scholarly journals Myrtenal and β-caryophyllene oxide screened from Liquidambaris Fructus suppress NLRP3 inflammasome components in rheumatoid arthritis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wen-xuan Li ◽  
Ping Qian ◽  
Yi-tong Guo ◽  
Li Gu ◽  
Jessore Jurat ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Molecular Docking ◽  
Nlrp3 Inflammasome ◽  
Network Pharmacology ◽  
Caryophyllene Oxide ◽  
Active Ingredients ◽  
Caspase 1 ◽  
Tnf Α ◽  
Cartilage Erosion ◽  
And Cartilage

Abstract Background Liquidambaris Fructus (LF) is the infructescence of Liquidambar formosana. In Traditional Chinese Medicine, LF has been used to treat joint pain, a common symptom of arthritis and rheumatism; however, a lack of pharmacological evidence has limited its applications in modern clinics. Therefore, this study aims to explore the protective effect of LF on rheumatoid arthritis (RA) and to identify its active ingredients. Methods Rats with adjuvant-induced arthritis (AIA) were divided into 4 groups and administered petroleum ether extract of LF (PEL), ethyl acetate extract of LF (EEL), water extract of LF (WEL), or piroxicam (PIR) respectively for 3 weeks. Two additional groups were used as normal control (NC) and model control (MC) and administered distilled water as a placebo. The clinical scores for arthritis, bone surface, synovial inflammation and cartilage erosion were used to evaluate the therapeutic efficacy of each treatment. The serum IL-1β and TNF-α level and the expression of NLRP3, IL-1β and caspase-1 p20 in the synovial tissue of AIA rats were evaluated by ELISA and Western blot. The active ingredients of LF were investigated using network pharmacology and molecular docking methods, and their inhibition of NLRP3 inflammasome activation was verified in the human rheumatoid arthritis fibroblast-like synovial cells (RA-FLS) model. Results PEL could alleviate paw swelling, bone and joint destruction, synovial inflammation and cartilage erosion in the AIA rats, with significantly superior efficacy to that of EEL and WEL. PEL reduced IL-1β and TNF-α serum levels, and attenuated the upregulation of NLRP3, IL-1β and caspase-1 p20 expression in the synovial tissue of AIA rats. Network pharmacology and molecular docking results indicated that myrtenal and β-caryophyllene oxide were the main two active ingredients of PEL, and these two compounds showed significant inhibition on TNF-α, NLRP3, IL-1β and caspase-1 p20 expression in RA-FLS. Conclusions Myrtenal and β-caryophyllene oxide screened from PEL could suppress the activation of NLRP3 inflammasome, thereby alleviating RA symptoms.

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.

scholarly journals Identification of Tumor Necrosis Factor-Alpha (TNF-α) Inhibitor in Rheumatoid Arthritis Using Network Pharmacology and Molecular Docking

2021 ◽  
Vol 12 ◽  
Author(s):  
Liang Liang Bai ◽  
Hao Chen ◽  
Peng Zhou ◽  
Jun Yu
Keyword(s):  
Molecular Docking ◽  
Signaling Pathway ◽  
Target Genes ◽  
Network Pharmacology ◽  
Active Ingredients ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Receptor Signaling Pathway ◽  
Factor Alpha ◽  
Necrosis Factor

Background: This study aimed to investigate the molecular mechanism of Radix Paeoniae Alba (white peony, WP) in treating immune inflammatory diseases of rheumatoid arthritis (RA) and tumor necrosis factor-alpha (TNF-α) inhibitors (TNFis) by using network pharmacology and molecular docking.Methods: In this study, the ingredient of WP and the potential inflammatory targets of RA were obtained from the Traditional Chinese Medicine Systematic Pharmacology Database, GeneCard, and OMIM databases, respectively. The establishment of the RA–WP-potential inflammatory target gene interaction network was accomplished using the STRING database. Network maps of the WP–RA-potential inflammatory target gene network were constructed using Cytoscape software. Gene ontology (GO) and the biological pathway (KEGG) enrichment analyses were used to further explore the RA mechanism and therapeutic effects of WP. Molecular docking technology was used to analyze the optimal effective components from WP for docking with TNF-α.Results: Thirteen active ingredients and 71 target genes were screened from WP, and 49 of the target genes intersected with RA target inflammatory genes and were considered potential therapeutic targets. Network pharmacological analysis showed that the WP active ingredients such as mairin, DPHCD, (+)-catechin, beta-sitosterol, paeoniflorin, sitosterol, and kaempferol showed better correlation with RA inflammatory target genes such as PGR, PTGS1, PTGS2, NR3C2, TNFSF15, and CHRM2, respectively. The immune-inflammatory signaling pathways of the active ingredients for the treatment of RA are the TNF-α signaling pathway, Toll-like receptor signaling pathway, cell apoptosis, interleukin-17 signaling pathway, C-type lectin receptor signaling pathway, mitogen-associated protein kinase, etc. Molecular docking results suggested that mairin was the most appropriate natural TNFis.Conclusion: Our findings provide an essential role and basis for further immune-inflammatory studies into the molecular mechanisms of WP and TNFis development in RA.

scholarly journals Study on the Multitarget Mechanism and Key Active Ingredients of Herba Siegesbeckiae and Volatile Oil against Rheumatoid Arthritis Based on Network Pharmacology

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Xin Yang ◽  
Yahui Li ◽  
Runlin Lv ◽  
Haibing Qian ◽  
Xiangyun Chen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Molecular Docking ◽  
Essential Oil ◽  
Small Molecule ◽  
Molecular Mechanisms ◽  
Experimental Studies ◽  
Volatile Oil ◽  
Network Pharmacology ◽  
Chemical Components ◽  
Active Ingredients

Background. Herba Siegesbeckiae (HS, Xixiancao in Chinese) is widely used to treat inflammatory joint diseases such as rheumatoid arthritis (RA) and arthritis, and its molecular mechanisms and active ingredients have not been completely elucidated. Methods. In this study, the small molecule ligand library of HS was built based on Traditional Chinese Medicine Systems Pharmacology (TCMSP). The essential oil from HS was extracted through hydrodistillation and analyzed by Gas Chromatography-Mass Spectrometer (GC-MS). The target of RA was screened based on Comparative Toxicogenomics Database (CTD). The key genes were output by the four algorithms’ maximum neighborhood component (MNC), degree, maximal clique centrality (MCC), and stress in cytoHubba in Cytoscape, while biological functions and pathways were also analyzed. The key active ingredients and mechanism of HS and essential oil against RA were verified by molecular docking technology (Sybyl 2.1.1) in treating RA. The interaction between 6 active ingredients (degree ≥ 5) and CSF2, IL1β, TNF, and IL6 was researched based on the software Ligplot. Results. There were 31 small molecule constituents of HS and 16 main chemical components of essential oil (relative content >1%) of HS. There were 47 chemical components in HS. Networks showed that 9 core targets (TNF, IL1β, CSF2, IFNG, CTLA4, IL18, CD26, CXCL8, and IL6) of RA were based on Venn diagrams. In addition, molecular docking simulation indicated that CSF2, IL1β, TNF, and IL6 had good binding activity with the corresponding compounds (degree > 10).The 6 compounds (degree ≥ 5) of HS and essential oil had good interaction with 5 or more targets. Conclusion. This study validated and predicted the mechanism and key active ingredients of HS and volatile oil in treating RA. Additionally, this study provided a good foundation for further experimental studies.

scholarly journals Identification of Tumor Necrosis Factor-Alpha (Tnf-α) Inhibitor in Rheumatoid Arthritis Using Network Pharmacology and Molecular Docking

2021 ◽  
Author(s):  
Jun Yu ◽  
Peng Zhou
Keyword(s):  
Molecular Docking ◽  
Signaling Pathway ◽  
Target Genes ◽  
Network Pharmacology ◽  
Active Ingredients ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Receptor Signaling Pathway ◽  
Factor Alpha ◽  
Necrosis Factor

Abstract Background: This study aimed to investigate the molecular mechanism of Radix Paeoniae Alba (White peony, WP) in treating rheumatoid arthritis (RA) and tumor necrosis factor-alpha (TNF-α) inhibitor (TNFi) by using network pharmacology and molecular docking. Methods: In this study, the ingredient of WP and the potential targets of RA were obtained from the Traditional Chinese Medicine Systematic Pharmacology Database, GeneCard and OMIM databases, respectively. Establishment of RA-WP potential target genes interaction network using STRING database. Network maps of WP-RA-potential target genes network was constructed using Cytoscape software. gene ontology (GO), and biological pathway (KEGG) pathway enrichment analysis were used to further explore the RA mechanism and therapeutic effects of WP. Using molecular docking technology to analyze the optimal effective components from WP to docking with TNF-α. Results: 13 active ingredients and 71 target genes were screened from WP, 49 of which intersect with RA target genes and are considered as potential therapeutic targets.Network pharmacological analysis showed that the WP active ingredients of mairin, DPHCD, (+)-catechin, beta-sitosterol, paeoniflorin, sitosterol, and kaempferol showed better correlation with RA target genes such as PGR, PTGS1, PTGS2, NR3C2, TNFSF15, CHRM2. The signaling pathways of the active ingredients for the treatment of RA are TNF-α signaling pathway, toll-like receptor signaling pathway, cell apoptosis, interleukin-17 signaling pathway, C-type lectin receptor signaling pathway, mitogen-associated-protein kinase, etc. Molecular docking results suggest that mairin was the most appropriate natural TNFi.Conclusions: Our findings provide the essential role and basis, for further studies into the molecular mechanisms of WP and TNFi development in RA.

scholarly journals Network pharmacology and molecular docking study on the active ingredients of qidengmingmu capsule for the treatment of diabetic retinopathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mingxu Zhang ◽  
Jiawei Yang ◽  
Xiulan Zhao ◽  
Ying Zhao ◽  
Siquan Zhu
Keyword(s):  
Diabetic Retinopathy ◽  
Molecular Docking ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Enrichment Analysis ◽  
Docking Study ◽  
Network Pharmacology ◽  
Biological Processes ◽  
Active Ingredients ◽  
Molecular Docking Study

AbstractDiabetic retinopathy (DR) is a leading cause of irreversible blindness globally. Qidengmingmu Capsule (QC) is a Chinese patent medicine used to treat DR, but the molecular mechanism of the treatment remains unknown. In this study, we identified and validated potential molecular mechanisms involved in the treatment of DR with QC via network pharmacology and molecular docking methods. The results of Ingredient-DR Target Network showed that 134 common targets and 20 active ingredients of QC were involved. According to the results of enrichment analysis, 2307 biological processes and 40 pathways were related to the treatment effects. Most of these processes and pathways were important for cell survival and were associated with many key factors in DR, such as vascular endothelial growth factor-A (VEGFA), hypoxia-inducible factor-1A (HIF-1Α), and tumor necrosis factor-α (TNFα). Based on the results of the PPI network and KEGG enrichment analyses, we selected AKT1, HIF-1α, VEGFA, TNFα and their corresponding active ingredients for molecular docking. According to the molecular docking results, several key targets of DR (including AKT1, HIF-1α, VEGFA, and TNFα) can form stable bonds with the corresponding active ingredients of QC. In conclusion, through network pharmacology methods, we found that potential biological mechanisms involved in the alleviation of DR by QC are related to multiple biological processes and signaling pathways. The molecular docking results also provide us with sound directions for further experiments.

scholarly journals Molecular mechanism underlying the hypolipidemic effect of Shanmei Capsule based on network pharmacology and molecular docking

2021 ◽  
Vol 29 ◽  
pp. 239-256
Author(s):  
Qian Wang ◽  
Lijing Du ◽  
Jiana Hong ◽  
Zhenlin Chen ◽  
Huijian Liu ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Kegg Pathway ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Signal Pathways ◽  
Hypolipidemic Effect ◽  
Active Ingredients ◽  
Pathway Enrichment

BACKGROUND: Shanmei Capsule is a famous preparation in China. However, the related mechanism of Shanmei Capsule against hyperlipidemia has yet to be revealed. OBJECTIVE: To elucidate underlying mechanism of Shanmei Capsule against hyperlipidemia through network pharmacology approach and molecular docking. METHODS: Active ingredients, targets of Shanmei Capsule as well as targets for hyperlipidemia were screened based on database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed via Database for Annotation, Visualization, and Integrated Discovery (DAVID) 6.8 database. Ingredient-target-disease-pathway network was visualized utilizing Cytoscape software and molecular docking was performed by Autodock Vina. RESULTS: Seventeen active ingredients in Shanmei Capsule were screened out with a closely connection with 34 hyperlipidemia-related targets. GO analysis revealed 40 biological processes, 5 cellular components and 29 molecular functions. A total of 15 signal pathways were enriched by KEGG pathway enrichment analysis. The docking results indicated that the binding activities of key ingredients for PPAR-α are equivalent to that of the positive drug lifibrate. CONCLUSIONS: The possible molecular mechanism mainly involved PPAR signaling pathway, Bile secretion and TNF signaling pathway via acting on MAPK8, PPARγ, MMP9, PPARα, FABP4 and NOS2 targets.

Explore the active ingredients and mechanisms in Musa basjoo pseudostem juice against diabetes based on animal experiment, gas chromatography-mass spectrometer and network pharmacology

2021 ◽  
Vol 24 ◽  
Author(s):  
Feng Xu ◽  
Xiangpei Wang ◽  
Xiujuan Wei ◽  
Teng Chen ◽  
Hongmei Wu
Keyword(s):  
Gas Chromatography ◽  
Molecular Docking ◽  
Signaling Pathway ◽  
Mass Spectrometer ◽  
Diabetic Rats ◽  
Network Pharmacology ◽  
Receptor Interaction ◽  
Oral Glucose ◽  
Active Ingredients ◽  
Polar Parts

Background: Musa basjoo pseudostem juice (MBSJ) is a well-known Chinese medicine, and Miao people use MBSJ to treat diabetes. In this work, the active ingredients and molecular mechanism of MBSJ against diabetes were explored. Methods: Anti-diabetic activity of MBSJ was evaluated using diabetic rats, and then the ingredients in the small-polar parts of MBSJ were analyzed by gas chromatography-mass spectrometer (GC-MS). Targets were obtained from several databases to develop the "ingredient-target-disease" network by Cytoscape. A collaborative analysis was carried out using the tools in Cytoscape and R packages, and molecular docking was also performed. Results: MBSJ improved the oral glucose tolerance and insulin tolerance, and reduced fasting blood glucose, glycosylated hemoglobin, total cholesterol, triglyceride, and low-density lipoprotein levels in the serum of diabetic rats. 13 potential compounds were identified by GC-MS for subsequent analysis, including Dibutyl phthalate, Oleamide, Stigmasterol, Stigmast-4-en-3-one, etc. The anti-diabetic effect of MBSJ was related to multiple signaling pathways, including Neuroactive ligand-receptor interaction, Phospholipase D signaling pathway, Endocrine resistance, Rap1 signaling pathway, EGFR tyrosine kinase inhibitor resistance, etc. Molecular docking at least partially verified the screening results of network pharmacology. Conclusion: MBSJ had good anti-diabetic activity. The small-polar parts of MBSJ were rich in anti-diabetic active ingredients. Furthermore, the analysis results showed that the anti-diabetic effect of the small-polar parts of MBSJ may be the result of multiple components, multiple targets, and multiple pathways. The current research results can provide important support for studying the active ingredients and exploring the underlying mechanism of MBSJ against diabetes.

scholarly journals A Network Pharmacology Approach to Explore Mechanism of Action of Longzuan Tongbi Formula on Rheumatoid Arthritis

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
An Huang ◽  
Gang Fang ◽  
Yuzhou Pang ◽  
Zongran Pang
Keyword(s):  
Rheumatoid Arthritis ◽  
Signaling Pathway ◽  
Active Rheumatoid Arthritis ◽  
Trp Channels ◽  
Network Pharmacology ◽  
Mtor Signaling Pathway ◽  
Active Ingredients ◽  
Major Pathway ◽  
Pharmacological Mechanism ◽  
Ppar Signaling

Longzuan Tongbi Formula (LZTB) is an effective proved prescription in Zhuang medicine for treating active rheumatoid arthritis (RA). However, its active ingredients, underlying targets, and pharmacological mechanism are still not clear in treating RA. We have applied network pharmacology to study LZTB and found that 8 herbs in LZTB and 67 compounds in the 8 herbs are involved in the regulation of RA-related genes; we have conducted pathway analysis of overlapping genes and found that 7 herbs participate in the regulations of 24 pathways associated with RA and that 5 herbs in the 7 herbs and 25 compounds in the 5 herbs participate in the regulation of hsa05323 (rheumatoid arthritis). The results indicated that all herbs in LZTB and some compounds in those herbs participate in the treatment of RA; 25 compounds are main active ingredients and hsa05323 (rheumatoid arthritis) is the major pathway in the treatment of RA. We have also found that three pathways (inflammatory mediator regulation of TRP channels, PPAR signaling pathway, and mTOR signaling pathway) might have some effect on the treatment of RA.

scholarly journals Mechanism of Action of Bu-Fei-Yi-Shen Formula in Treating Chronic Obstructive Pulmonary Disease Based on Network Pharmacology Analysis and Molecular Docking Validation

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Longchuan Wu ◽  
Yu Chen ◽  
Jiao Yi ◽  
Yi Zhuang ◽  
Lei Cui ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Mechanism Of Action ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Chronic Obstructive ◽  
Biological Functions ◽  
Active Ingredients ◽  
Obstructive Pulmonary Disease ◽  
The Core ◽  
Target Network

Objective. To explore the mechanism of action of Bu-Fei-Yi-Shen formula (BFYSF) in treating chronic obstructive pulmonary disease (COPD) based on network pharmacology analysis and molecular docking validation. Methods. First of all, the pharmacologically active ingredients and corresponding targets in BFYSF were mined by the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, the analysis platform, and literature review. Subsequently, the COPD-related targets (including the pathogenic targets and known therapeutic targets) were identified through the TTD, CTD, DisGeNet, and GeneCards databases. Thereafter, Cytoscape was employed to construct the candidate component-target network of BFYSF in the treatment of COPD. Moreover, the cytoHubba plug-in was utilized to calculate the topological parameters of nodes in the network; then, the core components and core targets of BFYSF in the treatment of COPD were extracted according to the degree value (greater than or equal to the median degree values for all nodes in the network) to construct the core network. Further, the Autodock vina software was adopted for molecular docking study on the core active ingredients and core targets, so as to verify the above-mentioned network pharmacology analysis results. Finally, the Omicshare database was applied in enrichment analysis of the biological functions of core targets and the involved signaling pathways. Results. In the core component-target network of BFYSF in treating COPD, there were 30 active ingredients and 37 core targets. Enrichment analysis suggested that these 37 core targets were mainly involved in the regulation of biological functions, such as response to biological and chemical stimuli, multiple cellular life processes, immunity, and metabolism. Besides, multiple pathways, including IL-17, Toll-like receptor (TLR), TNF, and HIF-1, played certain roles in the effect of BFYSF on treating COPD. Conclusion. BFYSF can treat COPD through the multicomponent, multitarget, and multipathway synergistic network, which provides basic data for intensively exploring the mechanism of action of BFYSF in treating COPD.

scholarly journals Shiga Toxins Activate the NLRP3 Inflammasome Pathway To Promote Both Production of the Proinflammatory Cytokine Interleukin-1β and Apoptotic Cell Death

2015 ◽  
Vol 84 (1) ◽  
pp. 172-186 ◽  
Author(s):  
Moo-Seung Lee ◽  
Haenaem Kwon ◽  
Eun-Young Lee ◽  
Dong-Jae Kim ◽  
Jong-Hwan Park ◽  
...  
Keyword(s):  
Cell Death ◽  
Nlrp3 Inflammasome ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Interleukin 1Β ◽  
Dependent Manner ◽  
Shiga Toxins ◽  
Caspase 1 ◽  
Immune Signaling Pathway ◽  
Tnf Α

Shiga toxin (Stx)-mediated immune responses, including the production of the proinflammatory cytokines tumor necrosis-α (TNF-α) and interleukin-1β (IL-1β), may exacerbate vascular damage and accelerate lethality. However, the immune signaling pathway activated in response to Stx is not well understood. Here, we demonstrate that enzymatically active Stx, which leads to ribotoxic stress, triggers NLRP3 inflammasome-dependent caspase-1 activation and IL-1β secretion in differentiated macrophage-like THP-1 (D-THP-1) cells. The treatment of cells with a chemical inhibitor of glycosphingolipid biosynthesis, which suppresses the expression of the Stx receptor globotriaosylceramide and subsequent endocytosis of the toxin, substantially blocked activation of the NLRP3 inflammasome and processing of caspase-1 and IL-1β. Processing and release of both caspase-1 and IL-1β were significantly reduced or abolished in Stx-intoxicated D-THP-1 cells in which the expression of NLRP3 or ASC was stably knocked down. Furthermore, Stx mediated the activation of caspases involved in apoptosis in an NLRP3- or ASC-dependent manner. In Stx-intoxicated cells, the NLRP3 inflammasome triggered the activation of caspase-8/3, leading to the initiation of apoptosis, in addition to caspase-1-dependent pyroptotic cell death. Taken together, these results suggest that Stxs trigger the NLRP3 inflammasome pathway to release proinflammatory IL-1β as well as to promote apoptotic cell death.

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