Network analysis and experimental approach to investigate the potential therapeutic mechanism of zishen yutai pills on premature ovarian insufficiency.

Background: As society continues to develop, women are more at risk of gonadotoxic substance exposure. Consequently, the incidence of premature ovarian insufficiency (POI) has increased significantly in the past decades. Hormone replacement therapy (HRT) is recommended as the standard treatment to relieve hypoestrogenic symptoms; however, its potential side effects and contraindications have drawn widespread controversy and concern. As such, the Chinese medicine Zishen Yutai Pill (ZSYTP) commonly used for treating miscarriage and menoxenia, is a highly promising alternative drug candidate against POI, however its therapeutic mechanism has not been completely elucidated. Objective: To systematically analyze the potential therapeutic targets of ZSYTP on POI, we combined network pharmacology analysis and molecular docking to predict critical target genes, with experimental validation on POI murine models. Methods: The active compounds of ZSYTP were collected from three online databases, and the candidate targets were predicted based on the chemical structure. The POI-related targets were obtained from four databases. A PPI network was constructed to find the key target genes between ZSYTP and POI, while GO and KEGG enrichment analyses were employed to study the mechanism of ZSYTP against POI. The binding capability of the key co-targets with active components was examined by molecular docking. We used a cyclophosphamide (CTX)-inducible POI mouse model to verify our predictions by histopathological observation, immunohistochemical staining (caspase-3, TUNEL assay), hormone determination (FSH, AMH) and ribonucleic acid sequencing (RNA Seq). Progynova was also used to study the difference between ZSYTP and HRT. Result: We identified 21 target genes as the hub between ZSYTP and POI. The GO and KEGG analyses revealed that the molecular mechanism of ZSYTP against POI were mainly based on the regulation of gene and protein expression. A variety of signaling pathways may be involved in the treatment of ZSYTP against POI, especially PI3K-AKT, HIF-1 and the AGE-RAGE cascades. Docking simulation showed that G1, C1, SR5, and F1 had relatively lower binding energy. In vivo, ZSYTP significantly reversed CTX-induced ovarian damage in follicle number, hormone level and apoptosis, with an overall improved therapeutic effect compared to Progynova. Results from RNA-Seq revealed that the PI3K-AKT, Hippo, AGE-RAGE, and Rap1 signaling pathways and regulation of inflammation, immune response, and lipid metabolism may mediate the protective effects of ZSYTP against POI, which is different than Progynova's mechanism of action. Conclusions: Collectively, this study indicates that ZSYTP could be a highly promising alternative as a non-HRT-based therapy for POI. Its mechanism involves multiple signaling pathways, alleviating ovarian apoptosis and recovering AMH and FSH level. However, the discrepancy between different research techniques highlight the necessity of further experimental verification from other aspects such as translation and posttranslational modification.

Ultrastrong and Tough Urushiol-Based Ionic Conductive Double Network Hydrogels as Flexible Strain Sensors.

Ionic conductive hydrogels have attracted increasing research interest in flexible electronics. However, the limited resilience and poor fatigue resistance of current ionic hydrogels significantly restrict their practical application. Herein, an urushiol-based ionic conductive double network hydrogel (PU/PVA-Li) was developed by one-pot thermal initiation polymerization assisted with freeze-thaw cycling and subsequent LiCl soaking. Such a PU/PVA-Li hydrogel comprises a primary network of covalently crosslinked polyurushiol (PU) and a secondary network formed by physically crosslinked poly(vinyl alcohol) (PVA) through crystalline regions. The obtained PU/PVA-Li hydrogel demonstrates exceptional mechanical properties, including ultrahigh strength (up to 3.4 MPa), remarkable toughness (up to 1868.6 kJ/m3), and outstanding fatigue resistance, which can be attributed to the synergistic effect of the interpenetrating network structure and dynamic physical interactions between PU and PVA chains. Moreover, the incorporation of LiCl into the hydrogels induces polymer chain contraction via ionic coordination, further enhancing their mechanical strength and resilience, which also impart exceptional ionic conductivity (2.62 mS/m) to the hydrogels. Based on these excellent characteristics of PU/PVA-Li hydrogel, a high-performance flexible strain sensor is developed, which exhibits high sensitivity, excellent stability, and reliability. This PU/PVA-Li hydrogel sensor can be effectively utilized as a wearable electronic device for monitoring various human joint movements. This PU/PVA-Li hydrogel sensor could also demonstrate its great potential in information encryption and decryption through Morse code. This work provides a facile strategy for designing versatile, ultrastrong, and tough ionic conductive hydrogels using sustainable natural extracts and biocompatible polymers. The developed hydrogels hold great potential as promising candidate materials for future flexible intelligent electronics.

Dual-Mode Porous Polymeric Films with Coral-like Hierarchical Structure for All-Day Radiative Cooling and Heating.

Passive radiative cooling (PRC) and passive radiative heating (PRH) have drawn increasing attention as green and sustainable cooling and heating approaches, respectively. Existing material designs for PRC/PRH are usually static and unsuitable for dynamic seasonal and weather changes. Herein, we demonstrate an all-day dual-mode film fabricated by decorating MXene nanosheets on porous poly(vinylidene fluoride) with abundant coral-like hierarchical structures obtained via phase inversion. The cooling side of the dual-mode film exhibits high solar reflectivity (96.7%) and high infrared emissivity (96.1%). Consequently, daytime subambient radiative cooling of 9.8 °C is achieved with a theoretical cooling power of 107.5 W/m2 and nighttime subambient cooling of 11.7 °C is achieved with a theoretical cooling power of 140.7 W/m2. Meanwhile, the heating side of the dual-mode film exhibits low infrared emissivity (11.6%) and high solar absorptivity (75.7%), contributing to a PRH capability of 8.1 °C, and excellent active solar and Joule heating as effective compensation for PRH. The dual-mode film could be easily switched between cooling and heating modes by flipping it to adapt to dynamic cooling and heating scenarios, which is important for alleviating the energy crisis and reducing greenhouse emissions.

Emerging roles of APLN and APELA in the physiology and pathology of the female reproductive system.

APLN, APELA and their common receptor APLNR (composing the apelinergic axis) have been described in various species with extensive body distribution and multiple physiological functions. Recent studies have witnessed emerging intracellular cascades triggered by APLN and APELA which play crucial roles in female reproductive organs, including hypothalamus-pituitary-gonadal axis, ovary, oviduct, uterus and placenta. However, a comprehensive summary of APLN and APELA roles in physiology and pathology of female reproductive system has not been reported to date. In this review, we aim to concentrate on the general characteristics of APLN and APELA, as well as their specific physiological roles in female reproductive system. Meanwhile, the pathological contexts of apelinergic axis dysregulation in the obstetrics and gynecology are also summarized here, suggesting its potential prospect as a diagnostic biomarker and/or therapeutic intervention in the polycystic ovary syndrome, ovarian cancer, preeclampsia and gestational diabetes mellitus.

Outer Membrane Vesicles of Helicobacter pylori 7.13 as Adjuvants Promote Protective Efficacy Against Helicobacter pylori Infection.

Helicobacter pylori(H. pylori), a gram-negative bacterium in the human stomach with global prevalence, is relevant to chronic gastrointestinal diseases. Due to its increasing drug resistance and the low protective efficacy of some anti-H. pylori vaccines, it is necessary to find a suitable adjuvant to improve antigen efficiency. In our previous study, we determined that outer membrane vesicles (OMVs), a multicomponent secretion generated by gram-negative bacteria, of H. pylori were safe and could induce long-term and robust immune responses against H. pylori in mice. In this study, we employed two common vaccines, outer membrane proteins (OMPs) and whole cell vaccine (WCV) to assess the adjuvanticity of OMVs in mice. A standard adjuvant, cholera toxin (CT), was used as a control. Purified H. pylori OMVs used as adjuvants generated lasting anti-H. pylori resistance for 12 weeks. Additionally, both systematic and gastric mucosal immunity, as well as humoral immunity, of mice immunized with vaccine and OMVs combinations were significantly enhanced. Moreover, OMVs efficiently promoted Th1 immune response, but the response was skewed toward Th2 and Th17 immunity when compared with that induced by the CT adjuvant. Most importantly, OMVs as adjuvants enhanced the eradication of H. pylori. Thus, OMVs have potential applications as adjuvants in the development of a new generation of vaccines to treat H. pylori infection.

Gestational Perfluorooctanoic Acid Exposure Inhibits Placental Development by Dysregulation of Labyrinth Vessels and uNK Cells and Apoptosis in Mice.

Perfluorooctanoic acid (PFOA) is a widely used perfluorinated compound and known to cause developmental toxicity which includes the increase of resorbed embryo, decrease of fetal survival, and fetal growth retardation. Nevertheless, whether it is associated with alteration of placental development remains unknown. Pregnant mice were gavaged with 0, 2.5, 5, 10 mg PFOA /kg/day from pregnancy day (PD) 1 to PD 13. Results showed that PFOA exposure markedly decreased the placental weight and caused interstitial edema of placenta. Laminin staining indicated that blood sinusoids area was shrunken in placenta of PFOA-exposed mice. Furthermore, PFOA treatment significantly reduced numbers of uNK cells. Western blot analysis revealed that levels of Bax and cleaved-caspase 3 proteins were markedly up-regulated in PFOA-treated groups. In addition, TEM examination showed that PFOA treatment caused rupture of nuclear membrane and nuclear pyknosis and fragmentation. Thus, our results suggested that gestational PFOA exposure significantly inhibited development of early placenta through shrinkage of labyrinth vessels and downregulation of uNK cells and apoptosis induction, which may result in adverse gestational outcomes.

sncRNAs packaged by Helicobacter pylori outer membrane vesicles attenuate IL-8 secretion in human cells.

Bacterial outer membrane vesicles (OMVs) play a vital role in the mechanism of host-pathogen communication, while emerging evidence suggests that OMVs regulate host immune responses through differentially packaged small noncoding RNAs (sncRNAs) to target host mRNA function. Therefore, we identified differentially packaged sncRNAs in Helicobacter pylori OMVs and showed transfer of OMV sncRNAs to human gastric adenocarcinoma cells in this study. Our data revealed that sncRNAs (sR-2509025 and sR-989262) were enriched in OMVs, and reduced lipopolysaccharide or OMV-induced interleukin 8 (IL-8) secretion by cultured AGS cells. Collectively, these findings are consistent with the hypothesis that sncRNAs in H. pylori OMVs play a novel role in the mechanism of host-pathogen interaction, whereby H. pylori evades the host immune response.

Orally-administered outer-membrane vesicles from Helicobacter pylori reduce H. pylori infection via Th2-biased immune responses in mice.

As the trend of antibiotic resistance has increased, prevention and treatment of Helicobacter pylori infection have been challenged by the fact that no vaccines preventing H. pylori infection are available. Scientists continue to make sustained efforts to find better vaccine formulations and adjuvants to eradicate this chronic infection. In this study, we systemically analyzed the protein composition and potential vaccine function of outer-membrane vesicles (OMVs) derived from gerbil-adapted H. pylori strain 7.13. In total, we identified 169 proteins in H. pylori OMVs and found that outer-membrane, periplasmic and extracellular proteins (48.9% of the total proteins) were enriched. Furthermore, we evaluated the immune protective response of H. pylori OMVs in a C57BL/6 mouse model, and mice were orally immunized with OMVs or the H. pylori whole cell vaccine (WCV) alone, with or without cholera toxin (CT) as an adjuvant. The data demonstrated that oral immunization with OMVs can elicit a strong humoral and significantly higher mucosal immune response than the group immunized with the WCV plus the CT adjuvant. Moreover, our results also confirmed that OMVs predominantly induced T helper 2 (Th2)-biased immune responses that can significantly reduce bacterial loads after challenging with the H. pylori Sydney Strain 1 (SS1). In summary, OMVs as new antigen candidates in vaccine design would be of great value in controlling H. pylori infection.