Current status and future prospects of p38α/MAPK14 kinase and its inhibitors

Madkour, Moustafa M.; Anbar, Hanan S.; El–Gamal, Mohammed I.

doi:10.1016/j.ejmech.2021.113216

Cited by 64 publications

(31 citation statements)

References 114 publications

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“…The rst two have been shown to be associated with in ammatory disease and angiogenesis. 37,38 PIK3CA is one of the most common mutation genes found in tumor types in recent years. 39 It is reported that mutations in this gene involve the occurrence of ovarian cancer in EM.…”

Section: Discussionmentioning

confidence: 99%

An Investigation Into the Mechanism of Li Chong Pill for Treating Endometriosis Based on Network Pharmacology and Molecular Docking Verification

Liu¹,

Han²,

Zhang³

et al. 2021

Preprint

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Background and objective: Li Chong Wan (Li Chong pill, LCP) origin from Yi Xue Zhong Zhong Can Xi Lu, (Records of Chinese Medicine with Reference to Western Medicine), widely used in the treatment of endometriosis (EM) in China. The purpose of this study is to investigate the intrinsic mechanisms of LCP against EM and to provide new evidence for its clinical application.Methods: Chemical compounds of LCP were screened and evaluated via retrieving public databases and literature. We also acquired their putative targets and obtained EM-related targets. The above-mentioned data were visualized as a component-target network. In addition, we use Cytoscape3.8.0 to build a protein-protein interaction network and identified hub genes and key active ingredients. Furthermore, through GO and KEGG pathway analyses, which were actualized by R3.6.1 (based on clusterProfiler, org.Hs.eg.Db, and pathview package), we obtained effective signaling pathways and biological functions. Molecular docking was used to verify binding activity between compounds and the key targets at last.Results: Finally, a total of 122 possible active targets and 47 components were screened. Identify the core network and screen out 10 main targets; GO and KEGG enrichment analysis revealed that LCP may have functions of anti-inflammatory, anti-angiogenesis, inhibition of cell proliferation, regulation of hormone secretion, etc. The effect of LCP on EM might be achieved by PI3K/Akt signaling pathway, HIF-1 signaling pathway, estrogen signaling pathway, and VEGF signaling pathway, etc. Finally, molecular docking results demonstrated that 14 components were exhibited good binding property to the key targets of EM.Conclusion: This research ocularly demonstrated the multi-component, multi-target, and multi-channel pharmacological effects for LCP in the treatments of EM and provides evidence for further clinical research and verification of the mechanism.

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Section: Discussionmentioning

confidence: 99%

An Investigation Into the Mechanism of Li Chong Pill for Treating Endometriosis Based on Network Pharmacology and Molecular Docking Verification

Liu¹,

Han²,

Zhang³

et al. 2021

Preprint

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“…The downregulated expression of RUNX3 is consistent with the findings of these previous studies, suggesting that RUNX3 may protect against the development of sepsis. The other differentially expressed TF, MAPK14, plays an important role in initiating numerous conditions, including inflammation, cardiovascular diseases, and cancer [26] . MAPK14 can be activated by environmental stress and by various proinflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Identification of the TF-miRNA-mRNA Co-regulatory Networks Involved in Sepsis

Luo

Zhao

et al. 2021

Preprint

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BackgroundSepsis is a life-threatening medical condition caused by a dysregulated host response to infection. Recent studies have found that the expression of miRNAs is associated with the pathogenesis of sepsis and septic shock. Our study aimed to reveal which miRNAs may be involved in the dysregulated immune response in sepsis and how these miRNAs interact with transcription factors (TFs) using a computational approach with in vitro validation studies. MethodsTo determine the network of TFs, miRNAs and target genes involved in sepsis, GEO datasets GSE94717 and GSE131761 were used to identify differentially expressed miRNAs and DEGs. TargetScan and miRWalk databases were used to predict biological targets that overlap with the identified DEGs of differentially expressed miRNAs. The TransmiR database was used to predict the differential miRNA TFs that overlap with the identified DEGs. The TF-miRNA-mRNA network was constructed and visualized. Finally, qRT-PCR was used to verify the expression of TFs and miRNA in HUVECs. ResultBetween the healthy and sepsis groups, there were 146 upregulated and 98 downregulated DEGs in the GSE131761 dataset, and there were 1 upregulated and 183 downregulated DEMs in the GSE94717 dataset. A regulatory network of the TF-miRNA-target genes was established. According to the experimental results, RUNX3 was found to be downregulated while MAPK14 was upregulated, which corroborates the result of the computational expression analysis. In a HUVECs model, miR-19b-1-5p and miR-5009-5p were found to be significantly downregulated. Other TFs and miRNAs did not correlate with our bioinformatics expression analysis. ConclusionWe constructed a TF-miRNA-target gene regulatory network and identified potential treatment targets RUNX3, MAPK14, miR-19b-1-5p and miR-5009-5p. This information provides an initial basis for understanding the complex sepsis regulatory mechanisms.

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“…Compound 1m showed a concentrationdependent inhibitory effect against COX-2 and iNOS protein expression, especially at 10 µM concentration. Moreover, compound 1m markedly suppressed the phosphorylation of p38, a key molecule in regulating inflammation [20].…”

Section: Biological Evaluationmentioning

confidence: 96%

Evaluation of the Inhibitory Effects of Pyridylpyrazole Derivatives on LPS-Induced PGE2 Productions and Nitric Oxide in Murine RAW 264.7 Macrophages

et al. 2021

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A series of thirteen triarylpyrazole analogs were investigated as inhibitors of lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) and nitric oxide (NO) production in RAW 264.7 macrophages. The target compounds 1a–m have first been assessed for cytotoxicity against RAW 264.7 macrophages to determine their non-cytotoxic concentration(s) for anti-inflammatory testing to make sure that the inhibition of PGE2 and NO production would not be caused by cytotoxicity. It was found that compounds 1f and 1m were the most potent PGE2 inhibitors with IC50 values of 7.1 and 1.1 μM, respectively. In addition, these compounds also showed inhibitory effects of 11.6% and 37.19% on LPS-induced NO production, respectively. The western blots analysis of COX-2 and iNOS showed that the PGE2 and NO inhibitory effect of compound 1m are attributed to inhibition of COX-2 and iNOS protein expression through inactivation of p38.

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Current status and future prospects of p38α/MAPK14 kinase and its inhibitors

Cited by 64 publications

References 114 publications

An Investigation Into the Mechanism of Li Chong Pill for Treating Endometriosis Based on Network Pharmacology and Molecular Docking Verification

An Investigation Into the Mechanism of Li Chong Pill for Treating Endometriosis Based on Network Pharmacology and Molecular Docking Verification

Identification of the TF-miRNA-mRNA Co-regulatory Networks Involved in Sepsis

Evaluation of the Inhibitory Effects of Pyridylpyrazole Derivatives on LPS-Induced PGE2 Productions and Nitric Oxide in Murine RAW 264.7 Macrophages

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