Metalloproteinases in medicine最新文献

Selective gene activation with the dCas9 (deactivated clustered regularly interspaced short palindromic repeats [CRISPR] associated protein 9)/CRISPR targeting of a transcriptional activator effector is now well established. However, the optimal targeting of guide RNA (gRNA) for a given gene is largely a matter of trial and error. We explored the optimal targeting site for tissue inhibitor of metalloproteinases (TIMPs) by first screening multiple gRNA target sites using a luciferase-based promoter-reporter system and next confirmed the effective TIMP induction in the mouse motor neuron-like neuron-enriched spinal cord 34 (NSC34) cells. Screening of many gRNAs targeting the 1-1.9 kB promoter regions of TIMP1-3 identified several hot-spots for optimal gene induction, however, no general pattern defining the optimal target site with respect to the proximity of known transcription factor binding sites or distance from the start ATG was apparent. TIMP2 with a larger basal transcriptional activity showed a greater fold-induction with gRNA compared with TIMP1 or 3 supporting the importance of an open-chromatin for best gRNA-mediated transcriptional induction. The rank order of induction potency for different gRNA identified in the promoter-reporter screening held true for the NSC34 cells. Co-activation with multiple gRNAs greatly increased the gene induction.

We review select aspects of the biology of matrix metalloproteinases (MMPs) with a focus on the modulation of inflammatory responses by MMP-2. MMP-2 is a zinc- and calcium-dependent endoprotease with substrates including extracellular matrix proteins, vasoactive peptides and chemokines. Humans and mice with MMP-2 deficiency exhibit a predominantly inflammatory phenotype. Recent research shows that MMP-2 deficient mice display elevated activity of a secreted phospholipase A₂ in the heart. Additionally, MMP-2 deficient mice exhibit abnormally high prostaglandin E₂ levels in various organs (i.e., the heart, brain and liver), signs of inflammation and exacerbated lipopolysaccharide-induced fever. We briefly review the biology of sPLA₂ enzymes to propose the existence of a heart-centric MMP-2/sPLA₂ axis of systemic inflammation. Moreover, we postulate that PLA₂ activation is induced by chemokines, whose ability to signal inflammation is regulated in a tissue-specific fashion by MMPs. Thus, genetic and pharmacologically induced MMP-deficiencies can be expected to perturb PLA₂-mediated inflammatory mechanisms.

Following myocardial infarction (MI), the left ventricle (LV) undergoes a series of molecular, cellular, and functional alterations that are both part of the wound healing response to form a scar in the infarct region and the consequence of that response. Using the laws of thermodynamics as an analogy, we present here three laws for categorizing the post-MI LV remodeling process. The first law is that the LV will attempt to maintain equilibrium and compensate as a way to maximize function, the second law is that remodeling is progressive and unidirectional, and the third law is that the final goal is (ideally, but not always achievable) a stable, equilibrated scar. This comparison helps to define the boundaries of the system, whether it be the infarct zone, the LV, the heart, or the entire body. This review provides an overview for those not directly in the field and establishes a framework to help prioritize future research directions.