Protective effects of St. John's wort extract and its component hyperforin against cytokine-induced cytotoxicity in a pancreatic beta-cell line.
In both type 1 and type 2 diabetes, increased production of cytokines on autoimmune or metabolic basis is supposed to trigger an inflammatory process leading to dysfunction and death of pancreatic beta-cells. Therefore, anti-inflammatory pharmacological approaches aimed at blocking cytokine signalling pathways and consequent cytotoxicity in beta-cells are highly advisable. Based on previous evidence of cytokine antagonistic effects in other cell types, we explored the protective action of Hypericum perforatum (St-John's-wort) extract and its component hyperforin against cytokine-induced functional impairment and apoptosis in the INS-1E beta-cell line, searching for the underlying mechanisms. The results showed that either St-John's-wort extract or hyperforin (at 1-3 microM) prevented cytokine-induced impairment in glucose-stimulated insulin secretion and protected cells against apoptosis in a dose-dependent fashion. Inducible-NO-synthase expression was also potently hindered by the vegetal compounds. Interestingly, cytokine-induced activations of the signal-transducer-and-activator-of-transcription-1 (STAT-1) and the nuclear-factor-kappaB (NF-kappaB) were both down-regulated by SJW extract or HPF (range 0.5-5 microM) when evaluated by electrophoretic-mobility-shift-assay. Other transcription factors (CBF-1, SP-1) were unaffected. Components of SJW extract other than HPF were much less effective in down-regulating cytokine signalling. Significantly, inhibition of cytokine-elicited STAT-1 and NF-kappaB activation was confirmed in isolated rat and human islets incubated in the presence of these vegetal compounds. In conclusion, St-John's-wort extract and hyperforin are non-peptidyl compounds which, at low concentrations, target key mechanisms of cytokine-induced beta-cell injury, thereby improving beta-cell function and survival. Thus, they are potentially valuable for the prevention or limitation of beta-cell loss in diabetes.
Menegazzi
Marta
M
Dipartimento di Scienze Morfologiche e Biomediche, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy.
Novelli
Michela
M
Beffy
Pascale
P
D'Aleo
Valentina
V
Tedeschi
Elisa
E
Lupi
Roberto
R
Zoratti
Elisa
E
Marchetti
Piero
P
Suzuki
Hisanori
H
Masiello
Pellegrino
P
D000818:Animals; D000873:Anthracenes; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D020902:Hypericum / Q000737:chemistry*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010569:Perylene / Q000031:analogs & derivatives / Q000494:pharmacology; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors; D013729:Terpenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000873:Anthracenes; D000970:Antineoplastic Agents; D001643:Bridged Bicyclo Compounds; D007328:Insulin; D053583:Interleukin-1beta; D016328:NF-kappa B; D010936:Plant Extracts; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D013729:Terpenes; D014409:Tumor Necrosis Factor-alpha; D010569:Perylene; C004965:hypericin; D007371:Interferon-gamma; D010696:Phloroglucinol; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C001654:hyperforin