P-gp expression inhibition mediates placental glucocorticoid barrier opening and fetal weight loss

Background Prenatal adverse environments can cause fetal intrauterine growth retardation (IUGR) and higher susceptibility to multiple diseases after birth, related to multi-organ development programming changes mediated by intrauterine overexposure to maternal glucocorticoids. As a glucocorticoid barrier, P-glycoprotein (P-gp) is highly expressed in placental syncytiotrophoblasts; however, the effect of P-gp on the occurrence of IUGR remains unclear. Methods Human placenta and fetal cord blood samples of IUGR fetuses were collected, and the related indexes were detected. Pregnant Wistar rats were administered with 30 mg/kg·d (low dose) and 120 mg/kg·d (high dose) caffeine from gestational day (GD) 9 to 20 to construct the rat IUGR model. Pregnant mice were administered with caffeine (120 mg/kg·d) separately or combined with sodium ferulate (50 mg/kg·d) from gestational day GD 9 to 18 to confirm the intervention target on fetal weight loss caused by prenatal caffeine exposure (PCE). The fetal serum/placental corticosterone level, placental P-gp expression, and related indicator changes were analyzed. In vitro, primary human trophoblasts and BeWo cells were used to confirm the effect of caffeine on P-gp and its mechanism. Results The placental P-gp expression was significantly reduced, but the umbilical cord blood cortisol level was increased in clinical samples of the IUGR neonates, which were positively and negatively correlated with the neonatal birth weight, respectively. Meanwhile, in the PCE-induced IUGR rat model, the placental P-gp expression of IUGR rats was decreased while the corticosterone levels of the placentas/fetal blood were increased, which were positively and negatively correlated with the decreased placental/fetal weights, respectively. Combined with the PCE-induced IUGR rat model, in vitro caffeine-treated placental trophoblasts, we confirmed that caffeine decreased the histone acetylation and expression of P-gp via RYR/JNK/YB-1/P300 pathway, which inhibited placental and fetal development. We further demonstrated that P-gp inducer sodium ferulate could reverse the inhibitory effect of caffeine on the fetal body/placental weight. Finally, clinical specimens and other animal models of IUGR also confirmed that the JNK/YB-1 pathway is a co-regulatory mechanism of P-gp expression inhibition, among which the expression of YB-1 is the most stable. Therefore, we proposed that YB-1 could be used as the potential early warning target for the opening of the placental glucocorticoid barrier, the occurrence of IUGR, and the susceptibility of a variety of diseases. Conclusions This study, for the first time, clarified the critical role and epigenetic regulation mechanism of P-gp in mediating the opening mechanism of the placental glucocorticoid barrier, providing a novel idea for exploring the early warning, prevention, and treatment strategies of IUGR.

Renal protective effect of sodium ferulate on pulmonary hypertension patients undergoing computed tomography pulmonary angiography

This study aimed to explore the correlation of sodium ferulate and the renal protective effect on computed tomography pulmonary angiography in patients suffering from pulmonary hypertension. This prospective study enrolled 92 consecutive patients with pulmonary hypertension diagnosed by echocardiography, and all included patients underwent computed tomography pulmonary angiography after admission. The participants were randomized, divided into sodium ferulate group ( n = 49) and control group ( n = 43), of which patients in the sodium ferulate group received intravenous sodium ferulate 3.0 g per day from 12 h before computed tomography pulmonary angiography examination to 72 h after that, and patients in the control group were provided with routine treatment. Renal function was assessed by measuring serum creatinine, estimated glomerular filtration rate, Cystatin-C as well as 24 h, 48 h, and 72 h after computed tomography pulmonary angiography, followed by the calculation of the incidence of contrast-induced nephropathy for contrast-induced nephropathy and non-contrast-induced nephropathy grouping. Besides, renal resistive index was determined via Doppler ultrasound examination before, after 1 h and 24 h after computed tomography pulmonary angiography. There were no significant differences between the two groups in serum creatinine at baseline and 24 h after computed tomography pulmonary angiography ( P > 0.05, respectively), but at 48 h and 72 h, it was lower in the sodium ferulate group ( P < 0.05). There were no significant differences of estimated glomerular filtration rate between the two groups ( P > 0.05). The level of Cystatin-C at 48 h and 72 h after computed tomography pulmonary angiography was lower than in the sodium ferulate group ( P < 0.05). Contrast-induced nephropathy was identified in nine patients (9.78%). Sodium ferulate was associated with a decline in the incidence of contrast-induced nephropathy (4.08 vs. 16.28 %, P < 0.05). Compared to patients with contrast-induced nephropathy, lower renal resistive index were observed at 1 h and 24 h after computed tomography pulmonary angiography in patients without contrast-induced nephropathy ( P < 0.05). Infusion of sodium ferulate before and after computed tomography pulmonary angiography was associated with a decline in incidence of contrast-induced nephropathy.

Influence of sodium ferulate on miR-133a and left ventricle remodeling in rats with myocardial infarction

To explore the influence of sodium ferulate (SF) on miR-133a and left ventricle remodeling (LVR) in rats with myocardial infarction (MI). The left coronary artery was ligated to create 36 ischemia-reperfusion (IR) rat models that were randomly divided into mock surgical group (MSG) (not ligated), model group (MG), and sodium ferulate group (SFG). After the successful modeling, SFG was intravenously injected with SF at the dose of 10 mg/kg, and the other two groups were injected with the same volume of normal saline. After 28 days, cardiac hemodynamic indices of all groups were measured; the myocardial infarction size (MIS), left ventricular mass index (LVMI), and collagen volume fraction (CVF) were calculated, the content of serum malondialdehyde (MDA) and activities of catalase (CAT), superoxide dismutase (SOD) and glutathione catalase (GSH-px) were detected by ELISA, and miR-133a expression in myocardial tissues of the left ventricle (LV) was detected by RT-qPCR. SF improved the cardiac hemodynamic indices of rat model and reduced the MIS, LVMI and CVF. SF decreased the serum MDA level and increased the serum CAT, SOD and GSH-px levels in rat model. SF increased the expression of miR-133a in myocardial tissue of rat model. Therefore, SF could effectively reduce the myocardial injury of IR rats and improve the LVR. Its mechanism may be related to the antioxygenation and upregulation of miR-133a.

A versatile genetic control system in mammalian cells and mice responsive to clinically licensed sodium ferulate

Dynamically adjustable gene- and cell-based therapies are recognized as next-generation medicine. However, the translation of precision therapies into clinics is limited by lack of specific switches controlled by inducers that are safe and ready for clinical use. Ferulic acid (FA) is a phytochemical with a wide range of therapeutic effects, and its salt sodium ferulate (SF) is used as an antithrombotic drug in clinics. Here, we describe an FA/SF-adjustable transcriptional switch controlled by the clinically licensed drug SF. We demonstrated that SF-responsive switches can be engineered to control CRISPR-Cas9 systems for on-command genome/epigenome engineering. In addition, we integrated FA-controlled switches into programmable biocomputers to process logic operations. We further demonstrated the dose-dependent SF-inducible transgene expression in mice by oral administration of SF tablets. Engineered switches responsive to small-molecule clinically licensed drugs to achieve adjustable transgene expression profiles provide new opportunities for dynamic interventions in gene- and cell-based precision medicine.

Effects of Sodium Ferulate on Cognitive Function in Hippocampus of Chronic Cerebral Hypoperfusion Rats

Objective: To assess sodium ferulate’s effect on cognitive function and p38MAPK signaling in hippocampus of rats with chronic cerebral hypoperfusion (CCH). Methods: 45 male Sprague-Dawley (SD) rats were separated into sham-operation group, CCH model group and treatment group (intraperitoneal injection of 50 mg/kg sodium ferulate). The cognitive function was detected via open-field test, novel object recognition test and Morris water maze test. The activity of superoxide dismutase (SOD) in hippocampal tissues was detected using ELISA kit. Moreover, the neuronal damage in hippocampal tissues was assessed by immunohistochemical method, and apoptosis was assessed via TUNEL staining. Finally, p-p38MAPK signaling protein level in hippocampal tissues was detected via Western blotting. Results: No difference was found in rat autonomic activity among three groups (P > 0.05). The novel object recognition ability of model rats was significantly impaired along with longer escape latency and shorter retention time in the target quadrant (P < 0.01), which were all improved after sodium ferulate treatment (P < 0.01). SOD activity in hippocampal tissues in model rats was significantly reduced and sodium ferulate could significantly increase SOD activity (P < 0.01). There were a large number of damaged neurons and apoptotic cells in hippocampal tissues in model group and sodium ferulate could protect neurons (P < 0.01). The levels of p-p38MAPK, GSP3β and P-tau protein in hippocampal tissues in model group were significantly increased, which were significantly reduced after treatment with sodium ferulate (P < 0.01). Conclusion: Sodium ferulate can protect the CCH-induced cognitive impairment in rats and reduce the CCH-induced damage and apoptosis of hippocampal neurons, possibly through inhibition of p38MAPK signaling pathway.