Effects of folic acid supplementation in pregnant mice on glucose metabolism disorders in male offspring induced by lipopolysaccharide exposure during pregnancy.

The DOHaD theory suggests that adverse environmental factors in early life may lead to the development of metabolic diseases including diabetes and hypertension in adult offspring through epigenetic mechanisms such as DNA methylation. Folic acid (FA) is an important methyl donor in vivo and participates in DNA replication and methylation. The preliminary experimental results of our group demonstrated that lipopolysaccharide (LPS, 50 µg/kg/d) exposure during pregnancy could lead to glucose metabolism disorders in male offspring, but not female offspring; however, the effect of folic acid supplementation on glucose metabolism disorders in male offspring induced by LPS exposure remains unclear. Therefore, in this study, pregnant mice were exposed to LPS on gestational day (GD) 15-17 and were given three doses of FA supplementation (2 mg/kg, 5 mg/kg, or 40 mg/kg) from mating to lactation to explore its effect on glucose metabolism in male offspring and the potential mechanism. This study confirmed that FA supplementation of 5 mg/kg in pregnant mice improved glucose metabolism in LPS-exposed offspring during pregnancy by regulating gene expression.

Association of Folic Acid Supplementation, Dietary Folate Intake and Serum Folate Levels with Risk of Gestational Diabetes Mellitus: A Matched Case-Control Study.

Periconceptional folate supplementation is prevalent, raising concerns about possible side effects. The aim of this study was to investigate the associations of folic acid supplementation, dietary folate, serum folate with gestational diabetes mellitus (GDM) risk. In this matched case-control study, 81 pregnant women with GDM (cases) and 81 pregnant women with non-GDM (controls) were identified through age difference (≤3 y) and parity (Both primipara or multipara women) matching, and serum folate levels were measured during the GDM screening (24-28 gestational wk). Folic acid supplementation and dietary folate intake from three months prepregnancy through midpregnancy were assessed using a self-reported questionnaire and food frequency questionnaire. Multivariate binary logistic regression models were used to evaluate the association between folate and GDM. After adjusting for confounding factors, we observed that compared with folic acid supplementation dose ≤400 µg/d, pregnancies without folic acid supplementation and supplemental dose >800 µg/d were associated with GDM risk (adjusted odds ratio=7.25, 95% confidence interval: 1.34-39.36; adjusted odds ratio=4.20, 95% confidence interval: 1.03-17.22), while no significant association with a 400-800 µg/d dose of folic acid supplementation and GDM. Compared with folic acid supplementation dose ≤24 wk, pregnancies without folic acid supplementation were associated with GDM risk (adjusted odds ratio=6.70, 95% confidence interval: 1.22-36.77), while no significant association with folic acid supplementation dose >24 wk and GDM. No significant association of dietary folate and serum folate with GDM was found. No or a higher dose of folic acid supplementation would increase GDM risk and a dose of <800 µg/d is the safe dose.

Relationship between gut microbiome characteristics and the effect of nutritional therapy on glycemic control in pregnant women with gestational diabetes mellitus.

The purpose of this study was to explore the relationship between the characteristics of gut microbiome and the effect of medical nutrition therapy (MNT) on glycemic control in pregnant women with gestational diabetes mellitus (GDM). Seventy-four pregnant women newly diagnosed with GDM received MNT for one-week. The effect of glycemic control was evaluated by fasting and 2-hour postprandial blood glucose; and stool samples of pregnant women were collected to detect the gut microbiome before and after MNT. We used a nested case-control study design, with pregnant women with GDM who did not meet glycemic standards after MNT as the ineffective group and those with an age difference of ≤5 years, matched for pre-pregnancy body mass index (BMI) 1:1, and meeting glycemic control criteria as the effective group. Comparison of the gut microbiome characteristics before MNT showed that the ineffective group was enriched in Desulfovibrio, Aeromonadales, Leuconostocaceae, Weissella, Prevotella, Bacillales_Incertae Sedis XI, Gemella and Bacillales, while the effective group was enriched in Roseburia, Clostridium, Bifidobacterium, Bifidobacteriales, Bifidobacteriaceae, Holdemania and Proteus. After treatment, the effective group was enriched in Bifidobacterium and Actinomycete, while the ineffective group was enriched in Holdemania, Proteus, Carnobacteriaceae and Granulicatella. In conclusion, the decrease in the abundance of characteristic gut microbiome positively correlated with blood glucose may be a factor influencing the poor hypoglycemic effect of MNT in pregnant women with GDM. Abundance of more characteristic gut microbiome negatively correlated with blood glucose could help control blood glucose in pregnant women with GDM.

Effects of chronic folate deficiency and sex differences on depression-like behavior in mice.

Although previous studies have reported that serum folate levels are negatively associated with depression in women but not men, it remains unclear whether folate deficiency can directly lead to depression and whether sex difference serves a role in this condition, since the potential mechanism remains elusive. Therefore, the present study aimed to investigate whether folate deficiency results in differences in parameters associated with depression between males and females. CD-1 mice received either a standard control diet or a folate-deficient diet from 10 to 38 weeks of age, following which behavioral assays, such as an open field test, sucrose preference test and forced swim test were performed throughout week 38. Serum and cerebral cortex samples were subsequently collected for assessment. Serum folate, homocysteine, estradiol (E2) and testosterone levels were measured using chemiluminescence, enzymatic cycling assay and electrochemiluminescence immunoassays. The cerebral cortex was used for western blot analysis, to detect the expression levels of estrogen receptor ß (ERß), PI3K/AKT pathway and caspase-3. The results revealed that compared with those in female mice that received standard control diet, female mice that received folate-deficient diet exhibited lower E2 concentrations, lower sucrose preferences (as determined through the sucrose preference test), longer durations of immobility (as determined in the forced swim test) and less time spent in the central areas of the open field test. Western blotting demonstrated that the expression levels of ERß and the phosphorylation levels of PI3K and AKT were decreased, whilst the expression levels of cleaved caspase-3 were increased, in the cerebral cortex of female mice that received folate-deficient diet. However, no differences in E2 concentration, behavioral assay parameters or protein levels of ERß, phosphorylated (p-)PI3K, p-AKT and cleaved caspase-3 could be observed in male mice regardless of whether they received standard control or folate-deficient diets. Collectively, these results revealed that folate deficiency only led to depression-like behavior in female mice. This may be associated with reduced E2 levels, which may inhibit the PI3K/AKT pathway and upregulate the expression of cleaved caspase-3 to promote neuronal apoptosis.

Dietary Intake of n-6:n-3 Polyunsaturated Fatty Acids among Pregnant Chinese Women in Different Trimesters.

This study aimed to investigate the dietary n-6:n-3 PUFA (polyunsaturated fatty acids) intake of pregnant Chinese women in different trimesters. We conducted a cross-sectional study for 300 singleton pregnant women in Hefei city, China. The dietary intake of pregnant women were measured by a 3-d food record. Energy and nutrient intake for the 3 d were calculated according to the Chinese food composition table (Standard Version). The ANOVA and Kruskal-Wallis test were performed to analyze the dietary fatty acids intake of pregnant women. In the first, second and third trimester, the intake of n-6:n-3 PUFA were 5.87±2.37, 6.03±2.89, 6.14±2.26, respectively, without significant difference (p>0.05). But it was all slightly higher than the recommendation for general population (4-6) of Chinese Nutrition Society. An adequate and balanced intake of n-6 and n-3 fatty acids, from a well-balanced diet, should be recommended for pregnant women.

Maternal and fetal metabolomic alterations in maternal lipopolysaccharide exposure-induced male offspring glucose metabolism disorders.

Maternal lipopolysaccharide (LPS) exposure during pregnancy induces metabolic abnormalities in male offspring, but the underlying mechanisms remain unclear. The purpose of this study was to investigate the effects of maternal LPS exposure during pregnancy on metabolic profiling of maternal serum and male fetal liver using Liquid Chromatograph Mass Spectrometer techniques. From day 15 to day 17 of gestation, pregnant mice were administered intraperitoneal LPS (experimental group) (50 µg/kg/d) or saline (control group). On day 18 of gestation, maternal serum and male fetal liver were collected. After LPS exposure, levels of 38 and 75 metabolites, mainly glycerophospholipid and fatty acid metabolites, were altered in maternal serum and male fetal liver, respectively. It was found that in maternal serum and male fetal livers, the glycerophospholipids containing saturated fatty acids (SFAs) and the SFAs were upregulated, while the glycerophospholipids containing polyunsaturated fatty acids (PUFAs) and the PUFAs were downregulated. This concordance between maternal and fetal alterations in glycerophospholipid and fatty acid metabolites may be a metabolomic signature of the early intrauterine period and may provide insight into the mechanisms by which maternal LPS exposure induces disorders of glucose metabolism in male offspring.

Quaternary enteric solid dispersion prepared by hot-melt extrusion to mask the bitter taste and enhance drug stability.

To mask the bitterness of drug is profoundly important especially in children's medication. This study designed and investigated a quaternary enteric solid dispersion (QESD) by secondary hot-melt-extrusion. Erythromycin (EM) was chosen as a model drug. The optimal QESD contained enteric polymer HPMCP-55, plasticizer and water-soluble polymer copovidone VA64. Raman and Atomic force microscope has exploited that majority EM was distributed in VA64 matrix, nanometer-sized EM-VA64 system was entrapped within enteric continuous phase to form a solid emulsion-like structure. For the prepared QESD, EM released concentration was far less than bitterness threshold (7 µg/mL to 20 µg/mL) in artificial saliva within the first 30 s. And dissolution rate was increased by 10% in article intestine fluid, which dominated by water-soluble VA64. Stress testing after two months at high-humidity (75% RH) and high-temperature (60 °C) revealed, compared with traditional enteric SDs, the chemical degradation of EM was slowed down in QESD. Furthermore, hydrogen and salt bonds were respectively formed between EM and VA64 and between leaking EM and HPMCP-55, which increasing the system stability and taste-masking. The effect of masking bitter taste can be satisfied as well as enhance drug dissolution rate in the intestine, and formulation physicochemical stability during storage.

Targeting therapy for prostate cancer by pharmaceutical and clinical pharmaceutical strategies.

For the past few years, nanotechnology has provided a lot of new treatment opportunities for prostate cancer patients, and brilliant achievements have been acquired indeed. It not only prolonged circulation time in vivo but also increased bio-availability of drugs. Among them, nanoparticles with specificity ligand can be better targeted at prostate cancer, which improves the curative effect and reduces side effects. What's more, in terms of combined administration, the synergistic effect of chemotherapeutic drugs and hormones, or co-delivery two or more different drugs into the same delivery system, has achieved good therapeutic progress as well. In this paper, a comprehensive overview of nano-technology and the combination therapy for prostate cancer by pharmaceutical and clinical pharmaceutical strategies have been proposed to further appreciate and recommend the design and development of prostate cancer treatment.

In Vitro and In Vivo Evaluation of SP94 Modified Liposomes Loaded with N-14NCTDA, a Norcantharimide Derivative for Hepatocellular Carcinoma-Targeting.

The purpose of this research is to develop a liposomal drug delivery system, which can selectively target hepatocellular carcinoma (HCC) to deliver the antitumor agent N-14NCTDA, a C14 alkyl chain norcantharimide derivative of norcantharidin. N-14NCTDA-loaded liposomes were successfully prepared by lipid membrane hydration and extrusion methods. SP94, a targeting peptide for HCC cells, was attached to the liposomes loaded with N-14NCTDA by the post-insertion method to obtain SP94 modified liposomes (SP94-LPs). SP94-LPs had a significant cytotoxicity against Hep G2 cells with the IC50 of 15.395 ± 0.89 µg/mL, which is lower than that of NCTD-S (IC50 = 20.863 ± 0.56 µg/mL) and GAL-LPs (IC50 = 24.589 ± 1.02 µg/mL). Compared with conventional liposomes (Con-LPs), SP94-LPs showed greater cellular uptake in Hep G2 cells. Likewise, significant tumor suppression was achieved in H22 tumor-bearing mice which were treated with SP94-LPs. The tumor inhibition rate (IRw) of SP94-LPs was 82 ± 0.98%, obviously higher than that of GAL-LPs (69 ± 1.39%), Con-LPs (60 ± 2.78%), and NCTD-S (51 ± 3.67%). SP94-LPs exhibited a significant hepatocellular carcinoma-targeting activity in vitro and in vivo, which will provide a new alternative for hepatocellular carcinoma treatment in future. Graphical Abstract.

Studies on the in vitro ion exchange kinetics and thermodynamics and in vivo pharmacokinetics of the carbinoxamine-resin complex.

The short half-life and bitter taste of carbinoxamine maleate2 (CAM) lead to poor compliance by pediatric patients who are being treated for allergic rhinitis. To address these issues, carbinoxamine-resin complexes3 (CRCs) were prepared by ion exchange and then coated with Kollicoat SR 30D. The resultant microencapsulated carbinoxamine-resin complexes4 (MCRCs) were dispersed into the medium to obtain the final suspensions. The drug loading kinetics and thermodynamics of CRCs, anti-swelling mechanism of the impregnant in MCRCs, in vitro release, and in vivo pharmacokinetics of the suspensions were systematically evaluated. The drug loading process was found to obey a first-order kinetic process that was spontaneous, entropy-reduced and exothermic, and the diffusion of CAM into the resin was the rate-limiting step. During microencapsulation, the impregnant could create a certain buffer space to control the swelling of CRCs and maintain the coating film intact. The homemade preparations had release behaviors similar to that of the reference in vitro and achieved sustained release in vivo. The low drug loading preparation had a higher relative bioavailability of 109% owing to its faster release and better dispersibility. Therefore, the suspensions based on MCRCs could be successfully applied to treating allergic rhinitis in children.

Entrapping of Nanoparticles in Yeast Cell Wall Microparticles for Macrophage-Targeted Oral Delivery of Cabazitaxel.

In this work, a nano-in-micro carrier was constructed by loading polymer-lipid hybrid nanoparticles (NPs) into porous and hollow yeast cell wall microparticles (YPs) for macrophage-targeted oral delivery of cabazitaxel (CTX). The YPs, primarily composed of natural ß-1,3-d-glucan, can be recognized by the apical membrane receptor, dectin-1, which has a high expression on macrophages and intestinal M cells. By combining electrostatic force-driven self-deposition with solvent hydration/lyophilization methods, the positively charged NPs loaded with CTX or fluorescence probes were efficiently packaged into YPs, as verified by scanning electron microscope (SEM), atomic force mircoscope (AFM), and confocal laser scanning microscopy (CLSM) images. NP-loaded YPs (NYPs) showed a slower in vitro drug release and higher drug stability compared with NPs in a simulated gastrointestinal environment. Biodistribution experiments confirmed a widespread distribution and extended retention time of NYPs in the intestinal tract after oral administration. Importantly, a large amount of NYPs were primarily accumulated and transported in the intestinal Peyer's patches as visualized in distribution and absorption site studies, implying that NYPs were mainly absorbed through the lymphatic pathway. In vitro cell evaluation further demonstrated that NYPs were rapidly and efficiently taken up by macrophages via receptor dectin-1-mediated endocytosis using a mouse macrophage RAW 264.7 cell line. As expected, in the study of in vivo pharmacokinetics, the oral bioavailability of CTX was improved to 32.1% when loaded in NYPs, which is approximately 5.7 times higher than that of the CTX solution, indicating the NYPs are efficient for oral targeted delivery. Hence, this nano-in-micro carrier is believed to become a hopeful alternative strategy for increasing the oral absorption of small molecule drugs.