Verbascoside-Rich Abeliophyllum distichum Nakai Leaf Extracts Prevent LPS-Induced Preterm Birth Through Inhibiting the Expression of Proinflammatory Cytokines from Macrophages and the Cell Death of Trophoblasts Induced by TNF-α

Abstract

Background: Preterm birth is a known leading cause of neonatal mortality and morbidity. The underlying causes of pregnancy-associated complications are numerous, but infection and inflammation are the essential high-risk factors. However, there are no safe and effective preventive drugs that can be applied to pregnant women. Objective: The objectives of the study were to investigate a natural product, Abeliophyllum distichum leaf (ADL) extract, to examine the possibility of preventing preterm birth caused by inflammation. Methods: We used a mouse preterm birth model by intraperitoneally injecting lipopolysaccharides (LPS). ELISA, Western blot, real-time PCR and immunofluorescence staining analyses were performed to confirm the anti-inflammatory efficacy and related mechanisms of the ADL extracts. Cytotoxicity and cell death were measured using Cell Counting Kit-8 (CCK-8) analysis and flow cytometer. Results: A daily administration of ADL extract significantly reduced preterm birth, fetal loss, and fetal growth restriction after an intraperitoneal injection of LPS in mice. The ADL extract prevented the LPS-induced expression of TNF-α in maternal serum and amniotic fluid and attenuated the LPS-induced upregulation of placental proinflammatory genes, including IL-1β, IL-6, IL-12p40, and TNF-α and the chemokine gene CXCL-1, CCL-2, CCL3, and CCL-4. LPS-treated THP-1 cell-conditioned medium accelerated trophoblast cell death, and TNF-α played an essential role in this effect. The ADL extract reduced LPS-treated THP-1 cell-conditioned medium-induced trophoblast cell death by inhibiting MAPKs and the NF-κB pathway in macrophages. ADL extract prevented exogenous TNF-α-induced increased trophoblast cell death and decreased cell viability. Conclusions: We have demonstrated that the inhibition of LPS-induced inflammation by ADL extract can prevent preterm birth, fetal loss, and fetal growth restriction.

Puerarin attenuates preeclampsia‐induced trophoblast mobility loss and inflammation by modulating miR‐181b‐5p/RBAK axis

“…Human villous trophoblast HTR‐8/SVneo was purchased from Procell (China) and cultured routinely in RPMI 1640 medium (Nacalai Tesque, Kyoto, Japan) containing 5% fetal bovine serum (FBS) (Sigma‐Aldrich) at 37˚C in an atmosphere consisting of 5% CO 2 and 95% air. To induce disorders and explore miRs responding to Pue treatment in dys‐functioned trophoblasts, the cells were firstly exposed to 1 μg/mL TNF‐α for 72 h 23 and then treated with 50 μg/mL Pue (purity > 98%, Sigma‐Aldrich, St. Louis, USA) for 24 h (concentration selected based on data in Figure S1). To determine miRs expression levels under Pue treatment, the cells after Pue treatment were collected, and total RNA in cells treated with TNF‐α alone or with Pue together was extracted using Trizol method.…”

“…The effects of Pue on trophoblasts further confirmed its antagonizing function against PE development. Based on the study performed by Kim et al, the inflammatory responses associated with PE were the major factor impairing the mobility of trophoblasts 23.…”

Ameliorative effect ofAbeliophyllum distichumNakai on benign prostatic hyperplasiain vitroandin vivo

“…The PI3K/AKT pathway is expressed by growth factors that determine cell proliferation and apoptosis. In addition, the extract of A. distichum also suppresses overexpressed PI3K/AKT, thereby controlling cell death and cell proliferation [ 31 ]. BPH develops due to the indiscriminate proliferation of stromal cells and epithelial cells caused by AR signaling [ 46 ].…”

“…'s study [ 25 ], the LD50 value was judged to be more than 2,000 mg/kg because A. distichum leaves did not show genotoxicity in mice. In a recently reported study, A. distichum has showed efficacy in anti-osteoporosis [ 27 ], anti-colorectal cancer [ 28 ], anti-melanoma [ 29 ], anti-DNA damage related oxidative stress [ 30 ], anti-inflammatory [ 31 ] and anti-obesity [ 32 ]. On the other hand, no research results have been reported on BPH using A. distichum .…”

CCL2: An important cytokine in normal and pathological pregnancies: A review

“…The knockdown of GPR91 had effect on the reduction of IL1b-mediated rather than TNF-mediated CCL2 mRNA expression and secretion, which might attribute to their recruitment of different messengers to regulate downstream genes (149). Other experiments focusing on the therapy of PTL mainly acted on different targets but ended up with NF-kB signal pathway to decrease the secretion of CCL2 (150)(151)(152). Therefore, CCL2 seems to make a difference in terminal inflammatory pathway and it is worth intensive studying how CCL2 exerts its function (153).…”