Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With the approval of alteplase (tPA) therapy for stroke, it is likely that combination therapy with tPA to restore blood flow, and agents like glutamate receptor antagonists to halt or reverse the cascade of neuronal damage, will dominate the future of stroke care. The authors describe events and potential targets of therapeutic intervention that contribute to the excitotoxic cascade underlying cerebral ischemic cell death. The focal and global animal models of stroke are the basis for the identification of these events and therapeutic targets. The signalling pathways contributing to ischemic neuronal death are discussed based on their cellular localization. Cell surface signalling events include the activities of both voltage-gated K+, Na+, and Ca2+ channels and ligand-gated glutamate, gamma-aminobutyric acid and adenosine receptors and channels. Intracellular signalling events include alterations in cytosolic and subcellular Ca2+ dynamics, Ca2+ -dependent kinases and immediate early genes whereas intercellular mechanisms include free radical formation and the activation of the immune system. An understanding of the relative importance and temporal sequence of these processes may result in an effective stroke therapy targeting several points in the cascade. The overall goal is to reduce disability and enhance quality of life for stroke survivors.
 ...
PMID:Biology of ischemic cerebral cell death. 1059 20

The serine protease, tissue-type plasminogen activator (tPA) is a key regulator of extracellular proteolytic cascades. We demonstrate a requirement for tPA signaling in the experience-dependent plasticity of mouse visual cortex during the developmental critical period. Proteolytic activity by tPA in the binocular zone was typically increased within 2 days of monocular deprivation (MD). This regulation failed to occur in glutamic acid decarboxylase (GAD) 65 knockout mice, an animal model of impaired ocular dominance plasticity because of reduced gamma-aminobutyric acid (GABA)-mediated transmission described previously. Loss of responsiveness to the deprived eye consequent to MD was conversely suppressed in mice lacking tPA despite normal levels of neuronal activity. Plasticity was restored in a gene dose-dependent manner, or by direct tPA infusion. Permissive amounts of tPA may, thus, couple functional to structural changes downstream of the excitatory-inhibitory balance that triggers visual cortical plasticity. Our results not only support a molecular cascade leading to neurite outgrowth after sensory deprivation, but also identify a valuable tool for further proteomic and genomic dissection of experience-dependent plasticity downstream of electrical activity.
 ...
PMID:Permissive proteolytic activity for visual cortical plasticity. 1203 49

The Group IVA cytosolic phospholipase A(2) (GIVA PLA(2)) is a particularly attractive target for drug development because it is the rate-limiting provider of proinflammatory mediators. We previously reported the discovery of novel 2-oxoamides that inhibit GIVA PLA(2) [Kokotos, G.; et al. J. Med. Chem. 2002, 45, 2891-2893]. In the present work, we have further explored this class of inhibitors and found that the 2-oxoamide functionality is more potent when it contains a long 2-oxoacyl residue and a free carboxy group. Long-chain 2-oxoamides based on gamma-aminobutyric acid and gamma-norleucine are potent inhibitors of GIVA PLA(2). Such inhibitors act through a fast and reversible mode of inhibition in vitro, are able to block the production of arachidonic acid and prostaglandin E(2) in cells, and demonstrate potent in vivo anti-inflammatory and analgesic activity.
 ...
PMID:Inhibition of group IVA cytosolic phospholipase A2 by novel 2-oxoamides in vitro, in cells, and in vivo. 1521 89

Autophagy is an evolutionarily conserved pathway to degrade damaged proteins and organelles for subsequent recycling in cells during times of nutrient deprivation. This process plays an important role in tumor development and progression, allowing cancer cells to survive in nutrient-poor environments. The plant kingdom provides a powerful source for new drug development to treat cancer. Several plant extracts induce autophagy in cancer cells. However, little is known about the role of plant extracts in autophagy inhibition, particularly autophagy-related (ATG) proteins. In this study, we employed S-tagged gamma-aminobutyric acid receptor associated protein like 2 (GABARAPL2) as a reporter to screen 48 plant extracts for their effects on the activity of autophagy protease ATG4B. Xanthium strumarium and Tribulus terrestris fruit extracts were validated as potential ATG4B inhibitors by another reporter substrate MAP1LC3B-PLA2. The inhibitory effects of the extracts on cellular ATG4B and autophagic flux were further confirmed. Moreover, the plant extracts significantly reduced colorectal cancer cell viability and sensitized cancer cells to starvation conditions. The fruit extract of X. strumarium consistently diminished cancer cell migration and invasion. Taken together, the results showed that the fruit of X. strumarium may have an active ingredient to inhibit ATG4B and suppress the proliferation and metastatic characteristics of colorectal cancer cells.
 ...
PMID:Xanthium strumarium Fruit Extract Inhibits ATG4B and Diminishes the Proliferation and Metastatic Characteristics of Colorectal Cancer Cells. 3115 87