In professional immune cells, Toll-like receptor 4 (TLR4) induces tightly regulated inflammatory response to avoid tissue damage via the induction of "endotoxin tolerance", which is a transient state of cell desensitization in response to lipopolysaccharide (LPS) restimulation after a prior LPS exposure. However, in endothelial cells, the regulation of TLR4-induced inflammation is not fully understood. In this study, we found that the gene transcripts for a lot of Toll-like receptors were expressed in various endothelial cells, including human umbilical vein endothelial cells (HUVEC), human aortic endothelial cell (HAEC), and mouse microvascular endothelial cells (bEND.3). Proteins of TLR4 and its coreceptor CD14 were also detected in HUVEC. LPS treatment significantly upregulated the expression of proinflammation cytokines such as IL-1β, IL-6, and IL-8 only in HUVEC, but not in HAEC and bEND.3, suggesting that vein endothelial cells are important source of proinflammatory cytokines in response to LPS. Unexpectedly, "endotoxin tolerance" was not induced in endothelial cell, but was induced in control glial cells, as LPS pretreatment downregulated the cytokine expression in control glial cells, but did not in endothelial cells, when the cells were restimulated with LPS. The upregulation of cytokine gene expression was dependent on NF-κB signaling, and NF-κB inhibitor repressed the induction of cytokines. Two important signal molecules MyD88 and TRIF, which are TLR4 downstream and NF-κB upstream, were upregulated in vein endothelial cells but were downregulated in control glial cells. These results suggested that vein endothelial cells may play important roles in the pathophysiology of systemic inflammation-associated diseases such as sepsis and septic cardiomyopathy.

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Preterm birth continues to be an important problem in modern obstetrics and a large public health concern and is related to increased risk for neonatal morbidity and mortality. The aim of this study was to evaluate the data in the literature to determine the relationships between mode of delivery (cesarean section and vaginal birth) in the first pregnancy and the risk of subsequent preterm birth from a multi-year population based cohorts (PROSPERO registration number: 42018090788). Five electronic databases were searched. Observational studies that provided mode of delivery and subsequent preterm birth were eligible. Ten cohort studies, involving 10333501 women, were included in this study. Compared with vaginal delivery, women delivering by previous cesarean section had a significantly higher risk of preterm birth in subsequent births (RR 1.10, 95%CI 1.01–1.20). After adjusting confounding factors, there was still statistical significance (aRR 1.12, 95%CI 1.01–1.24). However, both before and after adjustment, there was no difference among very preterm birth (RR 1.14, 95%CI 0.90–1.43; aRR 1.16, 95%CI 0.80–1.68; respectively). To the best of our knowledge, this is the first systematic review and meta-analysis that suggests previous cesarean section could increase the risk of preterm birth in subsequent pregnancies. The result could provide policy makers, clinicians, and expectant parents to reduce the occurrence of unnecessary cesarean section.

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Cardiac hypertrophy is a major determinant of heart failure. The epidermal growth factor receptor (EGFR) plays an important role in cardiac hypertrophy. Since silibinin suppresses EGFR in vitro and in vivo, we hypothesized that silibinin would attenuate cardiac hypertrophy through disrupting EGFR signaling. In this study, we examined this hypothesis using neonatal cardiac myocytes and fibroblasts induced by angiotensin II (Ang II) and animal model by aortic banding (AB) mice. Our data revealed that silibinin obviously blocked cardiac hypertrophic responses induced by pressure overload. Meanwhile, silibinin markedly reduced the increased generation of EGFR. Moreover, these beneficial effects were associated with attenuation of the EGFR-dependent ERK1/2, PI3K/Akt signaling cascade. We further demonstrated silibinin decreased inflammation and fibrosis by blocking the activation of NF-kappaB and TGF-beta1/Smad signaling pathways in vitro and in vivo. Our results indicate that silibinin has the potential to protect against cardiac hypertrophy, inflammation, and fibrosis through blocking EGFR activity and EGFR-dependent different intracellular signaling pathways.