Esophageal cancer (EC) is a highly prevalent malignant tumor worldwide, with a particularly high incidence in regions such as Asia. The poor prognosis of EC is attributed mainly to late detection, high invasiveness, and limited treatment efficacy. Growing evidence has revealed a close association between the adverse outcomes of EC and the tumor microenvironment (TME). This review comprehensively summarizes advances made from 2020 to 2025 in understanding the TME of EC based on single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. First, we illustrate the heterogeneity of major cellular components within the TME, with a focus on subtype classification, dynamic phenotypic changes, and the clinical significance of T cells, B cells, tumor-associated macrophages (TAMs), dendritic cells (DCs), and cancer-associated fibroblasts (CAFs). Then, we highlight the functional crosstalk mechanisms underlying anti-tumor immunity and the dual regulatory role of tertiary lymphoid structures (TLS) in the TME. Finally, we address current challenges in EC TME research, including inconsistencies in cell subtype classification, significant inter-patient heterogeneity, and incomplete understanding of cellular crosstalk signaling networks. We aim to provide a foundation for further mechanistic exploration of the EC TME and to support the development of novel therapeutic strategies.
Toludesvenlafaxine, a novel serotonin-norepinephrine-dopamine reuptake inhibitor, has shown promise in treating depression, yet direct comparisons with venlafaxine, a standard serotonin-norepinephrine reuptake inhibitor (SNRI), remain limited, especially in the anhedonia facet. To address this gap, an 8-week multicenter, open-label, randomized controlled trial was conducted to compare toludesvenlafaxine with venlafaxine as a monotherapy for major depressive disorder (MDD). Assessments were performed at baseline and Weeks 2, 4, and 8, including evaluations of anhedonia (Snaith–Hamilton Pleasure Scale [SHAPS] and Dimensional Anhedonia Rating Scale [DARS]), general depressive symptoms (Montgomery–Åsberg Depression Rating Scale [MADRS], 17-item Hamilton Depression Rating Scale [HAMD-17], and Self-Rating Depression Scale [SDS]), and quality of life (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form [Q-LES-Q-SF]), as well as safety (Treatment Emergent Symptom Scale [TESS]) and sexual function (Arizona Sexual Experience Scale [ASEX]). The results showed that compared with venlafaxine, toludesvenlafaxine had an earlier onset of action at Week 2 in improving MADRS and HAMD-17 scores, along with alleviating anhedonia and suicidal ideation. At Week 8, however, the SHAPS scores were comparable between the two groups, indicating their similar efficacy in treating anhedonia. In terms of safety, toludesvenlafaxine exhibited significantly lower levels of triglycerides and total bilirubin, while other indices demonstrated no significant difference. Overall, both drugs showed comparable efficacy and safety profiles for MDD over the 8-week treatment period, with toludesvenlafaxine potentially acting more rapidly.
DNA methylation, a key epigenetic modification, contributes to regulatory diversity in plants and plays important roles in phenotypic plasticity and environmental adaptation. Recent population epigenomic studies have revealed extensive methylation variation across plant genomes, characterized genomic distribution and genetic architecture, and demonstrated both its dependence on and partial independence from underlying DNA sequence variation. These studies have further linked methylation variation to gene expression regulation, domestication, local adaptation, and complex trait variation through integrative analyses and epigenome-wide association research. Advances in high-throughput sequencing have enabled the generation of population-scale plant methylomes across natural accessions, wild relatives, landraces, and breeding germplasm, providing new avenues to systematically investigate epigenomic diversity and its functional consequences. In parallel, public methylome resources, epigenomic databases, and multi-omics analytical platforms are accelerating comparative and cross-species analyses of plant epigenomic variation. Future efforts that integrate population methylomes with genomics, transcriptomics, chromatin accessibility, three-dimensional genome organization, deep learning-based analytical frameworks, and targeted epigenome editing are expected to facilitate the discovery of epigenetic breeding markers, promoting the application of epigenomic variation in crop improvement.
The bidirectional relationship between pathological microenvironments and mesenchymal stem/stromal cells (MSCs) is known as a pivotal factor influencing the progression of bone-related disease and therapeutic outcomes. MSCs, characterized by their remarkable plasticity and excellent immunomodulatory abilities, play central roles in various physiological and pathological processes, especially in bone regeneration and repair. Under pathological conditions, such as osteoarthritis, osteoporosis, or bone tumors, the tissue microenvironment can significantly alter MSC behavior, leading to impaired differentiation, dysregulated immune responses, or abnormal tissue remodeling. This dynamic relationship is regulated by diverse molecular signals, where long non-coding RNAs (lncRNAs) emerge as critical regulators of MSC biology. LncRNAs influence MSC differentiation, immunomodulatory functions, and responses to microenvironmental cues through diverse molecular mechanisms. The systematic review elucidates the roles of various lncRNAs involved in different aspects of MSC biology under pathological conditions and their potential as therapeutic targets or biomarkers for bone-related disorders.
Apelin receptor (APLNR) is a crucial G protein-coupled receptor that plays a central role in cardiovascular homeostasis; therefore, it represents a promising therapeutic target for heart failure, myocardial infarction, cardiac hypertrophy, and pulmonary arterial hypertension. However, the activation of APLNR simultaneously engages inhibitory G protein (Gi)-mediated protective signaling and β-arrestin pathways that are associated with pathological cardiac remodeling, thereby imposing significant limitations and challenges for the therapeutic development of conventional balanced agonists. Recent advances in structural biology and pharmacology have provided valuable mechanistic insights into receptor activation and biased signaling. High-resolution cryoelectron microscopy (cryo-EM) structures revealed the conformational basis of signal bias, enabling the rational design of fully G protein-biased agonists that retain cardiovascular benefits while avoiding hypertrophic effects. This review summarizes recent progress in APLNR signaling mechanisms and biased ligand development, highlighting a number of emerging strategies for the precision pharmacological targeting of this receptor.
