scholarly journals Ellagic Acid Alleviates Rheumatoid Arthritis in Rats through Inhibiting MTA1/HDAC1-Mediated Nur77 Deacetylation

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Huanjin Song ◽  
Hao Wu ◽  
Jun Dong ◽  
Sihua Huang ◽  
Jintao Ye ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Oxidative Stress ◽  
Ellagic Acid ◽  
Oxidative Stress Marker ◽  
Dependent Manner ◽  
Histone Deacetylase 1 ◽  
Protein Levels ◽  
Tnf Α ◽  
And Oxidative Stress

Ellagic acid (EA) was reported to play protective roles in rheumatoid arthritis (RA). It was found that the level of metastasis-associated gene 1 (MTA1)/histone deacetylase 1 (HDAC1) protein complex was downregulated by polyphenols in several human disorders. Notably, inhibition of MTA1 or HDAC1 has anti-inflammatory effects on RA. Therefore, our study is aimed at investigating whether EA prevents RA progression through regulating the MTA1/HDAC1 complex. Herein, the human fibroblast-like synoviocyte (FLS) cell line MH7A was treated with TNF-α to induce an inflammation model in vitro and then incubated with different concentrations of EA. Western blot analysis showed that EA reduced MTA1 expression in a dose-dependent manner in MH7A cells. Then, TNF-α-treated MH7A cells were incubated with EA alone or together with MTA1 overexpression plasmid (pcDNA-MTA1), and we found that EA inhibited proliferation, inflammation cytokine levels, and oxidative stress marker protein levels and promoted apoptosis in MH7A cells, while MTA1 overexpression abolished these effects. Moreover, coimmunoprecipitation assay verified the interaction between MTA1 and HDAC1. EA downregulated the MTA1/HDAC1 complex in MH7A cells. MTA1 knockdown inhibited proliferation, inflammation, and oxidative stress and promoted apoptosis in MH7A cells, while HDAC1 overexpression reversed these effects. Moreover, chromatin immunoprecipitation assay indicated that EA inhibited HDAC1-mediated Nur77 deacetylation. Rescue experiments demonstrated that Nur77 knockdown reversed the effects of EA on MH7A cell biological behaviors. Additionally, EA treatment attenuated arthritis index, paw swelling, synovial hyperplasia, and inflammation in collagen-induced arthritis (CIA) rats. In conclusion, EA inhibited proliferation, inflammation, and oxidative stress and promoted apoptosis in MH7A cells and alleviated the severity of RA in CIA rats though downregulating MTA1/HDAC1 complex and promoting HDAC1 deacetylation-mediated Nur77 expression.

scholarly journals Mn Inhibits GSH Synthesis via Downregulation of Neuronal EAAC1 and Astrocytic xCT to Cause Oxidative Damage in the Striatum of Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Xinxin Yang ◽  
Haibo Yang ◽  
Fengdi Wu ◽  
Zhipeng Qi ◽  
Jiashuo Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Dependent Manner ◽  
Protein Levels ◽  
Key Factor ◽  
Protein Sulfhydryl ◽  
Mrna And Protein Expression ◽  
The Brain

Excessive manganese (Mn) can accumulate in the striatum of the brain following overexposure. Oxidative stress is a well-recognized mechanism in Mn-induced neurotoxicity. It has been proven that glutathione (GSH) depletion is a key factor in oxidative damage during Mn exposure. However, no study has focused on the dysfunction of GSH synthesis-induced oxidative stress in the brain during Mn exposure. The objective of the present study was to explore the mechanism of Mn disruption of GSH synthesis via EAAC1 and xCT in vitro and in vivo. Primary neurons and astrocytes were cultured and treated with different doses of Mn to observe the state of cells and levels of GSH and reactive oxygen species (ROS) and measure mRNA and protein expression of EAAC1 and xCT. Mice were randomly divided into seven groups, which received saline, 12.5, 25, and 50 mg/kg MnCl2, 500 mg/kg AAH (EAAC1 inhibitor) + 50 mg/kg MnCl2, 75 mg/kg SSZ (xCT inhibitor) + 50 mg/kg MnCl2, and 100 mg/kg NAC (GSH rescuer) + 50 mg/kg MnCl2 once daily for two weeks. Then, levels of EAAC1, xCT, ROS, GSH, malondialdehyde (MDA), protein sulfhydryl, carbonyl, 8-hydroxy-2-deoxyguanosine (8-OHdG), and morphological and ultrastructural features in the striatum of mice were measured. Mn reduced protein levels, mRNA expression, and immunofluorescence intensity of EAAC1 and xCT. Mn also decreased the level of GSH, sulfhydryl, and increased ROS, MDA, 8-OHdG, and carbonyl in a dose-dependent manner. Injury-related pathological and ultrastructure changes in the striatum of mice were significantly present. In conclusion, excessive exposure to Mn disrupts GSH synthesis through inhibition of EAAC1 and xCT to trigger oxidative damage in the striatum.

scholarly journals Honokiol Alleviates Methionine-Choline Deficient Diet-Induced Hepatic Steatosis and Oxidative Stress in C57BL/6 Mice by Regulating CFLAR-JNK Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Ting Zhai ◽  
Wei Xu ◽  
Yayun Liu ◽  
Kun Qian ◽  
Yanling Xiong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Regulatory Gene ◽  
Deficient Diet ◽  
Jnk Pathway ◽  
Beneficial Effects ◽  
Protein Levels ◽  
And Oxidative Stress

Background. Honokiol (HNK) has been reported to possess various beneficial effects in the context of metabolic disorders, including fatty liver, insulin resistance, and oxidative stress which are closely related to nonalcoholic steatohepatitis (NASH), however with no particular reference to CFLAR or JNK. Methods. C57BL/6 mice were fed methionine-choline-deficient (MCD) diet and administered simultaneously with HNK (10 and 20 mg/kg once a day, ig) for 6 weeks, and NCTC1469 cells were pretreated, respectively, by oleic acid (OA, 0.5 mmol/L) plus palmitic acid (PA, 0.25 mmol/L) for 24 h, and adenovirus-down Cflar for 24 h, then exposed to HNK (10 and 20 μmol/L) for 24 h. Commercial kits, H&E, MT, ORO staining, RT-qPCR, and Western blotting were used to detect the biomarkers, hepatic histological changes, and the expression of key genes involved in NASH. Results. The in vivo results showed that HNK suppressed the phosphorylation of JNK (pJNK) by activating CFLAR; enhanced the mRNA expression of lipid metabolism-related genes Acox, Cpt1α, Fabp5, Gpat, Mttp, Pparα, and Scd-1; and decreased the levels of hepatic TG, TC, and MDA, as well as the levels of serum ALT and AST. Additionally, HNK enhanced the protein expression of oxidative stress-related key regulatory gene NRF2 and the activities of antioxidases HO-1, CAT, and GSH-Px and decreased the protein levels of prooxidases CYP4A and CYP2E1. The in vivo effects of HNK on the expression of CLFAR, pJNK, and NRF2 were proved by the in vitro experiments. Moreover, HNK promoted the phosphorylation of IRS1 (pIRS1) in both tested cells and increased the uptake of fluorescent glucose 2-NBDG in OA- and PA-pretreated cells. Conclusions. HNK ameliorated NASH mainly by activating the CFLAR-JNK pathway, which not only alleviated fat deposition by promoting the efflux and β-oxidation of fatty acids in the liver but also attenuated hepatic oxidative damage and insulin resistance by upregulating the expression of NRF2 and pIRS1.

scholarly journals DNA Damage Responses and Oxidative Stress in Dyskeratosis Congenita.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2359-2359
Author(s):  
Larisa Pereboeva ◽  
Erik Westin ◽  
Toral Patel ◽  
Ian Flaniken ◽  
Lawrence S. Lamb ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cellular Proliferation ◽  
Dyskeratosis Congenita ◽  
Dependent Manner ◽  
Radiation Induced ◽  
Anti Oxidant ◽  
And Control ◽  
And Oxidative Stress

Abstract Abstract 2359 Introduction: Dyskeratosis congenita (DC) is an inherited multisystem disorder consisting of premature aging, cancer predisposition, bone marrow failure and the characteristic triad of mucosal leukoplakia, skin dyspigmentation and nail dystrophy. Symptomology associated with DC arises as a consequence of mutations within genes associated with telomeres and telomerase activity manifested by critically shortened telomeres in affected cells. We have previously reported a growth disadvantage and increased intracellular oxidative stress in cultured somatic cells obtained from patients with DC. We hypothesize that telomere maintenance is closely linked to dysregulation in oxidative pathways and consequent DNA damage. Our objective was to discern whether pharmacologic intervention to alleviate oxidative stress imparts a protective effect in DC cells. Methods: T lymphocytes from both DC subjects with hTERC mutations and age-matched controls were cultured and expanded in vitro using CD3/CD28 beads. DNA damage to cells was induced using paclitaxel, etoposide, or ionizing radiation during log-phase of cell growth. Cellular proliferation and apoptosis were monitored by cell counting and flow cytometry (FACS) using Annexin V antibody and propidium iodide. Western blotting was used to measure basal and radiation-induced expression of DNA damage response (DDR) proteins, including total p53 and its activated form (serine 15 phosphorylated; p53S15), p21WAF, and phosphorylated H2AX (gH2AX). Level of oxidative stress was determined by FACS using the cell-permeable fluorogenic probe DCFH and dihydroethedium (DHE) detecting reactive oxygen species (ROS). Anti-oxidants, including vitamin E and N acetyl cysteine (NAC), were used in vitro to modulate levels of oxidative stress in control and radiated cells. Results: Comparison of growth curves demonstrated a significant decrease in proliferation of T cells obtained from DC patients versus control T cells. This growth disadvantage was more pronounced following cell exposure to radiation, paclitaxel, and etoposide. To explain these differences we investigated several parameters indicative of DNA damage. DC lymphocytes had higher basal levels of apoptosis, while radiation resulted in comparable levels of apoptosis in both DC and control cultures. Similarly, DDR markers p53 and p53S15, but not p21 and g-H2AX, were basally expressed at higher levels in DC lymphocytes while radiation, in a dose-dependent manner, upregulated expression of p53, p53S15, p21 and g-H2AX in both DC and control lymphocytes. Consistent with DDR data, elevated basal levels of ROS were found in short term DC cultures. Additionally, in a dose dependent manner, the anti-oxidant NAC partially ameliorated the growth disadvantage of DC cells. Importantly, NAC also decreased radiation-induced apoptosis and oxidative stress in DC cells. Studies are ongoing to characterize the modulation of DDR markers in NAC-treated cells. Conclusions: DC is an important disease model for studying the effects of telomere shortening on cellular proliferation and other molecular pathways involved in cell senescence and aging. Our findings of elevated basal levels of apoptosis, DDR proteins and oxidative stress in DC lymphocytes, as well as increased sensitivity of DC cells to cytotoxic agents suggests a role of telomerase and/or telomere length in regulating oxidative and DNA damage response pathways. This data also validates the clinical finding of DC patients' intolerance to myeloablative therapy. Finally a pharmacologic approach to reduce oxidative stress may alleviate some of the untoward toxicities associated with current cytotoxic treatments in DC. Clinical trials testing various anti-oxidant therapies are currently under design. Disclosures: No relevant conflicts of interest to declare.

Di-2-ethylhexyl phthalate (DEHP) induces apoptosis of mouse HT22 hippocampal neuronal cells via oxidative stress

2020 ◽  
Vol 36 (11) ◽  
pp. 844-851
Author(s):  
Wei Tu ◽  
Weifeng Li ◽  
Xingen Zhu ◽  
Linlin Xu
Keyword(s):  
Oxidative Stress ◽  
Cell Viability ◽  
Neuronal Cell ◽  
Underlying Mechanism ◽  
Treated Group ◽  
Dependent Manner ◽  
Ht22 Cells ◽  
Protein Levels ◽  
Ethylhexyl Phthalate

Di-2-ethylhexyl phthalate (DEHP) has been widely used as a plasticizer in industry and can affect memory; however, the underlying mechanism remains unclear. In the present study, mouse HT22 cells, an immortalized hippocampal neuronal cell line, was utilized as an in vitro model. We showed that DEHP dramatically inhibited cell viability and increased lactate dehydrogenase (LDH) release from the cells in a dose-dependent manner, suggesting that DEHP could cause cytotoxicity of mouse HT22 cells. The protein levels of cleaved Caspase-8, cleaved Caspase-3, and Bax markedly increased in the DEHP-treated cells, whereas there was a significant decrease in the Bcl-2 protein level, implying that DEHP could induce apoptosis of mouse HT22 cells. DEHP exposure significantly increased the content of malondialdehyde, whereas it markedly decreased the level of glutathione and the activities of glutathione peroxidase and superoxide dismutase, suggesting that DEHP induced oxidative stress of the cells. Compared with the DEHP-treated group, the inhibition of cell viability and the release of LDH were rescued in the N-acetyl-l-cysteine plus DEHP group. Furthermore, inhibition of oxidative stress could rescue the induction of apoptosis by DEHP. Collectively, our results indicated that DEHP could induce apoptosis of mouse HT22 cells via oxidative stress.

scholarly journals Inhibitory Effects of Raw-Extract Centella asiatica (RECA) on Acetylcholinesterase, Inflammations, and Oxidative Stress Activities via In Vitro and In Vivo

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 892 ◽  
Author(s):  
Zetty Zulikha Hafiz ◽  
Muhammad ‘Afif Mohd Amin ◽  
Richard Muhammad Johari James ◽  
Lay Kek Teh ◽  
Mohd Zaki Salleh ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Centella Asiatica ◽  
Raw 264.7 Cells ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Concentration Dependent Manner ◽  
Sprague Dawley Rats ◽  
And Oxidative Stress

Centella asiatica (C. asiatica) is one of the medicinal plants that has been reported to exert comprehensive neuroprotection in vitro and in vivo. In view of this, the present study was performed to investigate the effect of ethanolic extract of C. asiatica, designated as raw-extract of C. asiatica (RECA) in reducing the acetylcholinesterase (AChE), inflammations, and oxidative stress activities via both in vitro (SH-SY5Y and RAW 264.7 cells) and in vivo (Sprague Dawley rats). Quantitative high-performance liquid chromatography analysis reveals that RECA contains a significantly high proportion of glycosides than the aglycones with madecassoside as the highest component, followed by asiaticoside. Treatment of SH-SY5Y cells with RECA significantly reduced the AChE activity in a concentration-dependent manner with an IC50 value of 31.09 ± 10.07 µg/mL. Furthermore, the anti-inflammatory and antioxidant effects of RECA were evaluated by lipopolysaccharides (LPS)-stimulated RAW 264.7 cells. Our results elucidated that treatment with RECA significantly suppressed the level of pro-inflammatory cytokine/mediators and oxidative stress released in a concentration-dependent manner. Interestingly, these patterns of inhibition were consistent as observed in the LPS-induced neuroinflammation Sprague Dawley rats’ model. The highest concentration used in the two models presented the most significant results. Herein, our findings strongly suggest that RECA may offer therapeutic potential for the treatment of Alzheimer’s disease through inhibiting the AChE, inflammation, and oxidative stress activities.

Etanercept Improves Lipid Profile and Oxidative Stress Measures in Patients with Juvenile Idiopathic Arthritis

2013 ◽  
Vol 40 (6) ◽  
pp. 943-948 ◽  
Author(s):  
Sara De Sanctis ◽  
M. Loredana Marcovecchio ◽  
Stefania Gaspari ◽  
Marianna Del Torto ◽  
Angelika Mohn ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Juvenile Idiopathic Arthritis ◽  
Disease Activity ◽  
Lipid Profile ◽  
Proinflammatory Cytokines ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Oxidative Stress Marker ◽  
Tnf Α ◽  
And Oxidative Stress

Objective.To investigate the effect of 1-year treatment with the anti-tumor necrosis factor-α (TNF-α) drug etanercept on lipid profile and oxidative stress in children and adolescents with juvenile idiopathic arthritis (JIA).Methods.Thirty children with JIA (22 females; mean age 12.3 ± SD 5.7 yrs), all eligible for anti-TNF-α treatment, were assessed at baseline and after 6- and 12-month treatment with etanercept. Disease activity was determined using the Juvenile Arthritis Disease Activity Score (JADAS). Blood samples were drawn to measure the acute-phase reactants C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), lipids, and the proinflammatory cytokines TNF-α, interleukin-1β (IL-1β), IL-6 and interferon-γ. To measure the oxidative stress marker 8-iso-prostaglandin F2α, 24-h urine samples were collected.Results.Inflammatory indicators (CRP and ESR) and JADAS scores improved significantly after 1 year of etanercept treatment (all p < 0.001). Proinflammatory cytokines showed significant reduction during the study period (all p < 0.001). Similar reductions were detected in total cholesterol (p < 0.001), low-density lipoprotein cholesterol (p = 0.04), and triglycerides (p < 0.001), whereas no significant change was found in high-density lipoprotein cholesterol. No side effects were observed during the treatment period.Conclusion.This study shows for the first time that anti-TNF-α therapy for JIA is associated not only with a beneficial effect on clinical disease activity and inflammatory indexes, but also with improved lipid profile and oxidative stress. These findings suggest that TNF-α blockers might reduce atherosclerotic risk in children with JIA.

scholarly journals Influence of TNF-α inhibition on oxidative stress of rheumatoid arthritis patients

Reumatismo ◽  
2016 ◽  
Vol 67 (3) ◽  
pp. 97 ◽  
Author(s):  
F. Cacciapaglia ◽  
M.G. Anelli ◽  
D. Rizzo ◽  
E. Morelli ◽  
C. Scioscia ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Oxidative Stress ◽  
Health Assessment ◽  
Good Control ◽  
Oxidative Stress Marker ◽  
Reactive Oxygen Metabolites ◽  
Necrosis Factor Alpha ◽  
Reactive Protein ◽  
Tnf Α ◽  
Oxidative Stress Status

The aim of this study was to assess circulating levels of reactive oxygen metabolites (ROMs) as a marker of oxidative stress in rheumatoid arthritis (RA) patients during an anti-tumor necrosis factor alpha (TNF-α) treatment. We enrolled 40 patients with RA (36 females; age 53±13 yrs) treated with different subcutaneously administered TNF-α inhibitors. The oxidative status was determined on the basis of plasma samples taken before, at 24 and 52 weeks of the anti-TNF-α treatment. Hydroperoxide levels were measured using the d-ROMs test, a useful clinically proven oxidative stress marker. During the anti-TNF-α therapy, we observed a significant reduction in serum ROMs levels in RA patients from 33.2±10 mg H2O2/L at baseline to 29.5±7 and 29.3±9 mg H2O2/L, at 24 and 52 weeks, respectively (p&lt;0.05). We also identified a significant correlation between the oxidative stress status and the disease activity score on 28 joints/C-reactive protein and health assessment questionnaire disability index. The results of our study demonstrate that a good control of the disease with anti-TNF-α agents can reduce oxidative stress in RA patients. However, further studies of larger patient cohorts are needed to confirm these preliminary data.

HPLC phenolic fingerprinting, antioxidant and anti-phosphodiesterase-5 properties of Rauwolfia vomitoria extract

2019 ◽  
Vol 30 (5) ◽  
Author(s):  
Ganiyu Oboh ◽  
Adeniyi A. Adebayo ◽  
Ayokunle O. Ademosun
Keyword(s):  
Oxidative Stress ◽  
Vascular Dysfunction ◽  
Radical Scavenging ◽  
Antioxidant Property ◽  
Dependent Manner ◽  
Antioxidant Power ◽  
Phosphodiesterase 5 ◽  
Rauwolfia Vomitoria ◽  
And Oxidative Stress

Abstract Background In Nigerian traditional medicine, Rauwolfia vomitoria has been reported to be useful in the management of various human diseases, but there is no relevant information to substantiate its involvement in managing diseases arising from vascular dysfunction and oxidative stress. However, this study sought to investigate the antioxidant property of R. vomitoria and its effect on phophodiesterase-5 activity in vitro. Methods The antioxidant property was assessed through ferric-reducing antioxidant power (FRAP), copper chelation, and ABTS radical-scavenging activity. In addition, the effect of R. vomitoria on phosphodiesterase-5 (PDE-5) activity was assessed in vitro. Furthermore, analysis of phenolic compounds present in R. vomitoria was carried out using high-performance liquid chromatography (HPLC). Results The findings in this study revealed that R. vomitoria inhibited PDE-5 in a dose-dependent manner (IC50 = 252.42 μg/mL). Furthermore, the antioxidant activity of R. vomitoria was established through FRAP (19.68 mg AAE/g), ABTS radical-scavenging ability (74.25 mmol TEAC/g), and Cu2+-chelating ability (IC50 = 0.13 mg/mL). Conclusions The antioxidant property of R. vomitoria and its inhibitory effect on PDE-5 could be useful in the management of diseases arising from vascular dysfunction and oxidative stress.

scholarly journals Biological effects induced by Gadolinium nanoparticles on Lymphocyte A20 cell line

2017 ◽  
Vol 1 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Cecilia Virginia Gheran ◽  
Sorina Nicoleta Voicu ◽  
Guillaume Rigaux ◽  
Maite Callewaert ◽  
Francoise Chuburu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Biological Effects ◽  
Reactive Oxygen Species Generation ◽  
Antioxidant Defense System ◽  
Dependent Manner ◽  
Lactate Dehydrogenase Activity ◽  
In Vitro Effects ◽  
Dose Dependent ◽  
And Oxidative Stress

Abstract Gadolinium nanoparticles (GdNPs) are potential agents for MRI of lymph nodes. The aim of this study was to evaluate the in vitro effects of 1 μM, 2.5 μM and 5 μM of GdDOTA⊂CS-TPP/HA and GdDOTP⊂CS-TPP/HA NPs on A20 lymphocyte cells exposed for 6 and 24 hours. The total cellular biomass (SRB), lactate dehydrogenase activity (LDH) and oxidative stress parameters, such as reactive oxygen species generation (ROS), reduced glutathione (GSH), malondialdehyde (MDA) and advanced oxidation protein products (AOPP) were analyzed by spectrophotometric and fluorimetric methods. After cells exposure to 1 μM, 2.5 μM and 5 μM of GdDOTP⊂CS-TPP/HA NPs their viability decreased in a time- and dose-dependent manner, whereas for GdDOTA⊂CS-TPP/HA no significant changes were noticed. Both NPs formulations in doses of 1 μM, 2.5 μM, 5 μM did not affect the plasma membrane at each time point tested. The levels of ROS, MDA and AOPP increased proportionally with the concentration and exposure time. GSH concentration decreased significantly for all doses of both NPs tested. Taken together our data suggest that, GdDOTP⊂CS-TPP/HA and GdDOTA⊂CS-TPP/HA NPs induced oxidative stress in A20 lymphocyte cells which was counteracted by the cells antioxidant defense system to a certain extend.

scholarly journals Sparstolonin B Exerts Therapeutic Effects on Collagen-Induced Arthritis by Inhibiting the NLRP3 Inflammasome and Reducing the Activity of α1,3-Fucosyltransferase

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Yue Sun ◽  
Yun Guo ◽  
Jing Zhang ◽  
Lihua Chang ◽  
Haiyan Zhao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Oxidative Stress ◽  
Western Blotting ◽  
Nlrp3 Inflammasome ◽  
Synovial Cells ◽  
Expression Levels ◽  
Caspase 1 ◽  
Tnf Α ◽  
Sparstolonin B

Objective. To explore the role of α1,3-fucosyltransferase in the mediation of rheumatoid arthritic inflammation, the protective effect of Sparstolonin B on rheumatoid arthritis (RA), and the mechanisms that regulate the NLRP3 inflammasome. Methods. Forty, weighing from 260-300 g, male Sprague-Dawley rats were randomly divided into the following groups: a sham operation group (Sham group), a rheumatoid arthritis model group (RA group), an RA+Sparstolonin B treatment group (RAS group), an RA+Iguratimod group (RAI group), and an RA+SsnB+NLRP3 inflammasome activator (Nigericin) group (RASN group); ten animals were allocated to each group. We determined the arthritis index for each group of rats, and pathological changes were evaluated by hematoxylin-eosin staining. We also used ELISAs to determine the serum levels of IL-17, IL-6, TNF-α, TGF-β, IL-18, and IL-1β. TUNEL staining was used to investigate apoptosis in synovial cells. IF was used to detect the release of ROS, ASC formation, and the expression levels of FucT-V and NLRP3. Western blotting was used to detect the protein expression levels of Bc1-2, Bax, TLR4, MYD88, NF-κB, pro-caspase-1, NLRP3, FucT-V, E-Selectin, and P-Selectin. We also performed in vitro experiments with Sparstolonin B and detected changes in 1,3-fucosyltransferase activity by ELISA. The pyroptosis-related phenotype, including ASC, was identified by immunofluorescence, while levels of NLRP-3, pro-IL-1, and pro-caspase-1 were detected by western blotting. Results. Sparstolonin B was showed to alleviate joint swelling in RA rats, inhibited inflammatory cell infiltration and the release of ROS, reduced damage caused by oxidative stress, and suppressed the rate of apoptosis in synovial cells. The administration of Sparstolonin B inhibited the secretion of IL-17 from Th17 cells and triggered the secretion of TGF-β from Treg cells, thus leading to the reduced expression of TLR4, MyD88, and NF-κB, and the suppression of TNF-α secretion. Moreover, Sparstolonin B downregulated the expression of NLRP3, inhibited ASC formation in vivo and in vitro, and reduced the levels of IL-18 and IL-1β. The expression levels of FucT-V, E-Selectin, and P-Selectin were also inhibited. Interestingly, these protective effects of Sparstolonin B could be blocked in RA rats by inhibiting the activation of the NLRP3 inflammasome. Conclusion. Sparstolonin B improved inflammatory responses and oxidative stress by inhibiting the NLRP3 inflammasome, inhibiting the expression of FucT-V and downregulating the TLR4/MYD88/NF-𝜅B signaling pathway in order to rescue RA.

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