Thioredoxin-2 impacts the inflammatory response via suppression of NF-κB and MAPK signaling in sepsis shock

Novel coronaviruses (CoV) have emerged periodically around the world in recent years. The recurrent spreading of CoVs imposes an ongoing threat to global health and the economy. Since no specific therapy for these CoVs is available, any beneficial approach (including nutritional and dietary approach) is worth investigation. Based on recent advances in nutrients and phytonutrients research, a novel combination of vitamin C, curcumin and glycyrrhizic acid (VCG Plus) was developed that has potential against CoV infection. System biology tools were applied to explore the potential of VCG Plus in modulating targets and pathways relevant to immune and inflammation responses. Gene target acquisition, gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment were conducted consecutively along with network analysis. The results show that VCG Plus can act on 88 hub targets which are closely connected and associated with immune and inflammatory responses. Specifically, VCG Plus has the potential to regulate innate immune response by acting on NOD-like and Toll-like signaling pathways to promote interferons production, activate and balance T-cells, and regulate the inflammatory response by inhibiting PI3K/AKT, NF-κB and MAPK signaling pathways. All these biological processes and pathways have been well documented in CoV infections studies. Therefore, our findings suggest that VCG Plus may be helpful in regulating immune response to combat CoV infections and inhibit excessive inflammatory responses to prevent the onset of cytokine storm. However, further in vitro and in vivo experiments are warranted to validate the current findings with system biology tools. Our current approach provides a new strategy in predicting formulation rationale when developing new dietary supplements.

Download Full-text

CCR5 silencing reduces inflammatory response, inhibits viability, and promotes apoptosis of synovial cells in rat models of rheumatoid arthritis through the MAPK signaling pathway

Journal of Cellular Physiology ◽

10.1002/jcp.28514 ◽

2019 ◽

Vol 234 (10) ◽

pp. 18748-18762 ◽

Cited By ~ 3

Author(s):

You‐Yu Lan ◽

You‐Qiang Wang ◽

Yi Liu

Keyword(s):

Rheumatoid Arthritis ◽

Inflammatory Response ◽

Signaling Pathway ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Synovial Cells ◽

Rat Models

Download Full-text

METTL3 Regulates Osteoblast Differentiation and Inflammatory Response via Smad Signaling and MAPK Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms21010199 ◽

2019 ◽

Vol 21 (1) ◽

pp. 199 ◽

Cited By ~ 6

Author(s):

Yiwen Zhang ◽

Xiaofei Gu ◽

Di Li ◽

Luhui Cai ◽

Qiong Xu

Keyword(s):

Inflammatory Response ◽

Osteoblast Differentiation ◽

Mapk Signaling ◽

Cytokine Expression ◽

Biological Processes ◽

Bone Homeostasis ◽

Smad Signaling ◽

Mrna Transcripts ◽

Inflammatory Stimuli ◽

Inhibitor Treatment

Osteoblasts are crucial bone-building cells that maintain bone homeostasis, whereas inflammatory stimuli can inhibit osteogenesis and activate inflammatory response. N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotes and plays important roles in multiple biological processes. However, whether m6A modification affects osteoblast differentiation and inflammatory response remains unknown. To address this issue, we investigated the expression of the N6-adenosine methyltransferase METTL3 and found that it was upregulated during osteoblast differentiation and downregulated after LPS stimulation. We then knocked down METTL3 and observed decreased levels of osteogenic markers, ALP activity, and mineralized nodules, as well as Smad1/5/9 phosphorylation, in LPS-induced inflammation. METTL3 knockdown promoted the mRNA expression and stability of negative regulators of Smad signaling, Smad7 and Smurf1, the same regulatory pattern identified when the m6A-binding protein YTHDF2 was silenced. Moreover, METTL3 depletion enhanced proinflammatory cytokine expression and increased the phosphorylation of ERK, p38, JNK, and p65 in MAPK and NF-κB signaling pathways. The increase in cytokine expression was inhibited after MAPK signaling inhibitor treatment. All data suggest that METTL3 knockdown inhibits osteoblast differentiation and Smad-dependent signaling by stabilizing Smad7 and Smurf1 mRNA transcripts via YTHDF2 involvement and activates the inflammatory response by regulating MAPK signaling in LPS-induced inflammation.

Download Full-text

Downregulation of FPR1 abates lipopolysaccharide-induced inflammatory injury and apoptosis by upregulating MAPK signaling pathway in murine chondrogenic ATDC5 cells

Allergologia et Immunopathologia ◽

10.15586/aei.v49i5.455 ◽

2021 ◽

Vol 49 (5) ◽

pp. 56-62

Author(s):

Hongtao Chen ◽

Li Zhang

Keyword(s):

Inflammatory Response ◽

Western Blot ◽

Signaling Pathway ◽

Quantitative Polymerase Chain Reaction ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Mitogen Activated Protein Kinase ◽

Expression Level ◽

Formyl Peptide Receptor ◽

Western Blot Assay

Background and objective: Osteoarthritis is the most common chronic osteoarthrosis disease. There are complex factors that lead to osteoarthritis. Therefore, it is essential to investigate the molecular mechanism of osteoarthritis, especially the mechanism of articular cartilage degeneration. In this study, the mechanism of FPR1 (formyl peptide receptor 1) in LPS (lipopolysaccharide) induced chondrogenic cell ATDC5 was investigated.Materials and methods: We employed real-time quantitative polymerase chain reaction (RT-qPCR) and western blot assay to analyze the expression level of FPR1 in ATDC5 cell linesinduced by LPS at 0, 2.5, 5, and 10 μg/mL concentrations. Then we constructed the FPR1 knockdown plasmid to transfect the LPS-ATDC5. MTT assay was used to test cell viability in control, LPS, LPS+shNC and LPS+shFPR1 groups. ELISA and RT-qPCR assay were employed to examine the TNF-α (tumor necrosis factor-α)、IL-6 and IL-1β expression level. Flow cytometry and western blot assay were employed to analyze the apoptosis of LPS-ATDC5. Finally, we utilized the western blot assay to text related protein expression level of MAPK (mitogen-activated protein kinase) signaling pathway.Results: In this study, we found the expression level of FPR1 was increased in LPS-ATDC5, downregulation of FPR1 improves the survival rate and alleviates inflammatory response of LPS-ATDC5. Meanwhile, downregulation of FPR1 alleviates apoptosis of LPS-ATDC5. Finally, downregulation of FPR1 inhibits the MAPK signal pathway.Conclusion: Present study revealed that FPR1 was highly expressed in LPS-induced chondrocytes ATDC5, and the downregulation of FPR1 abated the inflammatory response and apoptosis of LPS-ATDC5 cells by regulating the MAPK signaling pathway.

Download Full-text

m6A Reader YTHDF2 Regulates LPS-Induced Inflammatory Response

International Journal of Molecular Sciences ◽

10.3390/ijms20061323 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1323 ◽

Cited By ~ 14

Author(s):

Ruiqing Yu ◽

Qimeng Li ◽

Zhihui Feng ◽

Luhui Cai ◽

Qiong Xu

Keyword(s):

Inflammatory Response ◽

Rna Binding ◽

Rna Binding Proteins ◽

Mapk Signaling ◽

Raw 264.7 Cells ◽

Raw 264.7 ◽

Tnf Α ◽

Mrna Transcripts ◽

The Stability ◽

Cell Stress Response

N6-methyladenosine (m6A) is an abundant mRNA modification that affects multiple biological processes, including those involved in the cell stress response and viral infection. YTH domain family 2 (YTHDF2) is an m6A-binding protein that affects the localization and stability of targeted mRNA. RNA-binding proteins (RBPs) can regulate the stability of inflammatory gene mRNA transcripts, thus participating in the regulation of inflammatory processes. As an RBP, the role of YTHDF2 in the LPS-induced inflammatory reaction has not been reported. To elucidate the function of YTHDF2 in the inflammatory response of macrophages, we first detected the expression level of YTHDF2 in RAW 264.7 cells, and found that it was upregulated after LPS stimulation. YTHDF2 knockdown significantly increased the LPS-induced IL-6, TNF-α, IL-1β, and IL-12 expression and the phosphorylation of p65, p38, and ERK1/2 in NF-κB and MAPK signaling. Moreover, the upregulated expression of TNF-α and IL-6 in cells with silenced YTHDF2 expression was downregulated by the NF-κB, p38, and ERK inhibitors. YTHDF2 depletion increased the expression and stability of MAP2K4 and MAP4K4 mRNAs. All of these results suggest that YTHDF2 knockdown increases mRNA expression levels of MAP2K4 and MAP4K4 via stabilizing the mRNA transcripts, which activate MAPK and NF-κB signaling pathways, which promote the expression of proinflammatory cytokines and aggravate the inflammatory response in LPS-stimulated RAW 264.7 cells.

Download Full-text