TNF-α stimulates MMP-2 and MMP-9 activities in human corneal epithelial cells via the activation of FAK/ERK signaling.

AIMS: Herpes simplex virus type-1-induced herpes simplex keratitis (HSK) is a common immunological cornea disease. While previous studies have addressed the role of tumor necrosis factor (TNF)-α and matrix metalloproteinases (MMPs) in HSK, the mechanistic link between TNF-α and MMPs in the pathogenesis of HSK remains elusive. METHODS: We first established a HSK mice model and measured the levels of TNF-α, MMP-2 and MMP-9 in the corneas at different time points by ELISA. Next, we employed cultured human corneal epithelial (HCE) cells as an in vitro model and performed gelatin zymography analysis. RESULTS: We observed that the change in the TNF-α level shared a similar pattern to that of MMP-2 and MMP-9 in the HSK mice model. Furthermore, TNF-α stimulated MMP-2 and MMP-9 activities in a dose-dependent manner, but either knockdown of focal adhesion kinase (FAK) by short interference RNA or inhibition of extracellular regulated protein kinase (ERK) by chemical inhibitor could block TNF-α-stimulated MMP-2 and MMP-9 activities in vitro. Taken together, our results provide in vivo evidence that the TNF-α level is positively correlated with MMP-2 and MMP-9 levels in a HSK model and in vitro evidence that TNF-α stimulates MMP-2 and MMP-9 activities via the activation of FAK/ERK signaling in HCE cells. CONCLUSIONS: Our findings shed new light on the pathogenesis of HSK and open up new possibility of modulating the TNF-α-FAK-ERK signaling cascade to pursue therapeutic measures for HSK.

{4,4',6,6'-Tetra-chloro-2,2'-[(spiro-[4.4]nonane-1,6-di-yl)bis-(nitrilo-methyl-idyne)]diphenolato-κO,N,N',O'}nickel(II).

The title compound, [Ni(C(23)H(20)Cl(4)N(2)O(2))], has an Ni(II) ion in a square-planar coordination formed by two imine N and two phenolato O atoms.

Bone marrow mesenchymal stromal cells with CD47 high expression via the signal transducer and activators of transcription signaling pathway preventing myocardial fibrosis.

UNLABELLED: This study was initiated to investigate the efficacy of myocardial fibrosis intervention via signal transducer and activators of transcription (STAT) signaling using bone marrow (BM) mesenchymal stromal cells (MSC) in which being over-expressed with the aid of bispecific antibody (BiAb) and ultrasound-mediated microbubbles (MB). BiAb was prepared and combined with isolated MSC with CD47 overexpression from male mice and trans-fused into female mice with isoproterenol-induced myocardial fibrosis via the tail vein, followed by MB. This study included five groups. Five weeks after treatment, expression levels of the sex-determining region of Y-chromosome (SRY), matrix metalloproteinases (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1 and vascular endothelial growth factor (VEGF) in myocardium were detected by fluorescent quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of signal transducer and activators of transcription (STAT) 1 and STAT 3 was detected by Western blot. RESULTS: The highest homing number of MSC was in the CD47 + MSC + BiAb + MB group, second highest in the CD47 + MSC + BiAb group, and lowest in MSC alone. Compared with the Control group, CD47 + MSC + BiAb + MB, CD47 + MSC + BiAb, CD47 + MSC and MSC groups had decreased levels of MMP-9, TIMP-1, STAT 1 and collagen deposition, and increased levels of STAT 3. Up regulated STAT 3 and down regulated TIMP-1 were significantly different in CD47 + MSC + BiAb + MB compared with CD47 + MSC or CD47 + MSC + BiAb. CONCLUSION: CD47 can enhance the homing rate and repairing efficacy of MSC. MSC can improve MMP-TIMP expression in injured myocardium and interfere with myocardial fibrosis after homing, a mechanism that may be related to the STAT-mediated signaling pathway.