Production and Expression of Inflammatory Mediators in Leukocytes of Sickle Cell Anaemia Patients and Effects of Hydroxyurea Therapy on This Production

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2490-2490
Author(s):  
Carolina Lanaro ◽  
Carla Fernanda Franco-Penteado ◽  
Dulcinéia M Albuquerque ◽  
Sara T.O. Saad ◽  
Nicola Conran ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell ◽  
Inflammatory Mediators ◽  
Healthy Controls ◽  
Gene Expressions ◽  
Tnf Α ◽  
Ifn Γ ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Hydroxyurea Therapy

Abstract Leukocytosis is frequently observed in sickle cell disease (SCD) in the absence of bacterial infection. An elevated baseline leukocyte count is associated with an increased risk of early death and leukocytes play a significant role in the initiation of vaso-occlusive events. Inflammation, cell adhesion to vascular endothelium, and subsequent endothelial injury appear to contribute to sickle cell anemia (SCA) vaso-occlusion. Furthermore, blood levels of inflammatory and anti-inflammatory cytokines are reported to be elevated (TNF-α, IL-6, IL-10, GM-CSF), both in steady state and during crisis, but reports have been conflicting and a conclusive role for these molecules in the disease remains to be established. Furthermore, the effect of hydroxyurea therapy (HU) on the release of inflammatory mediators is not understood. The aim of this study was to determine plasma levels and leukocyte gene expressions of inflammatory mediators in healthy controls (n=30), steady-state SCA patients (n=45) and SCA patients on HU therapy (n=24). qRT-PCR analysis was use to examine gene expression and ELISA protein production. TNF-α, IL-8 and PGE2 plasma levels were significantly higher in the plasma of steady-state SCA individuals, when compared to control individuals (2.95 ± 0.4 pg/ml; 16.5 ± 2.5 pg/ml; 5.7 ± 0.6 pg/ml; 128.3 ± 12.2 pg/ml vs 1.43 ± 0.2 pg/ml, 88.5 ± 5.9 pg/ml, P=0.006; P<0.0001; P=0.012, respectively). HU therapy significantly reversed augmented TNF-α (1.6 ± 0.2 pg/ml, P=0.006) and, interestingly, increased plasma anti-inflammatory IL-10 (P<0.05). IL-10, IFN-γ, COX-2 and iNOS gene expressions were unaltered in SCA mononuclear cells (MC), however gene expressions of TNF-α, IL-8 and the protective enzyme, heme oxygenase-1 (HO-1), were significantly higher compared to healthy controls (0.46 ± 0.01; 0.08 ± 0.02; 0.21 ± 0.05 vs 0.18 ± 0.04; 0.02 ± 0.005; 0.035 ± 0.008; respectively, P<0.02). HU therapy was not associated with significantly altered SCA MC inflammatory gene expression, although COX-2 mRNA expression was decreased (0.11 ± 0.05; 0.37 ± 0.12, SCAHU and SCA, respectively; P<0.05). In SCA neutrophils, gene expressions of IL-8, IFN-γ, iNOS and HO-1 were significantly higher compared to those of control subjects (0.32 ± 0.07; 0.69 ± 0.19; 0.19 ± 0.06; 0.33 ± 0.09, P=0.02, P=0.025, P<0.05; P=0.027, respectively). Patients on HU therapy demonstrated lower iNOS and higher IL-10 neutrophil gene expressions compared to SCA not on HU therapy (0.038 ± 0.03; 0.72 ± 0.13, P<0.05; P<0.05, respectively). Taken together, data suggest that alterations in the gene expressions and productions of a number of pro-and anti-inflammatory mediators are present in SCA and knowledge of these pathways may be important for identifying novel drug targets for the disease.

Fermentation Improves Anti-Inflammatory Effect of Sipjeondaebotang on LPS-Stimulated RAW 264.7 Cells

2012 ◽  
Vol 40 (04) ◽  
pp. 813-831 ◽  
Author(s):  
You-Chang Oh ◽  
Won-Kyung Cho ◽  
Yun Hee Jeong ◽  
Ga Young Im ◽  
Min Cheol Yang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Mediators ◽  
High Performance ◽  
Biological Effects ◽  
Inhibitory Effect ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory

Sipjeondaebotang (SJ) has been used as a traditional drug in east-Asian countries. In this study, to provide insight into the biological effects of SJ and SJ fermented by Lactobacillus, we investigated their effects on lipopolysaccharide (LPS)-mediated inflammation in macrophages. The investigation was focused on whether SJ and fermented SJ could inhibit the production of pro-inflammatory mediators such as prostaglandin (PG) E2 and nitric oxide (NO) as well as the expressions of cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB in LPS-stimulated RAW 264.7 cells. We found that SJ modestly inhibited LPS-induced PGE2, NO and TNF-α production as well as the expressions of COX-2 and iNOS. Interestingly, fermentation significantly increased its inhibitory effect on the expression of all pro-inflammatory mediators. Furthermore, fermented SJ exhibited increased inhibition of p38 MAPK and c-Jun NH2-terminal kinase (JNK) MAPK phosphorylation as well as NF-κB p65 translocation by reduced IκBα degradation compared with either untreated controls or unfermented SJ. High performance liquid chromatography (HPLC) analysis showed fermentation by Lactobacillus increases liquiritigenin and cinnamyl alcohol contained in SJ, which are known for their anti-inflammatory activities. Finally, SJ fermented by Lactobacillus exerted potent anti-inflammatory activity by inhibiting MAPK and NF-κB signaling in RAW 264.7 cells.

scholarly journals N-Butanol Extract fromMelilotus suaveolens LedebAffects Pro- and Anti-Inflammatory Cytokines and Mediators

2010 ◽  
Vol 7 (1) ◽  
pp. 97-106 ◽  
Author(s):  
Lei Zhao ◽  
Jun-Yan Tao ◽  
Shu-Ling Zhang ◽  
Feng Jin ◽  
Ran Pang ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Inflammatory Mediator ◽  
Hplc Fingerprint ◽  
Butanol Extract ◽  
Real Time Quantitative Pcr ◽  
Inflammatory Mechanism ◽  
Tnf Α ◽  
Raw264.7 Cell ◽  
Cox 2 ◽  
Anti Inflammatory

Melilotus suaveolens Ledebis a traditional medicinal plant for treating inflammation-related disease. This explores the inner anti-inflammatory mechanism ofn-butanol extract fromM. suaveolens Ledeb. Inflammatory cellular model was established by lipopolysaccharide intervention on RAW264.7 cell line. Levels of secreted cytokines TNF-α, IL-1β, IL-6, NO and IL-10 in supernatant, mRNA expression of TNF-α, COX-2, iNOS and HO-1, protein expression of COX-2 and HO-1, activation of NF-κB and ingredients in the extract were assayed by ELISA, real time quantitative PCR, western blot, immunocytochemical test and HPLC fingerprint test, respectively. As a result, the extract could not only markedly reduce the production of pro-inflammatory mediators to different extents by blocking NF-κB activation but also promote the release of anti-inflammatory mediator HO-1 significantly. Each 1 g extract contained 0.023531 mg coumarin and another two high polar ingredients, probably saponins. It can be concluded that the extract has similar effects on antagonizing pro-inflammatory mediators and cytokines like Dexamethasone, and has effects on promoting the production of anti-inflammatory mediators.

Anti-Inflammatory Effect of Hydroxyurea Therapy in Sickle Cell Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3806-3806 ◽  
Author(s):  
Carolina Lanaro ◽  
Carla F. Franco-Penteado ◽  
Nicola Conran ◽  
Sara T.O. Saad ◽  
Fernando F. Costa
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Healthy Controls ◽  
Cell Disease ◽  
Inflammatory Biomarker ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine ◽  
Hydroxyurea Therapy

Abstract There is growing evidence that inflammatory stresses within the microvasculature may play a significant role in the vaso-occlusion that is characteristic of sickle cell disease. Inflammation, leukocyte adhesion to vascular endothelium, and subsequent endothelial injury appear to contribute to the pathogenesis of SCD. Whilst alterations in a number of inflammatory, anti-inflammatory cytokines and inflammatory biomarkers have been previously related, reports have been conflicting and a conclusive role for cytokines in SCD remains to be established. Furthermore, the effect of hydroxyurea therapy (HU) on the release of inflammatory mediators is not well understood. This study was undertaken to determine plasma levels of IL-8, IL-10, TNF-a and PGE2 in healthy controls, SCD patients in steady-state and in SCD patients on HU therapy (SCDHU; 20–30 mg/kg/day; 3-month minimum treatment duration) using specific ELISA assays (R&D Research). TNF-a levels were significantly higher in SCD individuals when compared to controls (2.95 ± 0.44 pg/ml, n=17; vs 1.43 ± 0.20 pg/ml, n=8, p=0.006). HU therapy, however, was observed to significantly reverse augmented TNF-a levels (SCDHU; 1.61 ± 0.18 pg/ml, n=15, p=0.007). Plasma IL-8 levels were significantly elevated in SCD individuals (16.58 ± 2.52 pg/ml, n=29, p<0.001) compared to healthy controls (5.67 ± 0.62 pg/ml, n=16); however HU therapy did not significantly alter augmented IL-8 in SCD (14.59 ± 1.57 pg/ml, n=22). Interestingly, detectable levels of the anti-inflammatory cytokine, IL-10 (>3.8 pg/ml), were found in 3 (15%) of 20 SCD patients, and 1 (11%) of 9 controls, whilst 7 (50%) of 14 HU-treated patients demonstrated detectable IL-10 levels. Levels of plasma PGE2, an inflammatory biomarker, were significantly increased in SCD patients compared to control individuals (128.35 ± 12.25 pg/ml, n=26; vs 88.45 ± 5.95 pg/ml, n=14, p=0.01) and similar levels were detected in patients treated with HU (143.6 ± 16.75 pg/ml, n=17, p=0.004, compared to control). Data demonstrate that the inflammatory cytokines, TNFa and IL-8, and the inflammatory biomarker, PGE2, are augmented in a population of SCD patients studied during steady-state, contributing to clarify conflicting data. Furthermore, HU therapy reversed augmented TNFa levels, and appears to have an augmenting effect on the anti-inflammatory cytokine, IL-10, suggesting an anti-inflammatory action of HU therapy that may be important for the prevention of vaso-occlusion.

Inflammatory Mediators Are Increased in Leukocytes of IVS-I-6 (T→C) Homozygous β-Thalassemia Intermedia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4068-4068
Author(s):  
Marcos André C Bezerra ◽  
Carla Fernanda Franco-Penteado ◽  
Carolina Lanaro ◽  
Mariana R. B. Mello ◽  
Sheley Gambero ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Mediators ◽  
Plasma Levels ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Thalassemia Intermedia ◽  
Gene Expressions ◽  
Survivin Protein ◽  
Tnf Α

Abstract Abstract 4068 Poster Board III-1003 Thalassemia is characterized by chronic inflammatory state and inflammation may play an important role in the pathogenesis of this diseases. Endothelial adhesion molecules, reactive oxygen species (ROS), C reactive protein and cytokines were increased in thalassemia patients. In addition, adherence of red blood cells, neutrophils and platelets to extracellular matrix protein and neutrophils chemotaxis has been shown to be markedly enhanced in β-thalassemia intermedia (TI) patients. Although alterations in inflammatory biomarkers have been related previously, most studies have been carried out with patients either polytransfused, receiving hydroxyurea (HU) therapy or with β-thalassemia major. An investigation of the role of inflammatory mediators in TI may further contribute to the understanding the pathogenesis of the disease. The aim of this study was to determine plasma levels and leukocyte gene expressions of inflammatory mediators/cytokines in neutrophils and mononuclear cells (MC) of untransfused patients and those not on HU therapy TI IVS-I-6 (T→C) homozygous (n≤20) and healthy controls (n≤20). ELISA was used to determine cytokine production; survivin protein expression was determined by flow cytometry with survivin-specific antibodies and qRT-PCR analysis to examine gene expression of cytokines, the protective enzyme heme oxygenase-1 (HO-1) and BIRC-5 (survivin). TNF-α, IL-6, IL-8 and IL-1β plasma levels were significantly higher in the plasma of TI individuals, when compared to control individuals (3.78 ± 0.4 vs 2.18 ± 0.3; 0.93 ± 0.1 vs 0.46 ± 0.08; 18.97 ± 5.6 vs 6.09 ± 1.1; 1.88 ± 0.7 vs 0.34 ± 0.05, pg/ml, P<0.05, respectively). Survivin protein levels in MC from TI was significantly increased when compared to healthy controls (45.9 ± 1.8 × 39.74 ± 1.74, MFI, P=0.022, respectively). IL-8, IL-10 and HO-1 gene expressions were unaltered in TI neutrophils (0.31 ± 0.13; 0.1 ± 0.08; 0.44 ± 0.2; A.U., respectively) compared to healthy controls neutrophils (0.45 ± 0.13; 0.17 ± 0.04; 0.22 ± 0.07, A.U., respectively), however in TI neutrophils gene expression of TNF-α was significantly higher than those of control subjects (0.76 ± 0.3 vs 0.24 ± 0.05, A.U., P=0.03, respectively). Expressions of genes encoding IL-8, IL-10, HO-1 and BIRC-5 were higher in MC of TI patients, compared with those of healthy controls (0.75 ± 0.3 vs 0.02 ± 0.005; 0.36 ± 0.07 vs 0.19 ± 0.04; 1.69 ± 0.28 vs 0.27 ± 0.09; 1.13 ± 0.12 vs 0.55 ± 0.17, A.U., P=0.02; P=0.04; P=0.0002, P=0.019, respectively). No significant alterations in the TNF-α mRNA levels were found in the MC of TI patients compared with healthy controls (0.21 ± 0.06 vs 0.16 ± 0.03, A.U., respectively). Taken together our data showed a higher production of inflammatory cytokines in MC, which could contribute to the pathophysiology of TI. Anti-inflammatory mechanisms (IL-10 and HO-1) were also up-regulated in these individuals, indicating efforts to counteract these alterations. These results are strong indications of the presence of chronic inflammatory processes and knowledge of these pathways may contribute to the understanding of the pathophysiology of TI. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Sickle Cell Inflammatory Environment Is Associated with Products of the Eicosanoid Synthesis Pathways

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4586-4586
Author(s):  
Magda Oliveira Seixas Carvalho ◽  
Joao Henrique Oliveira Reis ◽  
Larissa Carneiro Rocha ◽  
Bruno Cerqueira ◽  
Theo de Araujo Santos ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell ◽  
Inflammatory Mediators ◽  
Conflicts Of Interest ◽  
Leukotriene B4 ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tgf Beta ◽  
Eicosanoid Synthesis ◽  
Significant Difference ◽  
Anti Inflammatory

Abstract Background: Sickle cell disease (SCD) is a group of inherited anemia characterized by heterogeneous clinical outcome, including hemolysis, chronic inflammation, and vaso-occlusive/painful crisis. Aims: We evaluated inflammatory and anti-inflammatory mediators, such as TNFα, IL-10, IL-12, IL-1β, IL-6, and IL-8, TGF-beta, tissue inhibitor of metalloproteinase (TIMP1), matrix metalloproteinase 9 (MMP9), heme, and leukotriene B4 (LTB4), and prostaglandin E2 (PGE2), the last two are products of the eicosanoid synthesis pathways, in SCD patients (in steady-state and in crisis-state) and healthy controls. For the same groups, in order to establish biomarkers of crisis and steady-state, we also investigated association among inflammatory/anti-inflammatory mediators and markers of hemolysis, inflammation, hepatic dysfunction, renal and lipid metabolism. Methods. We assessed 129 SCD steady-state patients (SP), 23 SCD in crisis patients (CP), and 67 healthy individuals (HC) age- and sex-matched with patients groups. Hematological analyzes were performed by automatic cell counter and hemoglobin profile by HPLC. Biochemistry analyses of inflammation and infection markers, as well as lipid, hepatic, and kidney metabolism markers were investigated by immunochemistry assays. Plasma levels of TNFα, IL-10, IL-12, IL-1β, IL-6 and IL-8 were measured using Cytometric Bead Array (CBA) according to the manufacturer's protocol. Plasma concentration of total heme was measured by QuantiChrom Heme Assay Kit. PGE2, LTB4, TGF-beta, TIMP1 and MMP9 levels were estimated in plasma samples and supernatants by ELISA, according to the manufacturer's instructions. Results . Steady-state SCD patients had the highest values of LTB4, PGE2, TIMP1, MMP9, IL-8, and IL-12 concentration compared with CP and HC groups (p < 0.0001). However, crisis-state SCD patients had the highest values of IL-1β, IL-6, IL-10, TNFα compared to HC and SP groups, and had a the lowest levels of LTB4, PGE2,TGF-β, MMP9, IL-8 and IL-12 levels (p < 0.0001 for both analysis). Significant difference of heme levels was not finding among the three groups. The ROC curve showed that LTB4, PGE2 and TGF- β are important markers related to steady state and IL-1β, IL-6, and TNFα are markers of crisis in SCD. Conclusions: The finding of difference in inflammatory markers level in steady state and crisis SCD patients suggest that these markers can be used to monitoring patients and to predict crisis events. The finding of similar heme concentration between steady-state and crisis-state SCD patients may be explained by the hyperhemolysis phenomenon, showing that even in steady-state, these patients continuous to have hemolysis and, consequently, continuous to generate heme and reactive oxygen species. Disclosures No relevant conflicts of interest to declare.

Canine mesenchymal stem cells treated with TNF-α and IFN-γ enhance anti-inflammatory effects through the COX-2/PGE2 pathway

2018 ◽  
Vol 119 ◽  
pp. 19-26 ◽  
Author(s):  
Hye-Mi Yang ◽  
Woo-Jin Song ◽  
Qiang Li ◽  
Su-Yeon Kim ◽  
Hyeon-Jin Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tnf Α ◽  
Ifn Γ ◽  
Cox 2 ◽  
Anti Inflammatory

CD4+CD25- effector T cells from healthy controls and MS patients do not differ in mRNA expression of IFN-γ, IL-2, and TNF-α

2004 ◽  
Vol 31 (S 1) ◽  
Author(s):  
A Hug ◽  
J Haas ◽  
A Viehöver ◽  
B Fritz ◽  
B Storch-Hagenlocher ◽  
...  
Keyword(s):  
T Cells ◽  
Mrna Expression ◽  
Effector T Cells ◽  
Healthy Controls ◽  
Tnf Α ◽  
Ifn Γ

Piper sarmentosum Roxb. Root Extracts Confer Neuroprotection by Attenuating Beta Amyloid-Induced Pro-Inflammatory Cytokines Released from Microglial Cells

2019 ◽  
Vol 16 (3) ◽  
pp. 251-260 ◽  
Author(s):  
Elaine Wan Ling Chan ◽  
Emilia Tze Ying Yeo ◽  
Kelly Wang Ling Wong ◽  
Mun Ling See ◽  
Ka Yan Wong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Mrna Expression ◽  
Inflammatory Mediators ◽  
Beta Amyloid ◽  
Microglial Cells ◽  
Root Extracts ◽  
Tnf Α ◽  
P38α Mapk ◽  
Anti Inflammatory ◽  
Bv2 Microglial Cells

<P>Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that eventually leads to severe cognitive impairment. Although the exact etiologies of AD still remain elusive, increasing evidence suggests that neuroinflammation cascades mediated by microglial cells are associated with AD. Piper sarmentosum Roxb. (PS) is a medicinal plant reported to possess various biological properties, including anti-inflammatory, anti-psychotic and anti-oxidant activity. However, little is known about the anti-inflammatory activity of PS roots despite their traditional use to treat inflammatory- mediated ailments. Objective: This study aimed to evaluate the anti-inflammatory and neuroprotective properties of extracts obtained from the roots of PS against beta-amyloid (Aβ)-induced microglial toxicity associated with the production of pro-inflammatory mediators. Method: BV2 microglial cells were treated with hexane (RHXN), dichloromethane (RDCM), ethyl acetate (REA) and methanol (RMEOH) extracts of the roots of PS prior to activation by Aβ. The production and mRNA expression of pro-inflammatory mediators were evaluated by Griess reagent, ELISA kits and RT-qPCR respectively. The phosphorylation status of p38α MAPK was determined via western blot assay. BV2 conditioned medium was used to treat SH-SY5Y neuroblastoma cells and the neuroprotective effect was assessed using MTT assay. Results: PS root extracts, in particular RMEOH significantly attenuated the production and mRNA expression of IL-1β, IL-6 and TNF-α in Aβ-induced BV2 microglial cells. In addition, RHXN, REA and RMEOH extracts significantly reduced nitric oxide (NO) level and the inhibition of NO production was correlated with the total phenolic content of the extracts. Further mechanistic studies suggested that PS root extracts attenuated the production of cytokines by regulating the phosphorylation of p38α MAPK in microglia. Importantly, PS root extracts have protective effects against Aβ-induced indirect neurotoxicity either by inhibiting the production of NO, IL-1β, IL-6, and TNF-α in BV2 cells or by protecting SHSY5Y cells against these inflammatory mediators. Conclusions: These findings provided evidence that PS root extracts confer neuroprotection against Aβ- induced microglial toxicity associated with the production of pro-inflammatory mediators and may be a potential therapeutic agent for inflammation-related neurological conditions including Alzheimer’s disease (AD).</P>

scholarly journals Processed Scutellaria baicalensis Georgi Extract Alleviates LPS-Induced Inflammatory and Oxidative Stress through a Crosstalk between NF-κB and KEAP1/NRF2 Signaling in Macrophage Cells

2021 ◽  
Vol 11 (13) ◽  
pp. 6055
Author(s):  
Akhtar Ali ◽  
En-Hyung Kim ◽  
Jong-Hyun Lee ◽  
Kang-Hyun Leem ◽  
Shin Seong ◽  
...  
Keyword(s):  
Scutellaria Baicalensis ◽  
Raw 264.7 Cells ◽  
Prostaglandin E ◽  
Scutellaria Baicalensis Georgi ◽  
Anticancer Effects ◽  
Tnf Α ◽  
Clinical Benefits ◽  
Anti Oxidant ◽  
Cox 2 ◽  
Anti Inflammatory

Prolonged inflammation results in chronic diseases that can be associated with a range of factors. Medicinal plants and herbs provide synergistic benefits based on the interaction of multiple phytochemicals. The dried root of Scutellaria baicalensis Georgi and its compounds possess anti-inflammatory, anti-oxidative, and anticancer effects. Processing is a traditional method to achieve clinical benefits by improving therapeutic efficacy and lowering toxicity. In this study, we investigated the anti-inflammatory and anti-oxidant effect of processed Scutellaria baicalensis Georgi extract (PSGE) against lipopolysaccharide (LPS) stimulated RAW 264.7 cells. Data using Griess assay and ELISA showed that PSGE decreased nitric oxide and prostaglandin E2 (PGE2) levels against LPS. PSGE treatment up-regulated 15-hydroxyprostaglandin dehydrogenase (PGDH), while cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1 expression did not change. Interestingly, PGE2 inhibition was regulated by prostaglandin catabolic enzyme 15-PGDH rather than COX-2/mPGES-1, enzymes essential for PGE2 synthesis. Additionally, PSGE-suppressed LPS-induced IL-6 and TNF-α production through NF-κB signaling. NF-κB release from an inactive complex was inhibited by HO-1 which blocked IκBα phosphorylation. The ROS levels lowered by PSGE were measured with the H2DCFDA probe. PSGE activated NRF2 signaling and increased antioxidant Hmox1, Nqo1, and Txn1 gene expression, while reducing KEAP1 expression. In addition, pharmacological inhibition of HO-1 confirmed that the antioxidant enzyme induction by PSGE was responsible for ROS reduction. In conclusion, PSGE demonstrated anti-inflammatory and anti-oxidant effects due to NRF2/HO-1-mediated NF-κB and ROS inhibition.

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