作者: Whitley, Guy S. ; Aziz, Miriam ; Tryfonos, Zoe ; Ashton, Sandra ; Lagzouli, Nora ; Tinsley, Holly ; Longhurst, Charlotte ; Frick, Alexander ; Cartwright, Judith E.

ABSTRACT:

Maternal uterine spiral arteries (SpA) undergo significant structural changes in early pregnancy, resulting in increased blood flow to the developing fetus. Endothelial cells (EC) and vascular smooth muscle cells (VSMC) are lost from the SpA wall and are replaced by trophoblasts. We have previously shown that matrix metalloproteinase 10 (MMP‐10) and Heparin binding‐EGF like growth factor (HB‐EGF) gene expression is increased in a 3D EC/VSMC co‐culture system in response to trophoblast secreted factors. This study investigated trophoblast mediated MMP‐10 and HB‐EGF expression and determined if there was a relationship between the secretion of MMP‐10 and the release of soluble HB‐EGF (sHB‐EGF) from EC. MMP‐10 was widely expressed in first trimester decidual tissue including trophoblast, and EC, but not VSMC. MMP‐10 expression was significantly lower in decidual tissue from pregnancies at increased risk of developing pre‐eclampsia compared to low‐risk pregnancies. In vitro, SGHEC‐7 cells, a human EC line, but not SGHVMC‐9, a human VSMC cell line, secreted MMP‐10 in response to trophoblast conditioned medium (TCM). TCM contains several growth factors and cytokines, but only interleukin‐1β (IL1β) significantly stimulated MMP‐10 secretion by SGHEC‐7 cells. Interleukin‐1 receptor antagonist (IL‐1Ra) significantly inhibited TCM‐induced MMP‐10 secretion. Interrogation of intracellular pathways established the involvement of MEK and JNK in TCM and IL‐1β stimulated MMP‐10 secretion. Although IL‐1β also significantly increased sHB‐EGF, inhibition of MMP‐10 activity using a broad spectrum MMP inhibitor had no effect on sHB‐EGF. Western blot analysis indicated that MMP‐10 secreted by EC in response to IL‐1β stimulation was the enzymatically inactive pro form.

2025-05-01·STEROIDS

Isoxazolyl steroid blocks the Shh signaling pathway and the expression of MMP-2 and MMP-9 in cervical carcinoma cell lines

Article

作者: Timoshenko, Olga ; Lisitsa, Andrey ; Kugaevskaya, Elena ; Mekhtiev, Arif ; Lupatov, Alexey ; Gureeva, Tatiana ; Rudovich, Anton ; Zhabinskii, Vladimir ; Khripach, Vladimir ; Morozevich, Galina

Cervical cancer is the fourth leading cause of cancer death among women worldwide. Matrix metalloproteinases MMP-2 and MMP-9 play a leading role in the processes of invasion and metastasis in cervical cancer. Research on the development of MMP inhibitors not yielded the expected results due to their serious side effects. Study of signaling pathways involved in regulation of MMPs expression is of great importance for search of new classes of therapeutic drugs. Aberrant activation of the Sonic Hedgehog (Shh) signaling pathway is associated with increased MMPs in many types of human cancer. This study investigated the inhibitory action of 17β-((3-butylisoxazol-5-yl)methyl)-androst-5-en-3β-ol on the Shh signaling pathway key genes (Ptch, Smo, Gli) expression and MMP-2, MMP-9 genes expression in human cervical carcinoma cell lines (SiHa and CaSki) and keratinocytes (HaCaT). Cyclopamine was used for comparative analysis. Gene expression analysis was performed using real-time PCR; the effects on survival and cell cycle were studied using the MTT test and flow cytometry method. 17β-((3-butylisoxazol-5-yl)methyl)-androst-5-en-3β-ol had higher cytotoxicity and more effectively blocked the Shh signaling pathway genes and MMP-2 and MMP-9 genes compared to cyclopamine in all cell lines. The results obtained demonstrate potential of 17β-((3-butylisoxazol-5-yl)methyl)-androst-5-en-3β-ol as the anticancer drug that simultaneously block the Shh signaling pathway and MMP expression. We are confident that the search for substances capable of simultaneously affecting several key components involved in tumor progression is of great importance for the creation of next-generation therapeutic agents.

2025-04-30·COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING

QbD Assisted Development of a Compartment and Sequential Drug Delivery System for Periodontotherapy

Article

作者: Iqbal, Zeenat ; Jain, Pooja

Furthermore, the current work is a pursuit of studying the quality by design aspects for the fabrication of a compartment system, i.e., in-situ gel for periodontal delivery. The proposed system in-situ gel consists of antibiotic and nano-encapsulating microcapsules. Furthermore, the microcapsules contain a COX-II inhibitor and nanoparticles of MMP inhibitor and bone regenerating agent for complete amelioration of periodontitis. To develop the system as per the QbD approach, the first initial trials and runs were conducted, which helped to decide the quality target product profile (QTPP). However, based on QTPP, critical quality attributes (CQA), critical process parameters (CPP), and critical material attributes (CMAs) were decided for each stage product, i.e., in-situ gel, microcapsules, and nanoparticles. To assess the influence of CPPs and CMAs on CQAs, Pareto charts were constructed, and various risks, along with possible failure modes were studied. In conclusion, the above work will serve as a well-designed scientific mouthpiece for developing a compartment system for periodontotherapy.

100 项与 MMP inhibitor(Paratek Pharmaceuticals) 相关的药物交易

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