St. John’s wort extract and hyperforin inhibit multiple phosphorylation steps of cytokine signaling and prevent inflammatory and apoptotic gene induction in pancreatic β cells

Persistence of STAT-1 inhibition and induction of cytokine resistance in pancreatic β cells treated with St John's wort and its component hyperforin

“…We have evidence from previous work that the inhibitory effect of SJW and HPF on cytokine‐induced STAT‐1 activation is due to the prevention of STAT‐1 phosphorylation in both tyrosine‐701 and serine‐727 residue. The former is responsible for STAT‐1 dimer formation with subsequent nuclear transfer and DNA binding and the latter for improvement of its transcriptional efficiency .…”

“…The former is responsible for STAT-1 dimer formation with subsequent nuclear transfer and DNA binding [7] and the latter for improvement of its transcriptional efficiency. [19] We have hypothesized that intracellular availability of HPF after pre-exposure of b cells to either SJW extract or HPF itself may favour its direct and probably prolonged interaction with STAT-1 phosphorylation sites, making them unavailable for cytokine signals, [28] similarly to what has been reported for other plant extracts, like natural and synthetic catechins tightly interacting with STAT-1 [29] or the flavonoids myricetin and delphinidin. [23] As STAT-1 phosphorylation is an early event, already occurring 10-20 min after cytokine treatment, [28] yet long lasting, [14] it is more difficult to explain why SJW extract and in particular HPF may counteract STAT-1 DNA binding when added after cytokine treatment, at time intervals ranging from 15 to 90 min, although with a progressively decreasing efficiency.…”

“…We have hypothesized that intracellular availability of HPF after pre‐exposure of β cells to either SJW extract or HPF itself may favour its direct and probably prolonged interaction with STAT‐1 phosphorylation sites, making them unavailable for cytokine signals, similarly to what has been reported for other plant extracts, like natural and synthetic catechins tightly interacting with STAT‐1 or the flavonoids myricetin and delphinidin . As STAT‐1 phosphorylation is an early event, already occurring 10–20 min after cytokine treatment, yet long lasting, it is more difficult to explain why SJW extract and in particular HPF may counteract STAT‐1 DNA binding when added after cytokine treatment, at time intervals ranging from 15 to 90 min, although with a progressively decreasing efficiency. One reason is probably related to the fact that as soon as they are added, SJW and HPF limit the ongoing progressive effect of cytokines, but it can also be suggested that they might act by different mechanisms, such as reversal of STAT‐1 phosphorylation by activation of a nuclear tyrosine phosphatase or other phosphatases .…”

“…[32] With regard to the late harmful consequences of the activation of cytokine signalling in b cells and the protection afforded by SJW and HPF, in this study, we extended to 24 h the exposure period of INS-1E cells to cytokines in the presence of such compounds, before monitoring a number of paradigmatic events (insulin secretion, apoptosis, expression of key target genes), previously explored at earlier times. [8,28] Preservation of glucose-stimulated insulin release and prevention of apoptosis were similarly achieved in the presence of either SJW or HPF. However, at 24 h, SJW extract was more effective than HPF in antagonizing cytokine effects on functional, regulatory, anti-and proapoptotic genes.…”

Potentially Beneficial Effects of St. John’s Wort (Hypericum perforatum) in Patients with Metabolic Syndrome

“…Koeberle et al also indicated that hyperforin suppressed production of PGE2 by inhibiting PGE2 synthase-1, which is the major PGE2 synthase present under pathologic conditions related to inflammation and cancer [50] in vivo [27]. Furthermore, hyperforin inhibited activation of NF-κB in various types of cells both in vivo and in vitro, affording effective protection against inflammatory damage or tumor growth [51][52][53]. Hyperforin also inhibited 5-lipoxygenase, which catalyzes the formation of pro-inflammatory lipid mediators known as leukotrienes in vitro and in vivo [24,25].…”