High Levels of BPA and BPF Exposure during Pregnancy Are Associated with Lower Birth Weight in Shenyang in Northeast China.

Animal studies indicate that bisphenol A (BPA) has obesogenic effects. Recent experiments reported similar endocrine-disrupting effects of bisphenol F (BPF) and bisphenol S (BPS), which are substitutes of BPA. The aim of this study was to investigate the exposure levels of these bisphenols in pregnant women and their effects on the physical development of infants aged 0-12 months. This study recruited pregnant women who gave birth at a hospital between February 2019 and September 2020. Urine samples from these pregnant women in the third trimester of pregnancy were detected by using ultrahigh-performance liquid chromatography-triple quadruple mass spectrometry. Follow-ups at 6 and 12 months of age were conducted by telephone by pediatricians using a structured questionnaire. Multiple linear regressions were used to determine the associations between bisphenol concentrations and infant weight. A total of 113 mother-child pairs had complete questionnaires and urine samples as well as data on newborns aged 6 months and 12 months. The detection rates of urinary BPA, BPF, and BPS in pregnant women were 100, 62.83, and 46.02%, respectively. Their median levels are 5.84, 0.54, and 0.07 µg/L, respectively. Increased urinary BPA and BPF concentrations during pregnancy were significantly associated with lower birth weight (standardized regression coefficients [ß] = -0.081 kg, 95% confidence interval [CI]: -0.134 to -0.027; ß = -0.049 kg, 95% CI: -0.097 to -0.001). In addition, urinary BPA and BPF concentrations during pregnancy were positively associated with weight growth rate from 0 to 6 months (ß = 0.035 kg/mouth, 95% CI: 0.00-0.064; ß = 0.028 kg/mouth, 95% CI: 0.006-0.050), especially in female infants (ß = 0.054 kg/mouth, 95% CI: 0.015-0.093; ß = 0.035 kg/mouth, 95% CI: 0.005-0.065). Therefore, maternal BPA and BPF levels during pregnancy were negatively correlated with birth weight and positively correlated with the growth rate of infant weight at 0-6 months of age, especially in female infants.

Enantioselective Synthesis of Axially Chiral Diaryl Ethers via NHC Catalyzed Desymmetrization and Following Resolution.

Axially chiral diaryl ethers are present in numerous natural products and bioactive molecules. However, only few catalytic enantioselective approaches have been established to access diaryl ether atropisomers. Herein, we report the N-heterocyclic carbene-catalyzed enantioselective synthesis of axially chiral diaryl ethers via desymmetrization of prochiral 2-aryloxyisophthalaldehydes with aliphatic alcohols, phenol derivatives, and heteroaromatic amines. This reaction features mild reaction conditions, good functional group tolerance, broad substrate scope and excellent enantioselectivity. The utility of this methodology is illustrated by late-stage functionalization, gram-scale synthesis, and diverse enantioretentive transformations. Control experiments and DFT calculations support the association of NHC-catalyzed desymmetrization with following kinetic resolution to enhance the enantioselectivity.

Evolution under Spatially Heterogeneous Selection in Solid Tumors.

Spatial genetic and phenotypic diversity within solid tumors has been well documented. Nevertheless, how this heterogeneity affects temporal dynamics of tumorigenesis has not been rigorously examined because solid tumors do not evolve as the standard population genetic model due to the spatial constraint. We therefore, propose a neutral spatial (NS) model whereby the mutation accumulation increases toward the periphery; the genealogical relationship is spatially determined and the selection efficacy is blunted (due to kin competition). In this model, neutral mutations are accrued and spatially distributed in manners different from those of advantageous mutations. Importantly, the distinctions could be blurred in the conventional model. To test the NS model, we performed a three-dimensional multiple microsampling of two hepatocellular carcinomas. Whole-genome sequencing (WGS) revealed a 2-fold increase in mutations going from the center to the periphery. The operation of natural selection can then be tested by examining the spatially determined clonal relationships and the clonal sizes. Due to limited migration, only the expansion of highly advantageous clones can sweep through a large part of the tumor to reveal the selective advantages. Hence, even multiregional sampling can only reveal a fraction of fitness differences in solid tumors. Our results suggest that the NS patterns are crucial for testing the influence of natural selection during tumorigenesis, especially for small solid tumors.

Association between maternal metabolic profiles in pregnancy, dietary patterns during lactation and breast milk leptin: a retrospective cohort study.

Breast milk leptin plays a potential role in preventing childhood obesity. However, the associations of breast milk leptin with maternal metabolism in pregnancy and dietary patterns during lactation are still unclear. We aimed to explore associations of breast milk leptin with maternal metabolic profiles in pregnancy and dietary patterns during lactation. A total of 332 participants were recruited for this retrospective cohort study. Breast milk samples were collected at approximately 6 weeks postpartum. Breast milk leptin and twenty-three metabolic profiles in pregnancy were measured in this study. A semi-quantitative FFQ was used to gather dietary information during lactation. Both principal component analysis and the diet balance index were used to derive dietary patterns. Among twenty-three maternal metabolic profiles, maternal serum glucose (ß = 1·61, P = 0·009), γ-glutamyl transferase (ß = 0·32, P = 0·047) and albumin (ß = -2·96, P = 0·044) in pregnancy were correlated with breast milk leptin. All dietary patterns were associated with breast milk leptin. Given the joint effects of maternal metabolism in pregnancy and dietary patterns during lactation, only diet quality distance was significantly associated with leptin concentrations in breast milk (low level v. almost no diet problem: ß = -0·46, P = 0·011; moderate/high level v. almost no diet problem: ß = -0·43, P = 0·035). In conclusion, both maternal metabolism in pregnancy and dietary patterns during lactation were associated with breast milk leptin. Maternal diet balance during lactation was helpful to improve breast milk leptin concentration.

Maternal dietary patterns during pregnancy and the risk of infantile eczema during the first year of life: a cohort study in northeast China.

BACKGROUND: There are few studies on the relationship between diet during pregnancy and infantile eczema and the conclusions are inconsistent. The aim of the present study was to explore the impact of dietary patterns during pregnancy on infantile eczema. METHODS: A total of 495 mother-child pairs from a prospective cohort in Shenyang, China was recruited. Information on maternal dietary intake during pregnancy was assessed with a validated self-administered food frequency questionnaire. The data of infantile eczema was assessed using a structured questionnaire. Factor analysis to derive dietary patterns. The relationship between the dietary pattern and infantile eczema was examined by the logistic regression analysis. RESULTS: The cumulative incidence of eczema in 6 months and 12 months in northeast China was 45.7% and 57.8%, respectively. Three dietary patterns were identified. There was a tendency for an expose-response relationship between the maternal high-protein dietary pattern during pregnancy and the risk of infantile eczema within 12 months (P for trend = 0.023): the adjusted odds ratio (95% confidence interval) in the Q1, Q2, Q3, Q4 were 1.00 (reference), 1.63 (0.96-2.76), 1.81 (1.06-3.06), and 1.87 (1.09-3.20), respectively. No association between Western and plant-based patterns during pregnancy and infantile eczema within 12 months was found. Infantile eczema within 6 months was not associated with any of the three dietary patterns. CONCLUSION: The maternal high-protein pattern during pregnancy may be a risk factor for infantile eczema during the first year of life.

Alkyne Insertion Enabled Vinyl to Acyl 1,5-Palladium Migration: Rapid Access to Substituted 5-Membered-Dihydrobenzofurans and Indolines.

"Through space" palladium/hydrogen shift is an efficient strategy to achieve selective functionalization of a specific remote C-H bond. Compared with relatively extensive exploited 1,4-palladium migration process, the relevant 1,5-Pd/H shift was far less investigated. We herein report a novel 1,5-Pd/H shift pattern between a vinyl and an acyl group. Through the pattern, rapid access to 5-membered-dihydrobenzofuran and indoline derivatives has been achieved. Further studies have unveiled an unprecedented trifunctionalization (vinylation, alkynylation and amination) of a phenyl ring through 1,5-palladium migration relayed decarbonylative Catellani type reaction. A series of mechanistic investigations and DFT calculations have provided insights into the reaction pathway. Notably, it was unveiled that the 1,5-palladium migration in our case prefers a stepwise mechanism involving a PdIV intermediate.

Identification of dominant conformational epitopes from the whole structure of the proprotein convertase subtilisin/kexin type 9.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of LDLR, has emerged as an important target for the treatment of hypercholesterolemic cardiovascular disease, and monoclonal antibodies alirocumab and evolocumab against it have been widely used in clinical practice. The vaccine research of PCSK9 is considered a promising option for the long-term treatment and prevention of cardiovascular disease, but progress has been slow. The selection of safe and effective epitopes is one of the key steps in vaccine development. In this study, we designed a phage display library of cascaded peptides for affinity screening with two antibody drugs, and found that the two peptides PC3 and PS6, which are adjacent to each other in protein spatial structure, both have superior binding activity to the screening antibodies. We performed in vitro recombination design on the dominant sequences, and obtained recombinant sequences that can respond to the dominant conformational epitope of PCSK9, which provides a meaningful reference for epitope selection in subsequent PCSK9 vaccine development.

BF3 -Catalyzed Mukaiyama aldol reaction of acetaldehyde with 2-siloxy-1-propene.

The Mukaiyama aldol reaction is a powerful tool for the construction of the carbon-carbon bond and the formation of ß-hydroxycarbonyl compounds. In this work, the mechanism of acetaldehyde and 2-siloxy-1-propene both in the absence and presence of the catalyst BF3 was investigated based on density functional theory. The mechanism includes two major steps: the formation of the carbon-carbon bond and the removal of SiH3 /BF2 by water. The energy barrier of the carbon-carbon bond formation process in the presence of BF3 is obviously lower, indicating that BF3 is a good catalyst for this reaction. In terms of molecular configuration, the different tensions between the five-membered-ring and six-membered-ring can be considered as the possible reason for the catalytic effect of BF3 . In terms of charge transfer, the charges of natural population analysis in the carbon atom of the carbonyl group in acetaldehyde becomes more positive, which is easier to attack by nucleophiles and promote the nucleophilic process.

Blood Neutrophil-to-Lymphocyte Ratio as a Predictor of Cerebral Small-Vessel Disease.

BACKGROUND In recent studies, neutrophil-to-lymphocyte ratio (NLR) was reported to be a good predictor of acute ischemic stroke (AIS), but its role in cerebral small-vessel disease (CSVD) is still controversial. We aimed to explore the value of NLR to identify CSVD. MATERIAL AND METHODS We enrolled 466 CSVD patients and 413 controls. The total burden score of CSVD was calculated according to MRI results, and imaging subgroups were divided according to MRI. The 90-day outcome was evaluated using the modified Rankin scale (mRS). NIHSS score, mRS, clinical information, biochemical parameters, and NLR were recorded, and we analyzed the relationship between NLR and CSVD. RESULTS NLR was a risk factor for CSVD (OR 1.58, 95%CI 1.015~1.322; P=0.029). NLR was positively correlated with CSVD (r=0.259; P=0.001). The AUC was 0.774, with a cut-off value of 1.89 (95% CI 0.742~0.806), P=0.000. NLR was significantly different among the different total burden score groups of CSVD (P=0.009). NLRs were significant different among enlarged perivascular space (EPVS) groups (P=0.017), periventricular white matter high signal (PWMHS) groups (P=0.028), and deep white matter high signal (DWMHS) groups (P=0.004), but no significant difference was found among cerebral microbleeds (CMBs) groups (P=0.118). NLR was correlated with short-term outcome of CSVD (P=0.000). The AUC was 0.732 (95% CI 0.684~0.779), with a cut-off value of 2.413 for predicting a poor CSVD prognosis. CONCLUSIONS NLR has potential diagnostic value for CSVD, and it can predict the short-term outcome of CSVD. Therefore, NLR may be a useful biomarker to predict CSVD and its outcome.

Sex-specific relationship between serum uric acid levels and the prevalence of large vessel occlusion in acute ischemic stroke.

PURPOSE: Previous studies have found that uric acid (UA) plays a neuroprotective role in ischemic stroke patients. However, the relationship between serum UA of acute ischemic stroke (AIS) and large vessel occlusion (LVO) strokes is unclear. METHODS: In this retrospective study, 1318 AIS patients were enrolled. All patients underwent imaging examinations to assess the intracranial and carotid vessels. Multivariate logistic regression analysis was conducted to evaluate the relationship between UA levels and the prevalence of LVO. RESULTS: The 1318 enrolled AIS patients were comprised of 287 LVO and 1031 non-LVO patients. UA levels in males were higher than females (321.04 ± 91.28 vs. 274.43 ± 82.11, p < .001). The association between serum UA levels and LVO was modified by sex (p = .007). When serum UA levels were continuous, after adjusting for related risk factors, higher serum UA levels were still associated with a lower prevalence of LVO in males (odds ratio (OR) 0.997, 95% confidence interval (CI) 0.994-0.999), but not in female subjects (OR 0.998, 95% CI 0.995-1.001). When serum UA levels were divided into tertiles, higher UA levels had a lower risk of LVO than the moderate (p = .006) and lower tertiles of UA levels (p = .010) in males, but not in females (p = .402 and p = .206 for moderate and low tertiles, respectively). CONCLUSIONS: AIS patients with higher serum UA levels tend to be associated with a lower risk of LVO in males, but not in females.

Prenatal ultrasound diagnosis of primary myxomatous degeneration of cardiac valves in a fetus: Case report.

Primary myxomatous degeneration of cardiac valves is a rare cardiac malformation. We discovered a case of fetal primary myxomatous degeneration of cardiac valves during routine prenatal ultrasound examination. This is the first time such a case has been detected on prenatal ultrasound.

Metagenomic assembly and binning analyses the prevalence and spread of antibiotic resistome in water and fish gut microbiomes along an environmental gradient.

The pristine river and urban river show an environmental gradient caused by anthropogenic impacts such as wastewater treatment plants and domestic wastewater discharges. Here, metagenomic and binning analyses unveiled antibiotic resistance genes (ARGs) profiles, their co-occurrence with metal resistance genes (MRGs) and mobile genetic elements (MGEs), and their host bacteria in water and Hemiculter leucisculus samples of the river. Results showed that the decrease of ARG abundances from pristine to anthropogenic regions was attributed to the reduction of the relative abundance of multidrug resistance genes in water microbiomes along the environmental gradient. Whereas anthropogenic impact contributed to the enrichment of ARGs in fish gut microbiomes. From pristine to anthropogenic water samples, the dominant host bacteria shifted from Pseudomonas to Actinobacteria. Potential pathogens Vibrio parahaemolyticus, Enterobacter kobei, Aeromonas veronii and Microcystis aeruginosa_C with multiple ARGs were retrieved from fish gut microbes in lower reach of Ba River. The increasing trends in the proportion of the contigs carrying ARGs (ARCs) concomitant with plasmids along environmental gradient indicated that plasmids act as efficient mobility vehicles to enhance the spread of ARGs under anthropogenic pressures. Moreover, the higher co-occurrence of ARGs and MRGs on plasmids revealed that anthropogenic impacts accelerated the co-transfer potential of ARGs and MRGs and the enrichment of ARGs. Partial least squares path modeling revealed anthropogenic contamination could shape fish gut antibiotic resistome mainly via affecting ARG host bacteria in water microbiomes, following by ARGs co-occurrence with MGEs and MRGs in gut microbiomes. This study enhanced our understanding of the mechanism of the anthropogenic activities on the transmission of antibiotic resistome in river ecosystem and emphasized the risk of ARGs and pathogens transferring from an aquatic environment to fish guts.

Kinetic metrics of 18F-FDG in normal human organs identified by systematic dynamic total-body positron emission tomography.

PURPOSE: To investigate the kinetic metrics of 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) in normal organs by using dynamic total-body (TB) positron emission tomography (PET). METHODS: Dynamic TB-PET was performed for nine healthy volunteers. Time-to-activity curves (TACs) were obtained by drawing regions of interest in the organs. A two-tissue compartment model was fitted for each tissue TAC. Constant rates, including k1, k2, and k3, and the metabolic rate of FDG (MRFDG) were obtained. The parameter statistics, including the average, standard deviation, coefficient of variance, and inter-site and inter-individual variances, were compared. RESULTS: Constant rates and MRFDG varied significantly among organs and subjects, but not among sides or sub-regions within an organ. The mean k1 and k2 ranged from 0.0158 min-1 in the right lower lung to 1.1883 min-1 in the anterior wall of the left ventricle (LV) myocardium and from 0.1116 min-1 in the left parietal white matter to 4.6272 min-1 in the left thyroid, respectively. The k3 was lowest in the right upper area of the liver and highest in the septal wall of the LV myocardium. Mean MRFDG ranged from 23.1696 µmol/100 g/min in the parietal cortex to 0.5945 µmol/100 g/min in the lung. Four groups of organs with similar kinetic characteristics were identified: (1) the cerebral white matter, lung, liver, muscle, bone, and bone marrow; (2) cerebral and cerebellar cortex; (3) LV myocardium and thyroid; and (4) pancreas, spleen, and kidney. CONCLUSION: The kinetic rates and MRFDG significantly differed among organs. The kinetic metrics of FDG parameters in normal organs can serve as a reference for future dynamic PET imaging and research.

Prenatal exposure to bisphenols, immune responses in cord blood and infantile eczema: A nested prospective cohort study in China.

Increasing evidence shows that human exposure to bisphenols can increase the risk of allergic disease, such as child asthma. However, the mechanism by which exposure to bisphenols causes allergic disease is unclear. In addition, the effects of exposure to bisphenols during pregnancy on infantile eczema have been poorly studied. The aim of our study was to investigate the effect of bisphenols (BPA, BPF and BPS) exposure during pregnancy on immune cells in cord blood, and on the occurrence of infantile eczema. 111 mother-child pairs with urine samples from pregnant women and cord blood were recruited from a birth cohort established in February 2019 in Shenyang, China. The levels of urinary bisphenols and Th1-, Th2-, Treg- and Th17-related genes, and cytokines in cord blood, as well as the incidence of infantile eczema at 6 and 12 months follow up were determined. Our results show that BPA, BPF and BPS were detected in 100%, 63.1% and 46.8% of the urine samples, respectively. The median concentration of urine specific gravity adjusted BPA (SG-BPA) was 7.46 ng/mL. High SG-BPA levels during pregnancy was independently associated with increased risk of infantile eczema (adjusted OR = 2.731, 95%CI: 1.064-7.012, P = 0.037). Higher levels of FOXP3 gene in cord blood had a significantly lower risk of developing eczema in infants (adjusted OR=0.430, 95%CI: 0.190-0.972, P = 0.042). However, BPS and BPF levels were not associated with infantile eczema. FOXP3 gene levels in cord blood mediated the relationship between SG-BPA levels during pregnancy and infantile eczema (indirect effect: ß = 0.350 [CI:0.011,1.077]). Our findings indicate that high levels of BPA exposure during pregnancy increase the risk of infantile eczema, which may be associated with down-regulation of FOXP3 gene expression in cord blood.

Influence of water matrix species on persulfate oxidation of phenol: reaction kinetics and formation of undesired degradation byproducts.

The present study explored the influence of Cl-, Br-, CO32-, HCO3-, PO43-, HPO42-, NO3-, SO32- and natural organic matter (NOM) on the reaction kinetics and the formation of undesired degradation byproducts during phenol oxidation by heat-activated persulfate (PS). CO32- and PO43- promoted the phenol degradation, because the hydrolysis of CO32- and PO43- created basic pH conditions which were conducive to enhanced PS oxidation rate. Br- promoted the reaction by reacting with sulfate radicals (SO4•-) to produce bromine radicals that can selectively react with electron-rich phenol. NOM scavenged reactive SO4•-, thus inhibiting the reaction. As a strong reducing agent, SO32- rapidly reduced PS, thus completely suppressing the reaction. HCO3-, HPO42-, Cl-, and NO3- had negligible impact on PS oxidation of phenol. Six intermediates were detected in the no anion control using gas chromatography-mass spectrometry (GC-MS). Various toxic halogenated phenols and halogenated hydroquinones were detected in the treatment containing Cl- and Br-. In contrast, in the treatment containing CO32-, HCO3-, PO43-, HPO42-, and NO3-, no new intermediates were identified except for the intermediates already detected in the control treatment. Based on intermediates identified, reaction pathways for PS oxidation of phenol without anions and in the presence of halides were proposed respectively.

Aggregation Behavior of Dissolved Black Carbon: Implications for Vertical Mass Flux and Fractionation in Aquatic Systems.

The fluvial export of dissolved black carbon (DBC) is a major land-ocean flux in the global black carbon cycle, affecting the size of refractory carbon pool in the oceans. The aggregation behavior of DBC is a significant determinant of its transport and vertical mass flux. In this study, the aggregation kinetics and interaction energy of DBC leached from biochar were investigated. DBC was mainly stabilized by hydration force and underwent structural compacting in divalent cation solutions. Na+ and Mg2+ had limited impact on the colloidal stability of DBC due to the strong hydration of these cations. Ca2+ and Ba2+ readily destabilized DBC by forming inner-sphere complexes, reducing its hydrophilicity. Consistently, charge reversal of DBC was observed with high concentrations of Ca2+ and Ba2+. Simulated sunlight exposure led to photo-oxidation of DBC, increasing its colloidal stability. DBC behaved nonconservatively in laboratory mixing experiments using estuary water samples due to aggregation/sedimentation; while model aquatic humic acid behaved conservatively. Our results infer that there is a vertical mass flux of DBC and possible fractionation from the dissolved organic matter pool in the fluvial and estuarine systems, which have been overlooked in efforts to determine global carbon budgets and associated climate change implications.

Evaluation of the in vitro and in vivo metabolic pathway and cytochrome P450 inhibition/induction profile of Huperzine A.

Huperzine A (HupA), one of the reversible and selective acetylcholinesterase inhibitors derived from Chinese herb Huperzia Serrata, possesses affirmative action of ameliorating cognitive dysfunction of Alzheimer's disease. Up to now, the effects of HupA on human cytochrome P450s (CYPs) have not been fully elucidated. The purpose of the present study was to clarify the metabolic pathway of HupA in vitro and in vivo, and to evaluate the CYPs inhibition/induction profile of HupA in vitro. The catalytic activity of CYP enzymes (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4) was measured by the quantification of specific enzyme substrates using validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods. The in vivo metabolic pathway evaluation was performed in an open, single-dose pharmacokinetic study of HupA in fourteen elderly subjects, with urine collecting at certain intervals. In human liver microsomes, HupA (10 ng/mL) was not metabolized within 90 min, and it showed negligible inhibition against these CYP isoforms within 0.2-100 ng/mL. In human liver hepatocytes, the activities of CYP1A2 and CYP3A4 were not significantly altered when incubated at 2 or 20 ng/mL of HupA. After oral administration of 0.1 mg HupA, the total proportion of HupA excreted through urine was relatively high, accounting to 35± 9% at the limited time period of 48 h. These results suggest that HupA is substantially excreted by kidney unchanged rather than metabolized by human liver, and is unlikely to cause clinically relevant drug-drug interaction (DDI) when co-administrated with drugs that are metabolized by CYP isoenzyme system.

Population pharmacokinetic modeling and simulation of huperzine A in elderly Chinese subjects.

AIM: Our preliminary results show that huperzine A, an acetylcholinesterase inhibitor used to treat Alzheimer's disease (AD) patients in China, exhibits different pharmacokinetic features in elderly and young healthy subjects. However, its pharmacokinetic data in elderly subjects remains unavailable to date. Thus, we developed a population pharmacokinetic (PPK) model of huperzine A in elderly Chinese people, and identified the covariate affecting its pharmacokinetics for optimal individual administration. METHODS: A total of 341 serum huperzine A concentration records was obtained from 2 completed clinical trials (14 elderly healthy subjects in a phase I pharmacokinetic study; 35 elderly AD patients in a phase II study). Population pharmacokinetic analysis was performed using the non-linear mixed-effect modeling software Phoenix NLME1.1.1. The effects of age, gender, body weight, height, creatinine, endogenous creatinine clearance rate as well as drugs administered concomitantly were analyzed. Bootstrap and visual predictive checks were used simultaneously to validate the final population pharmacokinetics models. RESULTS: The plasma concentration-time profile of huperzine A was best described by a one-compartment model with first-order absorption and elimination. Age was identified as the covariate having significant influence on huperzine A clearance. The final PPK model of huperzine A was: CL (L/h)=2.4649(*)(age/86)((-3.3856)), Ka=0.6750 h(-1), V (L)=104.216. The final PPK model was demonstrated to be suitable and effective by the bootstrap and visual predictive checks. CONCLUSION: A PPK model of huperzine A in elderly Chinese subjects is established, which can be used to predict PPK parameters of huperzine A in the treatment of elderly AD patients.

Preclinical pharmacokinetics of TPN729MA, a novel PDE5 inhibitor, and prediction of its human pharmacokinetics using a PBPK model.

AIM: TPN729MA is a novel selective PDE5 inhibitor currently under clinical development in China for the treatment of erectile dysfunction. In this study we characterized its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model. METHODS: The preclinical PK of TPN729MA was studied in rats and dogs. Human clearance (CL) values for TPN729MA were predicted from various allometric methods and from intrinsic CL determined in human liver microsomes. Human PK and plasma concentration versus time profiles of TPN729MA were predicted by using a PBPK model in GastroPlus. Considering the uncertainties in the prediction, a preliminary human study was conducted in 3 healthy male volunteers with an oral dose of 25 mg. RESULTS: After a single intravenous administration of TPN729MA at a dose of 1 mg/kg in rats and 3 mg/kg in dogs, the plasma CL was 69.7 mL·min(-1)·kg(-1) in rats and 26.3 mL·min(-1)·kg(-1) in dogs, and the steady-state volumes of distribution (V(ss)) were 7.35 L/kg in rats and 6.48 L/kg in dogs. The oral bioavailability of TPN729MA was 10% in rats and above 34% in dogs. Profiles of predicted plasma concentration versus time were similar to those observed in humans at 25 mg, and the predicted T(max), C(max) and AUC values were within 2-fold of the observed values. CONCLUSION: TPN729MA demonstrates good preclinical PK. This compound is a valuable candidate for further clinical development. This study shows the benefits of using a PBPK model to predict PK in humans.

Low vitamin D during pregnancy is associated with infantile eczema by up-regulation of PI3K/AKT/mTOR signaling pathway and affecting FOXP3 expression: A bidirectional cohort study.

Vitamin D has received increasing attention because of its association with atopic disease development. Limited studies that have been done on the impact of maternal vitamin D levels during pregnancy on infantile eczema are still debatable. We wanted to discover the effect of maternal vitamin D on infantile eczema and explore whether regulatory T cells (Treg) play a role in this process. 219 pairs of mothers and children were enrolled. Maternal fasting venous blood was collected in pregnancy's second and third trimesters to determine vitamin D levels. Cord blood and placenta samples were collected during childbirth for detecting levels of genes, proteins and cytokines. Pediatricians followed up the prevalence of eczema in infants within 1 year. The reported rate of vitamin D deficiency and insufficiency was 35.6% and 28.3%. Lower maternal 25(OH)D3 levels were related to a higher risk of infantile eczema. Foxp3 gene expression is lower in cord blood of infants with eczema compared to infants without eczema. There was a positive correlation between maternal 25(OH)D3 levels and the expression of FOXP3 gene in cord blood. Compared to vitamin D sufficiency women, vitamin D deficiency women's placental FOXP3 protein expression was decreased and PI3K/AKT/mTOR protein was up-regulated. Our study demonstrates that low prenatal maternal vitamin D levels increased the risk of infantile eczema aged 0-1 year, which might be related to the downregulating of the FOXP3 gene expression in cord blood and decreased placental FOXP3 protein expression. Low placental FOXP3 protein was related with activating PI3K/AKT/mTOR signaling pathway.