Journal club 2016. 06. 17.

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Anti-pruritic effect of baicalin and its metabolites, baicalein and oroxylin A, in mice

Anti-pruritic effect of baicalin and its metabolites, baicalein and oroxylin A, in mice

Hien-trung TRINH1, Eun-ha JOH1, Ho-young KWAK2, Nam-in BAEK2, Dong-hyun KIM1, *
1Department of Pharmaceutical Science and Department of Life and Pharmaceutical Sciences, Kyung Hee University, 1, Hoegi, Dongdaemun-ku, Seoul 130–701, Korea; 2Graduate School of Biotechnology and PMRC, Kyung Hee University, 1, Seochunri, Suwon, Kyunggi-Do 449–701, Korea
Aim: To explore whether intestinal micro ora plays a role in anti-pruritic activity of baicalin, a main constituent of the rhizome of Scutellaria baicalensis (SB).
Methods: Baicalin was anaerobically incubated with human fecal micro ora, and its metabolites, baicalein and oroxylin A, were isolated. The inhibitory effect of baicalin and its metabolites was accessed in histamine- or compound 48/80-induced scratching behavior in mice.
Results: Baicalin was metabolized to baicalein and oroxylin A, with metabolic activities of 40.2±26.2 and 1.2±1.1 nmol·h-1·mg-1 wet weight of human fecal micro ora, respectively. Baicalin (20, 50 mg/kg) showed more potent inhibitory effect on histamine-induced scratching behavior when orally administered than intraperitoneally. In contrast, baicalein and oroxylin A had more potent inhibitory effect when the intraperitoneally administered. The anti-scratching behavior activity of oral baicalin and its metabolites was in proportion to their inhibition on histamine-induced increase of vascular permeability with oroxylin A more potent than baicalein and baicalin. In Magnus test using guinea pig ileum, oroxylin A is more potent than baicalein and baicalin in inhibition of histamine-induced contraction. The anti-scratching behavioral effect of oral baicalin was signi cantly reduced when oral antibiotics were simultaneously administered, whereas the effect of baicalein and oroxylin A were not affected.
Conclusion: Oral baicalin may be metabolized by intestinal micro ora into baicalein and oroxylin A, which ameliorate pruritic reactions through anti-histamine action.
Keywords: Scutellaria baicalensis; baicalin; baicalein; oroxylin A; scratching behavior; metabolism; histamine Acta Pharmacologica Sinica (2010) 31: 718–724; doi: 10.1038/aps.2010.42; published online 10 May 2010

2016.06.10

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Cathepsin L in secretory vesicles functions as a prohormone-processing enzyme for production of the enkephalin peptide neurotransmitter.

Yasothornsrikul S1, Greenbaum D, Medzihradszky KF, Toneff T, Bundey R, Miller R, Schilling B, Petermann I, Dehnert J, Logvinova A, Goldsmith P, Neveu JM, Lane WS, Gibson B, Reinheckel T, Peters C, Bogyo M, Hook V.

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Abstract

Multistep proteolytic mechanisms are essential for converting proprotein precursors into active peptide neurotransmitters and hormones. Cysteine proteases have been implicated in the processing of proenkephalin and other neuropeptide precursors. Although the papain family of cysteine proteases has been considered the primary proteases of the lysosomal degradation pathway, more recent studies indicate that functions of these enzymes are linked to specific biological processes. However, few protein substrates have been described for members of this family. We show here that secretory vesicle cathepsin L is the responsible cysteine protease of chromaffin granules for converting proenkephalin to the active enkephalin peptide neurotransmitter. The cysteine protease activity was identified as cathepsin L by affinity labeling with an activity-based probe for cysteine proteases followed by mass spectrometry for peptide sequencing. Production of [Met]enkephalin by cathepsin L occurred by proteolytic processing at dibasic and monobasic prohormone-processing sites. Cellular studies showed the colocalization of cathepsin L with [Met]enkephalin in secretory vesicles of neuroendocrine chromaffin cells by immunofluorescent confocal and immunoelectron microscopy. Functional localization of cathepsin L to the regulated secretory pathway was demonstrated by its cosecretion with [Met]enkephalin. Finally, in cathepsin L gene knockout mice, [Met]enkephalin levels in brain were reduced significantly; this occurred with an increase in the relative amounts of enkephalin precursor. These findings indicate a previously uncharacterized biological role for secretory vesicle cathepsin L in the production of [Met]enkephalin, an endogenous peptide neurotransmitter.

Cathepsin L in secretory vesicles functions as a prohormone-processing enzyme for production of the enkephalin peptide neurotransmitter.

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