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Objective: This study aims to develop physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) predictive models for nifedipine in pregnant women, enhancing precision medicine and reducing adverse reactions for both mothers and infants. Methods: A PBPK/PD model was constructed using PK-Sim, MoBi, and MATLAB software, integrating literature and pregnancy-specific physiological information. The process involved: (1) establishing and validating a PBPK model for serum clearance after intravenous administration in non-pregnant individuals, (2) establishing and validating a PBPK model for serum clearance after oral administration in non-pregnant individuals, (3) constructing and validating a PBPK model for enzyme clearance after oral administration in non-pregnant individuals, and (4) adjusting the PBPK model structure and enzyme parameters according to pregnant women and validating it in oral administration. (5) PK/PD model was explored through MATLAB, and the PBPK and PK/PD models were integrated to form the PBPK/PD model. Results: The Nifedipine PBPK model's predictive accuracy was confirmed by non-pregnant and pregnant validation studies. The developed PBPK/PD model accurately predicted maximum antihypertensive effects for clinical doses of 5, 10, and 20 mg. The model suggested peak effect at 0.86 h post-administration, achieving blood pressure reductions of 5.4 mmHg, 14.3 mmHg, and 21.3 mmHg, respectively. This model provides guidance for tailored dosing in pregnancy-induced hypertension based on targeted blood pressure reduction. Conclusion: Based on available literature data, the PBPK/PD model of Nifedipine in pregnancy demonstrated good predictive performance. It will help optimize individualized dosing of Nifedipine, improve treatment outcomes, and minimize the risk of adverse reactions in mothers and infants. [ABSTRACT FROM AUTHOR]

Aberrant remodeling of uterine spiral arteries (SPA) is strongly associated with the pathogenesis of early-onset preeclampsia (EOPE). However, the complexities of SPA transformation remain inadequately understood. We conducted a single-cell RNA sequencing analysis of whole placental tissues derived from patients with EOPE and their corresponding controls, identified DAB2 as a key gene of interest and explored the mechanism underlying the communication between Extravillous trophoblast cells (EVTs) and decidual vascular smooth muscle cells (dVSMC) through cell models and a placenta-decidua coculture (PDC) model in vitro. DAB2 enhanced the motility and viability of HTR-8/SVneo cells. After exposure to conditioned medium (CM) from HTR-8/SVneoshNC cells, hVSMCs exhibited a rounded morphology, indicative of dedifferentiation, while CM-HTR-8/SVneoshDAB2 cells displayed a spindle-like morphology. Furthermore, the PDC model demonstrated that CM-HTR-8/SVneoshDAB2 was less conducive to vascular remodeling. Further in-depth mechanistic investigations revealed that C-X-C motif chemokine ligand 8 (CXCL8, also known as IL8) is a pivotal regulator governing the dedifferentiation of dVSMC. DAB2 expression in EVTs is critical for orchestrating the phenotypic transition and motility of dVSMC. These processes may be intricately linked to the CXCL8/PI3K/AKT pathway, underscoring its central role in intricate SPA remodeling. [ABSTRACT FROM AUTHOR]

Monitoring of skin scar thickness and structural properties is desirable when assessing the efficacy of the healing process. In this work, we report the use of single-sided, low-field nuclear magnetic resonance (NMR) for the analysis of the thickness and collagen structure of healthy and scarred skin. Acquisition of T2 relaxation profiles was proven to provide quantification of porcine skin thickness as accurate as standard histological techniques. Subsequent analysis of human participants highlighted the utility of this technique for identifying different types of scar and in identifying differences between the thickness of moderate hypertrophic scars and healthy skin. Using bead packings as a model system, determination of the surface-to-volume (S/V) ratio and tortuosity (k) was successfully measured on the single-sided apparatus based on time-resolved diffusion analysis. Application of this method to human skin was able to detect regional differences in collagen structures, consistent with qualitative expectations. It was also able to differentiate between healthy and scarred skin tissue. Preliminary results indicated that scarred tissue exhibited decreased S/V ratios and tortuosities, which is coherent with the formation of less-aligned collagen within scar tissue and indicated the potential for this technique to differentiate scar types. This novel application of single-sided low-field NMR has the potential to be deployed in clinical settings for the differentiation of scar types and for the assessment and monitoring of skin scarring and healing. [ABSTRACT FROM AUTHOR]

Background: Labetalol has an irreplaceable role in treating Hypertensive disorders of pregnancy (HDP), a common disease during pregnancy with a prevalence of 5.2–8.2%. However, there were big differences in dosage regimens between various guidelines. Purpose: A physiologically-based pharmacokinetics (PBPK) model was established and validated to evaluate the existing oral dosage regimens, and to compare the difference in plasma concentration between pregnant and non-pregnant women. Methods: First, non-pregnant woman models with specific plasma clearance or enzymatic metabolism (UGT1A1, UGT2B7, CYP2C19) were established and validated. For CYP2C19, slow, intermediate, and rapid metabolic phenotypes were considered. Then, a pregnant model with proper structure and parameters adjustment was established and validated against the multiple oral administration data. Results: The predicted labetalol exposure captured the experimental data well. The following simulations with criteria lowering 15 mmHg blood pressure (corresponding to around 108 ng/ml plasma labetalol) found that the maximum daily dosage in the Chinese guideline may be insufficient for some severe HDP patients. Moreover, similar predicted steady-state trough plasma concentration was found between the maximum daily dosage in the American College of Obstetricians and Gynecologists (ACOG) guideline, 800 mg Q8h and a regimen of 200 mg Q6h. Simulations comparing non-pregnant and pregnant women found that the difference in labetalol exposure highly depended on the CYP2C19 metabolic phenotype. Conclusions: In summary, this work initially established a PBPK model for multiple oral administration of labetalol for pregnant women. This PBPK model may lead to personalized labetalol medication in the future. [ABSTRACT FROM AUTHOR]

Decidualization of human endometrial stromal cells (hESCs) is essential for the maintenance of pregnancy, which depends on the fine-tuned regulation of hESCs survival, and its perturbation contributes to pregnancy loss. However, the underlying mechanisms responsible for functional deficits in decidua from recurrent spontaneous abortion (RSA) patients have not been elucidated. Here, we observed that JAZF1 was significantly downregulated in stromal cells from RSA decidua. JAZF1 depletion in hESCs resulted in defective decidualization and cell death through apoptosis. Further experiments uncovered G0S2 as a important driver of hESCs apoptosis and decidualization, whose transcription was repressed by JAZF1 via interaction with G0S2 activator Purβ. Moreover, the pattern of low JAZF1, high G0S2 and excessive apoptosis in decidua were consistently observed in RSA patients. Collectively, our findings demonstrate that JAZF1 governs hESCs survival and decidualization by repressing G0S2 transcription via restricting the activity of Purβ, and highlight the clinical implications of these mechanisms in the pathology of RSA. JAZF1 regulates human endometrial stromal cells survival and decidualization by restricting the activity of Purβ, which induces the expression of G0S2, a factor that is involved in the mitochondrial apoptotic pathway in recurrent spontaneous abortion. [ABSTRACT FROM AUTHOR]

Human uterine stromal cell undergoes decidualization for pregnancy establishment and maintenance, which involved extensive proliferation and differentiation. Increasing studies have suggested that recurrent spontaneous abortion (RSA) may result from defective endometrial stromal decidualization. However, the critical molecular mechanisms underlying impaired decidualization during RSA are still elusive. By using our recently published single-cell RNA sequencing (scRNA-seq) atlas, we found that MYC-associated factor X (MAX) was significantly downregulated in the stromal cells derived from decidual tissues of women with RSA, followed by verification with immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR). MAX knockdown significantly impairs human endometrial stromal cells (HESCs) proliferation as determined by MTS assay and Ki67 immunostaining, and decidualization determined by F-actin, and decidualization markers. RNA-seq together with chromatin immunoprecipitation sequencing (ChIP-seq) and cleavage under targets and release using nuclease sequencing (CUT&RUN-seq) analysis were applied to explore the molecular mechanisms of MAX in regulation of decidualization, followed by dual-luciferase reporter assay to verify that MAX targets to (odd-skipped related transcription factor 2) OSR2 directly. Reduced expression of OSR2 was also confirmed in decidual tissues in women with RSA by IHC and qRT-PCR. OSR2 knockdown also significantly impairs HESCs decidualization. OSR2-overexpression could at least partly rescue the downregulated insulin-like growth factor binding protein 1 (IGFBP1) expression level in response to MAX knockdown. Collectively, MAX deficiency observed in RSA stromal cells not only attenuates HESCs proliferation but also impairs HESCs decidualization by downregulating OSR2 expression at transcriptional level directly. [ABSTRACT FROM AUTHOR]

Obstetric posterior reversible encephalopathy syndrome (PRES), caused by preeclampsia (PE) or eclampsia, is a clinical imaging syndrome and a critical maternal complication, with vasogenic edema in white matter as a typical imaging characteristic. Serum neurofilament light (NFL) is a marker of neuroaxonal injury. Therefore, we performed this study to explore the diagnostic and prognostic role of NFL in obstetric PRES. We used stored serum samples and clinical data obtained from 2148 PE or eclampsia patients from the Guangzhou Medical Centre for Critical Pregnant Women from January 2015 to January 2020. The serum NFL concentration was measured by Simoa assay. Patients without complete data and MRI examinations were excluded. All patients were grouped into the PRES and non-PRES groups based on the PRES diagnostic criteria. In total, 222 patients met the inclusion criteria and were grouped into the PRES (n = 123) and non-PRES (n = 99) groups. The NFL level was significantly higher in the PRES group than in the non-PRES group (p < 0.0001). The discriminatory accuracy of diagnostic panels (headaches + NFL, NFL) in receiver operating characteristic curve analysis (area under the curve) was 0.9338 and 0.7664. Importantly, the NFL level was significantly correlated with edema severity (Spearman's correlation, p < 0.0001), and a poorer pregnancy outcome was observed in the PRES group. In conclusion, an increased NFL level can add predictive value for diagnosing obstetric PRES, and its level is associated with both clinical severity and pregnancy outcome, suggesting that NFL could serve as a diagnostic and prognostic biomarker for obstetric PRES. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) results in more than half of the mortality and the majority of morbidity in patients with type 2 diabetes. We aim to evaluate the associations of urinary concentrations of phthalate metabolites with CVD in diabetic patients and explore whether CVD risk factors mediate or interact with these associations. A total of 675 type 2 diabetic participants were enrolled from Shanghai, China, in 2018. CVD was defined as a self-reported diagnosis by a physician including coronary heart disease, myocardial infarction, or stroke; it was further reconfirmed in the records from the registration platform. Ten phthalate metabolites were measured in urine. We found positive associations were found among the level of monoethyl phthalate and monoisobutyl phthalate and CVD (OR 1.138, 95% CI 1.032, 1.254; OR 1.369, 95% CI 1.049, 1.786, respectively). Monoisobutyl phthalate and monobenzyl phthalate were marginally and positively associated with carotid intima-media thickness and common carotid artery diameter, respectively. None of the CVD risk factors, including HOMA-IR, body mass index, lipid profile, or blood pressure, significantly mediated the association between the metabolites and CVD. The conditional indirect effect on CVD was significantly stronger for current smoking and dyslipidemia for monoethyl phthalate and for no statin usage and men for monoisobutyl phthalate. In conclusion, phthalate exposure was positively associated with CVD in Chinese with type 2 diabetes. Type 2 diabetic men who are currently smoking, have an uncontrolled lipid profile, and are not using statins might be more susceptible to CVD when exposed to phthalates. [ABSTRACT FROM AUTHOR]

Lead (Pb) exposure has been reported to have nephrotoxicity. However, such an effect has not been well investigated in type 2 diabetes (T2D) patients, especially when taking into account the nutrition status of the patients. Therefore, we explore the association between blood lead levels (BLLs), dietary intake of nutrients, and impaired renal function among patients with T2D. We measured BLLs and biochemical parameters of renal injury in 780 patients. Dietary nutrients intake was assessed by a food frequency questionnaire in 420 of 780 participants. We found high BLLs were significantly associated with certain parameters of renal injury, and dietary intake of specific nutrients (mainly micronutrients) was associated with reduced BLLs at high percentile distribution of concentration. BLLs were also found to have moderation effects on the association between specific dietary nutrients and specific renal function parameters. [ABSTRACT FROM AUTHOR]

Purpose: Through this study, we aimed to evaluate the effects of different types of placenta previa (PP) on maternal and neonatal outcomes. Methods: This study was conducted in The Third Affiliated Hospital of Guangzhou Medical University and Tongji Hospital between January 2009 and 2019. PP was traditionally classified into four types, namely low-lying placenta, marginal, partial, and complete PP. Previous studies have classified PP into two types, namely low-lying placenta and PP. Based on our clinical experience, we proposed the classification of PP into three types, for the first time, which included low-lying placenta, "marpartial" (marginal and partial) PP, and complete PP. Multivariate logistic regression analysis was performed to determine the effects of different types of PP on maternal and neonatal outcomes. Results: In total, 4490 singleton pregnancies were complicated with PP. In the four-classification method, compared with women with low-lying placenta, women with complete PP had a risk of placenta accrete spectrum disorders, postpartum hemorrhage (PPH), hemorrhagic shock, severe PPH, blood transfusion, hysterectomy, puerperal infection, preterm labor, NICU admission, and low birth weight. There was no difference in maternal and neonatal outcomes between marginal and partial PP, except for increased chances of preterm labor and low birth weight in partial PP. In the two-classification method, PP was the risk factor for most of the adverse maternal and neonatal outcomes, compared with low-lying placenta. Conclusion: Complete PP and low-lying placenta were associated with the highest and lowest risks of adverse pregnancy outcomes, respectively, whereas clinically similar outcomes were observed between marginal and partial PP. The three-classification of PP may be practical from the clinical perspective. [ABSTRACT FROM AUTHOR]

Phthalates are used in a wide variety of personal care products (PCPs) as solubilizer, denaturant or color fixative. However, there are few studies referring the correlation between phthalate exposure and PCPs use among general population in China. In this study, ten metabolites of phthalates in spot urine samples (N = 500) were quantified using ultra-performance liquid chromatography tandem mass spectrometry. The frequency and duration of 12 types of PCPs were collected by questionnaire survey. The associations of phthalate metabolites and PCPs use were assessed by multivariable liner regression models. Median concentration of mono-benzylphthalate (MBzP) was significantly higher among frequent users of almost all PCPs. Low molecular weight phthalates (monomethyl phthalate (MMP), mono-n-butylphthalate (MnBP) and monoisobutylphthalate (MiBP)) were significantly lower among frequent user of some rinse-off PCPs (e.g., shampoo, facial cleanser, and body wash). Meanwhile, monoethylphthalate (MEP) was positive correlated with frequently use of facial moisturizer. Mono-2-ethylhexylphthalate (MEHP) and MBzP showed a significant positive association with frequently use of body lotion. Univariate linear analyses indicated a significant decreasing trend between urinary concentrations of MMP, MnBP, and the number of rinse-off PCPs being frequently used, and a significant increasing trend between urinary MBzP and the number of leave-on products being frequently used. These findings indicated that the use of some PCPs, especially leave-on PCPs, could be a potential source of exposure to some phthalates. [ABSTRACT FROM AUTHOR]

Few studies were conducted to assess safety and efficacy of continuous antiviral therapy administrated from preconception. In the present study, 136 eligible women with chronic HBV infection were recruited, and assigned to active chronic hepatitis B (CHB) (Group A, B or C) or chronic HBV carrier (Group D). Antiviral therapy was administrated in preconception (Group A), in early (Group B) or late pregnancy (Group C and Group D). Immunoprophylaxis was administrated to all infants. Mothers' HBV status and ALT were assessed at delivery and 7 months postpartum. Offspring's HBV status was examined at 7 months old. Group A women showed low HBV DNA level and normal ALT throughout pregnancy. All women at delivery had an HBV DNA level of less than 106 IU/ml, but the proportion of patients with lower HBV DNA level in Group A was higher than any of other three groups (P < 0.05). No differences in obstetrical complications were found among the four groups. None of infants who completed follow-up showed positive HBsAg at age of 7 months. Congenital malformation and infant growth indicators were similar among study cohorts. Continuous antiviral therapy from preconception to entire pregnancy is effective and safe for active CHB mothers and their infants. [ABSTRACT FROM AUTHOR]

The common flame retardant decabrominated diphenyl ether (BDE-209) is a persistent organic pollutant. Epidemiological studies have revealed that prenatal or postnatal exposure to BDE-209 can result in delayed cognitive development, and BDE-209 has been shown to be toxic to cultured neurons with maturation interference effects. However, its neurotoxic mechanism remains unclear. Nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling plays an important role in regulating neuronal maturation. We examined the influence of BDE-209 (100, 200, and 400 nM) on NO production and cGMP levels signaling in rodent neurons in vitro, with or without pretreatment N-methyl-D-aspartate (NMDA) receptor antagonism. We found that nanomolar concentrations of BDE-209 affected levels of the second messengers NO and cGMP, and that these effects could be blocked by NMDA receptor antagonism. Moreover, BDE-209 activation of NMDA receptors inhibited the expression of phosphodiesterases (PDEs), which modulate intracellular cGMP levels, and increased the Bcl-2/Bax ratio, favoring apoptosis induction. Our studies implicate the NMDA-NO/cGMP pathway in the pathogenic mechanism through which BDE-209 induces neurotoxicity. [ABSTRACT FROM AUTHOR]

Phthalate exposure has been reported to be associated with obesity (measured by body mass index [BMI]) and central obesity (measured by waist circumference [WC]). Yet, reported associations and the potential gender and age differences are inconsistent. We conducted a cross-sectional study involving 2330 participants in the fall of 2012. Urinary metabolites of ten phthalates were measured. Height, body weight, and waist circumference (WC) were measured using standardized methods. We performed logistic regression analyses to estimate the association between each urine phthalate metabolite (categorized into quartiles) and obesity and central obesity and conducted an additional, stratified analysis to explore the gender and age differences. In the overall study population, higher urinary levels of MMP, MEHHP, and MECPP were associated with increased ratios of central obesity. When stratifying by gender and central obesity, higher urinary levels of MMP, MEHHP, and MEOHP were associated with increased odds of central obesity in females, whereas MBP was significantly associated inversely with central obesity in females. In males, it showed no significant P value for trend ( P trend). When stratifying by age in females, higher urinary levels of MEHP, MEOHP, MEHHP, and MECPP were associated with increased odds of central obesity in women aged ≤45 years. In females aged >45 years, it showed no significant P trend. In conclusion, we found that association between phthalates and central obesity was stronger than between phthalates and obesity; association between phthalates and central obesity was stronger in females than in males and was stronger in younger females (aged ≤45 years) than in older females (aged >45 years). [ABSTRACT FROM AUTHOR]

This study establishes the primary culture method for red carp ( Cyprinus carpio) macrophages in vitro and lays the foundation for further research in the fish immune system. The healthy adult red carp was chosen, and mechanical separation and cell adherent culture methods were used to isolate the primary macrophages. Compared to the traditional method of Percoll discontinuous density gradient isolation, the protocol we reported here makes cell isolation steps more concise and obtains more healthy cells with high macrophage purity. The cells were uniform in size with a clearly visible nucleus. Trypan blue staining and non-radioactive cell proliferation assay were used to detect the cell survival rate. Further, we provide optimum culture conditions which include cell density (1 × 10 cells/mL), culture medium (Leibovitz's L-15), pH (7.2-7.4), temperature (26°C), and adherent time (24 h). Macrophages have been identified by nonspecific esterase and Wright-Giemsa staining and have shown to grow very well. In addition, the macrophages have a very strong bactericidal activity against three kinds of bacteria, further verifying good growth conditions and proper function. [ABSTRACT FROM AUTHOR]

Evidence is presented that Tim18, a mitochondria translocase, plays a role in the previously described apoptosis induced by arsenite in Saccharomyces cerevisiae. Tim18 deletion mutant exhibited resistance to arsenite. After arsenite treatment, both the wild type and Tim18-deficient cells showed reactive oxygen species (ROS) production. Arsenite induced the higher expression of tim18 in wild type yeast cells. We found that the tim18 deletion mutant also exhibited resistance to other apoptotic stresses such as acetic acid, H2O2, and hyperosmotic stress. These results suggest that Tim18 is important for yeast cell death induced by arsenic, and it may act downstream of ROS production. [ABSTRACT FROM AUTHOR]