Carbon Monoxide-Neuroglobin Axis Targeting Metabolism Against Neuroinflammation

Abstract Microglia are the immune competent cell of the central nervous system (CNS), promoting brain homeostasis and regulating inflammatory response against infection and injury. Chronic or exacerbated neuroinflammation is a cause of damage in several brain pathologies. Endogenous carbon monoxide (CO), produced from the degradation of heme, is described as anti-apoptotic and anti-inflammatory in several contexts, including in the CNS. Neuroglobin (Ngb) is a haemoglobin-homologous protein, which upregulation triggers antioxidant defence and prevents neuronal apoptosis. Thus, we hypothesized a crosstalk between CO and Ngb, in particular, that the anti-neuroinflammatory role of CO in microglia depends on Ngb. A novel CO-releasing molecule (ALF826) based on molybdenum was used for delivering CO in microglial culture.BV-2 mouse microglial cell line was challenged with lipopolysaccharide (LPS) for triggering inflammation, and after 6h ALF826 was added. CO exposure limited inflammation by decreasing inducible nitric oxide synthase (iNOS) expression and the production of nitric oxide (NO) and tumour necrosis factor-a (TNF-a), and by increasing interleukine-10 (IL-10) release. CO-induced Ngb upregulation correlated in time with CO’s anti-inflammatory effect. Moreover, knocking down Ngb reversed the anti-inflammatory effect of CO, suggesting that dependents on Ngb expression. CO-induced Ngb upregulation was independent on ROS signalling, but partially dependent on the transcriptional factor SP1. Finally, microglial cell metabolism is also involved in the inflammatory response. In fact, LPS treatment decreased oxygen consumption in microglia, indicating a switch to glycolysis, which is associated with a proinflammatory. While CO treatment increased oxygen consumption, reverting LPS effect and indicating a metabolic shift into a more oxidative metabolism. Moreover, in the absence of Ngb this phenotype was no longer observed, indicating Ngb is needed for CO’s modulation of microglial metabolism. Finally, the metabolic shift induced by CO did not depend on alteration of mitochondrial population. In conclusion, neuroglobin emerges for the first time as a key player for CO signalling against exacerbated neuroinflammation in microglia.

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Induction of Heme Oxygenase-1 by Sodium 9-Hydroxyltanshinone IIA Sulfonate Derivative Contributes to Inhibit LPS-Mediated Inflammatory Response in Macrophages

Cellular Physiology and Biochemistry ◽

10.1159/000430299 ◽

2015 ◽

Vol 36 (4) ◽

pp. 1316-1330 ◽

Cited By ~ 5

Author(s):

Xin-Hua Liu ◽

Xi-Ling Wang ◽

Hong Xin ◽

Dan Wu ◽

Xiao-Ming Xin ◽

...

Keyword(s):

Nitric Oxide ◽

Inflammatory Response ◽

Heme Oxygenase ◽

Inos Expression ◽

Heme Oxygenase 1 ◽

Zinc Protoporphyrin ◽

Nuclear Factor ◽

Anti Inflammatory ◽

Underlying Mechanisms ◽

Inflammatory Effect

Background/Aim: Sodium 9-acetoxyltanshinone IIA sulfonate (ZY-1A4), a novel compound derived from sodium 9-hydroxyltanshinone IIA sulfonate, was synthesized with potential biological activities. This study aimed to explore the effects of ZY-1A4 on lipopolysaccharide (LPS)-triggered inflammatory response and the underlying mechanisms. Methods: Activation of RAW264.7 macrophages was induced by LPS. The effects of ZY-1A4 on inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) generation, nuclear factor-κB (NF-κB) activation, heme oxygenase-1 (HO-1) expression, and nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway were evaluated to elucidate its underlying mechanisms on inflammatory responses. Results: ZY-1A4 concentration-dependently reduced iNOS expression and NO production, and inhibited c-Jun-N-terminal kinase 1/2 (JNK1/2) phosphorylation and NF-κB activation in LPS-stimulated macrophages. In addition, ZY-1A4 concentration- and time-dependently induced HO-1 expression associated with degradation of Kelch-like ECH-associated protein 1 (Keap1) and nuclear translocation of Nrf2, while the effect of ZY-1A4 was abolished by a phosphoinositide 3-kinase (PI3K) inhibitor LY294002. Intriguingly, pharmacological inactivation of HO-1 with zinc protoporphyrin IX reversed anti-inflammatory effect of ZY-1A4, but the anti-inflammatory effect of ZY-1A4 was largely mimicked by HO-1 by-products carbon monoxide and bilirubin. Furthermore, the inhibitory effect of ZY-1A4 on LPS-induced iNOS expression and NO release was abolished by HO-1 siRNA or LY294002. Conclusion: Our results demonstrated that ZY-1A4 suppressed LPS-induced iNOS expression and NO generation via modulation of NF-κB activation and HO-1 expression. This new finding might shed light to the prevention and therapy of cardiovascular diseases.

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The Haptoglobin-CD163-Heme Oxygenase-1 Pathway for Hemoglobin Scavenging

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/523652 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 75

Author(s):

Jens Haugbølle Thomsen ◽

Anders Etzerodt ◽

Pia Svendsen ◽

Søren K. Moestrup

Keyword(s):

Carbon Monoxide ◽

Plasma Concentration ◽

Inflammatory Response ◽

Heme Oxygenase ◽

Enzyme System ◽

Limiting Factor ◽

Heme Oxygenase 1 ◽

Future Studies ◽

Anti Inflammatory ◽

Inflammatory Effect

The haptoglobin- (Hp-) CD163-heme oxygenase-1 (HO-1) pathway is an efficient captor-receptor-enzyme system to circumvent the hemoglobin (Hb)/heme-induced toxicity during physiological and pathological hemolyses. In this pathway, Hb tightly binds to Hp leading to CD163-mediated uptake of the complex in macrophages followed by lysosomal Hp-Hb breakdown and HO-1-catalyzed conversion of heme into the metabolites carbon monoxide (CO), biliverdin, and iron. The plasma concentration of Hp is a limiting factor as evident during accelerated hemolysis, where the Hp depletion may cause serious Hb-induced toxicity and put pressure on backup protecting systems such as the hemopexin-CD91-HO pathway. The Hp-CD163-HO-1 pathway proteins are regulated by the acute phase mediator interleukin-6 (IL-6), but other regulatory factors indicate that this upregulation is a counteracting anti-inflammatory response during inflammation. The heme metabolites including bilirubin converted from biliverdin have overall an anti-inflammatory effect and thus reinforce the anti-inflammatory efficacy of the Hp-CD163-HO-1 pathway. Future studies of animal models of inflammation should further define the importance of the pathway in the anti-inflammatory response.

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Anti-Inflammatory Effect of Phytoncide in an Animal Model of Gastrointestinal Inflammation

Molecules ◽

10.3390/molecules26071895 ◽

2021 ◽

Vol 26 (7) ◽

pp. 1895

Author(s):

Azra Memon ◽

Bae Yong Kim ◽

Se-eun Kim ◽

Yuliya Pyao ◽

Yeong-Geun Lee ◽

...

Keyword(s):

Nitric Oxide ◽

Animal Model ◽

Gastric Ulcer ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Inos Expression ◽

Gastrointestinal Inflammation ◽

Anti Inflammatory ◽

Oxide Synthase ◽

Inflammatory Effect

Background: Phytoncide is known to have antimicrobial and anti-inflammatory properties. Purpose: This study was carried out to confirm the anti-inflammatory activity of two types of phytoncide extracts from pinecone waste. Methods: We made two types of animal models to evaluate the efficacy, an indomethacin-induced gastroenteritis rat model and a dextran sulfate sodium-induced colitis mouse model. Result: In the gastroenteritis experiment, the expression of induced-nitric oxide synthase (iNOS), a marker for inflammation, decreased in the phytoncide-supplemented groups, and gastric ulcer development was significantly inhibited (p < 0.05). In the colitis experiment, the shortening of the colon length and the iNOS expression were significantly suppressed in the phytoncide-supplemented group (p < 0.05). Conclusions: Through this study, we confirmed that phytoncide can directly inhibit inflammation in digestive organs. Although further research is needed, we conclude that phytoncide has potential anti-inflammatory properties in the digestive tract and can be developed as a functional agent.

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Anti-Inflammatory Activity of Extract Mixture of Annona senegalensis Pers. and Piliostigma thonningii (Schum.)

Journal of Drug Delivery and Therapeutics ◽

10.22270/jddt.v10i6-s.4605 ◽

2020 ◽

Vol 10 (6-s) ◽

pp. 103-108

Author(s):

Komlatsè Togbenou ◽

Kokou Idoh ◽

Kossivi Dosseh ◽

Tchazou Kpatcha ◽

Amégnona Agbonon

Keyword(s):

Nitric Oxide ◽

Ethanolic Extract ◽

No Production ◽

Leukocyte Infiltration ◽

Inflammation Markers ◽

Asthma Model ◽

Piliostigma Thonningii ◽

Anti Inflammatory ◽

Inflammatory Component ◽

Inflammatory Effect

Introduction: Annona senegalensis Pers (Annonaceae) and Piliostigma thonningii (Schum.) (Leguminoseae) are two medicinal plants used, often in combination, in traditional Togolese medicine for the treatment of diseases with an inflammatory component. Objective: The aim of this study is to evaluate the anti-inflammatory effect of the hydro-ethanolic extract (EHEM) of the combination of A. senegalensis and P. thonningii (1: 1, m: m). Methods: The ovalbumin-induced allergic airway asthma model was used. Animals made asthmatic were treated with EHEM at doses of 250 and 500 mg / kg. Inflammation markers including histamine, nitric oxide (NO), vascular leakage, leukocyte infiltration in the airways, and malondialdehyde (MDA), were measured. Results: Compared to the SNT group, EHEM inhibits the infiltration of the airways by leukocytes (850,00 × 103 ± 50 cells / mL vs 1830 × 103 ± 53,85 cells / mL for ST500 mg / kg, P <0,05). It inhibited vascular permeability to Evans Blue (10,40 ± 0,270 μg / mL vs ST500, p<0,05). It inhibited histamine release (13,95 ± 0,937 μg / mL vs 32,78 ± 1,044 μg / mL, p<0,05) and NO production (0,211 ± 0,008 Μm vs 0,315 ± 0,022 μM, p<0,05). It finally inhibited MDA production (14,66 ± 0,533 nM / mL vs 9,014 ± 0,366 nM / mL and 7,149 ± 0,300 nM / mL, p<0,05) in lung tissue. Conclusion: Our results suggest that EHEM inhibits OVA-induced inflammation. These results justify the use of this combination of plants in traditional Togolese medicine. Keywords: Inflammation, malondialdehyde, Annona senegalensis, Piliostigma thonningii.

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Obesity Affects β2 Adrenergic Regulation of the Inflammatory Profile and Phenotype of Circulating Monocytes from Exercised Animals

Nutrients ◽

10.3390/nu11112630 ◽

2019 ◽

Vol 11 (11) ◽

pp. 2630 ◽

Cited By ~ 5

Author(s):

Isabel Gálvez ◽

Leticia Martín-Cordero ◽

María Dolores Hinchado ◽

Alberto Álvarez-Barrientos ◽

Eduardo Ortega

Keyword(s):

Inflammatory Response ◽

Adrenergic Receptor ◽

Acute Exercise ◽

Inflammatory Responses ◽

Adrenergic Regulation ◽

Immune Stress ◽

Β2 Adrenergic Receptor ◽

Anti Inflammatory ◽

Inflammatory Profile ◽

Inflammatory Effect

Anomalous immune/inflammatory responses in obesity take place along with alterations in the neuroendocrine responses and dysregulation in the immune/stress feedback mechanisms. Exercise is a potential anti-inflammatory strategy in this context, but the influence of exercise on the β2 adrenergic regulation of the monocyte-mediated inflammatory response in obesity remains completely unknown. The first objective of this study was to analyze the effect of exercise on the inflammatory profile and phenotype of monocytes from obese and lean animals, and the second aim was to determine whether obesity could affect monocytes’ inflammatory response to β2 adrenergic activation in exercised animals. C57BL/6J mice were allocated to different lean or obese groups: sedentary, with acute exercise, or with regular exercise. The inflammatory profile and phenotype of their circulating monocytes were evaluated by flow cytometry in the presence or absence of the selective β2 adrenergic receptor agonist terbutaline. Exercise caused an anti-inflammatory effect in obese individuals and a pro-inflammatory effect in lean individuals. β2 adrenergic receptor stimulation exerted a global pro-inflammatory effect in monocytes from exercised obese animals and an anti-inflammatory effect in monocytes from exercised lean animals. Thus, β2 adrenergic regulation of inflammation in monocytes from exercised animals seems to depend on the inflammatory basal set-point.

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Asperuloside and Asperulosidic Acid Exert an Anti-Inflammatory Effect via Suppression of the NF-κB and MAPK Signaling Pathways in LPS-Induced RAW 264.7 Macrophages

International Journal of Molecular Sciences ◽

10.3390/ijms19072027 ◽

2018 ◽

Vol 19 (7) ◽

pp. 2027 ◽

Cited By ~ 18

Author(s):

Jingyu He ◽

Xianyuan Lu ◽

Ting Wei ◽

Yaqian Dong ◽

Zheng Cai ◽

...

Keyword(s):

Nitric Oxide ◽

Methyl Ester ◽

Signaling Pathways ◽

Mapk Signaling ◽

Raw 264.7 Cells ◽

Raw 264.7 ◽

Tnf Α ◽

Anti Inflammatory ◽

Mapk Signaling Pathways ◽

Inflammatory Effect

Hedyotis diffusa is a folk herb that is used for treating inflammation-related diseases in Asia. Previous studies have found that iridoids in H. diffusa play an important role in its anti-inflammatory activity. This study aimed to investigate the anti-inflammatory effect and potential mechanism of five iridoids (asperuloside (ASP), asperulosidic acid (ASPA), desacetyl asperulosidic acid (DAA), scandoside methyl ester (SME), and E-6-O-p-coumaroyl scandoside methyl ester (CSME)) that are presented in H. diffusa using lipopolysaccharide (LPS)—induced RAW 264.7 cells. ASP and ASPA significantly decreased the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in parallel with the inhibition of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, and IL-6 mRNA expression in LPS-induced RAW 264.7 cells. ASP treatment suppressed the phosphorylation of the inhibitors of nuclear factor-kappaB alpha (IκB-α), p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). The inhibitory effect of ASPA was similar to that of ASP, except for p38 phosphorylation. In summary, the anti-inflammatory effects of ASP and ASPA are related to the inhibition of inflammatory cytokines and mediators via suppression of the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways, which provides scientific evidence for the potential application of H. diffusa.

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Anti-inflammatory effect and inhibition of nitric oxide production by targeting COXs and iNOS enzymes with the 1,2-diphenylbenzimidazole pharmacophore

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2020.115427 ◽

2020 ◽

Vol 28 (9) ◽

pp. 115427

Author(s):

Mónica I. García-Aranda ◽

Jazmin E. Gonzalez-Padilla ◽

Carlos Z. Gómez-Castro ◽

Yolanda M. Gómez-Gómez ◽

Martha C. Rosales-Hernández ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Production ◽

Oxide Production ◽

Anti Inflammatory ◽

Inflammatory Effect

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Anti-inflammatory Effect of Pratol in LPS-stimulated RAW 264.7 Cells via NF-κB Signaling Pathways

Natural Product Communications ◽

10.1177/1934578x1801300509 ◽

2018 ◽

Vol 13 (5) ◽

pp. 1934578X1801300

Author(s):

You Chul Chung ◽

Sung-Min Park ◽

Jin Hwa Kim ◽

Geun Soo Lee ◽

Jung No Lee ◽

...

Keyword(s):

Nitric Oxide ◽

Trifolium Pratense ◽

Skin Diseases ◽

Inflammatory Diseases ◽

Red Clover ◽

Raw 264.7 Cells ◽

Prostaglandin E ◽

Raw 264.7 ◽

Anti Inflammatory ◽

Inflammatory Effect

The Trifolium pratense L. (red clover), which blossoms, leaves and stems can be used as medicines for treatment of burns, skin diseases, diabetes and other diseases. Recently study shown that pratol (7-hydroxy-4-methoxyflavone), an O-methylated flavone in T. pratense has been evaluated to induce melanogenesis in B16F10 melanoma cells. However, the anti-inflammatory effect of pratol has not been reported. In this study, we investigated the effects of pratol on anti-inflammation. We also studied the mechanism of action of pratol in LPS-stimulated RAW 264.7 cells. The cells were treated with various concentration of pratol (25, 50, or 100 μM) and 25 μM ammonium pyrrolidinedithiocarbamate (APDC) was used as control. The results in LPS-stimulated RAW 264.7 cells showed that pratol significantly reduced nitric oxide (NO) and prostaglandin E2 (PGE2) production without any cytotoxic. In addition, pratol strongly decreased the expression of inducible nitric oxide synthase (iNOS) and cyclooygenase (COX-2). Furthermore, pratol reduced proinflammatory cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. We also found that pratol strongly inhibited activation of nuclear factor kappa B (NF-κB) by reducing the p65 phosphorylation and protecting inhibitory factor kappa B alpha (IκBα) degradation. The results suggest that, pratol may be used to treat or prevent inflammatory diseases such as dermatitis, arthritis, cardiovascular and cancer.

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