the pathogenesis of vascular dysfunction associated with endotoxin-induced uveitis. Methods. Lipopolysaccharides (LPS) (100 ng of Salmonella Minnesota) was injected into foot- pads of Lewis rats randomly assigned to an untreated group or to a group treated with subcuta- neous injections of aminoguanidine, a selective

Ronald G. Tilton; Kathy Chang; John A. Corbett; Thomas P. Misko; Mark G. Currie; Nalini S. Bora; Henry J. Kaplan; Joseph R. Williamson

1994-01-01

292

Intersection of Interferon and Hypoxia Signal Transduction Pathways in Nitric Oxide-induced Tumor Apoptosis1  

Microsoft Academic Search

Activated macrophages play a central role in antitumor immunity. However, the stimuli that activate macrophages to kill tumor cells are not completely understood. Because the center of solid tumors can be hypoxic, we hypothesized that hypoxia may be an important signal in activating macrophages to kill tumor cells. Hypoxia stimulates IFN-primed macro- phages to express the inducible nitric oxide synthase

Drory S. Tendler; Clare Bao; Tianhong Wang; Eric L. Huang; Edward A. Ratovitski; Drew A. Pardoll; Charles J. Lowenstein

2001-01-01

293

Effect of allicin and ajoene, two compounds of garlic, on inducible nitric oxide synthase  

Microsoft Academic Search

Inducible nitric oxide synthase (iNOS) has recently been shown to be present in human atherosclerotic lesions and to promote the formation of deleterious peroxynitrite. Allicin and ajoene are discussed as active compounds with regard to the beneficial effects of garlic in atherosclerosis. The aim of this study was to investigate the effect of allicin and ajoene on the iNOS system

Verena M Dirsch; Alexandra K Kiemer; Hildebert Wagner; Angelika M Vollmar

1998-01-01

294

The Mosquito Anopheles stephensi Limits Malaria Parasite Development with Inducible Synthesis of Nitric Oxide  

Microsoft Academic Search

We have discovered that the mosquito Anopheles stephensi, a natural vector of human malaria, limits parasite development with inducible synthesis of nitric oxide (NO). Elevated expression of A. stephensi NO synthase (NOS), which is highly homologous to characterized NOS genes, was detected in the midgut and carcass soon after invasion of the midgut by Plasmodium. Early induction is likely primed

Shirley Luckhart; Yoram Vodovotz; Liwang Cui; Ronald Rosenberg

1998-01-01

295

The effects of synthetic organoselenium compounds on nitric oxide in DMBA-induced rat liver.  

PubMed

DMBA (7, 12-dimethylbenz[a]anthracene) is known to generate DNA-reactive species during their metabolism, which may enhance oxidative stress in cells. Since selenium is known as a non-enzymic antioxidant, health problems induced by many environmental pollutants, have stimulated the evaluation of relative antioxidant potential of selenium and synthetic organoselenium compounds. Therefore, we aimed to evaluate chemopreventive potential of synthetic organoselenium compounds by monitoring level of liver nitric oxide. In this study, adult female Wistar rats were treated with DMBA and the novel organoselenium compounds (Se I) and (Se II) in the determined doses. DMBA-induced in rats, the effects of organoselenium compounds on nitric oxide levels in rat liver was studied. In this study it has been observed a statistically significant increase in (Nitric Oxide) levels for the liver of rat exposed to DMBA (p<0.05). However with administration of Se I and Se II there was a statistically significant decrease in NO levels (p<0.05). The ability of the organoselenium compounds to prevent oxidative damage induced by DMBA in rat livers was rationalized. Protection against nitric oxide measured in Se I and Se II treated groups were provided by synthesized organoselenium compounds. Se I and Se II both provided chemoprevention against DMBA-induced oxidative stress in rat liver. PMID:20120501

Talas, Zeliha Selamoglu; Bayraktar, Nihayet; Ozdemir, Ilknur; Gok, Yetkin; Yilmaz, Ismet

2009-07-01

296

The Natural Product Noformycin Is an Inhibitor of Inducible-Nitric Oxide Synthase  

Microsoft Academic Search

Inducible-Nitric oxide synthase (iNOS, EC 1.14.13.39) catalyzes the formation of nitric oxide (NO) andL-citrulline fromL-Arg, NADPH and dioxygen. The natural product, (?)-noformycin was found to be a potent, competitive inhibitor of recombinant human iNOS with respect toL-Arg with aKi= 1.3 ± 0.3 ?M. The reversible binding of noformycin caused a high spin type I spectral perturbation of the iNOS heme

Barbara Gordon Green; Renee Chabin; Stephan K. Grant

1996-01-01

297

Anmindenols A and B, inducible nitric oxide synthase inhibitors from a marine-derived Streptomyces sp.  

PubMed

Anmindenols A (1) and B (2), inhibitors of inducible nitric oxide synthase (iNOS), were isolated from a marine-derived bacterium Streptomyces sp. Their chemical structures were elucidated by interpreting various spectroscopic data, including IR, MS, and NMR. Anmindenols A and B are sesquiterpenoids possessing an indene moiety with five- and six-membered rings derived from isoprenyl units. The absolute configuration of C-4 in anmindenol B was determined by electronic circular dichroism (ECD) of a dimolybdenum complex. Anmindenols A (1) and B (2) inhibited nitric oxide production in stimulated RAW 264.7 macrophage cells with IC50 values of 23 and 19 ?M, respectively. PMID:24878306

Lee, Jihye; Kim, Hiyoung; Lee, Tae Gu; Yang, Inho; Won, Dong Hwan; Choi, Hyukjae; Nam, Sang-Jip; Kang, Heonjoong

2014-06-27

298

Regulatory Effect of 25-hydroxyvitamin D3 on Nitric Oxide Production in Activated Microglia  

PubMed Central

Microglia are activated by inflammatory and pathophysiological stimuli in neurodegenerative diseases, and activated microglia induce neuronal damage by releasing cytotoxic factors like nitric oxide (NO). Activated microglia synthesize a significant amount of vitamin D3 in the rat brain, and vitamin D3 has an inhibitory effect on activated microglia. To investigate the possible role of vitamin D3 as a negative regulator of activated microglia, we examined the effect of 25-hydroxyvitamin D3 on NO production of lipopolysaccharide (LPS)-stimulated microglia. Treatment with LPS increased the production of NO in primary cultured and BV2 microglial cells. Treatment with 25-hydroxyvitamin D3 inhibited the generation of NO in LPS-activated primary microglia and BV2 cells. In addition to NO production, expression of 1-?-hydroxylase and the vitamin D receptor (VDR) was also upregulated in LPS-stimulated primary and BV2 microglia. When BV2 cells were transfected with 1-?-hydroxylase siRNA or VDR siRNA, the inhibitory effect of 25-hydroxyvitamin D3 on activated BV2 cells was suppressed. 25-Hydroxyvitamin D3 also inhibited the increased phosphorylation of p38 seen in LPS-activated BV2 cells, and this inhibition was blocked by VDR siRNA. The present study shows that 25-hydroxyvitamin D3 inhibits NO production in LPS-activated microglia through the mediation of LPS-induced 1-?-hydroxylase. This study also shows that the inhibitory effect of 25-hydroxyvitamin D3 on NO production might be exerted by inhibiting LPS-induced phosphorylation of p38 through the mediation of VDR signaling. These results suggest that vitamin D3 might have an important role in the negative regulation of microglial activation. PMID:25352759

Hur, Jinyoung; Lee, Pyeongjae; Kim, Mi Jung

2014-01-01

299

Regulation of Injury-Induced Neurogenesis by Nitric Oxide  

PubMed Central

The finding that neural stem cells (NSCs) are able to divide, migrate, and differentiate into several cellular types in the adult brain raised a new hope for restorative neurology. Nitric oxide (NO), a pleiotropic signaling molecule in the central nervous system (CNS), has been described to be able to modulate neurogenesis, acting as a pro- or antineurogenic agent. Some authors suggest that NO is a physiological inhibitor of neurogenesis, while others described NO to favor neurogenesis, particularly under inflammatory conditions. Thus, targeting the NO system may be a powerful strategy to control the formation of new neurons. However, the exact mechanisms by which NO regulates neural proliferation and differentiation are not yet completely clarified. In this paper we will discuss the potential interest of the modulation of the NO system for the treatment of neurodegenerative diseases or other pathological conditions that may affect the CNS. PMID:22997523

Carreira, Bruno P.; Carvalho, Caetana M.; Araújo, Inęs M.

2012-01-01

300

Quercetin and its principal metabolites, but not myricetin, oppose lipopolysaccharide-induced hyporesponsiveness of the porcine isolated coronary artery  

PubMed Central

BACKGROUND AND PURPOSE Quercetin is anti-inflammatory in macrophages by inhibiting lipopolysaccharide (LPS)-mediated increases in cytokine and nitric oxide production but there is little information regarding the corresponding effect on the vasculature. We have examined the effect of quercetin, and its principal human metabolites, on inflammatory changes in the porcine isolated coronary artery. EXPERIMENTAL APPROACH Porcine coronary artery segments were incubated overnight at 37°C in modified Krebs-Henseleit solution with or without 1 µg·mL?1 LPS. Some segments were also co-incubated with quercetin-related flavonoids or Bay 11-7082, an inhibitor of NF?B. Changes in isometric tension of segments to vasoconstrictor and vasodilator agents were recorded. Nitrite content of the incubation solution was estimated using the Griess reaction, while inducible nitric oxide synthase was identified immunohistochemically. KEY RESULTS Lipopolysaccharide reduced, by 35–50%, maximal contractions to KCl and U46619, thromboxane A2 receptor agonist, and impaired endothelium-dependent relaxations to substance P. Nitrite content of the incubation medium increased 3- to 10-fold following exposure to LPS and inducible nitric oxide synthase was detected in the adventitia. Quercetin (0.1–10 µM) opposed LPS-induced changes in vascular responses, nitrite production and expression of inducible nitric oxide synthase. Similarly, 10 µM Bay 11-7082, 10 µM quercetin 3?-sulphate and 10 µM quercetin 3-glucuronide prevented LPS-induced changes, while myricetin (10 µM) was inactive. Myricetin (10 µM) prevented quercetin-induced modulation of LPS-mediated nitrite production. CONCLUSION AND IMPLICATIONS Quercetin, quercetin 3?-suphate and quercetin 3-glucuronide, exerted anti-inflammatory effects on the vasculature, possibly through a mechanism involving inhibition of NF?B. Myricetin-induced antagonism of the effect of anti-inflammatory action of quercetin merits further investigation. PMID:21375526

Al-Shalmani, Salmin; Suri, Sunita; Hughes, David A; Kroon, Paul A; Needs, Paul W; Taylor, Moira A; Tribolo, Sandra; Wilson, Vincent G

2011-01-01

301

Inhibitory effects of N-(substituted benzoylamino)-4-ethyl-1,2,3,6-tetrahydropyridines on nitric oxide generation in stimulated raw 264.7 macrophages.  

PubMed

There has been great interest in reactive nitrogen intermediates and nitric oxide production in macrophages, particularly because of their contributory role in several pathophysiological conditions during acute and chronic inflammation. Several N-(substituted benzoylamino)-4-ethyl-1,2,3,6-tetrahydropyridines were previously synthesized as potential antiinflammatory agents. In the present study, the effects of four previously synthesized tetrahydropyridines (THPs) on cyclooxygenase (COX)-1 and COX-2 were screened and the effects of these compounds on lipopolysaccharide (LPS)-induced (2 micrograms/ml) nitric oxide and inducible nitric oxide synthase (iNOS) activity in RAW 264.7 macrophages were examined. 4-Bromo THP showed 9.4 microM of IC50 as the most potent derivative among the tested THPs followed by 4-nbuthyl, 4-fuoro, and 4-methyl THP with IC50 values of 30.9, 38.9 and 80.3 microM, respectively (indomethacin IC50 = 53.8 microM). None of the tested compounds showed cytotoxic effects to the RAW 264.7 macrophages. All of the tested THPs exhibited COX-1 and COX-2 nonselective inhibition. These results suggest that previously synthesized THP derivatives may have dual effects through inhibiting both COX and nitric oxide by inhibiting iNOS. PMID:12224381

Yoon, K; Soliman, K; Redda, K

2002-01-01

302

Anisodamine Counteracts Lipopolysaccharide-Induced Tissue Factor and Plasminogen Activator Inhibitor1 Expression in Human Endothelial Cells: Contribution of the NF-?B Pathway  

Microsoft Academic Search

In this study we aimed to investigate whether the therapeutic efficacy of anisodamine in the treatment of bacteraemic shock could – at least in part – be brought about by its direct interference with the lipopolysaccharide (LPS)-induced activation of endothelial cells. Thus, we investigated the effect of anisodamine on LPS-induced expression of plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF),

Qiu-Rong Ruan; Wei-Jian Zhan g; Peter Hufnagl; Christoph Kaun; Bernd R. Binder; Johann Wojta

2001-01-01

303

Dual role of inducible nitric oxide synthase in acute asbestos-induced lung injury.  

PubMed

Reactive oxygen and nitrogen species have been implicated in the pathogenesis of asbestos fibers-associated pulmonary diseases. By comparing the responses of inducible nitric oxide synthase (iNOS) knockout and wild-type mice we investigated the consequences of iNOS expression for the development of the inflammatory response and tissue injury upon intratracheal instillation of asbestos fibers. Exposure to asbestos fibers resulted in an increased iNOS mRNA and protein expression in the lungs from wild-type mice. Moreover, iNOS knockout mice exhibited an exceeded pulmonary expression and production of TNF-alpha as well as a higher influx of neutrophils into the alveolar space than wild-type mice. In contrast, iNOS knockout animals displayed an attenuated oxidant-related tissue injury reflected in a decrease in protein leakage and LDH release into the alveolar space as well as weaker nitrotyrosine staining of lung tissue compared to wild-type mice. Data presented here indicate that iNOS-derived NO exerts a dichotomous role in acute asbestos-induced lung injury in that iNOS deficiency resulted in an exacerbated inflammatory response but improved oxidant-promoted lung tissue damage. PMID:12160931

Dörger, Martina; Allmeling, Anne-Marie; Kiefmann, Rainer; Schropp, Alke; Krombach, Fritz

2002-08-15

304

Extract of Meretrix meretrix Linnaeus induces angiogenesis in vitro and activates endothelial nitric oxide synthase  

NASA Astrophysics Data System (ADS)

Meretrix meretrix Linnaeus has long been used as traditional Chinese medicine in oriental medicine. The angiogentic activity of the extract of M. meretrix was investigated in this study, using human umbilical vein endothelial cells (HUVECs). Extract of M. meretrix Linnaeus (AFG-25) was prepared with acetone and ethanol precipitation, and further separated by Sephadex G-25 column. The results show that AFG-25 promoted proliferation, migration, and capillary-like tube formation in HUVECs, and in the presence of eNOS inhibitor NMA, the tube formation induced by AFG-25 is inhibited significantly. Moreover, AFG-25 could also promote the activation of endothelial nitric oxide synthase (eNOS) and the resultant elevation of nitric oxide (NO) production. The results suggested that M. meretrix contains active ingredients with angiogentic activity and eNOS/NO signal pathway is in part involved in the proangiogenesis effect induced by AFG-25.

Liu, Ming; Wei, Jianteng; Wang, Hui; Ding, Lili; Zhang, Yuyan; Lin, Xiukun

2012-09-01

305

Suppression of Bleomycin-Induced Nitric Oxide Production in Mice by Taurine and Niacin  

Microsoft Academic Search

The effects of taurine (T) and niacin (N) on the influx of inflammatory cells and nitric oxide (NO) levels in bronchoalveolar lavage fluid (BALF) and expression of inducible NO synthase (iNOS) mRNA and iNOS protein in lungs were evaluated in the bleomycin (BL)–mouse model of lung fibrosis. Mice were placed into four groups: saline-instilled (SA) with a control diet (CD)

G. Gurujeyalakshmi; Yingjin Wang; Shri N. Giri

2000-01-01

306

Antidepressants inhibit interferon-?-induced microglial production of IL6 and nitric oxide  

Microsoft Academic Search

Circumstantial evidence has suggested that activated microglia may be associated with the pathogenesis of depression. Pro-inflammatory cytokines may also be involved. Therefore, we examined the effects of various types of antidepressants, as well as the mood-stabilizer lithium chloride, on interferon-? (IFN-?)-induced microglial production of the pro-inflammatory mediators interleukin-6 (IL-6) and nitric oxide (NO). Treatment of the murine microglial 6-3 cells

Sadayuki Hashioka; Andis Klegeris; Akira Monji; Takahiro Kato; Makoto Sawada; Patrick L. McGeer; Shigenobu Kanba

2007-01-01

307

Expression of Inducible Nitric Oxide Synthase Is Increased in Acute Myeloid Leukaemia  

Microsoft Academic Search

Significant activity of inducible nitric oxide synthase (iNOS) has been reported in tumour cells, including chronic lymphoid leukaemic cells. In this study, we analysed the expression of iNOS in 15 untreated patients with acute myeloid leukaemia (AML) and in 7 normal controls. Using flow cytometry and immunocytochemistry, we demonstrated that patients with AML had a high expression of iNOS when

Marcelo Mendes Brandăo; Elisabeth Soares; Tereza S. I. Salles; Sara T. O. Saad

2001-01-01

308

Involvement of Nitric Oxide, Neurotrophins and HPA Axis in Neurobehavioural Alterations Induced by Prenatal Stress.  

PubMed

Several studies suggest that negative emotions during pregnancy generate adverse effects on the cognitive, behavioural and emotional development of the descendants. The psychoneuroendocrine pathways involve the transplacentary passage of maternal glucocorticoids in order to influence directly on fetal growth and brain development.Nitric oxide is a gaseous neurotransmitter that plays an important role in the control of neural activity by diffusing into neurons and participates in learning and memory processes. It has been demonstrated that nitric oxide is involved in the regulation of corticosterone secretion. Thus, it has been found that the neuronal isoform of nitric oxide synthase (nNOS) is an endogenous inhibitor of glucocorticoid receptor (GR) in the hippocampus and that nNOS in the hippocampus may participate in the modulation of hypothalamic-pituitary-adrenal axis activity via GR.Neurotrophins are a family of secreted growth factors consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and NT4. Although initially described in the nervous system, they regulate processes such as cell survival, proliferation and differentiation in several other compartments. It has been demonstrated that the NO-citrulline cycle acts together with BDNF in maintaining the progress of neural differentiation.In the present chapter, we explore the interrelation between nitric oxide, glucocorticoids and neurotrophins in brain areas that are key structures in learning and memory processes. The participation of this interrelation in the behavioural and cognitive alterations induced in the offspring by maternal stress is also addressed. PMID:25287536

Maur, Damian G; Pascuan, Cecilia G; Genaro, Ana M; Zorrilla-Zubilete, Maria A

2015-01-01

309

Inducible Nitric Oxide Synthase Contributes to Ventilator-induced Lung Injury  

PubMed Central

Rationale: Inducible nitric oxide synthase (iNOS) has been implicated in the development of acute lung injury. Recent studies indicate a role for mechanical stress in iNOS and endothelial NOS (eNOS) regulation. Objectives: This study investigated changes in lung NOS expression and activity in a mouse model of ventilator-induced lung injury. Methods: C57BL/6J (wild-type [WT]) and iNOS-deficient (iNOS?/?) mice received spontaneous ventilation (control) or mechanical ventilation (MV; VT of 7 and 20 ml/kg) for 2 hours, after which NOS gene expression and activity were determined and pulmonary capillary leakage assessed by the Evans blue albumin assay. Results: iNOS mRNA and protein expression was absent in iNOS?/? mice, minimal in WT control mice, but significantly upregulated in response to 2 hours of MV. In contrast, eNOS protein was decreased in WT mice, and nonsignificantly increased in iNOS?/? mice, as compared with control animals. iNOS and eNOS activities followed similar patterns in WT and iNOS?/? mice. MV caused acute lung injury as suggested by cell infiltration and nitrotyrosine accumulation in the lung, and a significant increase in bronchoalveolar lavage cell count in WT mice, findings that were reduced in iNOS?/? mice. Finally, Evans blue albumin accumulation in lungs of WT mice was significant (50 vs. 15% increase in iNOS?/? mice compared with control animals) in response to MV and was prevented by treatment of the animals with the iNOS inhibitor aminoguanidine. Conclusion: Taken together, our results indicate that iNOS gene expression and activity are significantly upregulated and contribute to lung edema in ventilator-induced lung injury. PMID:15937288

Peng, Xinqi; Abdulnour, Raja-Elie E.; Sammani, Saad; Ma, Shwu-Fan; Han, Eugenia J.; Hasan, Emile J.; Tuder, Rubin; Garcia, Joe G. N.; Hassoun, Paul M.

2005-01-01

310

Histone deacetylase inhibitor, butyrate, attenuates lipopolysaccharide-induced acute lung injury in mice  

PubMed Central

Background Histone deacetylase (HDAC) inhibitors, developed as promising anti-tumor drugs, exhibit their anti-inflammatory properties due to their effects on reduction of inflammatory cytokines. Objective To investigate the protective effect of butyrate, a HDAC inhibitor, on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Methods ALI was induced in Balb/c mice by intratracheally instillation of LPS (1 mg/kg). Before 1 hour of LPS administration, the mice received butyrate (10 mg/kg) orally. The animals in each group were sacrificed at different time point after LPS administration. Pulmonary histological changes were evaluated by hematoxylin-eosin stain and lung wet/dry weight ratios were observed. Concentrations of interleukin (IL)-1? and tumor necrosis factor (TNF)-? in bronchoalveolar lavage fluid (BALF) and concentrations of nitric oxide (NO) and myeloperoxidase (MPO) activity in lung tissue homogenates were measured by enzyme-linked immunosorbent assay (ELISA). Expression of nuclear factor (NF)-?B p65 in cytoplasm and nucleus was determined by Western blot analysis respectively. Results Pretreatment with butyrate led to significant attenuation of LPS induced evident lung histopathological changes, alveolar hemorrhage, and neutrophils infiltration with evidence of reduced MPO activity. The lung wet/dry weight ratios, as an index of lung edema, were reduced by butyrate administration. Butyrate also repressed the production of TNF-?, IL-1? and NO. Furthermore, the expression of NF-?B p65 in nucleus was markedly suppressed by butyrate pretreatment. Conclusions Butyrate had a protective effect on LPS-induced ALI, which may be related to its effect on suppression of inflammatory cytokines production and NF-?B activation. PMID:20302656

2010-01-01

311

Vaccinium myrtillus ameliorates unpredictable chronic mild stress induced depression: possible involvement of nitric oxide pathway.  

PubMed

Chronic unpredictable stressors can produce a situation similar to clinical depression and such animal models can be used for the preclinical evaluation of antidepressants. Nitric oxide, a secondary messenger molecule, has been implicated in neurotransmission, synaptic plasticity, learning, aggression and depression. Vaccinium myrtillus (bilberry) extract is a potent inhibitor of reactive oxygen/nitrogen species and cytokine production. The present study investigated the role of nitric oxide in the antidepressant action of Vaccinium myrtillus in unpredictable chronic mild stress-induced depression in mice. Animals were subjected to different stress paradigms daily for a period of 21 days to induce depressive-like behavior. Pretreatment with L-arginine significantly reversed the protective effect of bilberry (500 mg/kg) on chronic stress-induced behavioral (immobility period, sucrose preference) and biochemical (lipid peroxidation and nitrite levels; endogenous antioxidant activities) in stressed mice. Furthermore, L-NAME (10 mg/kg) pretreatment with a sub-effective dose of bilberry (250 mg/kg) significantly potentiated the protective effect of bilberry extract. The study revealed that modulation of the nitric oxide pathway might be involved in antidepressant-like effects of Vaccinium myrtillus in stressed mice. PMID:22488796

Kumar, Baldeep; Arora, Vipin; Kuhad, Anurag; Chopra, Kanwaljit

2012-04-01

312

Auxin-induced nitric oxide, cGMP and gibberellins were involved in the gravitropism  

NASA Astrophysics Data System (ADS)

Gravitropism is the asymmetric growth or curvature of plant organs in response to gravistimulation. There is a complex signal transduction cascade which involved in the differential growth of plants in response to changes in the gravity vector. The role of auxin in gravitropism has been demonstrated by many experiments, but little is known regarding the molecular details of such effects. In our studies before, mediation of the gravitropic bending of soybean roots and rice leaf sheath bases by nitric oxide, cGMP and gibberellins, are induced by auxin. The asymmetrical distribution of nitric oxide, cGMP and gibberellins resulted from the asymmetrical synthesis of them in bending sites. In soybean roots, inhibitions of NO and cGMP synthesis reduced differential NO and cGMP accumulation respectively, which both of these effects can lead to the reduction of gravitropic bending. Gibberellin-induced OsXET, OsEXPA4 and OsRWC3 were also found involved in the gravitropic bending. These data indicated that auxin-induced nitric oxide, cGMP and gibberellins were involved in the gravitropism. More experiments need to prove the more detailed mechanism of them.

Cai, Weiming; Hu, Liwei; Hu, Xiangyang; Cui, Dayong; Cai, Weiming

313

Nitric oxide boosts TLR-4 mediated lipocalin 2 expression in chondrocytes.  

PubMed

Lipocalin 2 (LCN2) has recently emerged as a novel adipokine involved in different processes including arthritis and chondrocyte inflammatory response. However, little is known about its activity on chondrocyte homeostasis and its regulation by nitric oxide (NO) Hence, we performed a set of experiments aimed to achieve a better understanding of this relationship. Cell vitality was tested in the ATDC5 cell line by the MTT colorimetric assay. Protein expression and gene expression was evaluated by Western blot and real time RT-PCR, respectively. NO production (determined as nitrite accumulation) was assayed by the Griess reaction. First, we demonstrated that LCN2 decreased murine chondrocytes vitality. Next, LCN2 co-stimulation with LPS enhanced NOS2 protein expression by murine chondrocytes. In addition, inhibition of LPS-induced nitric oxide production by aminoguanidine, a selective NOS2 inhibitor, significantly reduced LPS-mediated LCN2 expression. In contrast, treatment of murine chondrocytes with sodium nitroprussiate (SNP), a classic NO donor, scarcely induced LCN2 expression. Intriguingly, SNP addition to LPS-challenged chondrocytes, treated with aminoguanidine, provoked a strong induction of LCN2 expression. Finally, murine ATDC5 cells, co-cultured with LPS pre-challenged macrophages, had higher LCN2 expression in comparison with murine chondrocytes co-cultured with non pre-challenged macrophages. In this work we have described for the first time that NO is able to exert a control on LCN2 expression, suggesting the existence of a feedback loop regulating its expression. PMID:23483583

Gómez, Rodolfo; Scotece, Morena; Conde, Javier; Lopez, Veronica; Pino, Jesus; Lago, Francisca; Gómez-Reino, Juan J; Gualillo, Oreste

2013-07-01

314

A Hypothesis: Hydrogen Sulfide Might Be Neuroprotective against Subarachnoid Hemorrhage Induced Brain Injury  

PubMed Central

Gases such as nitric oxide (NO) and carbon monoxide (CO) play important roles both in normal physiology and in disease. Recent studies have shown that hydrogen sulfide (H2S) protects neurons against oxidative stress and ischemia-reperfusion injury and attenuates lipopolysaccharides (LPS) induced neuroinflammation in microglia, exhibiting anti-inflammatory and antiapoptotic activities. The gas H2S is emerging as a novel regulator of important physiologic functions such as arterial diameter, blood flow, and leukocyte adhesion. It has been known that multiple factors, including oxidative stress, free radicals, and neuronal nitric oxide synthesis as well as abnormal inflammatory responses, are involved in the mechanism underlying the brain injury after subarachnoid hemorrhage (SAH). Based on the multiple physiologic functions of H2S, we speculate that it might be a promising, effective, and specific therapy for brain injury after SAH. PMID:24707204

Yu, Yong-Peng; Chi, Xiang-Lin; Liu, Li-Jun

2014-01-01

315

Exacerbated Transplant Arteriosclerosis in Inducible Nitric Oxide-Deficient Mice  

Microsoft Academic Search

Background—Inducible NO synthase (NOS2, or iNOS) is upregulated in grafts with transplant arteriosclerosis. However, the functional role of NOS2 in the pathogenesis of transplant arteriosclerosis remains unclear. NOS2 may regulate lesion development by modulating the early alloimmune response and\\/or late myointimal thickening. Methods and Results—To determine whether NOS2-mediated pathways protect against or promote transplant arterioscle- rosis, we used NOS2-deficient mice

Jorg Koglin; Troels Glysing-Jensen; John S. Mudgett; Mary E. Russell

2010-01-01

316

Macrophage and interleukin-1 induced nitric oxide production and cytostasis in hamster tumor cells varying in malignant potential.  

PubMed

Nitric oxide has been shown to contribute to cytotoxicity in mouse and rat tumor cells. In these studies we examined the role of nitric oxide in cytostasis in hamster tumor cells varying in their malignant potential. Spontaneously transformed hamster embryonic fibroblasts (STHE cells) with low metastatic activity produced significantly greater amounts of nitric oxide in response to interleukin-1 (IL-1) or lipopolysaccharide (LPS)-activated hamster alveolar macrophages (HAM) than did tumor cell lines with high experimental metastatic activity (HET-SR, HET-SR1, STHE-83/20 cells). HET-SR cells, which exhibit low spontaneous metastastic activity, also produced relatively high levels of nitric oxide in response to IL-1, whereas the response of the spontaneously metastatic lines, HET-SR1 and STHE-83/20 cells, was low. IL-1 and HAM also induced cytostasis in nitric oxide-producing STHE and HET-SR cells. However, the nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), had no effect on this activity. These findings, together with the observation that anti-tumor necrosis factor alpha antibody prevented HAM-mediated cytostasis in all of the tumor cell lines demonstrate that nitric oxide is not involved in hamster macrophage-induced tumor cell growth suppression. In contrast to HAM, rat alveolar macrophages, which produced nitric oxide in response to LPS, exerted similar levels of cytostasis toward all of the hamster tumor cell variants, an action that was blocked by L-NMMA in HET-SR, HET-SR1, and STHE-83/20 cells. Thus production of nitric oxide by hamster tumor cells is inversely correlated with their malignant potential. However, nitric oxide does not appear to be involved in IL-1- or HAM-mediated cytostasis toward hamster tumor cells. PMID:9103232

Lavnikova, N; Burdelya, L; Lakhotia, A; Patel, N; Prokhorova, S; Laskin, D L

1997-04-01

317

The naturally occurring flavolignan, deoxypodophyllotoxin, inhibits lipopolysaccharide-induced iNOS expression through the NF-kappaB activation in RAW264.7 macrophage cells.  

PubMed

Deoxypodophyllotoxin (DPT), a naturally occurring flavolignan with anti-inflammatory activity, was isolated from Anthriscus sylvestris HOFFM., and we examined its effects on the expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-stimulated, murine macrophage-like RAW264.7 cells. Western blot analysis performed with specific anti-iNOS antibodies showed that a decrease in nitric oxide (NO) was accompanied by a decrease in the iNOS protein level. To clarify the mechanistic basis for DPT's ability to inhibit iNOS induction, we examined the effect of DPT on nuclear factor (NF)-kappaB transcriptional activity and DNA binding activity. DPT potently suppressed both reporter gene activity and DNA binding activity. These findings suggest that DPT in RAW264.7 cells abolished LPS-induced iNOS expression by inhibiting the transcription factor, NF-kappaB. PMID:18591766

Jin, Meihua; Moon, Tae Chul; Quan, Zhejiu; Lee, Eunkyung; Kim, Yun Kyung; Yang, Ju Hae; Suh, Seok-Jong; Jeong, Tae Cheon; Lee, Seung Ho; Kim, Cheorl-Ho; Chang, Hyeun Wook

2008-07-01

318

Anti-inflammatory effect of Taraxacum officinale leaves on lipopolysaccharide-induced inflammatory responses in RAW 264.7 cells.  

PubMed

To investigate the efficacy and the mechanism of the anti-inflammatory effect of Taraxacum officinale leaves (TOLs), the effect of a methanol extract and its fractions recovered from TOLs on lipopolysaccharide (LPS)-induced responses was studied in the mouse macrophage cell line, RAW 264.7. Cells were pretreated with various concentrations of the methanol extract and its fractions and subsequently incubated with LPS (1 microg/mL). The levels of nitric oxide (NO), prostaglandin (PG) E(2), and pro-inflammatory cytokines including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 were determined using enzyme-linked immunosorbent assays. Expressions of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 and activation of mitogen-activated protein (MAP) kinases were analyzed using western blotting. The methanol extract and its fractions inhibited LPS-induced production of NO, pro-inflammatory cytokines, and PGE(2) in a dose-dependent manner. The chloroform fraction significantly suppressed production of NO, PGE(2), and two pro-inflammatory cytokines (TNF-alpha and IL-1beta) in a dose-dependent manner with 50% inhibitory concentration values of 66.51, 90.96, 114.76, and 171.06 microg/mL, respectively. The ethyl acetate fraction also inhibited production of the inflammatory molecules. The chloroform and ethyl acetate fractions reduced LPS-induced expressions of iNOS and COX-2 and activation of MAP kinases in a dose-dependent manner. Among the fractions of the methanol extract, the chloroform and ethyl acetate fractions exhibited the most effective anti-inflammatory activities. These results show that the anti-inflammatory effects of TOLs are probably due to down-regulation of NO, PGE(2), and pro-inflammatory cytokines and reduced expressions of iNOS and COX-2 via inactivation of the MAP kinase signal pathway. PMID:20673058

Koh, Yoon-Jeoung; Cha, Dong-Soo; Ko, Je-Sang; Park, Hyun-Jin; Choi, Hee-Don

2010-08-01

319

The Role of Photolabile Dermal Nitric Oxide Derivates in Ultraviolet Radiation (UVR)-Induced Cell Death  

PubMed Central

Human skin is exposed to solar ultraviolet radiation comprising UVB (280–315 nm) and UVA (315–400 nm) on a daily basis. Within the last two decades, the molecular and cellular response to UVA/UVB and the possible effects on human health have been investigated extensively. It is generally accepted that the mutagenic and carcinogenic properties of UVB is due to the direct interaction with DNA. On the other hand, by interaction with non-DNA chromophores as endogenous photosensitizers, UVA induces formation of reactive oxygen species (ROS), which play a pivotal role as mediators of UVA-induced injuries in human skin. This review gives a short overview about relevant findings concerning the molecular mechanisms underlying UVA/UVB-induced cell death. Furthermore, we will highlight the potential role of cutaneous antioxidants and photolabile nitric oxide derivates (NODs) in skin physiology. UVA-induced decomposition of the NODs, like nitrite, leads not only to non-enzymatic formation of nitric oxide (NO), but also to toxic reactive nitrogen species (RNS), like peroxynitrite. Whereas under antioxidative conditions the generation of protective amounts of NO is favored, under oxidative conditions, less injurious reactive nitrogen species are generated, which may enhance UVA-induced cell death. PMID:23344028

Opländer, Christian; Suschek, Christoph V.

2013-01-01

320

Endothelial nitric-oxide synthase activation generates an inducible nitric-oxide synthase-like output of nitric oxide in inflamed endothelium.  

PubMed

High levels of NO generated in the vasculature under inflammatory conditions are usually attributed to inducible nitric-oxide synthase (iNOS), but the role of the constitutively expressed endothelial NOS (eNOS) is unclear. In normal human lung microvascular endothelial cells (HLMVEC), bradykinin (BK) activates kinin B2 receptor (B2R) signaling that results in Ca(2+)-dependent activation of eNOS and transient NO. In inflamed HLMVEC (pretreated with interleukin-1? and interferon-?), we found enhanced binding of eNOS to calcium-calmodulin at basal Ca(2+) levels, thereby increasing its basal activity that was dependent on extracellular l-Arg. Furthermore, B2R stimulation generated prolonged high output eNOS-derived NO that is independent of increased intracellular Ca(2+) and is mediated by a novel G?(i)-, MEK1/2-, and JNK1/2-dependent pathway. This high output NO stimulated with BK was blocked with a B2R antagonist, eNOS siRNA, or eNOS inhibitor but not iNOS inhibitor. Moreover, B2R-mediated NO production and JNK phosphorylation were inhibited with MEK1/2 and JNK inhibitors or MEK1/2 and JNK1/2 siRNA but not with ERK1/2 inhibitor. BK induced Ca(2+)-dependent eNOS phosphorylation at Ser(1177), Thr(495), and Ser(114) in cytokine-treated HLMVEC, but these modifications were not dependent on JNK1/2 activation and were not responsible for prolonged NO output. Cytokine treatment did not alter the expression of B2R, G?(q/11), G?(i1,2), JNK, or eNOS. B2R activation in control endothelial cells enhanced migration, but in cytokine-treated HLMVEC it reduced migration. Both responses were NO-dependent. Understanding how JNK regulates prolonged eNOS-derived NO may provide new therapeutic targets for the treatment of disorders involving vascular inflammation. PMID:23255592

Lowry, Jessica L; Brovkovych, Viktor; Zhang, Yongkang; Skidgel, Randal A

2013-02-01

321

Nitric acid-induced surface disordering on ice.  

PubMed

We examined the interaction of HNO3 with water ice for partial pressures 2 × 10(-8) Torr to 1 × 10(-5) Torr and at temperatures from 216 to 256 K using (i) the surface-specific technique ellipsometry and (ii) a coated wall flow tube reactor, both coupled with chemical ionization mass spectrometry detection of HNO3 in the gas phase. Our ellipsometry results show that exposure to HNO3 induces surface disordering on ice at a range of environmentally relevant temperatures and HNO3 partial pressures, particularly in the vicinity of the boundary between the ice and the HNO3·3H2O phases. The coated wall flow tube studies indicate that the nature of HNO3 uptake changes from reversible adsorption to a continuous flux of HNO3 into the bulk in the presence of a disordered interfacial layer. These results have implications for atmospheric chemistry in the upper troposphere and in polar regions. PMID:23707989

Moussa, Samar G; Kuo, Min H; McNeill, V Faye

2013-07-14

322

Citral inhibits lipopolysaccharide-induced acute lung injury by activating PPAR-?.  

PubMed

Citral, a component of lemongrass oil, has been reported to have many pharmacological activities such as anti-bacterial and anti-inflammatory effects. However, the effects of citral on acute lung injury (ALI) and the molecular mechanisms have not been reported. The aim of this study was to detect the effects of citral on lipopolysaccharide (LPS)-induced acute lung injury and investigate the molecular mechanisms. LPS-induced acute lung injury model was used to detect the anti-inflammatory effect of citral in vivo. The alveolar macrophages were used to investigate the molecular mechanism of citral in vitro. The results showed that pretreatment with citral remarkably attenuated pulmonary edema, histological severities, TNF-?, IL-6 and IL-1? production in LPS-induced ALI in vivo. In vitro, citral inhibited LPS-induced TNF-?, IL-6 and IL-1? production in alveolar macrophages. LPS-induced NF-?B activation was also inhibited by citral. Furthermore, we found that citral activated PPAR-? and the anti-inflammatory effects of citral can be reversed by PPAR-? antagonist GW9662. In conclusion, this is the first to demonstrate that critral protects LPS-induced ALI in mice. The anti-inflammatory mechanism of citral is associated with activating PPAR-?, thereby inhibiting LPS-induced inflammatory response. PMID:25281205

Shen, Yongbin; Sun, Zhanfeng; Guo, Xiaotong

2015-01-15

323

Simvastatin Attenuates Contrast-Induced Nephropathy through Modulation of Oxidative Stress, Proinflammatory Myeloperoxidase, and Nitric Oxide  

PubMed Central

Contrast media- (CM-) induced nephropathy is a serious complication of radiodiagnostic procedures. Available data suggests that the development of prophylaxis strategies is limited by poor understanding of pathophysiology of CM-induced nephropathy. Present study was designed to determine the role of oxidative stress, myeloperoxidase, and nitric oxide in the pathogenesis of iohexol model of nephropathy and its modification with simvastatin (SSTN). Adult Sprague Dawley rats were divided into seven groups. After 24?h of water deprivation, all the rats except in control and SSTN-only groups were injected (10?ml/kg) with 25% glycerol. After 30?min, SSTN (15, 30, and 60?mg/kg) was administered orally, daily for 4 days. Twenty-four hours after the glycerol injection, iohexol was infused (8?ml/kg) through femoral vein over a period of 2?min. All the animals were sacrificed on day 5 and blood and kidneys were collected for biochemical and histological studies. The results showed that SSTN dose dependently attenuated CM-induced rise of creatinine, urea, and structural abnormalities suggesting its nephroprotective effect. A significant increase in oxidative stress (increased lipid hydroperoxides and reduced glutathione levels) and myeloperoxidase (MPO) and decreased nitric oxide in CM group were reversed by SSTN. These findings support the use of SSTN to combat CM-induced nephrotoxicity. PMID:23097681

Al-Otaibi, Ketab E.; Al Elaiwi, Abdulrahman M.; Tariq, Mohammad; Al-Asmari, Abdulrahman K.

2012-01-01

324

6-Dehydrogingerdione restrains lipopolysaccharide-induced inflammatory responses in RAW 264.7 macrophages.  

PubMed

6-Dehydrogingerdione (6-DG), one important component of ginger, has been reported to possess some medical effects, such as antitumor and antiatherosclerosis. Herein, the anti-inflammatory effects of 6-DG against lipopolysaccharides (LPS) induced pro-inflammation mediators in RAW 264.7 cells were investigated. Results show that 6-DG significantly attenuated inducible nitric oxide synthase (iNOS, NOS2), cyclooxygenase-2 (COX-2), interleukin-1? (IL-1?), interleukin 6 (IL-6), and tumor necrosis factor-? (TNF-?) in the LPS-mediated murine macrophages (RAW 264.7 cells). 6-DG inhibited LPS-induced phosphorylation of both p38 and nuclear factor of ? light polypeptide gene enhancer in B-cells inhibitor-? (I?B?), which further prevented p-p65 nuclear factor-?B (NF-?B-p65) translocation to the nucleus. Moreover, 6-DG increased the ratio of phosphorylated signal transducers and activators of transcription 1 (p-STAT1)/p-STAT3 and down-regulated the gene expression of IL-1?, IL-6, and IL-10. PMID:25162585

Huang, Shih-Han; Lee, Chien-Hsing; Wang, Hui-Min; Chang, Yu-Wei; Lin, Chun-Yu; Chen, Chung-Yi; Chen, Yen-Hsu

2014-09-17

325

Rabdosia japonica var. glaucocalyx Flavonoids Fraction Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Mice  

PubMed Central

Rabdosia japonica var. glaucocalyx (Maxim.) Hara, belonging to the Labiatae family, is widely used as an anti-inflammatory and antitumor drug for the treatment of different inflammations and cancers. Aim of the Study. To investigate therapeutic effects and possible mechanism of the flavonoids fraction of Rabdosia japonica var. glaucocalyx (Maxim.) Hara (RJFs) in acute lung injury (ALI) mice induced by lipopolysaccharide (LPS). Materials and Methods. Mice were orally administrated with RJFs (6.4, 12.8, and 25.6?mg/kg) per day for 7 days, consecutively, before LPS challenge. Lung specimens and the bronchoalveolar lavage fluid (BALF) were isolated for histopathological examinations and biochemical analysis. The level of complement 3 (C3) in serum was quantified by a sandwich ELISA kit. Results. RJFs significantly attenuated LPS-induced ALI via reducing productions of the level of inflammatory mediators (TNF-?, IL-6, and IL-1?), and significantly reduced complement deposition with decreasing the level of C3 in serum, which was exhibited together with the lowered myeloperoxidase (MPO) activity and nitric oxide (NO) and protein concentration in BALF. Conclusions. RJFs significantly attenuate LPS-induced ALI via reducing productions of proinflammatory mediators, decreasing the level of complement, and reducing radicals. PMID:25013450

Xu, Nai-yu; Li, Xian-lun; Xia, Long; Zhang, Jian; Liang, Zhi-tao; Zhao, Zhong-zhen; Chen, Dao-feng

2014-01-01

326

The inhibition of lipopolysaccharide-induced macrophage inflammation by 4 compounds in Hypericum perforatum extract is partially dependent on the activation of SOCS3  

PubMed Central

Our previous studies found that 4 compounds, namely pseudohypericin, amentoflavone, quercetin, and chlorogenic acid in Hypericum perforatum ethanol extract synergistically inhibited lipopolysaccharide (LPS)-induced macrophage production of prostaglandin E2 (PGE2). Microarray studies led us to hypothesize that these compounds inhibited PGE2 production by activating suppressor of cytokine signaling 3 (SOCS3). In the current study we used siRNA to knockdown the expression of SOCS3 in RAW 264.7 macrophages and investigated the impact of H. perforatum extract and the 4 compounds on inflammatory mediators and cytokines. We found SOCS3 knockdown significantly compromised the inhibition of PGE2 and nitric oxide (NO) by the 4 compounds, but not by the extract. The 4 compounds, but not the extract decreased interleukin-6 (IL-6) and tumor necrosis factor-? (TNF-?), while both of them lowered interleukine-1?. SOCS3 knockdown further decreased IL-6 and TNF-?. Pseudohypericin was the major contributor to the PGE2 and NO inhibition in cells treated with the 4 compounds and its activity was lost with SOCS3 knockdown. Cyclooxygenase-2 (COX-2) and inducible NO synthase protein expression were not altered by the treatments, while COX-2 activity was decreased by the extract and the 4 compounds and increased by SOCS3 knockdown. In summary, we demonstrated that the 4 compounds inhibited LPS-induced PGE2 and NO through SOCS3 activation. The reduction of PGE2 can be partially attributed to COX-2 enzyme activity, which was significantly elevated with SOCS3 knockdown. At the same time, our results also suggest that constituents in H. perforatum extract were alleviating LPS-induced macrophage response through SOCS3 independent mechanisms. PMID:22245632

Huang, Nan; Rizshsky, Ludmila; Hauck, Catherine C.; Nikolau, Basil J.; Murphy, Patricia A.; Birt, Diane F.

2012-01-01

327

Protective effect of inducible nitric oxide synthase inhibitor on pancreas transplantation in rats  

PubMed Central

AIM: To investigate the effect of inducible nitric oxide synthase inhibitor, aminoguanidine, on pancreas transplantation in rats. METHODS: A model of pancreas transplantation was established in rats. Streptozotocin-induced diabetic male Wistar rats were randomly assigned to sham-operation control group (n = 6), transplant control group (n = 6), and aminoguanidine (AG) treatment group (n = 18). In the AG group, aminoguanidine was added to intravascular infusion as the onset of reperfusion at the dose of 60 mg/kg, 80 mg/kg, 100 mg/kg body weight, respectively. Serum nitric oxide (NO) level, blood sugar and amylase activity were detected. Nitric oxide synthase (NOS) test kit was used to detect the pancreas cNOS and inducible NOS (iNOS) activity. Pancreas sections stained with HE and immunohistochemistry were evaluated under a light microscope. RESULTS: As compared with the transplant control group, the serum NO level and amylase activity decreased obviously and the evidence for pancreas injury was much less in the AG group. The AG (80 mg/kg body weight) group showed the most significant difference in NO and amylase (NO: 66.0 ± 16.6 vs 192.3 ± 60.0, P < 0.01 and amylase: 1426 ± 177 vs 4477 ± 630, P < 0.01).The expression and activity of tissue iNOS, and blood sugar in the AG (80 mg/kg body weight) group were much lower than those in the transplant control group (iNOS: 2.01 ± 0.23 vs 26.59 ± 5.78, P < 0.01 and blood sugar: 14.2 ± 0.9 vs 16.8 ± 1.1, P < 0.01). CONCLUSION: Selective iNOS inhibitor, aminoguanidine as a free radical, has a protective effect on pancreas transplantation in rats by inhibiting NO and reducing its toxicity. PMID:18023101

Li, Bai-Feng; Liu, Yong-Feng; Cheng, Ying; Zhang, Ke-Zhong; Li, Tie-Min; Zhao, Ning

2007-01-01

328

Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors  

SciTech Connect

Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate and brain GSH levels along with increase in serum and brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. - Highlights: • As has induced endothelial dysfunction (Edf) and vascular dementia (VaD). • As has increased oxidative stress, AChE activity and decreased serum NO. • Inhibitors of HDAC and iNOS have attenuated As induced Edf and VaD. • Both the inhibitors have attenuated As induced biochemical changes. • Inhibitor of HDAC and iNOS has shown good potential in As induced VaD.

Sharma, Bhupesh, E-mail: drbhupeshresearch@gmail.com; Sharma, P.M.

2013-11-15

329

Participation of the mitochondrial permeability transition pore in nitric oxide-induced plant cell death.  

PubMed

In the present study, we investigated the involvement of the mitochondrial permeability transition pore (PTP) in nitric oxide (NO)-induced plant cell death. NO donors such as sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine inhibited growth and caused death in suspension-cultured cells of Citrus sinensis. Cells treated with SNP showed chromatin condensation and fragmentation, characteristic of apoptosis. SNP caused loss of the mitochondrial membrane electrical potential, which was prevented by cyclosporin A (CsA), a specific inhibitor of PTP formation. CsA also prevented the nuclear apoptosis and subsequent Citrus cell death induced by NO. These findings indicate that mitochondrial PTP formation is involved in the signaling pathway by which NO induces apoptosis in cultured Citrus cells. PMID:11801241

Saviani, Elzira E; Orsi, Cintia H; Oliveira, Jusceley F P; Pinto-Maglio, Cecília A F; Salgado, Ione

2002-01-16

330

Nitric oxide mediates hypocrellin accumulation induced by fungal elicitor in submerged cultures of Shiraia bambusicola.  

PubMed

Multiple responses of Shiraia bambusicola, including nitric oxide (NO) generation, hypocrellins production and salicylic acid (SA) biosynthesis, were induced by a fungal elicitor prepared from the mycelium of Aspergillum niger. Both the NO donator, sodium nitroprusside, and SA enhanced hypocrellin production without the fungal elicitor. However, the NO scavenger, 2,4-carboxyphenyl-4,4, 5,5- tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) and the SA biosynthesis inhibitor, cinnamic acid (CA), inhibited hypocrellin accumulation in the presence of the elicitor. cPTIO also inhibited SA production induced by the A. niger elicitor. CA failed to inhibit NO production but it significantly inhibited hypocrellin accumulation. Aspergillum niger elicitor induced an NO burst, SA accumulation, and hypocrellin production in S. bambusicola. Therefore, the fungal elicitor was involved in the signaling pathway, which is a mechanism different from that of higher plants. PMID:25214226

Du, Wen; Liang, Jiandong; Han, Yanfeng; Yu, Jianping; Liang, Zongqi

2015-01-01

331

Metal allergens induce nitric oxide production by mouse dermal fibroblasts via the hypoxia-inducible factor-2?-dependent pathway.  

PubMed

Nickel (Ni) has been shown to be one of the most frequent metal allergens. We have already reported a murine metal allergy model with pathogen-associated molecular patterns (PAMPs) as adjuvants. Interleukin (IL)-1? plays a critical role in our mouse model. Because nonimmune cells, including fibroblasts, play important roles in local allergic inflammation, we investigated whether Ni induces inflammatory responses in mouse dermal fibroblasts (MDF). We also analyzed the synergistic effects between Ni, PAMPs, and IL-1?. MDF stimulated with Ni produced a significantly higher amount of nitric oxide (NO) in a dose-dependent manner. NO production was augmented by costimulation with IL-1? but not with PAMPs. On the other hand, IL-1? or PAMPs induced a significantly higher amount of IL-6 production by MDF, but no augmentation was detected in the presence of Ni. A specific inhibitor for inducible nitric oxide synthase (iNOS) inhibited Ni-induced NO production. iNOS mRNA expression was significantly higher in MDF stimulated with Ni, IL-1?, or both. A specific inhibitor for hypoxia-inducible factor (HIF)-2?, but not HIF-1?, inhibited NO production. Another frequent metal allergen, cobalt, also induced iNOS expression and NO production by MDF via the HIF-2?-dependent pathway. The inhibitor for iNOS augmented ear swelling in Ni allergy mouse model. On the other hand, HIF-2? inhibitor attenuates allergic inflammation. These results indicate that metal allergens induce NO production in MDF via the HIF-2?-dependent pathway and IL-1? augments NO production, which suggests that the NO induced by metal allergens plays a pathological role in metal allergies. PMID:23788631

Kuroishi, Toshinobu; Bando, Kanan; Endo, Yasuo; Sugawara, Shunji

2013-09-01

332

Role of nitric oxide in adenosine-induced vasodilation in humans  

NASA Technical Reports Server (NTRS)

Vasodilation is one of the most prominent effects of adenosine and one of the first to be recognized, but its mechanism of action is not completely understood. In particular, there is conflicting information about the potential contribution of endothelial factors. The purpose of this study was to explore the role of nitric oxide in the vasodilatory effect of adenosine. Forearm blood flow responses to intrabrachial adenosine infusion (125 microg/min) were assessed with venous occlusion plethysmography during intrabrachial infusion of saline or the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) (12.5 mg/min). Intrabrachial infusions of acetylcholine (50 microg/min) and nitroprusside (3 microg/min) were used as a positive and negative control, respectively. These doses were chosen to produce comparable levels of vasodilation. In a separate study, a second saline infusion was administered instead of L-NMMA to rule out time-related effects. As expected, pretreatment with L-NMMA reduced acetylcholine-induced vasodilation; 50 microg/min acetylcholine increased forearm blood flow by 150+/-43% and 51+/-12% during saline and L-NMMA infusion, respectively (P<.01, n=6). In contrast, L-NMMA did not affect the increase in forearm blood flow produced by 3 microg/min nitroprusside (165+/-30% and 248+/-41% during saline and L-NMMA, respectively) or adenosine (173+/-48% and 270+/-75% during saline and L-NMMA, respectively). On the basis of our observations, we conclude that adenosine-induced vasodilation is not mediated by nitric oxide in the human forearm.

Costa, F.; Biaggioni, I.; Robertson, D. (Principal Investigator)

1998-01-01

333

Nitric Oxide Acts as a Positive Regulator to Induce Metamorphosis of the Ascidian Herdmania momus  

PubMed Central

Marine invertebrates commonly have a biphasic life cycle in which the metamorphic transition from a pelagic larva to a benthic post-larva is mediated by the nitric oxide signalling pathway. Nitric oxide (NO) is synthesised by nitric oxide synthase (NOS), which is a client protein of the molecular chaperon heat shock protein 90 (HSP90). It is notable, then, that both NO and HSP90 have been implicated in regulating metamorphosis in marine invertebrates as diverse as urochordates, echinoderms, molluscs, annelids, and crustaceans. Specifically, the suppression of NOS activity by the application of either NOS- or HSP90-inhibiting pharmacological agents has been shown consistently to induce the initiation of metamorphosis, leading to the hypothesis that a negative regulatory role of NO is widely conserved in biphasic life cycles. Further, the induction of metamorphosis by heat-shock has been demonstrated for multiple species. Here, we investigate the regulatory role of NO in induction of metamorphosis of the solitary tropical ascidian, Herdmania momus. By coupling pharmacological treatments with analysis of HmNOS and HmHSP90 gene expression, we present compelling evidence of a positive regulatory role for NO in metamorphosis of this species, in contrast to all existing ascidian data that supports the hypothesis of NO as a conserved negative regulator of metamorphosis. The exposure of competent H. momus larvae to a NOS inhibitor or an NO donor results in an up-regulation of NOS and HSP90 genes. Heat shock of competent larvae induces metamorphosis in a temperature dependent manner, up to a thermal tolerance that approaches 35°C. Both larval/post-larval survival and the appearance of abnormal morphologies in H. momus post-larvae reflect the magnitude of up-regulation of the HSP90 gene in response to heat-shock. The demonstrated role of NO as a positive metamorphic regulator in H. momus suggests the existence of inter-specific adaptations of NO regulation in ascidian metamorphosis. PMID:24019877

Ueda, Nobuo; Degnan, Sandie M.

2013-01-01

334

Effect of honey bee venom on microglial cells nitric oxide and tumor necrosis factor-alpha production stimulated by LPS.  

PubMed

Abnormal activation of microglial cells has been implicated in various neurodegenerative diseases. Results showed that venom (KBV) produced and purified in Korea regulated lipopolysaccharides (LPS)-induced nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) in the murine microglia, BV-2 cell line. The production of proinflammatory cytokines, NO, and TNF-alpha was examined by LPS in BV-2 cell. The effect of KBV on the expression of inducible nitric oxide synthase (iNOS) and TNF-alpha was investigated by Western blot and RT-PCR in LPS-stimulated BV-2 cells. KBV suppressed the NO, iNOS, and TNF-alpha production, and decreased the levels of iNOS and TNF-alpha mRNA. These results suggest that KBV has anti-inflammatory properties that inhibit iNOS and TNF-alpha expression. KBV could be useful in inhibiting the production of inflammatory cytokine and NO production in neurodegenerative diseases. Further studies on the pharmacological aspects of the individual components of KBV are recommended. PMID:17166679

Han, SangMi; Lee, KwangGill; Yeo, JooHong; Kweon, HaeYong; Woo, SoonOk; Lee, MyeongLyeol; Baek, HaJu; Kim, SunYeou; Park, KwanKyu

2007-04-20

335

Glycyrrhizic acid and 18?-glycyrrhetinic acid modulate lipopolysaccharide-induced inflammatory response by suppression of NF-?B through PI3K p110? and p110? inhibitions.  

PubMed

The roots and rhizomes of licorice ( Glycyrrhia ) species have been used extensively as natural sweeteners and herbal medicines. The aim of this work was to determine the in vitro anti-inflammatory effects of glycyrrhizic acid (GA) and 18?-glycyrrhetinic acid (18?GA) from licorice in a lipopolysaccharide (LPS)-stimulated macrophage model. The results showed that treatment with 25-75 ?M GA or 18?GA did not reduce RAW 264.7 cell viability but did significantly inhibit the production of LPS-induced nitric oxide (NO), prostaglandin E(2) (PGE(2)), and intracellular reactive oxygen species (ROS). Western blotting and reverse transcriptase polymerase chain reaction (RT-PCR) analyses revealed that GA and 18?GA significantly reduced the protein and mRNA levels of iNOS and COX-2 in LPS-induced macrophages. Both GA and 18?GA inhibited the activation of NF-?B and the activities of phosphoinositide-3-kinase (PI3K) p110? and p110? isoforms and then reduced the production of LPS-induced tumor necrosis factor-? (TNF-?), interleukin (IL)-6, and IL-1? in a dose-dependent manner. In conclusion, these results indicate that GA and 18?GA may provide an anti-inflammatory effect by attenuating the generation of excessive NO, PGE(2), and ROS and by suppressing the expression of pro-inflammatory genes through the inhibition of NF-?B and PI3K activity. Thus, the results suggest that GA and 18?GA might serve as potential agents for the treatment of inflammatory-mediated diseases. PMID:21644799

Wang, Chung-Yi; Kao, Tzu-Chien; Lo, Wen-Hsieh; Yen, Gow-Chin

2011-07-27

336

Rutin improves endotoxin-induced acute lung injury via inhibition of iNOS and VCAM-1 expression.  

PubMed

Endotoxins exist anywhere including in water pools, dust, humidifier systems, and machining fluids. The major causal factor is endotoxins in many serious diseases, such as fever, sepsis, multi-organ failure, meningococcemia, and severe morbidities like neurologic disability, or hearing loss. Endotoxins are also called lipopolysaccharide (LPS) and are important pathogens of acute lung injury (ALI). Rutin has potential beneficial effects including anti-inflammation, antioxidation, anti-hyperlipidemia, and anti-platelet aggregation. Pre-treatment with rutin inhibited LPS-induced neutrophil infiltration in the lungs. LPS-induced expression of vascular cell adhesion molecule (VCAM)-1 and inducible nitric oxide synthase (iNOS) was suppressed by rutin, but there was no influence on expression of intercellular adhesion molecule-1 and cyclooxygenase-2. In addition, activation of the nuclear factor (NF)?B was reduced by rutin. Furthermore, we found that the inhibitory concentration of rutin on expression of VCAM-1 and iNOS was similar to NF?B activation. In conclusion, rutin is a potential protective agent for ALI via inhibition of neutrophil infiltration, expression of VCAM-1 and iNOS, and NF?B activation. © 2014 Wiley Periodicals, Inc. Environ Toxicol, 2014. PMID:25080890

Huang, Yi-Chun; Horng, Chi-Ting; Chen, Shyan-Tarng; Lee, Shiuan-Shinn; Yang, Ming-Ling; Lee, Chien-Ying; Kuo, Wu-Hsien; Yeh, Chung-Hsin; Kuan, Yu-Hsiang

2014-08-01

337

Inhibitory effects of 4-hydroxyderricin and xanthoangelol on lipopolysaccharide-induced inflammatory responses in RAW264 macrophages.  

PubMed

The Japanese herb, Ashitaba (Angelica keiskei Koidzumi), contains two prenylated chalcones, 4-hydroxyderricin and xanthoangelol, which are considered to be the major active compounds of Ashitaba. However, their effects on inflammatory responses are poorly understood. In the present study, we investigated the effects and underlying molecular mechanisms of 4-hydroxyderricin and xanthoangelol on lipopolysaccharide (LPS)-induced inflammatory responses in RAW264 mouse macrophages. LPS-mediated production of nitric oxide (NO) was markedly reduced by 4-hydroxyderricin (10 ?M) and xanthoangelol (5 ?M) compared with their parent compound, chalcone (25 ?M). They also inhibited LPS-induced secretion of tumor necrosis factor-alpha (TNF-?) and expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Although chalcone decreased the DNA-binding activity of both activator protein-1 (AP-1) and nuclear factor-kappa B (NF-?B), 4-hydroxyderricin and xanthoangelol suppressed only AP-1 and had no effect on NF-?B. On the other hand, all of the tested chalcones reduced the phosphorylation (at serine 536) level of the p65 subunit of NF-?B. 4-Hydroxyderricin and xanthoangelol may be promising for the prevention of inflammatory diseases. PMID:24369884

Yasuda, Michiko; Kawabata, Kyuichi; Miyashita, Miki; Okumura, Mayu; Yamamoto, Norio; Takahashi, Masakazu; Ashida, Hitoshi; Ohigashi, Hajime

2014-01-15

338

Aldose Reductase Inhibition Prevents Lipopolysaccharide –Induced Glucose Uptake and Glucose Transporter 3 Expression in RAW264.7 Macrophages  

PubMed Central

Macrophages which play a central role in the injury, infection and sepsis, use glucose as their primary source of metabolic energy. Increased glucose uptake in inflammatory cells is well known to be one of the responsible processes that cause inflammatory response and cytotoxicity. We have shown recently that the inhibition of aldose reductase (AR) prevents bacterial endotoxin, lipopolysaccharide (LPS)-induced cytotoxicity and inflammatory response in macrophages. However, it is not known how AR inhibition prevents LPS-induced inflammation. Here in, we examined the effect of AR inhibition on LPS-induced glucose uptake and the expression of glucose transporter 3 (GLUT-3) in RAW264.7 murine macrophages. Stimulation of macrophages with LPS-increased glucose uptake as measured by using C14 labeled methyl-D-glucose and inhibition of AR prevented it. Similarly, ablation of AR by using AR–siRNA also prevented the LPS-induced glucose uptake in macrophages. Further, AR inhibition also prevented the LPS-induced upregulation of GLUT-3 expression, cyclic adenosine monophosphate (cAMP) accumulation and protein kinase A (PKA) activation in RAW264.7 cells. Moreover, LPS-induced down-regulation of cAMP response element modulator (CREM), phosphorylation of cAMP response element-binding protein (CREB) and DNA binding of CREB were also prevented by AR inhibition. Further, inhibition of AR or PKA also prevented the LPS-induced levels of GLUT-3 protein as well as mRNA in macrophages. These results indicate that AR mediates LPS-induced glucose uptake and expression of glucose transporter-3 via cAMP/PKA/CREB pathway and thus represents a novel mechanism by which AR regulates LPS-induced inflammation. PMID:20348015

Reddy, Aramati BM; Srivastava, Satish K; Ramana, Kota V

2010-01-01

339

Carbon monoxide-induced stomatal closure in Vicia faba is dependent on nitric oxide synthesis.  

PubMed

Recently, in animals, carbon monoxide (CO), like nitric oxide (NO), was implicated as another important physiological messenger or bioactive molecule. Previous researches indicate that heme oxygenase (HO)-1 (EC 1.14.99.3) catalyzes the oxidative conversion of heme to CO and biliverdin IXa (BV) with the concomitant release of iron. However, little is known about the physiological roles of CO in plant, especially in stomatal movement of guard cells. In the present paper, the regulatory role of CO during stomatal movement in Vicia faba was surveyed. Results indicated that, like sodium nitroprusside (SNP), CO donor hematin induced stomatal closure in dose- and time-dependent manners. These responses were also proved by the addition of gaseous CO aqueous solution with different concentrations, showing for the first time that CO and NO exhibit similar regulation role in the stomatal movement. Moreover, our data showed that 2,4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO)/N(G)-nitro-L-arginine-methyl ester (L-NAME) not only reversed stomatal closure by CO, but also suppressed the NO fluorescence induced by CO, implying that CO-induced stomatal closure probably involves NO/nitric oxide synthase (NOS) signal system. Additionally, the CO/NO scavenger hemoglobin (Hb) and CO-specific synthetic inhibitor zinc protoporphyrin IX (ZnPPIX), NO scavenger cPTIO and NOS inhibitor L-NAME reversed the darkness-induced stomatal closure and NO fluorescence. These results show that, maybe like NO, the levels of CO in guard cells of V. faba is higher in dark than that in light, HO-1 and NOS are the enzyme systems responsible for generating endogenous CO and NO in darkness, respectively, and that CO being from HO-1 mediates darkness-induced NO synthesis in guard cells' stomatal closure of V. faba. PMID:18334004

Song, Xi-Gui; She, Xiao-Ping; Zhang, Bei

2008-04-01

340

Nitric oxide mediated intestinal injury is required for alcohol-induced gut leakiness and liver damage  

PubMed Central

Background Alcoholic liver disease (ALD) requires endotoxemia and is commonly associated with intestinal barrier leakiness. Using monolayers of intestinal epithelial cells as an in vitro barrier model, we showed that ethanol-induced intestinal barrier disruption is mediated by iNOS (inducible nitric-oxide synthase) upregulation, NO (nitric oxide) overproduction, and oxidation/nitration of cytoskeletal proteins. We hypothesized that iNOS inhibitors (L-NAME, L-NIL) in vivo will inhibit the above cascade and liver injury in an animal model of alcoholic steatohepatitis (ASH). Methods Male Sprague-Dawley rats were gavaged daily with alcohol (6 g/kg/day) or dextrose for 10 weeks ± L-NAME, L-NIL or vehicle. Systemic and intestinal NO levels were measured by nitrites and nitrates in urine and tissue samples, oxidative damage to the intestinal mucosa by protein carbonyl and nitrotyrosine, intestinal permeability by urinary sugar tests, and liver injury by histological inflammation scores, liver fat, and myeloperoxidase activity. Results Alcohol caused tissue oxidation, gut leakiness, endotoxemia and ASH. L-NIL and L-NAME, but not the D-enantiomers, attenuated all steps in the alcohol-induced cascade including NO overproduction, oxidative tissue damage, gut leakiness, endotoxemia, hepatic inflammation and liver injury. Conclusions The mechanism we reported for alcohol-induced intestinal barrier disruption in vitro – NO overproduction, oxidative tissue damage, leaky gut, endotoxemia and liver injury – appears to be relevant in vivo in an animal model of alcohol-induced liver injury. That iNOS inhibitors attenuated all steps of this cascade suggests that prevention of this cascade in alcoholics will protect the liver against the injurious effects of chronic alcohol and that iNOS may be a useful target for prevention of ALD. PMID:19389191

Tang, Yueming; Forsyth, Christopher B.; Farhadi, Ashkan; Rangan, Jayanthi; Jakate, Shriram; Shaikh, Maliha; Banan, Ali; Fields, Jeremy Z.; Keshavarzian, Ali

2010-01-01

341

Bursopentin (BP5) Protects Dendritic Cells from Lipopolysaccharide-Induced Oxidative Stress for Immunosuppression  

PubMed Central

Dendritic cells (DCs) play a vital role in the regulation of immune-mediated inflammatory diseases. Thus, DCs have been regarded as a major target for the development of immunomodulators. However, oxidative stress could disturb inflammatory regulation in DCs. Here, we examined the effect of bursopentine (BP5), a novel pentapeptide isolated from chicken bursa of fabricius, on the protection of DCs against oxidative stress for immunosuppression. BP5 showed potent protective effects against the lipopolysaccharide (LPS)-induced oxidative stress in DCs, including nitric oxide, reactive oxygen species and lipid peroxidation. Furthermore, BP5 elevated the level of cellular reductive status through increasing the reduced glutathione (GSH) and the GSH/GSSG ratio. Concomitant with these, the activities of several antioxidative redox enzymes, including glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD), were obviously enhanced. BP5 also suppressed submucosal DC maturation in the LPS-stimulated intestinal epithelial cells (ECs)/DCs coculture system. Finally, we found that heme oxygenase 1 (HO-1) was remarkably upregulated by BP5 in the LPS-induced DCs, and played an important role in the suppression of oxidative stress and DC maturation. These results suggested that BP5 could protect the LPS-activated DCs against oxidative stress and have potential applications in DC-related inflammatory responses. PMID:25659113

Qin, Tao; Yin, Yinyan; Yu, Qinghua; Yang, Qian

2015-01-01

342

Epigallocatechin-3-gallate attenuates lipopolysaccharide-induced inflammation in human retinal endothelial cells  

PubMed Central

AIM To investigate the mechanism underlying the anti-inflammatory effects of epigallocatechin-3-gallate (EGCG) in lipopolysaccharide (LPS)-stimulated human retinal endothelial cells (HRECs). METHODS HRECs pre-treated with EGCG (0-100 µmol/L) were stimulated with LPS (250 ng/mL). Levels of tumor necrosis factor alpha (TNF-?), vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1) and nitric oxide (NO) in the supernatants were determined by enzyme-linked immunosorbent assay (ELISA) and Griess assay. The protein expression of phosphorylated extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinases (p38) were determined by Western blot analysis. RESULTS EGCG pre-treatment significantly inhibited the secretion of TNF-?, VEGF, MCP-1 and NO in LPS-stimulated HRECs. Moreover, EGCG effectively attenuated LPS-induced activation and phosphorylation of ERK1/2 and p38 in HRECs in a dose-dependent manner. CONCLUSION EGCG exhibited inhibitory effects on LPS-induced pro-inflammatory cytokines production by modulating ERK1/2 and p38 pathways in HRECs, suggesting EGCG as a potential candidate for anti-inflammatory intervention. PMID:24967182

Zhang, Hui-Yan; Wang, Jian-Yong; Yao, Hang-Ping

2014-01-01

343

A common fungal volatile organic compound induces a nitric oxide mediated inflammatory response in Drosophila melanogaster  

PubMed Central

Using a Drosophila model, we previously demonstrated truncated life span and neurotoxicity with exposure to 1-octen-3-ol, the volatile organic compound (VOC) responsible for much of the musty odor found in mold-contaminated indoor spaces. In this report, using biochemical and immunological assays, we show that exposure to 0.5?ppm 1-octen-3-ol induces a nitric oxide (NO) mediated inflammatory response in hemocytes, Drosophila innate immune cells. Moreover, exposed Drosophila brains show increased peroxynitrite expression. An increase in nitrite levels is observed with toluene and 1-octen-3-ol but not with 1-butanol. Pharmacological inhibitors of nitric oxide synthase (NOS) namely, L-NAME, D-NAME and minocycline, and NOS mutants show improvements of life span among 1-octen-3-ol exposed flies. Exposure to 1-octen-3-ol also induces NOS expression in larval tracheal tissues and remodels tracheal epithelial lining. These findings suggest a possible mechanistic basis for some of the reported adverse health effects attributed to mold exposure and demonstrates the utility of this in vivo Drosophila model to complement existing model systems for understanding the role of inflammation in VOC-mediated toxicity. PMID:24509902

Inamdar, Arati A.; Bennett, Joan W.

2014-01-01

344

Identification of inducible nitric oxide synthase in human macrophages surrounding loosened hip prostheses.  

PubMed Central

Exposure of rodent macrophages to certain cytokines and endotoxin results in the synthesis of inducible nitric oxide synthase (iNOS or NOS-II) leading to the production of large amounts of nitric oxide (NO). Cultures of human macrophages, in contrast, do not produce iNOS after cytokine stimulation, and their ability to act as a physiological source of NO remains questionable. Here we have used immunohistochemistry and in situ hybridization to demonstrate the presence of iNOS within human macrophages present in the interfacial membrane and pseudocapsule that surround failed prosthetic hip joints. Synovial tissue recovered from normal human joints did not express iNOS. Many of the iNOS-positive macrophages within the interfacial membrane had phagocytosed large amounts of polyethylene wear debris, suggesting a role for phagocytic stimuli in inducing iNOS in human macrophages. These findings additionally support a role for NO in modulating the localized bone resorption that accompanies the aseptic loosening of prosthetic joints. Images Figure 1 Figure 2 Figure 3 PMID:9094976

Watkins, S. C.; Macaulay, W.; Turner, D.; Kang, R.; Rubash, H. E.; Evans, C. H.

1997-01-01

345

Monotropein isolated from the roots of Morinda officinalis ameliorates proinflammatory mediators in RAW 264.7 macrophages and dextran sulfate sodium (DSS)-induced colitis via NF-?B inactivation.  

PubMed

We previously demonstrated that monotropein isolated from the roots of Morinda officinalis (Rubiaceae) has anti-inflammatory effects in vivo. In the present study, we investigated the molecular mechanisms underlying the anti-inflammatory effects of monotropein in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and dextran sulfate sodium (DSS)-induced colitis mouse model. Monotropein was found to inhibit the expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-? (TNF-?), and interleukin-1? (IL-1?) mRNA in LPS-induced RAW 264.7 macrophages. Treatment with monotropein decreased the DNA binding activity of nuclear factor-?B (NF-?B). Consistent with these findings, monotropein also suppressed phosphorylation and degradation of inhibitory ?B-? (I?B-?), and consequently the translocations of NF-?B. In the DSS-induced colitis model, monotropein reduced disease activity index (DAI), myeloperoxidase (MPO) activity, and inflammation-related protein expressions by suppressing NF-?B activation in colon mucosa. Taken together, these findings suggest that the anti-inflammatory effects of monotropein are mainly related to the inhibition of the expressions of inflammatory mediators via NF-?B inactivation, and support its possible therapeutic role in colitis. PMID:23261679

Shin, Ji-Sun; Yun, Kyung-Jin; Chung, Kyung-Sook; Seo, Kyeong-Hwa; Park, Hee-Juhn; Cho, Young-Wuk; Baek, Nam-In; Jang, Daesik; Lee, Kyung-Tae

2013-03-01

346

Chemically Modified Tetracyclines Inhibit Inducible Nitric Oxide Synthase Expression and Nitric Oxide Production in Cultured Rat Mesangial Cells  

Microsoft Academic Search

Tetracyclines inhibit matrix metalloproteinases (MMP) and attenuate connective tissue degradation in a wide variety of human and animal disorders. Chemically modified tetracyclines (CMT) have been synthesized in which the antibacterial potency has been eliminated but in which the anti-MMP efficacy is retained. Nitric oxide (NO) modulates MMP synthesis and activity in mesangial cellsin vitro.Therefore, we examined whether CMT inhibit iNOS

Howard Trachtman; Stephen Futterweit; Robert Greenwald; Susan Moak; Pravin Singhal; Nicholas Franki; Ashok R. Amin

1996-01-01

347

Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons  

PubMed Central

Mitochondria are present as tubular organelles in neuronal projections. Here, we report that mitochondria undergo profound fission in response to nitric oxide (NO) in cortical neurons of primary cultures. Mitochondrial fission by NO occurs long before neurite injury and neuronal cell death. Furthermore, fission is accompanied by ultrastructural damage of mitochondria, autophagy, ATP decline and generation of free radicals. Fission is occasionally asymmetric and can be reversible. Strikingly, mitochondrial fission is also an early event in ischemic stroke in vivo. Mitofusin 1 (Mfn1) or dominant-negative Dynamin related protein 1 (Drp1K38A) inhibits mitochondrial fission induced by NO, rotenone and Amyloid-? peptide. Conversely, overexpression of Drp1 or Fis1 elicits fission and increases neuronal loss. Importantly, NO-induced neuronal cell death was mitigated by Mfn1 and Drp1K38A. Thus, persistent mitochondrial fission may play a causal role in NO-mediated neurotoxicity. PMID:16874299

Barsoum, Mark J; Yuan, Hua; Gerencser, Akos A; Liot, Géraldine; Kushnareva, Yulia; Gräber, Simone; Kovacs, Imre; Lee, Wilson D; Waggoner, Jenna; Cui, Jiankun; White, Andrew D; Bossy, Blaise; Martinou, Jean-Claude; Youle, Richard J; Lipton, Stuart A; Ellisman, Mark H; Perkins, Guy A; Bossy-Wetzel, Ella

2006-01-01

348

Inhibition of Lipopolysaccharide-Induced Cyclooxygenase2 and Inducible Nitric Oxide Synthase Expression by 4-[(2?-O-acetyl-?-L-Rhamnosyloxy)Benzyl]Isothiocyanate from Moringa oleifera  

Microsoft Academic Search

Moringa oleifera Lamarck is commonly consumed for nutritional or medicinal properties. We recently reported the isolation and structure elucidation of novel bioactive phenolic glycosides, including 4-[(2?-O-acetyl-?-L-rhamnosyloxy)benzyl]isothiocyanate (RBITC), which was found to suppress inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production in lipopolysaccharide-stimulated RAW 264.7 mouse macrophage cells. Inhibitors of proteins such as cyclooxygenase-2 (COX-2) and iNOS are

Eun-Jung Park; Sarot Cheenpracha; Leng Chee Chang; Tamara P. Kondratyuk; John M. Pezzuto

2011-01-01

349

CDr10b inhibits the expression of cyclooxygenase-2 and inducible nitric oxide synthase induced by lipopolysaccharide.  

PubMed

The pathophysiological processes of inflammation can lead to a host of diseases, such as periodontitis, atherosclerosis, rheumatoid arthritis, and even cancer. The dysregulated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) activation play important roles in the development of certain inflammatory diseases. Here, we investigated the effects of CDr10b which is originally developed for a microglia staining probe on inflammation, by modulating NF-?B activation and iNOS and COX-2 expression induced by lipopolysaccharide (LPS) in murine macrophages. The CDr10b suppressed NF-?B activation and iNOS and COX-2 expression induced by LPS. All the results suggest that CDr10b is a promising novel agent for the treatment of inflammatory diseases. PMID:25196213

Gu, Gyo-Jeong; Lim, Se-Jin; Ahn, Sang-Il; Lee, Sung-Chan; Chang, Young-Tae; Choi, Tae Hyun; Kim, Byoung Soo; Eom, Yong-Bin; Lee, Na Kyung; Youn, Hyung-Sun

2014-11-01

350

Expression of Inducible Nitric Oxide Synthase (iNOS) in Microglia of the Developing Quail Retina  

PubMed Central

Inducible nitric oxide synthase (iNOS), which produce large amounts of nitric oxide (NO), is induced in macrophages and microglia in response to inflammatory mediators such as LPS and cytokines. Although iNOS is mainly expressed by microglia that become activated in different pathological and experimental situations, it was recently reported that undifferentiated amoeboid microglia can also express iNOS during normal development. The aim of this study was to investigate the pattern of iNOS expression in microglial cells during normal development and after their activation with LPS by using the quail retina as model. iNOS expression was analyzed by iNOS immunolabeling, western-blot, and RT-PCR. NO production was determined by using DAR-4M AM, a reliable fluorescent indicator of subcellular NO production by iNOS. Embryonic, postnatal, and adult in situ quail retinas were used to analyze the pattern of iNOS expression in microglial cells during normal development. iNOS expression and NO production in LPS-treated microglial cells were investigated by an in vitro approach based on organotypic cultures of E8 retinas, in which microglial cell behavior is similar to that of the in situ retina, as previously demonstrated in our laboratory. We show here that amoeboid microglia in the quail retina express iNOS during normal development. This expression is stronger in microglial cells migrating tangentially in the vitreal part of the retina and is downregulated, albeit maintained, when microglia differentiate and become ramified. LPS treatment of retina explants also induces changes in the morphology of amoeboid microglia compatible with their activation, increasing their lysosomal compartment and upregulating iNOS expression with a concomitant production of NO. Taken together, our findings demonstrate that immature microglial cells express iNOS during normal development, suggesting a certain degree of activation. Furthermore, LPS treatment induces overactivation of amoeboid microglia, resulting in a significant iNOS upregulation. PMID:25170849

Sierra, Ana; Navascués, Julio; Cuadros, Miguel A.; Calvente, Ruth; Martín-Oliva, David; Ferrer-Martín, Rosa M.; Martín-Estebané, María; Carrasco, María-Carmen; Marín-Teva, José L.

2014-01-01

351

Retinal Protective Effects of Resveratrol via Modulation of Nitric Oxide Synthase on Oxygen-induced Retinopathy  

PubMed Central

Purpose Retinopathy of prematurity (ROP) is one of the leading causes of blindness, with retinal detachment occurring due to oxygen toxicity in preterm infants. Recently, advances in neonatal care have led to improved survival rates for preterm infants, and ROP has increased in incidence. In the present study, we aimed to determine whether or not resveratrol exhibits protective effects in an animal model of ROP and in primary retinal cell cultures of neonatal rat via nitric oxide (NO)-modulating actions using western blotting and real-time PCR with inducible nitric oxide synthase (iNOS), endothelial NOS (eNOS) and neuronal NOS (nNOS) antibodies and mRNAs. Methods In an in vivo oxygen-induced retinopathy (OIR) model, cyclic hyperoxia was induced with 80% O2 for one day and 21% O2 for one day from P1 to P14 in newborn Sprague-Dawley (SD) rats. Resveratrol was injected intravitreally for seven days and rats were sacrificed at P21. In vitro OIR primary retinal cell culture was performed using P0-2 SD rats. Hyperoxia injuries were induced through 100% O2 exposure for six hours. Western blotting and real-time PCR using iNOS, eNOS, nNOS antibodies and primers were performed in the rat model of ROP and the dispersed retinal cell culture. Results In both in vivo and in vitro OIR, the expression of iNOS antibody and mRNA was increased and of eNOS and nNOS were reduced in the resveratrol-treated group. Conclusions In conclusion, resveratrol appeared to exert retinal protective effects via modulation of NO-mediated mechanism in in vivo and in vitro OIR models. PMID:20379461

Kim, Woo Taek

2010-01-01

352

Nitric Oxide Is a Mediator of Antiproliferative Effects Induced by Proinflammatory Cytokines on Pancreatic Beta Cells  

PubMed Central

Nitric oxide (NO) is involved in several biological processes. In type 1 diabetes mellitus (T1DM), proinflammatory cytokines activate an inducible isoform of NOS (iNOS) in ? cells, thus increasing NO levels and inducing apoptosis. The aim of the current study is to determine the role of NO (1) in the antiproliferative effect of proinflammatory cytokines IL-1?, IFN-?, and TNF-? on cultured islet ? cells and (2) during the insulitis stage prior to diabetes onset using the Biobreeding (BB) rat strain as T1DM model. Our results indicate that NO donors exert an antiproliferative effect on ? cell obtained from cultured pancreatic islets, similar to that induced by proinflammatory cytokines. This cytokine-induced antiproliferative effect can be reversed by L-NMMA, a general NOS inhibitor, and is independent of guanylate cyclase pathway. Assays using NOS isoform specific inhibitors suggest that the NO implicated in the antiproliferative effect of proinflammatory cytokines is produced by inducible NOS, although not in an exclusive way. In BB rats, early treatment with L-NMMA improves the initial stage of insulitis. We conclude that NO is an important mediator of antiproliferative effect induced by proinflammatory cytokines on cultured ? cell and is implicated in ?-cell proliferation impairment observed early from initial stage of insulitis. PMID:23840099

Quintana-Lopez, Laura; Blandino-Rosano, Manuel; Perez-Arana, Gonzalo; Lechuga-Sancho, Alfonso; Aguilar-Diosdado, Manuel

2013-01-01

353

Effects of morphine on stress induced anxiety in rats: Role of nitric oxide and Hsp70.  

PubMed

The present study evaluated the effects of morphine on acute and chronic restraint stress (RS) induced anxiety modulation and the possible involvement of nitric oxide (NO) and heat shock proteins (Hsp70) during such effects. Acute RS (×1) induced anxiogenesis in the elevated plus maze (EPM) test which was associated with lowered brain NO metabolites (NOx) and elevated Hsp70 levels. Pretreatment with morphine (1 and 5mg/kg) and l-arginine (500mg/kg) attenuated the RS effects on EPM activity and brain NOx, whereas, Hsp70 levels were further augmented. Co-administration of both agents showed synergistic effects. By contrast, repeated RS (×15) did not induce any significant changes in EPM activity or brain NOx, but brain Hsp70 levels stayed elevated. Administration of morphine or l-arginine prior to chronic RS did not influence such chronic stress induced changes in behavioral and biochemical markers, but appreciably attenuated chronic RS induced elevation in Hsp70 levels. These results suggest that acute and chronic RS induced anxiety modulations were differentially influenced by morphine and l-arginine and that complex interactions involving brain NO and unregulated Hsp70 could regulate such effects. PMID:25460538

Joshi, Jagdish C; Ray, Arunabha; Gulati, Kavita

2015-02-01

354

Nitric Oxide Induces Cell Death by Regulating Anti-Apoptotic BCL-2 Family Members  

PubMed Central

Nitric oxide (NO) activates the intrinsic apoptotic pathway to induce cell death. However, the mechanism by which this pathway is activated in cells exposed to NO is not known. Here we report that BAX and BAK are activated by NO and that cytochrome c is released from the mitochondria. Cells deficient in Bax and Bak or Caspase-9 are completely protected from NO-induced cell death. The individual loss of the BH3-only proteins, Bim, Bid, Puma, Bad or Noxa, or Bid knockdown in Bim?/?/Puma?/? MEFs, does not prevent NO-induced cell death. Our data show that the anti-apoptotic protein MCL-1 undergoes ASK1-JNK1 mediated degradation upon exposure to NO, and that cells deficient in either Ask1 or Jnk1 are protected against NO-induced cell death. NO can inhibit the mitochondrial electron transport chain resulting in an increase in superoxide generation and peroxynitrite formation. However, scavengers of ROS or peroxynitrite do not prevent NO-induced cell death. Collectively, these data indicate that NO degrades MCL-1 through the ASK1-JNK1 axis to induce BAX/BAK-dependent cell death. PMID:19768117

Snyder, Colleen M.; Shroff, Emelyn H.; Liu, Jing; Chandel, Navdeep S.

2009-01-01

355

Increased expression and cellular localization of inducible nitric oxide synthase and cyclooxygenase 2 in Helicobacter pylori gastritis  

Microsoft Academic Search

Background & Aims: Inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 are important regulators of mucosal inflammation and epithelial cell growth. To determine the role of iNOS and COX-2 in Helicobacter pylori–induced tissue injury, we compared their gene expression in H. pylori–induced gastritis with that in normal gastric mucosa and in non–H. pylori gastritis. Methods: In 43 patients, we assessed

Sidong Fu; Kalathur S. Ramanujam; Annie Wong; George T. Fantry; Cinthia B. Drachenberg; Stephen P. James; Stephen J. Meltzer; Keith T. Wilson

1999-01-01

356

Nitric Oxide Synthase Inhibitor Improves De Novo and Long-Term l-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats  

PubMed Central

Inhibitors of neuronal and endothelial nitric oxide synthase decrease l-3,4-dihidroxifenilalanine (l-DOPA)-induced dyskinesias in rodents. The mechanism of nitric oxide inhibitor action is unknown. The aims of the present study were to investigate the decrease of l-DOPA-induced abnormal involuntary movements (AIMs) in 6-hydroxydopamine (6-OHDA)-lesioned rats by nitric oxide inhibitors following either acute or chronic treatment. The primary findings of this study were that NG-nitro-l-Arginine, an inhibitor of endothelial and neuronal nitric oxide synthase, attenuated AIMs induced by chronic and acute l-DOPA. In contrast, rotational behavior was attenuated only after chronic l-DOPA. The 6-OHDA lesion and the l-DOPA treatment induced a bilateral increase (1.5 times) in the neuronal nitric oxide synthase (nNOS) protein and nNOS mRNA in the striatum and in the frontal cortex. There was a parallel increase, bilaterally, of the FosB/?FosB, primarily in the ipsilateral striatum. The exception was in the contralateral striatum and the ipsilateral frontal cortex, where chronic l-DOPA treatment induced an increase of approximately 10 times the nNOS mRNA. Our results provided further evidence of an anti-dyskinetic effect of NOS inhibitor. The effect appeared under l-DOPA acute and chronic treatment. The l-DOPA treatment also revealed an over-expression of the neuronal NOS in the frontal cortex and striatum. Our results corroborated findings that l-DOPA-induced rotation differs between acute and chronic treatment. The effect of the NOS inhibitor conceivably relied on the l-DOPA structural modifications in the Parkinsonian brain. Taken together, these data provided a rationale for further evaluation of NOS inhibitors in the treatment of l-DOPA-induced dyskinesia. PMID:21713068

Padovan-Neto, Fernando Eduardo; Echeverry, Marcela Bermúdez; Chiavegatto, Silvana; Del-Bel, Elaine

2011-01-01

357

Protective effect of Ginkgo biloba leaves extract, EGb761, on endotoxin-induced acute lung injury via a JNK- and Akt-dependent NF?B pathway.  

PubMed

Acute lung injury (ALI) is a clinical syndrome mainly caused by Gram-negative bacteria which is still in need of an effective therapeutic medicine. EGb761, an extract of Ginkgo biloba leaves, has several bioeffects including anti-inflammation, cardioprotection, neuroprotection, and free radical scavenging. Preadministration of EGb761 inhibited lipopolysaccharide (LPS)-induced histopathological changes and exchange of arterial blood gas. In addition, LPS-induced expression of proinflammatory mediators, such as tumor necrosis factor (TNF)-?, interleukin (IL)-6, macrophage inflammatory protein (MIP)-2, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), were suppressed by EGb761. The activation of nuclear factor (NF)?B, a transcription factor of proinflammatory mediators, and phosphorylation of I?B, an inhibitor of NF?B, were also reduced by EGb761. Furthermore, we found the inhibitory concentration of EGb761 on phosphorylation of JNK and Akt was less than those of ERK and p38 MAPK. In conclusion, EGb761 is a potential protective agent for ALI, possibly via downregulating the JNK- and Akt-dependent NF?B activation pathway. PMID:24956234

Lee, Chien-Ying; Yang, Jiann-Jou; Lee, Shiuan-Shinn; Chen, Chun-Jung; Huang, Yi-Chun; Huang, Kuang-Hua; Kuan, Yu-Hsiang

2014-07-01

358

Nitric oxide protects anterior pituitary cells from cadmium-induced apoptosis.  

PubMed

Cadmium (Cd2+) is a potent toxic metal for both plants and animals. Chronic exposure to low doses of Cd2+ results in damage to several organs. We have previously reported that Cd2+ induces apoptosis in anterior pituitary cells by a caspase- and oxidative stress-dependent mechanism. Nitric oxide (NO) synthesis is affected by Cd2+ in several systems. NO has been shown to be either cytoprotective or cytotoxic in many systems. The aim of this study was to evaluate the possible participation of NO in the cytotoxic effect of Cd2+ on rat anterior pituitary cells. Cell viability was evaluated by mitochondrial dehydrogenase activity assay and confirmed by microscopy, studying nuclear morphology. Here we show that DETA NONOate ((Z)-1-[2 (2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate), a long-term NO donor, at concentrations below 0.5 mM, reduces nuclear condensation and fragmentation and reverses the decrease in cellular activity induced by Cd2+. Cd2+, by itself, induced NO synthesis, and inhibition of this synthesis enhanced Cd2+ cytotoxicity. NO also prevented caspase-3 activation and lipidic peroxidation induced by Cd2+. The NO/cGMP pathway does not seem to be involved in the cytoprotective effect of NO. These results indicate that NO has a cytoprotective role in Cd2+ -induced apoptosis, suggesting that endogenous NO could have a physiological role in protecting anterior pituitary cells. PMID:15454286

Poliandri, Ariel H B; Velardez, Miguel O; Cabilla, Jimena P; Bodo, Cristian C A; Machiavelli, Leticia I; Quinteros, Alnilan F; Duvilanski, Beatriz H

2004-11-01

359

Inhaled nitric oxide exacerbated phorbol-induced acute lung injury in rats.  

PubMed

In this study, we determined the effect of inhaled nitric oxide (NO) on the acute lung injury induced by phorbol myristate acetate (PMA) in isolated rat lung. Typical acute lung injury was induced successfully by PMA during 60 min of observation. PMA (2 microg/kg) elicited a significant increase in microvascular permeability, (measured using the capillary filtration coefficient Kfc), lung weight gain, lung weight/body weight ratio, pulmonary arterial pressure (PAP) and protein concentration of the bronchoalveolar lavage fluid. Pretreatment with inhaled NO (30 ppm) significantly exacerbated acute lung injury. All of the parameters reflective of lung injury increased significantly except PAP (P<0.05). Coadministration of Nomega-nitro-L-arginine methyl ester (L-NAME) (5 mM) attenuated the detrimental effect of inhaled NO in PMA-induced lung injury, except for PAP. In addition, L-NAME (5 mM) significantly attenuated PMA-induced acute lung injury except for PAP. These experimental data suggest that inhaled NO significantly exacerbated acute lung injury induced by PMA in rats. L-NAME attenuated the detrimental effect of inhaled NO. PMID:14643171

Lin, Hen I; Chu, Shi Jye; Hsu, Kang; Wang, David

2004-01-01

360

Spectroscopic measurement of cortical nitric oxide release induced by ascending activation.  

PubMed

The transition from sleep to the awake state is regulated by the activation of subcortical nuclei of the brainstem (BS) and basal forebrain (BF), releasing acetylcholine and glutamate throughout the cortex and inducing a tonic state of neural activity. It has been suggested that such activation is also mediated by the massive and diffuse cortical release of nitric oxide (NO). In this work we have combined the spectroscopic measurement of NO levels in the somatosensory cortex of the cat through its marker methemoglobin, as well as two other hemodynamic markers (oxyhemoglobin - oxyHb - and deoxyhemoglobin - deoxyHb), together with the electrical stimulation of BS and BF - to induce an experimental transition from a sleep-like state to an awake-like mode. The results show an increase of NO levels either after BS or BF activation. The response induced by BS stimulation was biphasic in the three studied markers, and lasted for up to 30s. The changes induced by BF were monophasic lasting for up to 20s. The systemic blockade of NO production abolished the observed responses to BS whereas responses to BF stimulation were much less affected. These results indicate a crucial role for NO in the neuronal activation induced by the ascending systems. PMID:25463513

Espinosa, N; Cudeiro, J; Marińo, J

2015-01-29

361

Taurine chloramine inhibits LPS-induced glucose uptake and glucose transporter 1 expression in RAW 264.7 macropages.  

PubMed

Inflammatory cells use glucose as a primary source of metabolic energy, and thus increased uptake of glucose and high rates of glycolysis are characteristics of inflamed cells. Taurine chloramine (TauCl) is the product of a reaction between cellular taurine and hypochlorous acid (HOCl/OCl-), the latter produced by the halide-dependent myeloperoxidase (MPO) system in inflammatory cells. Taurine, a major metabolite of cysteine, protects cells from inflammatory injury by removing toxic hypochlorous acid formed by the MPO system, and also by inhibiting the production of inflammatory mediators. In the present study, we examined the effect of TauCl on glucose uptake and the expression of the glucose transporter 1 (GLUT1) in RAW 264.7 murine macrophages stimulated with lipopolysaccharide (LPS). Glucose uptake was measured by employing labeled glucose analogue [18F]-2-fluoro-2-deoxy-D-glucose (FDG). Stimulation RAW 264.7 cells with LPS increased glucose uptake and led to an upregulation in GLUT1 expression, effects that were abrogated in macrophages treated with TauCl. These data suggest that TauCl can inhibit LPS-mediated enhancement of glucose uptake through inhibition of the upregulation of glucose transporter expression in activated macrophages. This represents one of the mechanisms by which TauCl modulates inflammatory cell function. PMID:19239179

Kim, Chaekyun; Kim, Seongtag

2009-01-01

362

Inhibition of inflammatory response in LPS-induced macrophages by 9-KOTE and 13-KOTE produced by biotransformation.  

PubMed

Lipid mediators such as the leukotrienes, resolvins and protectins have been considered excellent models for the development of new anti-inflammatory drugs, due to their high potentiality. Nevertheless, only tiny amounts are available from natural sources and they have to be prepared by total synthesis. It is known that besides chemical reagents, microorganisms can also promote fatty acid oxygenation, via enzymatic reactions. In this context, the aim of this work was to produce oxylipids analogues in structure to lipid mediators employing microbial biotransformation. To this end, ?-linolenic acid (ALA) was biotransformed by the fungi Aspergillus niger into oxylipids with different levels of oxygenation within 24h or 48h. The anti-inflammatory potential of products were evaluated by means of NO and TNF-? quantification in LPS-stimulated RAW264.7 macrophage cell line which guided the isolation of the regioisomers at m/z [M-H](-) 291, 9-keto-10E,12Z,15Z-octadecatrienoic acid (9-KOTE) and 13-keto-9Z,11E,15Z-octadecatrienoic acid (13-KOTE). We showed that biotransformation represents a powerful strategy for the production of potentially interesting candidates for development of anti-inflammation therapies. PMID:24731823

Petta, Tânia; Secatto, Adriana; Faccioli, Lúcia Helena; Moraes, Luiz Alberto Beraldo

2014-05-10

363

Inhibition of soluble epoxide hydrolase reduces LPS-induced thermal hyperalgesia and mechanical allodynia in a rat model  

E-print Network

in epoxides of linoleic acid. These data show that inhibition of sEH may become a viable therapeutic strategy mediators include K+ , neuropeptides such as substance P, peptides such as bradykinin, cytokines, monoamines are major therapeutic agents for inflammatory pain (Vane, 1971; Fabien et al., 2004). Another branch

Hammock, Bruce D.

364

Activation of the bile acid receptor TGR5 enhances LPS-induced inflammatory responses in a human monocytic cell line.  

PubMed

Abstract Introduction: Bile acids are recognized as signaling molecules, mediating their effects both through the cell surface receptor TGR5 and the nuclear receptor FXR. After a meal, approximately 95% of the bile acids are transported from terminal ileum and back to the liver via the portal vein, resulting in postprandial elevations of bile acids in blood. During the digestion of fat, components from the microbiota, including LPS, are thought to reach the circulation where it may lead to inflammatory responses after binding TLR4 immune cells. Both LPS and bile acids are present in blood after a high-fat meal; we therefore wanted to study consequences of a possible interplay between TGR5 and TLR4 in human monocytes. Methods: The monocytic cell line U937 stably transfected with the NF-?B reporter plasmid 3x-?B-luc was used as a model system to study the effects of TGR5 and TLR4. Activation of MAP kinases was studied to reveal functional consequences of triggering TGR5 in U937 cells. Effects of TGR5 and TLR4 activation were monitored using NF-?B luciferase assay and by quantification of the pro-inflammatory cytokines IL-6 and IL-8 using ELISA. Results: In this study, results show that triggering TGR5 with the specific agonist betulinic acid (BA), and the bile acids CDCA or DCA, activated both the main MAP kinases ERK1/2, p38 and JNK, and the NF-?B signaling pathway. We further demonstrated that co-triggering of TLR4 and TGR5 enhanced the activation of NF-?B and the release of inflammatory cytokines in a synergistic manner compared to triggering of TLR4 alone. Conclusions: Thus, two different and simultaneous events associated with the digestive process coordinately affect the function of human monocytes and contribute to enhanced inflammation. Because elevated levels of circulatory LPS may contribute to the development of insulin resistance, the results from this study suggest that bile acids through the activation of TGR5 may have a role in the development of insulin resistance as well. PMID:25418122

Mobraten, Kaia; Haugbro, Tarjei; Karlstrom, Ellen; Kleiveland, Charlotte R; Lea, Tor

2014-11-24

365

Protection against LPS-induced cartilage inflammation and degradation provided by a biological extract of Mentha spicata  

Microsoft Academic Search

BACKGROUND: A variety of mint [Mentha spicata] has been bred which over-expresses Rosmarinic acid (RA) by approximately 20-fold. RA has demonstrated significant anti-inflammatory activity in vitro and in small rodents; thus it was hypothesized that this plant would demonstrate significant anti-inflammatory activity in vitro. The objectives of this study were: a) to develop an in vitro extraction procedure which mimics

Wendy Pearson; Ronald S Fletcher; Laima S Kott; Mark B Hurtig

2010-01-01

366

PROCALCITONIN AND CALCITONIN GENE-RELATED PEPTIDE DECREASE LPS-INDUCED TNF PRODUCTION BY HUMAN CIRCULATING BLOOD CELLS  

Microsoft Academic Search

The pathogenesis of septic shock is mainly due to unregulated tumour necrosis factor-? (TNF-?) production. Procalcitonin (PCT) and calcitonin gene-related peptide (CGRP) are alternative transcription products of the calcitonin gene. Since high PCT levels have been described in human sepsis, and since CGRP inhibits TNF synthesis in rats, we examined the role of these peptides in the regulation of the

Guillaume Monneret; Alexandre Pachot; Beatrice Laroche; Josiane Picollet; Jacques Bienvenu

2000-01-01

367

Surfactant Protein A Differentially Regulates IFN g - and LPS-Induced Nitrite Production by Rat Alveolar Macrophages  

Microsoft Academic Search

Although several studies have demonstrated that the pulmo- nary collectins surfactant protein (SP)-A and SP-D contribute to innate immunity by enhancing pathogen phagocytosis, the role of SP-A and SP-D in regulating production of free radicals and cytokines is controversial. We hypothesized that the state and mechanism of activation of the immune cell influence its response to SP-A. The effects of

Cordula Stamme; Eric Walsh; Jo Rae

368

Sex steroid levels near the term of pregnancy do not alter lps-induced fever in oophorectomized rats.  

PubMed

Fever, an important component of the host's defence response to infection, is absent or attenuated in rats near the term of pregnancy concurrent with major changes in blood concentrations of the sex steroids, estrogen and progesterone. The present experiments were carried out to determine the potential role of estrogen and progesterone in mediating the altered core temperature response to bacterial pyrogen. For the experiments, estrogen and progesterone were administered alone or in combination to oophorectomized, non-pregnant rats in concentrations that mimicked plasma levels of these hormones measured in pregnant rats on days 17, 18, 19 and 20 of gestation. Treatment with estrogen or progesterone alone or in combination did not alter basal core temperature or the overall febrile response (i.e., 12 h fever index) to an EC50 dose of E. coli LPS (i.e., 20 ?g/kg). Administration of estrogen did, however, influence the early core temperature response and increase the latency to fever following administration of LPS. Thus, our data provide evidence that although estrogen may influence the early core temperature response to LPS, sex steroids in concentrations similar to those observed late in gestation do not alter the overall febrile response, and therefore, are unlikely to mediate the attenuated / absent febrile response to bacterial pyrogen in rats near the term of pregnancy. This article is protected by copyright. All rights reserved. PMID:25416311

Finley, Caitlin; Zhang, Chunfen; Fewell, James E

2014-11-20

369

A low-level diode laser therapy reduces the lipopolysaccharide (LPS)-induced periodontal ligament cell inflammation  

NASA Astrophysics Data System (ADS)

The purpose of this study was to investigate the cytologic effects of inflammatory periodontal ligament cells in vitro after low-level laser therapy. Human periodontal ligament cells were cultured, exposed to lipopolysaccharide and subjected to low-level laser treatment of 5?J?cm?2 or 10?J?cm?2 using a 920?nm diode laser. A periodontal ligament cell attachment was observed under a microscope, and the cell viability was quantified by a mitochondrial colorimetric assay. Lipopolysaccharide-treated periodontal ligament cells were irradiated with the low-level laser, and the expression levels of several inflammatory markers, iNOS, TNF-? and IL-1, and pErk kinase, were analyzed by reverse transcription polymerase chain reaction and western blot. The data were collected and analyzed by one-way analysis of variance; p < 0.05 indicated a statistically significant difference. The low-level laser treatment of periodontal ligament cells increased their ability to attach and survive. After irradiation, the expression levels of iNOS, TNF-? and IL-1 in lipopolysaccharide-exposed periodontal ligament cells decreased over time (p < 0.05). In periodontal ligament cells, low-level diode laser treatment increased the cells’ proliferative ability and decreased the expression of the examined inflammatory mediators.

Huang, T. H.; Chen, C. C.; Liu, S. L.; Lu, Y. C.; Kao, C. T.

2014-07-01

370

Homocysteine thiolactone-induced seizures in adult rats are aggravated by inhibition of inducible nitric oxide synthase.  

PubMed

Homocysteine and its metabolites (homocysteine thiolactone (HT)) induce seizures via different but still not well-known mechanisms. The role of nitric oxide (NO) in epileptogenesis is highly contradictory and depends on, among other factors, the source of NO production. The aim of the present study was to examine the effects of aminoguanidine, selective inhibitor of inducible NO synthase (iNOS), on HT-induced seizures. Aminoguanidine (50, 75, and 100 mg/kg, intraperitoneally (i.p.)) was injected to rats 30 min prior to inducing HT (5.5 mmol/kg, i.p.). Seizure behavior was assessed by seizure incidence, latency time to first seizure onset, number of seizure episodes, and their severity during observational period of 90 min. Number and duration of spike and wave discharges (SWDs) were determined in electroencephalogram (EEG). Seizure latency time was significantly shortened, while seizure incidence, number, and duration of HT-induced SWD in EEG significantly increased in rats receiving aminoguanidine 100 mg/kg before subconvulsive dose of HT. Aminoguanidine in a dose-dependent manner also significantly increased the number of seizure episodes induced by HT and their severity. It could be concluded that iNOS inhibitor (aminoguanidine) markedly aggravates behavioral and EEG manifestations of HT-induced seizures in rats, showing functional involvement of iNOS in homocysteine convulsive mechanisms. PMID:23760255

Hrn?i?, D; Raši?-Markovi?, A; Macut, D; Šuši?, V; Djuric, D; Stanojlovi?, O

2014-05-01

371

Chitosan and blueberry treatment induces arginase activity and inhibits nitric oxide production during acetaminophen-induced hepatotoxicity  

PubMed Central

Background: Liver diseases have become a major problem of the worldwide. More than 50% of all cases of liver failure can be attributed to drugs. Among these, acetaminophen is the most common cause. Objective: The aim of this study was to investigate the the hepatoprotective effects of blueberry and chitosan on tissue arginase activity, ornithine and nitric oxide levels during the acetaminophen-induced hepatotoxicity. Materials and Methods: Acetaminophen (250 mg/kg body weight per day), blueberry (60 mg/kg body weight per day) and, chitosan (200 mg/kg body weight per day) were administered to the rats by oral gavage during the experimental period. Results: Blueberry and chitosan significantly decreased liver arginase activity and ornithine levelsand and increased nitric oxide levels. Glutathione levels were remarkably increased by chitosan and blueberry treatments. Conclusion: The results of the present study indicate that blueberry and chitosan effectively protected against the acetaminophen-induced hepatotoxicity. The hepatoprotective effect afforded by blueberry and chitosan can be attributed to its antioxidant and anti-inflammatory activities. PMID:24991095

Ozcelik, Eda; Uslu, Sema; Burukoglu, Dilek; Musmul, Ahmet

2014-01-01

372

Renal Angiotensin-converting enzyme is essential for the hypertension induced by nitric oxide synthesis inhibition.  

PubMed

The kidney is an important source of angiotensin-converting enzyme (ACE) in many species, including humans. However, the specific effects of local ACE on renal function and, by extension, BP control are not completely understood. We previously showed that mice lacking renal ACE, are resistant to the hypertension induced by angiotensin II infusion. Here, we examined the responses of these mice to the low-systemic angiotensin II hypertensive model of nitric oxide synthesis inhibition with L-NAME. In contrast to wild-type mice, mice without renal ACE did not develop hypertension, had lower renal angiotensin II levels, and enhanced natriuresis in response to L-NAME. During L-NAME treatment, the absence of renal ACE was associated with blunted GFR responses; greater reductions in abundance of proximal tubule Na(+)/H(+) exchanger 3, Na(+)/Pi co-transporter 2, phosphorylated Na(+)/K(+)/Cl(-) cotransporter, and phosphorylated Na(+)/Cl(-) cotransporter; and greater reductions in abundance and processing of the ? isoform of the epithelial Na(+) channel. In summary, the presence of ACE in renal tissue facilitates angiotensin II accumulation, GFR reductions, and changes in the expression levels and post-translational modification of sodium transporters that are obligatory for sodium retention and hypertension in response to nitric oxide synthesis inhibition. PMID:25012170

Giani, Jorge F; Janjulia, Tea; Kamat, Nikhil; Seth, Dale M; Blackwell, Wendell-Lamar B; Shah, Kandarp H; Shen, Xiao Z; Fuchs, Sebastien; Delpire, Eric; Toblli, Jorge E; Bernstein, Kenneth E; McDonough, Alicia A; Gonzalez-Villalobos, Romer A

2014-12-01

373

Tyrosine phosphorylation of inducible nitric oxide synthase: implications for potential post-translational regulation.  

PubMed Central

The activation of cultured Raw 264.7 murine macrophages with interferon gamma and lipopolysaccharide results in the expression of inducible nitric oxide synthase (i_NOS) and the subsequent production of nitric oxide. In the present study, the i-NOS expressed in these activated cells was characterized for possible post-translational protein modification by endogenous tyrosine protein kinases. Western-blot analysis using phosphotyrosine antibodies revealed that i-NOS was phosphorylated on tyrosine residues and that this was an early event coinciding with the appearance of newly synthesized i-NOS. A brief exposure of activated cells to vanadate, a tyrosine phosphatase inhibitor, significantly increased the level of i-NOS tyrosine phosphorylation, suggesting that tyrosine phosphatases are dynamically involved in the regulation of this process. Vanadate treatment of activated cells also resulted in a rapid increase in enzyme activity, occurring within 5 min of exposure. Taken together, these results demonstrate that tyrosine kinases and phosphatases are involved in the post-translational modification of i-NOS and may potentially play a role in modulating the functional activity of the enzyme in macrophages. PMID:8615785

Pan, J; Burgher, K L; Szczepanik, A M; Ringheim, G E

1996-01-01

374

Inducible and endothelial nitric oxide synthase expression during development of transplant arteriosclerosis in rat aortic grafts.  

PubMed Central

In the vascular system, distinct isoforms of nitric oxide synthase (NOS) generate nitric oxide (NO), which acts as a biological messenger. Its role in the development of transplant arteriosclerosis (TA) is still unclear. To investigate whether NO is involved in TA, we studied the expression of NOS isoforms, inducible NOS (iNOS) and endothelial NOS (eNOS), by immunohistochemistry and in situ hybridization during the first two post-transplantation months and their relation with cold ischemia (1 to 24 hours) and reperfusion injury using an aortic transplantation model in the rat. We found an increased iNOS expression in the intima and adventitia and a decreased expression in the media, whereas eNOS expression was not significantly altered during the development of TA. Co-localization studies suggested that iNOS-positive cells were vascular smooth muscle cells, monocyte-derived macrophages, and endothelial cells. Prolonged ischemic storage time resulted in an increase in eNOS expression in the neointima. In situ hybridization showed iNOS mRNA expression by vascular cells in the neointima and media. NO produced by iNOS and eNOS may be involved, at least in part, in the pathogenesis of TA in aortic grafts. Additional studies are needed to confirm the modulatory mechanism of NO during the development of TA. Images Figure 3 Figure 4 Figure 6 PMID:8952533

Akyürek, L. M.; Fellström, B. C.; Yan, Z. Q.; Hansson, G. K.; Funa, K.; Larsson, E.

1996-01-01

375

Ventilation and oxygenation induce endothelial nitric oxide synthase gene expression in the lungs of fetal lambs.  

PubMed Central

At birth, ventilation and oxygenation immediately decrease pulmonary vascular resistance (PVR) and increase pulmonary blood flow (PBF); more gradual changes occur over the next several hours. Nitric oxide, produced by endothelial nitric oxide synthase (eNOS), mediates these gradual changes. To determine how ventilation and oxygenation affect eNOS gene expression, 12 fetal lambs were ventilated for 8 h without changing fetal descending aortic blood gases or pH (rhythmic distension) or with 100% oxygen (O2 ventilation). Vascular pressures and PBF were measured. Total RNA, protein, and tissue sections were prepared from lung tissue for RNase protection assays, Western blotting, and in situ hybridization. O2 ventilation increased PBF and decreased PVR more than rhythmic distension (P < 0.05). Rhythmic distension increased eNOS mRNA expression; O2 ventilation increased eNOS mRNA expression more and increased eNOS protein expression (P < 0.05). To define the mechanisms responsible for these changes, ovine fetal pulmonary arterial endothelial cells were exposed to 1, 21, or 95% O2 or to shear stress. 95% O2 increased eNOS mRNA and protein expression (P < 0.05). Shear stress increased eNOS mRNA and protein expression (P < 0.05). Increased oxygenation but more importantly increased PBF with increased shear stress induce eNOS gene expression and contribute to pulmonary vasodilation after birth. PMID:9294110

Black, S M; Johengen, M J; Ma, Z D; Bristow, J; Soifer, S J

1997-01-01