Deciphering decidual deficiencies in recurrent spontaneous abortion and the therapeutic potential of mesenchymal stem cells at single-cell resolution.

BACKGROUND: Recurrent spontaneous abortion (RSA) is a challenging condition that affects the health of women both physically and mentally, but its pathogenesis and treatment have yet to be studied in detail. In recent years, Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) have been shown to be effective in treating various diseases. Current understanding of RSA treatment using WJ-MSCs is limited, and the exact mechanisms of WJ-MSCs action in RSA remains largely unclear. In this study, we explored the decidual deficiencies in RSA and the therapeutic potential of WJ-MSCs at single-cell resolution. METHODS: Three mouse models were established: a normal pregnancy group, an RSA group, and a WJ-MSC treatment group. Decidual tissue samples were collected for single-cell RNA sequencing (scRNA-seq) and functional verification, including single-cell resolution in situ hybridization on tissues (SCRINSHOT) and immunofluorescence. RESULTS: We generated a single-cell atlas of decidual tissues from normal pregnant, RSA, and WJ-MSC-treated mice and identified 14 cell clusters in the decidua on day 14. Among these cell populations, stromal cells were the most abundant cell clusters in the decidua, and we further identified three novel subclusters (Str_0, Str_1, and Str_2). We also demonstrated that the IL17 and TNF signaling pathways were enriched for upregulated DEGs of stromal cells in RSA mice. Intriguingly, cell-cell communication analysis revealed that Str_1 cell-related gene expression was greatly reduced in the RSA group and rescued in the WJ-MSC treatment group. Notably, the interaction between NK cells and other cells in the RSA group was attenuated, and the expression of Spp1 (identified as an endometrial toleration-related marker) was significantly reduced in the NK cells of the RSA group but could be restored by WJ-MSC treatment. CONCLUSION: Herein, we implemented scRNA-seq to systematically evaluate the cellular heterogeneity and transcriptional regulatory networks associated with RSA and its treatment with WJ-MSCs. These data revealed potential therapeutic targets of WJ-MSCs to remodel the decidual subpopulations in RSA and provided new insights into decidua-derived developmental defects at the maternal-foetal interface.

Machine-Learning-Assisted Development of Gel Polymer Electrolytes for Protecting Zn Metal Anodes from the Corrosion of Water Molecules.

Rechargeable aqueous zinc-ion batteries (RAZIBs) offer low cost, high energy density, and safety but struggle with anode corrosion and dendrite formation. Gel polymer electrolytes (GPEs) with both high mechanical properties and excellent electrochemical properties are a powerful tool to aid the practical application of RAZIBs. In this work, guided by a machine learning (ML) model constructed based on experimental data, polyacrylamide (PAM) with a highly entangled structure was chosen to prepare GPEs for obtaining high-performance RAZIBs. By controlling the swelling degree of the PAM, the obtained GPEs effectively suppressed the growth of Zn dendrites and alleviated the corrosion of Zn metal caused by water molecules, thus improving the cycling lifespan of the Zn anode. These results indicate that using ML models based on experimental data can effectively help screen battery materials, while highly entangled PAMs are excellent GPEs capable of balancing mechanical and electrochemical properties.

Unveiling the Origin of Fast Hydride Ion Diffusion at Grain Boundaries in Nanocrystalline TiN Membranes.

Nanocrystalline titanium nitride (TiN) has been determined to be a promising alternative to noble metal palladium (Pd) for fabricating base membranes for the energy-efficient production of pure hydrogen. However, the mechanism of transport of hydrogen through a TiN membrane remains unclear. In this study, we established an atomistic model of the transport of grain boundary hydride ions through such a membrane. High-resolution transmission electron microscopy and X-ray reflectivity confirmed that a nanocrystalline TiN1.0 membrane with a (100) preferred growth orientation retained about 4 Å-wide interfacial spaces along its grain boundaries. First-principles calculations based on the density functional theory showed that these grain boundaries allowed the diffusion of interfacial hydride ion defects with very small activation barriers (<12 kJ mol-1). This was substantiated by the experiment. In addition, the narrow boundary produced a sieving effect, resulting in a selective H permeation. Both the experimental and theoretical results confirmed that the granular microstructures with the 4 Å-wide interlayer enabled the transition metal nitride to exhibit pronounced hydrogen permeability.

VIRMA promotes the progression of head and neck squamous cell carcinoma by regulating UBR5 mRNA and m6A levels.

Head and neck squamous cell carcinoma (HNSCC) is a globally prevalent and lethal cancer form, whose precise mechanisms remain incompletely understood. Increasing evidence suggests that N6-methyladenosine (m6A) plays a crucial role in cancer progression. This study aimed to explore the biological function of m6A modification and vir-like m6A methyltransferase associated (VIRMA) in HNSCC. We conducted an analysis of VIRMA expression in HNSCC cells using The Cancer Genome Atlas (TCGA) database and employed reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting to assess its expression levels in HNSCC cell lines. Additionally, m6A levels in HNSCC cells were quantified, and the correlation between VIRMA expression levels and the clinical and pathological features of other genes was analyzed. Upon knocking down VIRMA levels, we assessed HNSCC cell proliferation, migration, and invasion and validated downstream genes using RT-qPCR and western blot. Our findings suggested that VIRMA, as an m6A-related regulator, may significantly influence HNSCC progression by regulating ubiquitin protein ligase E3 component N-recognin 5 (UBR5) through m6A modification. Therefore, VIRMA may serve as a prognostic biomarker.

Myricetin, a natural inhibitor of CD147, increases sensitivity of cisplatin in ovarian cancer.

BACKGROUND: Ovarian cancer (OC) is the most lethal gynecological tumor, but it currently lacks effective therapeutic targets. CD147, which is overexpressed in OC, plays a crucial role in promoting malignant progression and is associated with poor prognosis in patients. Therefore, CD147 has been identified as a potential therapeutic target. However, there is a limited amount of research on the development of CD147 inhibitors. METHODS: Surface plasmon resonance (SPR) assay and virtual molecular docking analysis were performed to identify potential natural compounds targeting CD147. The anti­tumor effects of myricetin were evaluated using various assays, including CCK8, Alkaline comet, immunofluorescence and xenograft mouse models. The underlying mechanism was investigated through western blot analysis and lentivirus short hairpin RNA (LV-shRNA) transfection. RESULTS: Myricetin, a flavonoid commonly found in plants, was discovered to be a potent inhibitor of CD147. Our findings demonstrated that myricetin exhibited a strong affinity for CD147 and down-regulated the protein level of CD147 by facilitating its proteasome-dependent degradation. Additionally, we observed synergistic antitumor effects of myricetin and cisplatin both in vivo and in vitro. Mechanistically, myricetin suppressed the expression of FOXM1 and its downstream DNA damage response (DDR) genes E×O1and BRIP1, thereby enhancing the DDR induced by cisplatin. CONCLUSION: Our data demonstrate that myricetin, a natural inhibitor of CD147, may have clinical utility in the treatment of OC due to its ability to increase genomic toxicity when combined with cisplatin.

Inositol hexaphosphate enhances chemotherapy by reversing senescence induced by persistently activated PERK and diphthamide modification of eEF2.

Oxaliplatin is an important initial chemotherapy benefiting advanced-stage colorectal cancer patients. Frustratingly, acquired oxaliplatin resistance always occurs after sequential chemotherapy with diverse antineoplastic drugs. Therefore, an exploration of the mechanism of oxaliplatin resistance formation in-depth is urgently needed. We generated oxaliplatin-resistant colorectal cancer models by four representative compounds, and RNA-seq revealed that oxaliplatin resistance was mainly the result of cells' response to stimulus. Moreover, we proved persistent stimulus-induced endoplasmic reticulum stress (ERs) and associated cellular senescence were the core causes of oxaliplatin resistance. In addition, we screened diverse phytochemicals for ER inhibitors in silico, identifying inositol hexaphosphate (IP6), whose strong binding was confirmed by surface plasmon resonance. Finally, we confirmed the ability of IP6 to reverse colorectal cancer chemoresistance and investigated the mechanism of IP6 in the inhibition of diphthamide modification of eukaryotic elongation factor 2 (eEF2) and PERK activation. Our study demonstrated that oxaliplatin resistance contributed to cell senescence induced by persistently activated PERK and diphthamide modification of eEF2 levels, which were specifically reversed by combination therapy with IP6.