Ergosta-7,9(11),22-trien-3β-ol Attenuates Inflammatory Responses via Inhibiting MAPK/AP-1 Induced IL-6/JAK/STAT Pathways and Activating Nrf2/HO-1 Signaling in LPS-Stimulated Macrophage-like Cells

Huang, Yiping; Chen, Dar‐Ren; Lin, Wen–Jen; Lin, Yu‐Hsien; Chen, Jiann‐Yeu; Kuo, Yueh‐Hsiung; Chung, Jing Gung; Hsia, Te‐Chun; Hsieh, Wen‐Tsong

doi:10.3390/antiox10091430

Cited by 11 publications

(19 citation statements)

References 44 publications

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“…In this study, the functional enrichment of the collection of Co-genes and the Top 11 Hub Genes included the regulation of IL-6 production, and the Upstream Pathway of the key gene (CASP1) was closely related to the JAK-STAT signaling pathway. The JAK/STAT pathway, also called the IL-6 signaling pathway, can be activated by IL-6 ( 198 , 199 ), which is also a significant indication of COVID-19 severity ( 1 , 200 ). Activation of the JAK/STAT pathway, which produces pro-inflammatory cytokines, also a significant role in the development of rheumatoid arthritis (RA) ( 201 ).…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 induces “cytokine storm” hyperinflammatory responses in RA patients through pyroptosis

Zheng¹,

Lin²,

Chen³

et al. 2022

Front. Immunol.

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BackgroundThe coronavirus disease (COVID-19) is a pandemic disease that threatens worldwide public health, and rheumatoid arthritis (RA) is the most common autoimmune disease. COVID-19 and RA are each strong risk factors for the other, but their molecular mechanisms are unclear. This study aims to investigate the biomarkers between COVID-19 and RA from the mechanism of pyroptosis and find effective disease-targeting drugs.MethodsWe obtained the common gene shared by COVID-19, RA (GSE55235), and pyroptosis using bioinformatics analysis and then did the principal component analysis(PCA). The Co-genes were evaluated by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and ClueGO for functional enrichment, the protein-protein interaction (PPI) network was built by STRING, and the k-means machine learning algorithm was employed for cluster analysis. Modular analysis utilizing Cytoscape to identify hub genes, functional enrichment analysis with Metascape and GeneMANIA, and NetworkAnalyst for gene-drug prediction. Network pharmacology analysis was performed to identify target drug-related genes intersecting with COVID-19, RA, and pyroptosis to acquire Co-hub genes and construct transcription factor (TF)-hub genes and miRNA-hub genes networks by NetworkAnalyst. The Co-hub genes were validated using GSE55457 and GSE93272 to acquire the Key gene, and their efficacy was assessed using receiver operating curves (ROC); SPEED2 was then used to determine the upstream pathway. Immune cell infiltration was analyzed using CIBERSORT and validated by the HPA database. Molecular docking, molecular dynamics simulation, and molecular mechanics-generalized born surface area (MM-GBSA) were used to explore and validate drug-gene relationships through computer-aided drug design.ResultsCOVID-19, RA, and pyroptosis-related genes were enriched in pyroptosis and pro-inflammatory pathways(the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome complex, death-inducing signaling complex, regulation of interleukin production), natural immune pathways (Network map of SARS-CoV-2 signaling pathway, activation of NLRP3 inflammasome by SARS-CoV-2) and COVID-19-and RA-related cytokine storm pathways (IL, nuclear factor-kappa B (NF-κB), TNF signaling pathway and regulation of cytokine-mediated signaling). Of these, CASP1 is the most involved pathway and is closely related to minocycline. YY1, hsa-mir-429, and hsa-mir-34a-5p play an important role in the expression of CASP1. Monocytes are high-caspase-1-expressing sentinel cells. Minocycline can generate a highly stable state for biochemical activity by docking closely with the active region of caspase-1.ConclusionsCaspase-1 is a common biomarker for COVID-19, RA, and pyroptosis, and it may be an important mediator of the excessive inflammatory response induced by SARS-CoV-2 in RA patients through pyroptosis. Minocycline may counteract cytokine storm inflammation in patients with COVID-19 combined with RA by inhibiting caspase-1 expression.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 induces “cytokine storm” hyperinflammatory responses in RA patients through pyroptosis

Zheng¹,

Lin²,

Chen³

et al. 2022

Front. Immunol.

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“…Atomic force microscopy assay (AFM) can precisely measure the appearance of cells down to the nanometer scale, which can be used to explore the precise and subtle three‐dimensional morphology information of cells 23 . Cultured cells at the number of 5 × 10 4 cells in the well were attached to round glass coverslips in 6‐well plates and treated with PW06 0.2 μM for 24 hours.…”

Section: Methodsmentioning

confidence: 99%

PW06 suppresses cancer cell metastasis in human pancreatic carcinoma MIA PaCa‐2 cells via the inhibitions of p‐Akt/mTOR/NF‐κB and MMP2/MMP9 signaling pathways in vitro

Huang,

Yeh,

et al. 2024

Environmental Toxicology

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PW06 [(E)‐3‐(9‐ethyl‐9H‐carbazol‐3‐yl)‐1‐(2,5‐dimethoxyphenyl) prop‐2‐en‐1‐one], a kind of the carbazole derivative containing chalcone moiety, induced cell apoptosis in human pancreatic carcinoma in vitro. There is no investigation to show that PW06 inhibits cancer cell metastasis in human pancreatic carcinoma in vitro. Herein, PW06 (0.1–0.8 μM) significantly exists in the antimetastatic activities of human pancreatic carcinoma MIA PaCa‐2 cells in vitro. Wound healing assay shows PW06 at 0.2 μM suppressed cell mobility by 7.45 and 16.55% at 6 and 24 hours of treatments. PW06 at 0.1 and 0.2 μM reduced cell mobility by 14.72 and 21.8% for 48 hours of treatment. Transwell chamber assay indicated PW06 (0.1–0.2 μM) suppressed the cell migration (decreased 26.67–35.42%) and invasion (decreased 48.51–68.66%). Atomic force microscopy assay shows PW06 (0.2 μM) significantly changed the shape of cell morphology. The gelatin zymography assay indicates PW06 decreased MMP2's and MMP9's activities at 48 hours of treatment. Western blotting assay further confirms PW06 reduced levels of MMP2 and MMP9 and increased protein expressions of EGFR, SOS1, and Ras. PW06 also increased the p‐JNK, p‐ERK, and p‐p38. PW06 increased the expression of PI3K, PTEN, Akt, GSK3α/β, and E‐cadherin. Nevertheless, results also show PW06 decreased p‐Akt, mTOR, NF‐κB, p‐GSK3β, β‐catenin, Snail, N‐cadherin, and vimentin in MIA PaCa‐2 cells. The confocal laser microscopy examination shows PW06 increased E‐cadherin but decreased vimentin in MIA PaCa‐2 cells. Together, our findings strongly suggest that PW06 inhibited the p‐Akt/mTOR/NF‐κB/MMPs pathways, increased E‐cadherin, and decreased N‐cadherin/vimentin, suppressing the migration and invasion in MIA PaCa‐2 cells in vitro.

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“…demonstrated that LPS could also induce the production of IL-6, TNF-α, and phosphorylated janus kinase (JAK). This increasing pro-inflammatory mediator expression is associated with the phosphorylation of MAPKs within 15–30 min after LPS stimulation ( 46 – 48 ). MAPK signaling pathway leads to the release of TNF-α and IL-6.…”

Section: Pathogenic Mechanism Of Periodontitismentioning

confidence: 99%

“…The latter could bind to the transmembrane IL-6 receptor and subsequently activate JAK, followed by the phosphorylation of the signal transducer and activator of transcription (STAT) 1/3. STAT1/3 could bind to the specific target DNA and trigger the inflammatory cytokines of TNF-α, IL-2, and IL-6 eventually ( 46 ). Besides, in the NF-κB signaling pathway, the phosphorylation of MAPK could lead AP-1 together with JNK and p38 to translocate into the nucleus and result in the upregulation of the proinflammatory cytokines ( 29 , 30 ).…”

Section: Pathogenic Mechanism Of Periodontitismentioning

confidence: 99%

Recent progress and perspectives on the relationship between hyperuricemia and periodontitis

et al. 2022

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Periodontitis is one of the most prevalent diseases in oral cavity, which could not merely lead to the destruction of supporting or surrounding tooth structures but also affect the whole-body health such as the digestive and nervous systems. Epidemiological investigations suggested that in some developed countries, more than 45% or even 50% population were suffering from periodontitis. However, the prevalence increases with age remarkably and it is investigated that a high prevalence (>50%) is affecting the elderly who is over 65 years old. There is an increasing interest in the direct and indirect relationships between periodontitis and hyperuricemia. Currently, hyperuricemia has become the second major metabolic disease in modern society and the prevalence of hyperuricemia among adult males and females was 21.7% and 14.4% respectively. As an inflammatory disease associated with various systemic diseases, periodontitis may have certain connections with hyperuricemia. Partial existing research announced that hyperuricemia could act as an inhibitory factor for periodontitis, while other scholars presented that a high uric acid (UA) level was more likely to aggravate inflammatory immune response and lead to more serious tissue destruction. This article provides a detailed and comprehensive overview of the relationship underlying hyperuricemia and periodontitis in the molecular mechanisms. Given the impact of hyperuricemia, this review could provide insight into its comorbidities.

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Ergosta-7,9(11),22-trien-3β-ol Attenuates Inflammatory Responses via Inhibiting MAPK/AP-1 Induced IL-6/JAK/STAT Pathways and Activating Nrf2/HO-1 Signaling in LPS-Stimulated Macrophage-like Cells

Cited by 11 publications

References 44 publications

SARS-CoV-2 induces “cytokine storm” hyperinflammatory responses in RA patients through pyroptosis

SARS-CoV-2 induces “cytokine storm” hyperinflammatory responses in RA patients through pyroptosis

PW06 suppresses cancer cell metastasis in human pancreatic carcinoma MIA PaCa‐2 cells via the inhibitions of p‐Akt/mTOR/NF‐κB and MMP2/MMP9 signaling pathways in vitro

Recent progress and perspectives on the relationship between hyperuricemia and periodontitis

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