Epoxyeicosatrienoic acids (EETs), the metabolites of arachidonic acid derived from the cytochrome P450 (CYP450) epoxygenases, are mainly metabolized by soluble epoxide hydrolase (sEH) to their corresponding diols. EETs, but not their diols, have anti-inflammatory properties, and inhibition of sEH might provide protective effects against inflammatory fibrosis. In this study, we tested the effects of a selected sEH inhibitor, 1-trifluoromethoxyphenyl-3- (1-propionylpiperidin-4-yl) urea (TPPU), on bleomycin-induced pulmonary fibrosis (PF) in mice. A mouse model of PF was established by intratracheal injection of bleomycin, and TPPU was administered for 21 days after bleomycin injection. We found TPPU treatment improved the body weight loss and survival rate of bleomycin-stimulated mice. Histological examinations showed that TPPU treatment alleviated bleomycin-induced inflammation, and maintained alveolar structure of pulmonary tissues. TPPU also decreased bleomycin-induced deposition of collagen, and expression of the procollagen I mRNA in lung tissues of mice. TPPU decreased the TGF-β1, IL-1β and IL-6 levels in serum of bleomycin-stimulated mice. Moreover, TPPU inhibited proliferation, collagen synthesis of the mouse fibroblasts, and partially reversed TGF-β1-induced α-SMA expression. Our results indicated that inhibition of sEH attenuates bleomycin-induced inflammation, collagen deposition, and therefore prevents bleomycin-induced PF in mice model.
Chitinases
not only play vital roles in the human innate immune
system but are also essential for the development of pathogenic fungi
and pests. Chitinase inhibitors are efficient tools to investigate
the elusive role of human chitinases and to control pathogens and
pests. Via hierarchical virtual screening, we have discovered a series
of chitinase inhibitors with a novel scaffold that have high inhibitory
activities and selectivities against human and insect chitinases.
The most potent human chitotriosidase inhibitor, compound 40, exhibited a K
i of 49 nM, and the most
potent inhibitor of the insect pest chitinase OfChi-h,
compound 53, exhibited a K
i of 9 nM. The binding of these two most potent inhibitors was confirmed
by X-ray crystallography. In a murine model of bleomycin-induced pulmonary
fibrosis, compound 40 was found to suppress the chitotriosidase
activity by 60%, leading to a significant increase in inflammatory
cells and suggesting that chitotriosidase played a protective role.
Chitinases play important roles in pathogen invasion, arthropod molting, plant defense, and human inflammation. Inhibition of the activity of a typical chitinase by small molecules is of significance in drug development and biological research. On the basis of a recent reported crystal structure of OfChtI, the insect chitinase derived from the pest Ostrinia furnacalis, we computationally identified 17 compounds from a library of over 4 million chemicals by two rounds virtual screening. Among these, three compounds from one chemical class inhibited the activity of OfChtI with single-digit-micromolar IC values, and one compound from another chemical class exhibited a broad inhibitory activity not only toward OfChtI but also toward bacterial, fungal, and human chitinases. A new scaffold was discovered, and a structure-inhibitory activity relationship was proposed. This work may provide a novel starting point for the development of specific or broad-spectrum chitinase inhibitors.
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