Emodin retards renal cyst progression in ADPKD by inhibiting cell proliferation and decreasing oxidative stress.

Integrated methylome and hydroxymethylome analysis identifies CAMK2G, NFATC4, and SFRP2 as TET1-regulated drivers of odontoblastic differentiation in human dental pulp cells.

Da-Bu-Yin-Wan rescues cognitive deficits in aging and Alzheimer's disease models by Wnt/β-catenin-dependent restoration of lysosomal acidification.

Shell gland RNA-seq reveals key genes regulating eggshell quality and potential links between eggshell quality and hatchability across different laying stages.

Duhuo Jisheng decoction alleviates knee osteoarthritis via synovial mesenchymal stem cell-derived exosomes mediating the microRNA-194-5p/wnt signaling pathway.

Bone inflammation in postmenopausal women with type 2 diabetes or obesity in relation to Wnt signaling and bone strength.

METTL14 deficiency impairs chondrogenic differentiation via m6A-dependent TRAF4 mRNA regulation in Kashin-Beck disease.

From wrinkles to malignancy: small-molecule-mediated stem cell approaches in skin aging.

Analysis of WNT5A as a key regulator of intramuscular fat deposition in muscle-adipocyte co-cultures.

Investigating the effect of Dingxian Pill on hippocampal neuronal pyroptosis in epilepsy through regulation of the circRNA-Csnk1g3/Wnt/β-catenin pathway.

Integrative metabolome and transcriptome analyses provide insights into skeletal muscle development of two duck breeds during embryonic stage.

This review focuses on experimental models developed to study myeloma bone disease (MBD), a major cause of morbidity in multiple myeloma (MM). Under physiological conditions, bone remodeling is regulated by osteoclasts (OCs) and osteoblasts (OBs); in MM, this balance is disrupted, resulting in enhanced bone resorption and suppressed bone formation. Myeloma cells alter the bone marrow (BM) microenvironment by increasing the RANKL/OPG ratio and secreting Wnt pathway inhibitors such as DKK-1 and sclerostin, thereby promoting osteoclastogenesis and inhibiting osteoblast differentiation. To dissect these mechanisms and evaluate therapeutic strategies, diverse preclinical systems have been developed. Syngeneic murine models, notably the 5T series, remain the most established for reproducing both osteolysis and impaired bone formation, though interspecies differences limit translational relevance. Humanized mouse systems and three-dimensional (3D) in vitro models increasingly address these constraints by incorporating human stromal and hematopoietic elements. Emerging induced pluripotent stem cell-derived bone marrow organoids (iBMOs) offer a fully human platform capable of modeling both osteoclast and osteoblast dynamics. While current iBMOs lack mineralized bone and mature vascular or immune components, advances in differentiation control and matrix engineering are expected to bridge these gaps, providing physiologically relevant and ethically sustainable models for studying MBD and testing therapeutic interventions.

CTNNB1-mutated hepatocellular carcinomas are characterized by a distinctive morphology and activation of the Wnt pathway. AXIN1 also plays a key role in the Wnt pathway, but the morphology of AXIN1-mutated tumors has not been examined. In addition, there are ongoing questions on the ability of AXIN1 mutations to activate the Wnt pathway in hepatocellular carcinoma. AXIN1 mutated tumors (N=18) were studied, along with control groups: CTNNB1 (N=17), APC (6), or "Other" genes in the Wnt pathway (5). Wnt pathway activation was studied by immunostains for beta-catenin and glutamine synthetase. Findings were supplemented by gene expression analysis using TCGA data. On histologic examination, the classic morphology associated with beta-catenin mutations was found in all 4 groups: 8/18 AXIN1 (44%), 10/17 CTNNB1 (59%), 4/6 APC (67%), and 1/5 Other (20%). By immunohistochemistry, Wnt pathway activation was found in 11/18 AXIN1 (61%), 15/17 CTTNB1 (88%), 6/6 APC (100%), and 5/5 (100%) of Other. In AXIN1-mutated tumors, the Wnt pathway was weakly activated. Glutamine synthetase stains also highlighted a new "progressed pattern" associated with distinct subnodules of staining. Tertiary lymphoid structures were uncommon except for cases with CTTNNB1 mutations plus additional mutations in the Wnt pathway. In summary, the classic morphology associated with CTNNB1 mutations is found in hepatocellular carcinomas with mutations in AXIN1, APC, and other Wnt genes. AXIN1 mutated tumors have Wnt activation that is detectable but at lower levels than CTNNB1 mutated tumors. As tumors progress, their level of Wnt activation can change.

Trophoblast and amniotic lineages, representing key extra-embryonic tissues, can be differentiated from human pluripotent stem cells (hPSCs) under chemically defined conditions. However, the regulatory mechanisms coordinating the fate decision between these lineages during PSC differentiation remain incompletely understood. Leveraging CRISPR/Cas9-mediated loss-of-function screening in lineage-reporter PSCs, we identified the transcription factor HAND1 as a critical determinant controlling the bifurcation of trophoblast and amniotic lineages. Genetic ablation ofHAND1effectively abrogated the amniotic differentiation capacity of PSCs while concomitantly enhancing their trophoblast differentiation potential. Conversely, ectopic HAND1 overexpression impaired trophoblast differentiation. Notably, forced HAND1 expression in human trophoblast stem cells (TSCs) induced transcriptional reprogramming toward an amniotic fate, indicating its lineage-instructive capability. Mechanistic analyses demonstrated that HAND1 interacts with the TCFs and Wnt signaling effectors β-catenin to form a transcriptional complex that antagonistically modulates the balance between trophoblast- and amnion-associated gene regulatory networks. Collectively, our findings establish HAND1 as a master regulator orchestrating the amniotic versus trophoblast lineage choice during human PSC differentiation, thereby illuminating fundamental regulatory mechanism underlying extra-embryonic lineage specification.

Radiation proctitis (RP) is a frequent complication of pelvic radiotherapy that compromises treatment delivery and patient quality of life, yet the factors shaping injury severity remain incompletely defined. We prospectively profiled pretreatment fecal microbiomes and metabolomes from 55 patients and stratified them by outcome into mild versus severe RP. Baseline microbial composition showed Bacteroidales enriched in severe RP and Firmicutes enriched in mild cases. Multi-omics integration highlighted nicotinate/nicotinamide pathways; severe RP was characterized by concomitant reductions in both fecal and tissue NAD⁺ levels, along with an enrichment of microbial nicotinate/nicotinamide metabolism genes, primarily contributed by Bacteroides ovatus, B. xylanisolvens, and B. fragilis. In mice, fecal microbiota transplantation from severe-RP donors exacerbated radiation-induced colorectal injury and decreased colorectal NAD⁺, supporting a causal role for the microbiota. Gavage with Bacteroides similarly worsened pathology and lowered NAD⁺, whereas nicotinamide mononucleotide (NMN) supplementation attenuated the injury. Mechanistically, Bacteroides gavage reduced mitochondrial membrane potential, decreased the Lgr5⁺ stem-cell proportion and proliferative indices, associated with Wnt pathway modulation. NMN reversed these effects in parallel with NAD⁺ restoration. Together, these results identify a microbiota‒metabolite association wherein Bacteroidales enrichment is associated with NAD⁺ depletion, reduced mucosal proliferative capacity, and exacerbated radiation-induced colorectal injury. The work deepens insight into RP pathogenesis and suggests a potential basis for microbiome- and metabolite-targeted approaches to attenuate severe RP.

MicroRNAs (miRNAs) are key regulators of bone regeneration. We investigated the role of miR-21 in humeral fracture (HF) healing, focusing on its interaction with the SMAD7/Wnt/β-catenin signaling axis. Serum and tissue levels of miR-21 were analyzed in HF patients and healthy controls using qRT-PCR. A rat HF model was established, and agomiR-21 was administered to evaluate its effect on fracture healing. Histological analysis using hematoxylin and eosin (H&E) staining was performed to assess bone tissue morphology and fracture healing. In vitro, MC3T3-E1 osteoblasts were transfected with miR-21 mimics to assess cell viability (CCK-8), proliferation (EdU), apoptosis (flow cytometry), migration (Transwell assay), and osteogenic differentiation (Western blot). The downstream target of miR-21 was identified using bioinformatics and validated via luciferase reporter and RNA immunoprecipitation assays. Rescue experiments involving SMAD7 overexpression and Wnt/β-catenin inhibitors (DKK1) were conducted to explore the mechanism of action. Serum analysis revealed reduced β-catenin and phosphorylated GSK3β (p-GSK3β) levels in humeral fracture (HF) patients compared to healthy controls, indicating suppressed Wnt/β-catenin signaling. In MC3T3-E1 cells, miR-21 overexpression enhanced osteogenic markers and increased total β-catenin, active β-catenin, and p-GSK3β levels, confirming activation of the Wnt/β-catenin pathway. Dual-luciferase and expression analyses demonstrated that miR-21 directly targets SMAD7, a known Wnt pathway inhibitor. Co-transfection with SMAD7 reversed the effects of miR-21 on β-catenin activation, ALP activity, and osteogenic gene expression. Additionally, miR-21 knockdown impaired osteogenesis, further supporting its regulatory role. Importantly, in vivo, agomiR-21 treatment enhanced osteoblast activity and significantly promoted bone healing in a rat fracture model, reinforcing the therapeutic potential of miR-21-mediated SMAD7 suppression and Wnt/β-catenin pathway activation in bone regeneration. miR-21 promotes bone regeneration after humeral fracture by enhancing osteoblast function and activating Wnt/β-catenin signaling through direct inhibition of SMAD7.

The antiaging protein Klotho is a key factor in susceptibility to cerebral ischemia.

Colitis-associated carcinoma (CAC) represents ~1% of colorectal carcinomas and has important differences from sporadic colorectal carcinoma (sCRC). The precursors and carcinomas that arise in the setting of IBD are uniquely challenging to visualize by endoscopy and diagnose via histology, and the rising prevalence of IBD amplifies the challenges of surveillance to informed management. Although in broad strokes, CAC and sCRC share molecular features (~85% chromosomal instability pathway 15% microsatellite instability high (MSI-H)), CAC has a distinct distribution of molecular abnormalities, including lower frequencies of APC and KRAS mutations, greater prevalence of IDH1R132H, and more frequent copy number alterations (e.g., MYC amplifications), and functional data indicate that most CACs show far less dependence on Wnt signaling than sCRC, suggesting a distinct pathogenesis from the earliest stages. Although there are significant gaps in our knowledge of the pathogenesis of CAC, our understanding is growing. This review summarizes how chronic colitis reshapes epithelial homeostasis and somatic evolution, resulting in the distinctive pathogenesis of CAC, and highlights knowledge gaps that could be addressed by applying multimodal technologies to well-annotated clinical material. The review is structured in two sections, the first introducing the IBDs and the homeostatic mechanisms that preserve integrity and prevent colorectal neoplasia. The second section compares failure modes in sporadic and colitic settings and describes the differences in the resulting neoplasms.

ABSTRACT Endometrial polyps (EPs) are common uterine lesions associated with abnormal uterine bleeding and infertility, yet their pathogenesis remains poorly defined. Here, we performed single‐cell RNA sequencing of normal endometrium, para‐polyp, and polyp tissues, identifying distinct cellular compositions and transcriptional programs. EPs showed enhanced estrogen signaling and increased epithelial proliferation, accompanied by decreased expression of cytokines and reduced T cell cytotoxicity. Notably, we observed epithelial subpopulations with elevated copy number variations and transcription factors associated with hyperplasia. Cell–cell communication analyzes revealed aberrant stromal‐epithelial crosstalk, characterized by upregulated WNT, IGF, and VEGF signaling originating from stromal cells. Spatial transcriptomic analyzes further demonstrated enhanced WNT signaling between stromal and epithelial compartments in endometrial cancer. In vitro glandular organoid models showed that epithelial transcriptional alterations contribute to polyp formation. These findings highlight a critical role of stromal‐epithelial interactions in EP development and suggest potential therapeutic targets.

Starting from human colon cancer cells showing aberrant WNT/β-catenin/TCF signaling, hyperactivated MYC, and silenced BASP1, we generated stable cell lines overexpressing BASP1, either ectopically, or by reactivating the dormant BASP1 promoter using a lentiviral CRISPR-based system. BASP1 encodes a neuronal signaling protein and transcriptional corepressor, from which tumor-suppressive functions have been described in avian cell systems and in multiple human cancer cell types. Proteome and transcriptome analyses revealed activation of several tumor and metastasis suppressors in BASP1-expressing cells, which also show strong repression of the transformed phenotype in terms of contact inhibition, anchorage-independent growth, and tumor formation. Cells with reactivated BASP1 display a flat and differentiated morphology with enhanced migratory potential, accompanied by expression of multiple genes implicated in actin polymerization, focal adhesion, and neuronal migration. Furthermore, MYC protein expression is substantially repressed due to BASP1-mediated transcriptional MYC downregulation involving BASP1 interaction with β-catenin and binding to the MYC promoter. Upon BASP1 activation, multiple key proteins of the canonical WNT signaling pathway become suppressed. One of these BASP1 targets is the protein kinase TNIK catalyzing phosphorylation of TCF7L2, the latter required for transcriptional MYC activation. Results obtained with a preclinical TNIK inhibitor in human colorectal cancer cells show efficient abrogation of MYC expression and consequently impaired dimerization with its interaction partner MAX. The antagonistic BASP1 effect on MYC and the MYC dependency on TNIK could enhance the development of strategies to interfere with oncogenic functions of the cancer driver MYC.