scholarly journals SUN-254 Angiotensin II Stimulates Microglia Cell Inflammatory Responses

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Jean Paul Moliere Velez ◽  
Dra Yaritza Inostroza-Nieves ◽  
Jose R Romero ◽  
Claudia Arenas ◽  
Diego Capo
Keyword(s):  
Angiotensin Ii ◽  
Neurodegenerative Diseases ◽  
Inflammatory Responses ◽  
Renin Angiotensin System ◽  
Inos Mrna ◽  
No Production ◽  
Ros Production ◽  
Griess Reagent ◽  
Cns Inflammation ◽  
Microglia Cell

Abstract Angiotensin II (AngII) is the principal effector molecule of the renin-angiotensin system (RAS). It’s effects on the cardiovascular and renal system are well-documented. AngII acts mainly via interaction with the AngII type-1 receptor (AT1R). Disordered levels of AngII lead to hypertension and cardiovascular disease. Increasing evidence suggests that AngII may also play a role in the pathophysiology of neurodegenerative diseases through unclear mechanisms. We investigated AngII, AT1R and AT2R levels in a mouse model of neurodegenerative disease, the experimentally induced autoimmune encephalomyelitis (EAE) mouse. In EAE mice, AngII and AT1R gene expression in brain tissue were significantly increased when compared to control mice (3.2 folds ±1.9, p<0.05, n=5; and 2.6 folds ±1.1, p<0.01, n=5 respectively). In addition, iNOS mRNA expression by qRT-PCR was likewise upregulated in EAE mice compared to control (3.4 ± 1.4 folds, p<0.01, n=5). We then studied the effects of AngII in human microglial cells (HMC3) -resident innate immune cells of the central nervous system (CNS). In HMC3 cells, treatment with AngII up-regulated the expression IL-6 (3.9 folds ± 1.2, p<0.01, n=4) and increased IL-6 concentration by 83% (p<0.05, n=4) by ELISA; effects that were blocked by the AT1R antagonist, Losartan. Also, AngII induced TNF-α production, increasing its concentration by 90% (p<0.05, n=4), an increase that was blocked by Losartan. We also quantified Nitric Oxide (NO) production by using Griess Reagent and reactive oxygen species (ROS) production by the MUSE Oxidative Stress assay. In these cells, NO and ROS production were significantly increased by AngII (p<0.05, n=4) and treatment with Losartan reduced their production (p<0.05, n=4). In addition, AngII treatment induced iNOS overexpression (2.5 folds ±0.8, p<0.05, n=4); results that are consistent with increases in the EAE mice. These data suggest that AngII can activate microglia cell inflammatory responses and as such may contribute to the pathophysiology of CNS inflammation and neurodegenerative diseases.

scholarly journals Pseudane-VII Regulates LPS-Induced Neuroinflammation in Brain Microglia Cells through the Inhibition of iNOS Expression

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3196 ◽  
Author(s):  
Mi Kim ◽  
Inae Jung ◽  
Ju Na ◽  
Yujeong Lee ◽  
Jaewon Lee ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Inflammatory Responses ◽  
Neurological Diseases ◽  
Inos Expression ◽  
Nuclear Factor Kappab ◽  
Nuclear Factor ◽  
Ros Production ◽  
Proinflammatory Mediators ◽  
Cox 2 ◽  
Novel Target

We previously isolated pseudane-VII from the secondary metabolites of Pseudoalteromonas sp. M2 in marine water, and demonstrated its anti-inflammatory efficacy on macrophages. However, the molecular mechanism by which pseudane-VII suppresses neuroinflammation has not yet been elucidated in brain microglia. Microglia is activated by immunological stimulation or brain injury. Activated microglia secrete proinflammatory mediators which damage neurons. Neuroinflammation appears to be associated with certain neurological diseases, including Parkinson’s disease and Alzheimer’s disease. Natural compounds that suppress microglial inflammatory responses could potentially be used to prevent neurodegenerative diseases or slow their progression. In the present study, we found that pseudane-VII suppresses neuroinflammation in lipopolysaccaride (LPS)-stimulated BV-2 microglial cells and brain. Pseudane-VII was shown to inhibit the LPS-stimulated NO, ROS production and the expression of iNOS and COX-2. To identify the signaling pathway targeted by pseudane-VII, we used western blot analysis to assess the LPS-induced phosphorylation state of p38, ERK1/2, JNK1/2, and nuclear factor-kappaB (NF-κB). We found that pseudane-VII attenuated LPS-induced phosphorylation of MAPK and NF-κB. Moreover, administration of pseudane-VII in mice significantly reduced LPS-induced iNOS expression and microglia activation in brain. Taken together, our findings suggest that pseudane-VII may represent a potential novel target for treatment for neurodegenerative diseases.

scholarly journals Structure-Dependent Effects of Bisphosphonates on Inflammatory Responses in Cultured Neonatal Mouse Calvaria

Antioxidants ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 503
Author(s):  
Keiko Suzuki ◽  
Sadaaki Takeyama ◽  
Shinobu Murakami ◽  
Masahiro Nagaoka ◽  
Mirei Chiba ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Bone Diseases ◽  
Neonatal Mouse ◽  
Side Chain ◽  
Inos Mrna ◽  
No Production ◽  
Tyrosine Nitration ◽  
Mouse Calvaria ◽  
Neonatal Mouse Calvaria

Bisphosphonates (BPs) are classified into two groups, according to their side chain structures, as nitrogen-containing BPs (NBPs) and non-nitrogen-containing BPs (non-NBPs). In this study, we examined the effects of NBPs and non-NBPs on inflammatory responses, by quantifying the inflammatory mediators, prostaglandin E2 (PGE2) and nitric oxide (NO), in cultured neonatal mouse calvaria. All examined NBPs (pamidronate, alendronate, incadronate, risedronate, zoledronate) stimulated lipopolysaccharide (LPS)-induced PGE2 and NO production by upregulating COX-2 and iNOS mRNA expression, whereas non-NBPs (etidronate, clodronate, tiludronate) suppressed PGE2 and NO production, by downregulating gene expression. Additionally, [4-(methylthio) phenylthio] methane bisphosphonate (MPMBP), a novel non-NBP with an antioxidant methylthio phenylthio group in its side chain, exhibited the most potent anti-inflammatory activity among non-NBPs. Furthermore, results of immunohistochemistry showed that the nuclear translocation of NF-κB/p65 and tyrosine nitration of cytoplasmic protein were stimulated by zoledronate, while MPMBP inhibited these phenomena, by acting as a superoxide anion (O2−) scavenger. These findings indicate that MPMBP can act as an efficacious agent that causes fewer adverse effects in patients with inflammatory bone diseases, including periodontitis and rheumatoid arthritis.

scholarly journals Blueberries and insulin protect microglial cells against high glucose-induced inflammation and restore GLUT-1

2021 ◽  
pp. 1-16
Author(s):  
I. Hininger-Favier ◽  
N. Thangthaeng ◽  
D.F. Bielinski ◽  
D.R. Fisher ◽  
B. Shukitt-Hale ◽  
...  
Keyword(s):  
High Glucose ◽  
Glucose Concentration ◽  
Glucose Transporter ◽  
Dietary Intervention ◽  
Inflammatory Responses ◽  
Induced Response ◽  
No Production ◽  
Microglia Cell ◽  
Glut 1 ◽  
Transporter Protein

BACKGROUND: Growing evidence suggests that hyperglycemia could be harmful for cognitive function. That insulin (INS) has a neuro-modulatory role is supported by various findings, but its effect on microglia, the innate immune cells in the brain, is largely unknown. Blueberries have been shown to reduce neuro-inflammation. OBJECTIVE: We hypothesized that high glucose stimulated an inflammation in microglia and that BB and INS were able to reduce it and both might act through GLUT-1 transporter. METHODS: We examined the effects of low (5 mM), medium (25 mM), or high (50 mM) glucose, stimulated or not with lipopolysaccharide (LPS; 100 nM) with either BB extract (2 mg/ml) and/or INS, on inflammatory responses in a microglia cell line. Nitric oxide (NO) production and the expression levels of iNOS, TNF-α, NOX4 and glucose transporter protein-1 (GLUT1) were assessed. RESULTS: We observed that treatment with BB, similarly to INS treatments, reduced the high glucose concentration-induced response on oxidative stress and inflammation, and that this protective effect is more important with LPS added to glucose media. Interestingly, both BB and INS attenuated the LPS-induced inflammatory response on GLUT1. CONCLUSION: Increasing glucose concentration triggers inflammation by microglia. BB as well as INS protected microglia from high glucose levels, by reducing inflammation and altering glucose transport in microglia. These preliminary data compared for the first time BB to Insulin on microglia. Blueberries are promising dietary intervention to prevent diabetic neuropathy. Our preliminary results suggest a possible new mechanism involving GLUT-1 by which BB has insulin-like effects.

Abstract P106: The Role of Inflammasomes and Angiotensin II Type 1 Receptor in the Pressor Responses of Aged Mice to Angiotensin II

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Quynh N Dinh ◽  
Grant R Drummond ◽  
Barbara K Kemp-Harper ◽  
Henry Diep ◽  
Avril A Robertson ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Renin Angiotensin System ◽  
Low Grade ◽  
Ang Ii ◽  
Contractile Responses ◽  
Aged Mice ◽  
Pressor Responses ◽  
Young Mice

Introduction: The prevalence of hypertension increases with age. Chronic low-grade inflammation commonly occurs with ageing, and inflammasomes are important initiators of inflammatory responses. We tested whether aged mice have enhanced pressor responses to angiotensin II (Ang II) and whether this is associated with exaggerated pro-inflammatory and vascular contractile responses. We also tested whether MCC950, a NLRP3 inflammasome inhibitor, reduces blood pressure (BP) in Ang II-treated aged mice. Methods: Young (8-12 weeks) and aged (24-30 months) male C57Bl6 mice were left untreated, or either treated with vehicle or a slow-pressor dose of Ang II (0.28 mg/kg/day) for 28 days. Another group of aged mice were treated with either Ang II + saline or Ang II + MCC950 (10 mg/kg/day) for 10 days. We measured systolic BP, mRNA expression of inflammatory markers and components of the renin-angiotensin system, and vascular contractile responses. Results: In young mice, Ang II caused a gradual increase in BP (final BP: 141.6 ± 8.3 mmHg), whereas BP increased by ~20 mmHg from baseline in aged mice, and continued to increase for 28 days (final BP: 155 ± 12.4 mmHg) (n=8-9, P<0.05). Ageing alone increased renal expression of AT1a receptors, NLRP3, Caspase-1, IL-1β, IL-33, CCR2, CCL7 and CCL8 by at least 1.5-fold (n=7-8, all P<0.05). Maximum contractile responses of mesenteric artery were 1.8-fold greater to Ang II and 1.2-fold greater to phenylephrine in aged vs young mice (n=4, both P<0.05). BP was not different between Ang II + saline-treated aged mice (BP: 138.8 ± 6.8 mmHg) and Ang II + MCC950-treated aged mice (BP: 144.7 ± 9.6 mmHg) (n=6-7, P>0.05). Conclusions: Aged mice have enhanced pressor responses to Ang II and this is associated with exacerbated pro-inflammatory and vascular contractile responses. The NLRP3 inflammasome does not appear to contribute to Ang II-induced hypertension in aged mice.

scholarly journals Nuclear angiotensin II type 2 (AT2) receptors are functionally linked to nitric oxide production

2009 ◽  
Vol 296 (6) ◽  
pp. F1484-F1493 ◽  
Author(s):  
TanYa M. Gwathmey ◽  
Hossam A. Shaltout ◽  
Karl D. Pendergrass ◽  
Nancy T. Pirro ◽  
Jorge P. Figueroa ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Molecular Form ◽  
Rat Kidney ◽  
Renin Angiotensin System ◽  
Receptor Subtypes ◽  
No Production ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin

Expression of nuclear angiotensin II type 1 (AT1) receptors in rat kidney provides further support for the concept of an intracellular renin-angiotensin system. Thus we examined the cellular distribution of renal ANG II receptors in sheep to determine the existence and functional roles of intracellular ANG receptors in higher order species. Receptor binding was performed using the nonselective ANG II antagonist 125I-[Sar1,Thr8]-ANG II (125I-sarthran) with the AT1 antagonist losartan (LOS) or the AT2 antagonist PD123319 (PD) in isolated nuclei (NUC) and plasma membrane (PM) fractions obtained by differential centrifugation or density gradient separation. In both fetal and adult sheep kidney, PD competed for the majority of cortical NUC (≥70%) and PM (≥80%) sites while LOS competition predominated in medullary NUC (≥75%) and PM (≥70%). Immunodetection with an AT2 antibody revealed a single ∼42-kDa band in both NUC and PM extracts, suggesting a mature molecular form of the NUC receptor. Autoradiography for receptor subtypes localized AT2 in the tubulointerstitium, AT1 in the medulla and vasa recta, and both AT1 and AT2 in glomeruli. Loading of NUC with the fluorescent nitric oxide (NO) detector DAF showed increased NO production with ANG II (1 nM), which was abolished by PD and N-nitro-l-arginine methyl ester, but not LOS. Our studies demonstrate ANG II receptor subtypes are differentially expressed in ovine kidney, while nuclear AT2 receptors are functionally linked to NO production. These findings provide further evidence of a functional intracellular renin-angiotensin system within the kidney, which may represent a therapeutic target for the regulation of blood pressure.

scholarly journals DNA Damage and Augmented Oxidative Stress in Bone Marrow Mononuclear Cells from Angiotensin-Dependent Hypertensive Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Bianca P. Campagnaro ◽  
Clarissa L. Tonini ◽  
Breno V. Nogueira ◽  
Dulce E. Casarini ◽  
Elisardo C. Vasquez ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dna Damage ◽  
Angiotensin Ii ◽  
Dna Fragmentation ◽  
Mononuclear Cells ◽  
Renin Angiotensin System ◽  
Bone Marrow Mononuclear Cells ◽  
Ros Production ◽  
Superoxide Anion Production ◽  
System Activation

It has been proposed that the nonhemodynamic effects of angiotensin II are important for the damage observed in the two-kidney, one-clip (2K1C) renovascular hypertension model. Much evidence confirms that angiotensin II is directly involved in NAD(P)H oxidase activation and consequent superoxide anion production, which can damage DNA. The current study was performed to examine the effects of angiotensin-II-dependent hypertension in bone marrow mononuclear cells (BM-MNC); dihydroethidium staining was used to assess reactive oxygen species (ROS) production, and the comet assay was used to assess DNA fragmentation in 2K1C hypertensive mice 14 days after renal artery clipping. In this study we demonstrated that 2K1C hypertensive mice have an elevated lymphocyte count, while undifferentiated BM-MNC counts were diminished. 2K1C mice also showed an augmented ROS production and marked BM-MNC DNA fragmentation. In conclusion, endogenous renin angiotensin system activation-induced arterial hypertension is characterized by excessive ROS production in BM-MNC, which might cause marked DNA damage.

scholarly journals Diphenyleneiodonium inhibits NF-κB activation and iNOS expression induced by IL-1β: involvement of reactive oxygen species

2001 ◽  
Vol 10 (4) ◽  
pp. 209-215 ◽  
Author(s):  
A. Ferreira Mendes ◽  
A. Pato Carvalho ◽  
M. Margarida Caramona ◽  
M. Celeste Lopes
Keyword(s):  
Reactive Oxygen Species ◽  
Articular Chondrocytes ◽  
Reactive Oxygen ◽  
Inos Expression ◽  
Inos Mrna ◽  
No Production ◽  
Dependent Manner ◽  
Ros Production ◽  
Oxygen Species ◽  
Bovine Articular Chondrocytes

Aims:In this work, we studied the mechanisms by which diphenyleneiodonium chloride (DPI) inhibits nitric oxide (NO) synthesis induced by the pro-inflammatory cytokine interleukin-1β (IL-1) in bovine articular chondrocytes. To achieve this, we evaluated the ability of DPI to inhibit the expression and activity of the inducible isoform of the NO synthase (iNOS) induced by IL-1. We also studied the ability of DPI to prevent IL-1-induced NF-κB activation and reactive oxygen species (ROS) production.Results:Northern and Western blot analysis, respectively, showed that DPI dose-dependently inhibited IL-1-induced iNOS mRNA and protein synthesis in primary cultures of bovine articular chondrocytes. DPI effectively inhibited NO production (IC50= 0.03 Ī 0.004 μ M), as evaluated by the method of Griess. Nuclear factor-kappa B (NF- κB) activation, as evaluated by electrophoretic mobility shift assay, was inhibited by DPI (1-10 μ M) in a dose-dependent manner. IL-1-induced ROS production, as evaluated by measurement of dichlorofluorescein fluorescence, was inhibited by DPI at concentrations that also prevented NF-κB activation and iNOS expression.Conclusions:DPI inhibits IL-1-induced NO production in chondrocytes by two distinct mechanisms: (i) by inhibiting NOS activity, and (ii) by preventing iNOS expression through the blockade of NF-κB activation. These results also support the involvement of reactive oxygen species in IL-1-induced NF-κB activation and expression of NF-κB-dependent genes, such as iNOS.

scholarly journals Anti-inflammatory effects of resveratrol occur via inhibition of lipopolysaccharide-induced NF-κB activation in Caco-2 and SW480 human colon cancer cells

2012 ◽  
Vol 108 (9) ◽  
pp. 1623-1632 ◽  
Author(s):  
Maria Antonietta Panaro ◽  
Vito Carofiglio ◽  
Angela Acquafredda ◽  
Pasqua Cavallo ◽  
Antonia Cianciulli
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Human Colon ◽  
Sw480 Cell ◽  
Intestinal Cells ◽  
Inos Mrna ◽  
No Production ◽  
Human Colon Cancer ◽  
Anti Inflammatory ◽  
Pre Treatment

Resveratrol, a polyphenol abundantly found in grapes and red wine, exhibits beneficial health effects due to its anti-inflammatory properties. In the present study, we evaluated the effect of resveratrol on inflammatory responses induced by lipopolysaccharide (LPS) treatment of human intestinal Caco-2 and SW480 cell lines. In the LPS-treated intestinal cells, resveratrol dose-dependently inhibited the expression of inducible NO synthase (iNOS) mRNA as well as protein expression, resulting in a decreased production of NO. In addition, Toll-like receptor-4 expression was significantly diminished in LPS-stimulated cells after resveratrol pre-treatment. To investigate the mechanisms by which resveratrol reduces NO production and iNOS expression, we examined the activation of inhibitor of κB (IκB) in LPS-stimulated intestinal cells. Results demonstrated that resveratrol inhibited the phosphorylation, as well as the degradation, of the IκB complex. Overall, these results show that resveratrol is able to reduce LPS-induced inflammatory responses by intestinal cells, interfering with the activation of NF-κB-dependent molecular mechanisms.

scholarly journals The Methanol Seed Extract of Garcinia kola Attenuated Angiotensin II- and Lipopolyssacharide-Induced Vascular Smooth Muscle Cell Proliferation and Nitric Oxide Production

2016 ◽  
Vol 39 (2) ◽  
pp. 153-158
Author(s):  
Adeolu A. Adedapo ◽  
Temidayo O. Omobowale ◽  
Ademola A. Oyagbemi ◽  
Momoh A. Yakubu
Keyword(s):  
Nitric Oxide ◽  
Cell Proliferation ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Cellular Proliferation ◽  
Inflammatory Responses ◽  
Seed Extract ◽  
No Production ◽  
Garcinia Kola

AbstractAll over the world, cardiovascular diseases are a risk factor for poor health and early death with predisposing factors to include age, gender, tobacco use, physical inactivity, excessive alcohol consumption, unhealthy diet, obesity, family history of cardiovascular disease, hypertension, diabetes mellitus, hyperlipidemia, psychosocial factors, poverty and low educational status, and air pollution. It is envisaged that herbal products that can stem this trend would be of great benefit. Garcinia kola (GK), also known as bitter kola is one of such plants. Generally used as a social snack and offered to guests in some cultural settings, bitter kola has been indicated in the treatment of laryngitis, general inflammation, bronchitis, viral infections and diabetes. In this study, the effects of methanol seed extract of Garcinia kola on the proliferation of Vascular Smooth Muscle Cells (VSMCs) in cell culture by Angiotensin II (Ang II) and LPS-induced NO production were carried out. Confluent VSMCs were exposed to GK (25, 50 and 100 μg/ml) before or after treatment with lipopolyssacharide (100μg/ml), and Angiotensin II (10−8-10−6M). Cellular proliferation was determined by MTT assay and NO production by Griess assay. Treatment with Angiotensin II (10−8, 10−6) or LPS significantly enhanced proliferation of VSM cells while LPS significantly increased nitric oxide (NO) production. Treatment with GK (25, 50 & 100 μg/ml) attenuated VSM cell proliferation. The results indicate that GK has potential to inhibit mitogen activated vascular cell growth and possibly inhibit inflammatory responses to LPS. Thus GK may be useful in condition that is characterized by cellular proliferation and inflammatory responses.

A Review of Angiotensin Receptor Blocker-based Therapies at all Levels of Cardiovascular Risk

2011 ◽  
Vol 7 (4) ◽  
pp. 254 ◽  
Author(s):  
Giuliano Tocci ◽  
Lorenzo Castello ◽  
Massimo Volpe ◽  
◽  
◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Ventricular Hypertrophy ◽  
Renin Angiotensin System ◽  
Left Ventricular ◽  
Clinical Settings ◽  
Angiotensin Ii Receptor ◽  
Angiotensin System ◽  
Receptor Blockers ◽  
Artery Disease

The renin–angiotensin system (RAS) has a key role in the maintenance of cardiovascular homeostasis, and water and electrolyte metabolism in healthy subjects, as well as in several diseases including hypertension, left ventricular hypertrophy and dysfunction, coronary artery disease, renal disease and congestive heart failure. These conditions are all characterised by abnormal production and activity of angiotensin II, which represents the final effector of the RAS. Over the last few decades, accumulating evidence has demonstrated that antihypertensive therapy based on angiotensin II receptor blockers (ARBs) has a major role in the selective antagonism of the main pathological activities of angiotensin II. Significant efforts have been made to demonstrate that blocking the angiotensin II receptor type 1 (AT1) subtype receptors through ARB-based therapy results in proven benefits in different clinical settings. In this review, we discuss the main benefits of antihypertensive strategies based on ARBs in terms of their efficacy, safety and tolerability.

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