Comprehensive transcriptional atlas of human adenomyosis deciphered by the integration of single-cell RNA-sequencing and spatial transcriptomics.

Adenomyosis is a poorly understood gynecological disorder lacking effective treatments. Controversy persists regarding "invagination" and "metaplasia" theories. The endometrial-myometrial junction (EMJ) connects the endometrium and myometrium and is important for diagnosing and classifying adenomyosis, but its in-depth study is just beginning. Using single-cell RNA sequencing and spatial profiling, we mapped transcriptional alterations across eutopic endometrium, lesions, and EMJ. Within lesions, we identified unique epithelial (LGR5+) and invasive stromal (PKIB+) subpopulations, along with WFDC1+ progenitor cells, supporting a complex interplay between "invagination" and "metaplasia" theories of pathogenesis. Further, we observed endothelial cell heterogeneity and abnormal angiogenic signaling involving vascular endothelial growth factor and angiopoietin pathways. Cell-cell communication differed markedly between ectopic and eutopic endometrium, with aberrant signaling in lesions involving pleiotrophin, TWEAK, and WNT cascades. This study reveals unique stem cell-like and invasive cell subpopulations within adenomyosis lesions identified, dysfunctional signaling, and EMJ abnormalities critical to developing precise diagnostic and therapeutic strategies.

Pterostilbene: a potential therapeutic agent for fibrotic diseases.

Fibrosis is a prevailing pathology in chronic diseases and accounts for 45% of deaths in developed countries. This condition is primarily identified by the transformation of fibroblasts into myofibroblasts and the overproduction of extracellular matrix (ECM) by myofibroblasts. Pterostilbene (PTS) is a natural analogue of resveratrol and is most commonly found in blueberries. Research has shown that PTS exerts a wide range of pharmacological effects, such as antioxidant, anti-inflammatory, and anticancer effects. As a result, PTS has the potential to prevent and cure numerous diseases. Emerging evidence has indicated that PTS can alleviate myocardial fibrosis, renal fibrosis, pulmonary fibrosis, hepatic fibrosis, and colon fibrosis via the inhibition of inflammation, oxidative stress, and fibrogenesis effects in vivo and in vitro, and the potential mechanisms are linked to various pathways, including transforming growth factor-ß1 (TGF-ß1)/small mother against decapentaplegic proteins (Smads) signalling, the reactive oxygen species (ROS)-driven Pitx2c/mir-15b pathway, nuclear factor kappa B (NF-κB) signalling, Kelch-like epichlorohydrin-associated protein-1 (Keap-1)/NF-E2-related factor-2 (Nrf2) cascade, the NLR family pyridine structure domain 3 (NLRP3) pathway, the Janus kinase-2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, and the Src/STAT3 pathway. In this review, we comprehensively summarize the antifibrotic effects of PTS both in vivo and in vitro and the pharmacological mechanisms, pharmacokinetics, and toxicology of PTS and provide insights into and strategies for exploring promising agents for the treatment of fibrosis.

Melatonin supplementation in the culture medium rescues impaired glucose metabolism in IVF mice offspring.

Increasing evidence suggests that in vitro fertilization (IVF) may be associated with an increased risk of developing obesity and metabolic diseases later in life in the offspring. Notably, the addition of melatonin to culture medium may improve embryo development and prevent cardiovascular dysfunction in IVF adult mice. This study aimed to determine if melatonin supplementation in the culture medium can reverse impaired glucose metabolism in IVF mice offspring and the underlying mechanisms. Blastocysts used for transfer were generated by natural mating (control group) or IVF with or without melatonin (10-6  M) supplementation (mIVF and IVF group, respectively) in clinical-grade culture media. Here, we first report that IVF decreased hepatic expression of Fbxl7, which was associated with impaired glucose metabolism in mice offspring. Melatonin addition reversed the phenotype by up-regulating the expression of hepatic Fbxl7. In vitro experiments showed that Fbxl7 enhanced the insulin signaling pathway by degrading RhoA through ubiquitination and was up-regulated by transcription factor Foxa2. Specific knockout of Fbxl7 in the liver of adult mice, through tail intravenous injection of recombinant adeno-associated virus, impaired glucose tolerance, while overexpression of hepatic Fbxl7 significantly improved glucose tolerance in adult IVF mice. Thus, the data suggest that Fbxl7 plays an important role in maintaining glucose metabolism of mice, and melatonin supplementation in the culture medium may rescue the long-term risk of metabolic diseases in IVF offspring.

Inhibition of Aberrant DNA Re-methylation Improves Post-implantation Development of Somatic Cell Nuclear Transfer Embryos.

Somatic cell nuclear transfer (SCNT) enables cloning of differentiated cells by reprogramming their nuclei to a totipotent state. However, successful full-term development of SCNT embryos is a low-efficiency process and arrested embryos frequently exhibit epigenetic abnormalities. Here, we generated genome-wide DNA methylation maps from mouse pre-implantation SCNT embryos. We identified widespread regions that were aberrantly re-methylated, leading to mis-expression of genes and retrotransposons important for zygotic genome activation. Inhibition of DNA methyltransferases (Dnmts) specifically rescued these re-methylation defects and improved the developmental capacity of cloned embryos. Moreover, combining inhibition of Dnmts with overexpression of histone demethylases led to stronger reductions in inappropriate DNA methylation and synergistic enhancement of full-term SCNT embryo development. These findings show that excessive DNA re-methylation is a potent barrier that limits full-term development of SCNT embryos and that removing multiple epigenetic barriers is a promising approach to achieve higher cloning efficiency.