Effect of Silibinin in Reducing Inflammatory Pathways in In Vitro and In Vivo Models of Infection-Induced Preterm Birth

Abstract

Infection-induced preterm birth is the largest cause of infant death and of neurological disabilities in survivors. Silibinin, from milk thistle, exerts potent anti-inflammatory activities in non-gestational tissues. The aims of this study were to determine the effect of silibinin on pro-inflammatory mediators in (i) human fetal membranes and myometrium treated with bacterial endotoxin lipopolysaccharide (LPS) or the pro-inflammatory cytokine IL-1β, and (ii) in preterm fetal membranes with active infection. The effect of silibinin on infection induced inflammation and brain injury in pregnant mice was also assessed. Fetal membranes and myometrium (tissue explants and primary cells) were treated with 200 μM silibinin in the presence or absence of 10 μg/ml LPS or 1 ng/ml IL-1β. C57BL/6 mice were injected with 70 mg/kg silibinin with or without 50 μg LPS on embryonic day 16. Fetal brains were collected after 6 h. In human fetal membranes, silibinin significantly decreased LPS-stimulated expression of IL-6 and IL-8, COX-2, and prostaglandins PGE2 and PGF2α. In primary amnion and myometrial cells, silibinin also decreased IL-1β-induced MMP-9 expression. Preterm fetal membranes with active infection treated with silibinin showed a decrease in IL-6, IL-8 and MMP-9 expression. Fetal brains from mice treated with silibinin showed a significant decrease in LPS-induced IL-8 and ninjurin, a marker of brain injury. Our study demonstrates that silibinin can reduce infection and inflammation-induced pro-labour mediators in human fetal membranes and myometrium. Excitingly, the in vivo results indicate a protective effect of silibinin on infection-induced brain injury in a mouse model of preterm birth.

Endoplasmic Reticulum Stress Is Increased after Spontaneous Labor in Human Fetal Membranes and Myometrium Where It Regulates the Expression of Prolabor Mediators1

“…LPS does not induce matrix metalloproteinase (MMP) 9 expression in fetal membranes [59]; thus, primary amnion cells were used to determine if the ER stress inhibitors decreased IL1B-induced MMP9 expression. Fresh amnion was obtained from women who delivered healthy, singleton infants at term (37-39 wk gestation) undergoing elective Cesarean section in the absence of labor (n ¼ 4 patients).…”

Silibinin attenuates methotrexate-induced pulmonary injury by targeting oxidative stress

“…The compound is known to exhibit antioxidative activity, which has been previously reported to result in a number of biologically protective effects, including anti-inflammatory, antitumor and hepatoprotective effects (10)(11)(12)(13). Silibinin has been demonstrated to be a potent antioxidant, supporting the capacity of cellular antioxidative agents, such as glutathione (GSH) and superoxide dismutase (SOD), to target reactive oxygen species.…”

“…Furthermore, silibinin has been widely investigated for anticancer efficacy in a broad range of cancer models. As a consequence of the general anticancer properties associated with flavonoids collectively, there has been significant interest in the possibility of using silibinin as a chemopreventive agent (11,15). Silibinin has been traditionally used in folk medicine, and acute and chronic doses of silibinin administration in animals and humans have resulted in no significant toxicity.…”

Spleen content of selected polyphenols, splenocytes morphology and function in mice fed Rhodiola kirilowii extracts during pregnancy and lactation

“…Polyphenol silibilin in pregnant mice with infection-induced inflammation exerted a protective effect on infection-induced brain injury in this model of preterm birth (Lim et al 2014).…”