In vitro studies of antifibrotic and cytoprotective effects elicited by proto-berberine alkaloids in human dermal fibroblasts.
BACKGROUND
The pathogenic mechanisms of skin fibrosis are still not completely understood, unlike the profibrotic role played by inflammatory cytokines and transforming growth factor-β1 (TGF-β1). Few antifibrotic drugs are available. Nevertheless, folk medicine suggests numerous treatments of fibrotic conditions. Based on information from folk medicine and literature, the hypothesis was made that proto-berberine alkaloids could act as antifibrotic and cytoprotective agents.


METHODS
The effects of berberine, dihydroberberine, canadine, stylopine, and coptisine were investigated on an in vitro model of fibrosis purposely set up. The study is based on the use of human dermal fibroblasts (HDF). The ability of the proto-berberine alkaloids investigated to modulate mitochondrial dehydrogenase activity, cell proliferation, collagen production, and inflammatory cytokine (IL-1β and IL-6) production was tested on HDF cells grown under standard growth conditions, in the presence of 100 μM H(2)O(2), simulating oxidative stress conditions, and in the presence of 34 ng/ml TGF-β1, simulating fibrotic conditions. Antiradical activity was assayed as well, as it could contribute to cytoprotection.


RESULTS
Each alkaloid tested showed peculiar effects on HDF. In particular, all of the alkaloids tested, with the exception of coptisine, inhibited TGF-β1-induced collagen production.


CONCLUSIONS
Due to its irritant effects and the lack of desired properties, coptisine has low exploitation potentialities. The other proto-berberine alkaloids investigated resulted all endowed with activities for which they can be exploited as antifibrotic and cytoprotective agents. Stylopine globally proved to be the most promising compound, being endowed with revitalizing, anti-inflammatory, antifibrotic and wound-healing promoting activities, and showing no toxic effects.
Alidans S.r.l., San Giuliano Terme, Pisa, Italy. Electronic address: pietra@alidans.com.
Daniele
D
Pietra
Alidans S.r.l., San Giuliano Terme, Pisa, Italy.
Alice
A
Borghini
Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali (INSTM), Firenze, Italy.
Anna Maria
AM
Bianucci
D001599:Berberine / Q000031:analogs & derivatives / Q000494:pharmacology*; D001600:Berberine Alkaloids / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects*; D005355:Fibrosis / Q000517:prevention & control*; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors
D001600:Berberine Alkaloids; D005609:Free Radicals; D053583:Interleukin-1beta; D015850:Interleukin-6; D020011:Protective Agents; D053773:Transforming Growth Factor beta1; C034384:coptisine; D001599:Berberine; C039639:dihydroberberine; D003094:Collagen; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; C014212:stylopine; C004645:canadine
Anti-inflammatory agents; Antifibrotic agents; Antioxidant activity; Antiradical activity; Berberine analogs