Periodontitis and rheumatoid arthritis, as chronic inflammatory diseases that share epidemiological associations and immunopathological characteristics, have various forms of programmed cell death (PCD) that play a core role in their pathogenesis, which form an important link between the two. The comorbidity of periodontitis and rheumatoid arthritis suggests that there might be a common immune regulatory mechanism, with PCD pathways playing a key role in regulating immune responses. Particularly, the Th17/Treg imbalance and apoptosis resistance in CD4 + CD28 − T cells emerge as shared T cell–centered mechanisms bridging periodontal infection to rheumatoid autoimmunity. Studying how PCD works in periodontitis and rheumatoid arthritis can help uncover the potential links between the two diseases, which provides new targets for clinical treatment and improves patient prognosis. In this article, we’ll review relevant research and discuss how PCD is important for immune regulation in periodontitis and rheumatoid arthritis, which provides a theoretical basis for future treatment strategies for both conditions, helping to control the progression of inflammation more effectively.
Glioma is characterized by profound metabolic reprogramming and sustained lactate accumulation; however, the mechanisms by which lactate-rich metabolic stress is translated into stable malignant phenotypes remain incompletely understood. Lysine lactylation (Kla), a recently identified post-translational modification, has emerged as a critical nexus linking lactate metabolism to durable epigenetic and protein-state adaptations. In glioma, accumulating evidence indicates that Kla contributes to multiple dimensions of tumor biology, including oncogenic transcriptional activation, glioma stem-like cell (GSC) maintenance, immunosuppressive remodeling, and therapeutic resistance. Mechanistically, histone Kla rewires metabolic stress-responsive transcriptional programs, whereas non-histone Kla executes rapid, transcription-independent responses by directly modifying key regulatory proteins involved in DNA repair, signal transduction, and metabolic adaptation. This review systematically summarizes current progress on the lactate-Kla axis in glioma, encompassing the basis of lactate metabolism, the molecular regulatory network of Kla, and the distinct yet coordinated functions of histone and non-histone lactylation. We further discuss how Kla contributes to temozolomide (TMZ) resistance, radioresistance, and chemoradiotherapy adaptation, and outline a hierarchical therapeutic framework targeting this pathway. Despite rapid advances, important areas requiring further investigation include subtype-specific variation in lactate–Kla biology and the potential crosstalk between Kla and other post-translational modifications. A better understanding of these issues will help define the biological significance of the lactate–Kla axis and guide the future development of lactylation-based therapeutic strategies in glioma.
Chronic stress contributes to major depressive disorder (MDD) phenotypes by disrupting coordinated neuromodulatory systems and their corresponding computational frameworks. In this review, we explore how the dynamic interplay of ventral tegmental area dopamine (DA) signaling, microcircuit gating, and prediction error mechanics orchestrates stress-induced depressive behaviors, such as anhedonia and amotivation. Rather than acting as the sole driver of depression, pathway-specific neuroadaptations across mesolimbic ( VTA → NAc ) and mesocortical ( VTA → PFC ) dopaminergic projections operate within a broader multi-transmitter landscape, interacting with serotonergic, noradrenergic, cholinergic, and glutamatergic/GABAergic systems. These signaling anomalies often translate into computational deficits in reinforcement learning, manifesting as blunted striatal reward prediction error (RPE) signals that scale directly with anhedonia severity. Chronic stress also disrupts cortical microcircuit gating governed by dopamine D 1 and D 2 receptors, inducing cellular senescence and collapsing ensemble synchrony within the prefrontal cortex and interconnected networks. Furthermore, specialized subcortical loops, including inputs from the nucleus accumbens (NAc), ventral hippocampus (vHIPP), lateral habenula (LHb), and locus coeruleus (LC), recalibrate overall susceptibility versus resilience by altering DA firing dynamics and population activity pools, often in a sex-specific manner. By bridging synaptic dopamine dynamics, subcortical prediction errors, and cortical ensemble synchrony, we propose a unified, multi-level framework demonstrating how stress-induced depressive behaviors result from a progressive breakdown in the brain’s predictive coding and adaptive coping networks.
Embryonic stem cells are self-renewing, pluripotent cells, normally maintained by several pluripotency transcription factors. To respond to diverse differentiation and stress signaling pathways, the undifferentiated cell state must be destabilized before embryonic stem cells can properly interpret external signals to decide the cell fate. It remains incompletely understood how diverse signals promote the exit of the self-renewal state. Here, we show that both acute DNA damage and diverse differentiation signaling pathways converge at the proteasomal destruction of Estrogen-related receptor β (ESRRB), a key pluripotency transcription factor. Environmental agents such as UV light and genotoxic chemicals activate P-TEFb protein kinase to directly phosphorylate ESRRB to promote its proteasomal degradation. On the other hand, diverse differentiation signaling pathways also promote ESRRB degradation. Interestingly, the responsible kinase is GSK3β, instead of P-TEFb, in these biological contexts. Substituting five Ser residues in ESRRB with Ala confers resistance to GSK3β-dependent ESRRB degradation and compromises cell differentiation. These results demonstrate that conserved post-translational modifications in ESRRB integrate diverse signaling pathways to govern the fate of embryonic stem cells.
Xiaoling Wang, Zhaohua Lai, Hanlu Chen, Mei Yang, Huapei Kang, Fangsheng Wang, Junyun Huang, Yuxin Deng
Extracellular vesicles (EVs), as key mediators of intercellular communication, play a critical regulatory role in the pathogenesis and treatment of colorectal cancer (CRC). By carrying diverse bioactive molecules—including miRNAs, lncRNAs, circRNAs, and DNA—EVs influence multiple components of the tumor microenvironment (TME), such as promoting macrophage M2 polarization, reducing T and B Cell activity and proliferation, enabling evasion of natural killer (NK) cell surveillance, and regulating bidirectional fibroblast interactions in CRC. Furthermore, CRC-derived EVs can promote CRC metastasis by stimulating angiogenesis in endothelial cells, facilitating epithelial-mesenchymal transition (EMT), and promoting the formation of pre-metastatic niches. Through an analysis of the role of EVs in the pathogenesis of CRC, numerous studies have found that EVs can augment the efficacy of immunotherapy. At the same time, both mesenchymal stem cell-derived EVs and engineered EVs (such as plant-derived and microorganism-derived EVs) can play significant roles in the treatment of CRC. However, most current research remains in the in vitro and in vivo trial stages. Due to difficulties in purification and engineering, as well as inherent heterogeneity, clinical translation remains challenging; consequently, no related products have yet been brought to market. Most clinical studies remain focused on diagnostic applications, while trials for therapeutic applications are still recruiting participants. Against this backdrop, we highlight the limitations and challenges in EVs research, with the aim of providing better research directions for the clinical translation of CRC treatments.
