Anti-PKIA monoclonal antibody Made to order

BACKGROUND AND PURPOSE Airway remodelling is a consequence of long-term inflammation and MAPKs are key signalling molecules that drive pro-inflammatory pathways. The endogenous MAPK deactivator MAPK phosphatase 1 (MKP-1) is a critical negative regulator of the myriad pro-inflammatory pathways activated by MAPKs in the airway. EXPERIMENTAL APPROACH Herein we investigated the molecular mechanisms responsible for the upregulation of MKP-1 in airway smooth muscle (ASM) by the corticosteroid dexamethasone and the beta 2-agonist formoterol, added alone and in combination. KEY RESULTS MKP-1 is a corticosteroid-inducible gene whose expression is enhanced by long-acting beta 2-agonists in an additive manner. Formoterol induced MKP-1 expression via the beta 2-adrenoceptor and we provide the first direct evidence (utilizing overexpression of PKIa, a highly selective PKA inhibitor) to show that PKA mediates beta 2-agonist-induced MKP-1 upregulation. Dexamethasone activated MKP-1 transcription in ASM cells via a cis-acting corticosteroid-responsive region located between -1380 and -1266 bp of the MKP-1 promoter. While the 3'-untranslated region of MKP-1 contains adenylate + uridylate elements responsible for regulation at the post-transcriptional level, actinomycin D chase experiments revealed that there was no increase in MKP-1 mRNA stability in the presence of dexamethasone, formoterol, alone or in combination. Rather, there was an additive effect of the asthma therapeutics on MKP-1 transcription. CONCLUSIONS AND IMPLICATIONS Taken together, these studies allow us a greater understanding of the molecular basis of MKP-1 regulation by corticosteroids and beta 2-agonists and this new knowledge may lead to elucidation of optimized corticosteroid-sparing therapies in the future.

Since international federation of gynecology and obstetrics (FIGO) staging is mainly based on clinical assessment, an integrated approach for mining RNA based biomarkers for understanding the molecular deregulation of signaling pathways and RNAs in cervical cancer was proposed in this study. Publicly available data were mined for identifying significant RNAs after patient staging. Significant miRNA families were identified from mRNA-miRNA and lncRNA-miRNA interaction network analyses followed by stage specific mRNA-miRNA-lncRNA association network generation. Integrated bioinformatic analyses of selected mRNAs and lncRNAs were performed. Results suggest that HBA1, HBA2, HBB, SLC2A1, CXCL10 (stage I), PKIA (stage III) and S100A7 (stage IV) were important. miRNA family enrichment of interacting miRNA partners of selected RNAs indicated the enrichment of let-7 family. Assembly of collagen fibrils and other multimeric structures_Homosapiens_R-HSA-2022090 in pathway analysis and progesterone_CTD_00006624 in DSigDB analysis were the most significant and SLC2A1, hsa-miR-188-3p, hsa-miR-378a-3p and hsa-miR-150-5p were selected as survival markers.