Chiral Nanosilica Drug Delivery Systems Stereoselectively Interacted with the Intestinal Mucosa to Improve the Oral Adsorption of Insoluble Drugs.

Chiral nanoparticles (NPs) with nanoscale rough surfaces have enormous application prospects in drug delivery. However, the stereoselective interactions between the chiral NPs and biosurfaces remain challenging and mysterious. Herein, we designed mesoporous silica nanocarriers (l/d/dl-TA-PEI@CMSN) exhibiting the same structural parameters (hydrophilic, electroneutral, spherical NPs, ∼120 nm) but different geometrical chirality as oral nanodrug delivery systems (Nano-DDS) for insoluble drugs nimesulide (NMS) and ibuprofen (IBU) and demonstrated their stereoselective interactions with the intestinal mucosa, that is, l-TA-PEI@CMSN as well as Nano-DDS in the l-configuration displayed apparent superior behaviors in multiple microprocesses associated with oral adsorption, including adhesion, penetration, adsorption, retention and uptake, causing by the stereomatching between the chiral mesostructures of NPs and the inherent chiral topologies of the biosurfaces. As hosting systems, l/d/dl-TA-PEI@CMSN effectively incorporated drugs in amorphous states and helped to overcome the stability, solubility and permeability bottlenecks of drugs. Subsequently, Nano-DDS in the l-configuration (including IBU/l-TA-PEI@CMSN and NMS/d-TA-PEI@CMSN owing to a chiral inversion) showed higher oral delivery efficiency of NMS and IBU evidenced by the larger relative bioavailability (1055.06% and 583.17%, respectively) and stronger anti-inflammatory and analgesic effects. In addition, l/d/dl-TA-PEI@CMSN were stable, nonirritative, biocompatible and biodegradable, benefiting for their clinical applications. These findings provided insights into the rational design of functionalized Nano-DDS and contributed to the further knowledge in the field of chiral pharmaceutical science.

Amniotic membrane extract-enriched hydrogel augments the therapeutic effect of menstrual blood-derived stromal cells in a rat model of intrauterine adhesion.

We previously demonstrated that transplantation of menstrual blood-derived stromal cells (MenSCs) is a safe and effective therapy for treating intrauterine adhesions (IUA). However, improving the colonization and therapeutic efficiency of MenSCs is still needed before full clinical application. Here, we established an amniotic membrane extract (AME)-enriched RGD hydrogel, and evaluated the therapeutic effect of this adjuvant combined with MenSCs transplantation in an IUA rat model. Our results indicated that AME promoted the proliferation and secretion of MenSCs in vitro, up-regulated the expression of apoptosis-suppressing gene BCL2 and down-regulated the expression of apoptosis-related genes Caspase-3 and Caspase-8. The AME-enriched hydrogel was biocompatible, and improved the survival of MenSCs in vitro and in vivo. It also promoted the retention of MenSCs in IUA uterus and augmented the effects of MenSCs on improving uterus morphology, endometrial proliferation, endometrial receptivity and fibrosis suppression. In addition, co-transplantation of MenSCs with AME-enriched hydrogel markedly down-regulated the expressions of inflammation-related genes IL10 and TGFß while up-regulated the IL4/IFN-γ ratio in the IUA endometrium, and improved the expressions of cell proliferation-related antigen, gland-regeneration-related marker leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), angiogenesis-related marker platelet and endothelial cell adhesion molecule 1 (PECAM1), endometrial receptivity related genes ITGα5 and ITGß3. Our study suggested that AME and MenSCs had a synergistic effect. Co-transplantation of MenSCs with AME-enriched hydrogel provided a promising approach for stem cell-based IUA treatment.

Preconception Dietary Patterns and Associations With IVF Outcomes: An Ongoing Prospective Cohort Study.

There is a lack of research on preconception diet and reproductive outcomes conducted in the Chinese population using individual assessment. Between April 2017 and April 2020, 2,796 couples undergoing in vitro fertilization treatment were recruited in this ongoing prospective cohort, and 1,500 eligible couples were included in the final analysis. A validated semi-quantitative food frequency questionnaire was used to evaluate the maternal preconception diet. Other lifestyle factors, including smoking status, psycho-mental status, sleep quality, and physical activity, were also assessed. Five dietary patterns were identified using principal component analysis, namely "Fruits-Vegetables-Dairy-Eggs," "Fish/Seafood-Animal blood," "Tubers-Beans-Cereals," "Puffed food-Candy-Bakery," and "Dried Fruits-Organs-Rice." After adjusting for multiple confounders, we detected that the women who are more inclined to the "Fruits-Vegetables-Dairy-Eggs" pattern and less adherent to the "Tubers-Beans-Cereals" were more likely to achieve normally fertilized eggs and transferable embryos. Regarding pregnancy outcomes, we observed that a lower "Puffed food-Candy-Bakery" score and a higher "Dried fruits-Organs-Rice" score were related to a higher likelihood to achieve biochemical pregnancy. In terms of pregnancy complications, an inverse association between "Fish/Seafood-Animal blood" and hypertensive disorders was observed. We further clustered the dietary patterns based on the proportion of food groups consumed and found that dairy intake was beneficial to embryo quality, while frequent rice consumption was associated with a higher risk of macrosomia. Notably, in the stratified analysis, we observed that the positive relationship between the "Fruit-Dairy-Vegetables-Eggs" score and normal fertilization and the inverse association of the "Fish/Seafood-Animal blood" score with hypertensive disorders during pregnancy were exhibited only among women with body mass index ≥25 kg/m2. In conclusion, pre-treatment diets might be an important target for intervention to achieve a better reproductive outcome.

Association of the Cervical Microbiota With Pregnancy Outcome in a Subfertile Population Undergoing In Vitro Fertilization: A Case-Control Study.

The microorganisms of the reproductive tract have been implicated to affect in vitro fertilization (IVF) outcomes. However, studies on the reproductive tract microbiota of infertile women are limited and the correlation between cervical microbiota and IVF outcome remains elusive. This study aimed to characterize the cervical microbiota of IVF patients undergoing embryo transfer (ET) and assess associations between the cervical microbiota and pregnancy outcomes while exploring the underlying contributing factors. We launched a nested case-control study of 100 patients with two fresh or frozen-thawed cleavage embryos transferred per IVF cycle. Cervical swabs were collected on the day of ET and divided into four groups according to clinical pregnancy outcomes. Variable regions 3 and 4 (V3-V4) of the 16S rRNA gene were amplified and sequenced on the Illumina MiSeq platform. In fresh IVF-ET cycles, the clinical pregnancy group (FP, n = 25) demonstrated higher α diversity (P = 0.0078) than the non-pregnancy group (FN, n = 26). Analysis of similarity (ANOSIM) revealed a significant difference in ß diversity between the two groups (R = 0.242, P = 0.001). In frozen-thawed ET cycles, though not significant, similar higher α diversity was found in the clinical pregnancy group (TP, n = 27) compared to the non-pregnancy group (TN, n = 22) and ANOSIM analysis showed a significant difference between the two groups (R = 0.062, P = 0.045). For patients in fresh IVF-ET groups, Lactobacillus, Akkermansia, Desulfovibrio, Atopobium, and Gardnerella showed differentially abundance between pregnant and non-pregnant women and they accounted for the largest share of all taxa investigated. Among them, Lactobacillus was negatively correlated with the other genera and positively correlated with serum estradiol levels. Logistic regression analysis suggested that the composition of the cervical microbiota on the day of ET was associated with the clinical pregnancy in fresh IVF-ET cycles (P = 0.030). Our results indicate that cervical microbiota composition has an impact on the outcome of assisted reproductive therapy.

Concentrated small extracellular vesicles from menstrual blood-derived stromal cells improve intrauterine adhesion, a pre-clinical study in a rat model.

We previously reported that transplantation of menstrual blood-derived stromal cells (MenSCs) significantly improved fertility restoration in intrauterine adhesion (IUA). However, it is difficult to obtain menstrual blood samples in some severe IUA patients who have amenorrhea or oligomenorrhea. Thus, a safe and effective stem cell replacement therapy is necessary to promote endometrial regeneration. Recent studies demonstrated that the effects of MenSCs are partly mediated in a paracrine manner via small extracellular vesicles (sEVs). To explore this possibility, we performed a pre-clinical study to investigate whether concentrated MenSC-derived sEVs (MenSCs-sEVs) are sufficient to repair IUA and the mechanisms underlying their action. Rat IUA models were established by mechanical injury, followed by the administration of MenSCs or MenSCs-sEVs through intrauterine transplantation. Consistent with the efficacy of MenSCs, MenSCs-sEVs effectively recovered the morphology, promoted regeneration of the glands and angiogenesis, and reversed endometrial fibrosis in the IUA uterus. The endometrial receptivity and pregnancy outcome significantly improved after repeated MenSCs-sEVs transplantations. In addition, all rats in the MenSCs-sEVs group had no hematological or biochemical abnormalities. Three-dimensional fluorescence imaging suggested that MenSCs tended to migrate through the bloodstream, whereas MenSCs-sEVs had a better localized therapeutic effect. Moreover, MenSCs and MenSCs-sEVs inhibited the TGFß1/SMAD3 pathway in the IUA endometrium, while promoting the phosphorylation of SMAD1/5/8 and ERK 1/2 and upregulating the expression of BMP7. Thus, MenSCs-sEVs safely and effectively enhanced endometrial restoration, suggesting a promising non-cellular therapy for endometrial regeneration and a key role in MenSC-mediated IUA treatment.

Raman spectroscopy of follicular fluid and plasma with machine-learning algorithms for polycystic ovary syndrome screening.

Polycystic ovary syndrome (PCOS) is the main cause of anovulatory infertility and affects women throughout their lives. The specific diagnostic method is still under investigation. In the present study, we aimed to identify the metabolic tracks of the follicular fluid and plasma samples from women with PCOS by performing Raman spectroscopy with principal component analysis and spectral classification models. Follicular fluid and plasma samples obtained from 50 healthy (non-PCOS) and 50 PCOS women were collected and measured by Raman spectroscopy. Multivariate statistical methods and different machine-learning algorithms based on the Raman spectra were established to analyze the results. The principal component analysis of the Raman spectra showed differences in the follicular fluid between the non-PCOS and PCOS groups. The stacking classification models based on the k-nearest-neighbor, random forests and extreme gradient boosting algorithms yielded a higher accuracy of 89.32% by using follicular fluid than the accuracy of 74.78% obtained with plasma samples in classifying the spectra from the two groups. In this regard, PCOS may lead to the changes of metabolic profiles that can be detected by Raman spectroscopy. As a novel, rapid and affordable method, Raman spectroscopy combined with advanced machine-learning algorithms have potential to analyze and characterize patients with PCOS.