Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.4 (trypsin)
 42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Currently, an effective targeted therapy for pancreatitis is lacking. Hereditary pancreatitis (HP) is a heritable, autosomal-dominant disorder with recurrent acute pancreatitis (AP) progressing to chronic pancreatitis (CP) and a markedly increased risk of pancreatic cancer. In 1996, mutations in PRSS1 were linked to the development of HP. Here, we developed a mouse model by inserting a full-length human PRSS1R122H gene, the most commonly mutated gene in human HP, into mice. Expression of PRSS1R122H protein in the pancreas markedly increased stress signaling pathways and exacerbated AP. After the attack of AP, all PRSS1R122H mice had disease progression to CP, with similar histologic features as those observed in human HP. By comparing PRSS1R122H mice with PRSS1WT mice, as well as enzymatically inactivated Dead-PRSS1R122H mice, we unraveled that increased trypsin activity is the mechanism for R122H mutation to sensitize mice to the development of pancreatitis. We further discovered that trypsin inhibition, in combination with anticoagulation therapy, synergistically prevented progression to CP in PRSS1R122H mice. These animal models help us better understand the complex nature of this disease and provide powerful tools for developing and testing novel therapeutics for human pancreatitis.
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PMID:Trypsin activity governs increased susceptibility to pancreatitis in mice expressing human PRSS1R122H. 3155 Feb 38

Selectively targeting the endoplasmic reticulum (ER) of cancer cells, though promising a new strategy for cancer therapy, remains underdeveloped. Enzyme-instructed self-assembly (EISA) is emerging as a promising approach for selectively targeting ER of cancer cells. This work reports an easily accessible branched peptide that consists of a D-tetrapeptide backbone and a branch with the sequence of KYDKKKKDG (K: lysine; Y: tyrosine; D: aspratic acid; G: glycine), being an EISA substrate of typsin-1 (PRSS1), selectively inhibits cancer cells. Depending on the type of cells, the level of PRSS1 expression dictates the cytotoxicity of the branched peptide. Moreover, immunostaining and fluorescent imaging reveal that PRSS1 overexpresses on the ER of a high-grade serous ovarian cancer cell line (OVSAHO). The overexpression of PRSS1 renders the branched peptide to exhibit high selectivity against OVSAHO by the in situ formation of the peptide assemblies on the ER of OVSAHO cells, which causes ER stress and eventual cell death. This work, illustrating trypsin-guided EISA for inhibiting cancer cells by enzymatic reaction on ER for the first time, offers a new way to target the subcellular organelles of cancer cells for potential cancer therapy.
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PMID:Trypsin-Instructed Self-Assembly on Endoplasmic Reticulum for Selectively Inhibiting Cancer Cells: Dedicated to Professor George M. Whitesides on the occasion of his 80th birthday. 3234 47

Fossil evidence suggests that cetaceans evolved from artiodactylans. Thus, there was a major dietary change from herbivorous to carnivorous during their transition from a terrestrial to an aquatic environment. However, the molecular evolutionary mechanisms underlying this dietary switch have not been well investigated. Evidence of positive selection of digestive proteinases and lipases of cetaceans was detected: (1) For the four pancreatic proteinase families (carboxypeptidase, trypsin, chymotrypsin, and elastase) examined in this study, each family included only a single intact gene (e.g., CPA1, PRSS1, CTRC, and CELA3B) that had no ORF-disrupted or premature stop codons, whereas other members of each family had become pseudogenized. Further selective pressure analysis showed that three genes (PRSS1, CTRC, and CELA3B) were subjected to significant positive selection in cetaceans. (2) For digestive proteinases from the stomach, PGA was identified to be under positive selection. (3) Intense positive selection was also detected for the lipase gene PLRP2 in cetaceans. In addition, parallel /convergent amino acid substitutions between cetaceans and carnivores, two groups of mammals that have evolved similar feeding habits, were identified in 10 of the 12 functional genes. Although pseudogenization resulted in each family of pancreatic proteinases only retaining one intact gene copy in cetacean genomes, positive selection might have driven pancreatic proteinases, stomach proteinases, and lipases to adaptively evolve a stronger ability to digest a relatively higher proportion of proteins and lipids from animal foods. This study can provide some novel insights into the molecular mechanism of cetacean dietary changes during their transition from land to sea.
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PMID:Insights into Dietary Switch in Cetaceans: Evidence from Molecular Evolution of Proteinases and Lipases. 3245 5


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