Journal of Cellular Physiology最新文献

Sperm capacitation involves proteolytic remodeling of membrane proteins, including components of the CatSper calcium channel, which is essential for hyperactivation and male fertility. Here, we identify the seminal protease inhibitor SPINK3, a known decapacitation factor that suppresses premature capacitation in the female tract, as the first physiological inhibitor of CATSPER1 processing. In mouse sperm, SPINK3 blocks capacitation-induced CATSPER1 cleavage, preserving a subpopulation with intact CatSper channels and lacking pTyr development in the flagellum. SPINK3 localizes to the outer surface of the sperm principal piece membrane in a CatSper-dependent but non-quadrilateral pattern, stabilizes membrane organization, and delays cholesterol efflux. These results reveal SPINK3 as a multifunctional regulator of capacitation, shaping sperm subpopulations in the female reproductive tract.

Heart failure (HF) significantly limits survival and decreases quality of life. The global incidence of HF is rising. The pathogenesis of HF is not yet fully understood, which results in the present treatment options still being imperfect. Therefore, there is a need to deepen the knowledge about HF pathogenesis and identify potential therapeutic targets. Aging increases the risk of developing HF. Recently, cellular senescence, a stable state of cell cycle arrest induced by various stressors or genomic damage, has been recognized to be involved in HF pathogenesis. Senescent cells may be involved in the development of age-related diseases. However, cellular senescence may occur in correlation with aging or be age-independent. Its impact is complex, especially since the heart is composed of different cell types, each of which may undergo senescence in diverse ways. Elimination of senescent cells also emerges as a potential treatment option. This article extensively reviews relations between cellular senescence and HF. Moreover, it describes the role of plasma proteins related to cellular senescence as potential biomarkers and prognostic factors in HF. This review also summarizes data concerning therapeutics targeting senescence in the HF context and implicates future research perspectives.

Periodontitis is a predominant persistent inflammatory disease marked by consistent destruction of tooth-supporting tissues including periodontal ligament and alveolar bone. Although some cytokines have been identified as key mediators, the upstream regulatory molecules that drives this pathological bone loss remains elusive. This study explores the mechanistic role of lncRNA ZFAS1 in the dysregulated bone remodeling of periodontitis microenvironment. We utilized single-cell and bulk RNA sequencing to profile cellular and molecular landscape in healthy and diseased periodontal tissues. GSEA analysis of bulk transcriptomes confirmed a significant activation of osteoclast-related pathways in disease (NES = 1.7, FDR q = 0.025). Findings were validated through qPCR, histology, and immunohistochemistry. The gain- and loss-of-function models in RAW264.7 and MC3T3-E1 cells to characterize the role of lncRNA ZFAS1 in vitro. The scRNA-seq analysis unveiled a marked 11-fold increase in osteoclast-osteoblast ratio in periodontitis, which was further confirmed histologically. This shift was accompanied by a specific inflammatory profile, and a marked upregulation of lncRNA ZFAS1 in diseased tissues. Notably, ZFAS1 expression showed a robust positive correlation with early osteoclast marker genes NFATC1 (R² = 0.2056, p = 0.015) and TRAP1 (R² = 0.784, p < 0.0001) but not the late-stage effector CTSK (R² = 0.0011, p = 0.792). We confirmed that lncRNA ZFAS1 expression was precisely induced by the synergetic effect of differentiation (RANKL) and inflammatory (LPS) signals. Functionally, lncRNA ZFAS1 overexpression in RAW264.7 potentiated osteoclastogenesis, enhanced TRAP-positive osteoclasts and increased resorptive gene expression (NFATC1, Dcstamp, ACP5, CTSK, V-ATPase d2), while its knockdown exhibited the opposite effect. In contrast, lncRNA ZFAS1 knockdown in MC3T3-E1 boosted differentiation and matrix mineralization, augmented osteoblast-related gene expression (Runx2, ALP, OCN). In summary, lncRNA ZFAS1 is a critical driver of inflammatory bone loss, functioning as a dual-path regulator that promotes osteoclastogenesis and inhibits osteoblastogenesis. Its physiological role as a negative osteogenic regulator is evidenced by its downregulation during normal differentiation, highlighting its therapeutic potential for periodontitis and related conditions.

O-GlcNAcylation is a post-translational modification involved in various cellular processes, including cell cycle progression, signaling, transcription, and stress response. Mouse salivary gland morphogenesis shows specific localization patterns of O-GlcNAc transferase (OGT) and O-GlcNAc in developing acinar cells, suggesting a potential involvement of O-GlcNAcylation in acinar cell differentiation-related signaling molecules. To define its underlying mechanisms, this study used an OGT inhibitor, OSMI-1, and small interfering RNA (siRNA) targeting OGT, during in vitro cultivation of submandibular glands and assessed morphological and molecular alterations using histology, immunohistochemistry, Western blot, and RT-qPCR. As expected, OGT inhibition impaired terminal bud morphogenesis and altered cellular physiology. OSMI-1 treatment disrupted acinar cell differentiation, reflected by changes in expression patterns of signaling molecules crucial to acinar cell differentiation, including Sox9, Sox10, E-cadherin, and Mist1. Altered expression patterns of cytokeratins, including CK14 and CK18, confirmed altered ductal morphology. Therefore, our findings highlight the essential role of OGT-mediated O-GlcNAcylation in salivary gland morphogenesis with post-translational regulation of key signaling molecules governing functional differentiation of acinar cells.

Atherosclerosis (AS), the primary pathological basis of cardiovascular diseases, is driven by lipid deposition, chronic inflammation, and vascular wall fibrosis. Nevertheless, persistent inflammatory environments and plaque instability remain significant clinical challenges. G protein-coupled receptors (GPCRs), constituting the largest family of membrane receptors in humans, play a central role in AS progression by modulating macrophage polarization, vascular smooth muscle cells (VSMCs) proliferation and migration, and oxidized low-density lipoprotein (ox-LDL) metabolism. Macrophage polarization dictates the inflammatory microenvironment within plaques; GPCRs modulate macrophage phenotypes through downstream signaling pathways, thereby exacerbating or mitigating inflammation. Furthermore, GPCRs regulate VSMCs phenotypic switching, critically influencing the stability of the plaque fibrous cap. Additionally, the interplay between GPCRs and ox-LDL exacerbates endothelial dysfunction and amplifies inflammatory signaling. This review comprehensively summarizes the roles of GPCR family members in AS pathogenesis and explores targeting these molecules as a promising therapeutic strategy for AS, thus highlighting their potential for multi-targeted intervention.

Chronic metabolic disorders and aging cause accumulation of dicarbonyls that glycate and render biomolecules dysfunctional. Although systemic metabolic dysregulation is associated with faster cancer progression, their mechanistic determinants remain elusive. We move between time-lapse and end-point experiments and tissue-scale simulations to build a systems model of ovarian cancer colonization and show that confluent healthy serosal mesothelia can stall spheroidal adhesion and spread. However, mesothelial clearance by spheroids continues under increasing concentrations of the dicarbonyl methylglyoxal (MG). High MG levels glycate mesothelia and destabilize their adhesion and motility through mislocalization of F-actin, ezrin, and ZO-1. This explains preferential spheroidal spreading amidst sub-confluent mesothelia. Confluence is dependent on mesothelial viability, which is also decreased by MG. Intriguingly, cancer cells escape glycation and its cytopathological effects by expressing relatively higher levels of glyoxalase 1 (GLO1); pharmacological GLO1 inhibition renders cancer cells vulnerable to MG. Thus, inhibition of stromal glycation holds promise for incorporation into personalized oncotherapy.

Ghrelin is a multifunctional peptide hormone with receptors present in various brain tissues including the hippocampus and has been associated with neuroprotection, neuromodulation, and memory processing. Ghrelin is an endogenous ligand for growth hormone secretagogue receptors (GHSRs). Here we studied the roles and mechanisms of ghrelin in glutamatergic transmission at the perforant path (PP)-granule cell (GC) synapses in the dentate gyrus by recording AMPA EPSCs in hippocampal slices cut from both male and female C57BL/6 J mice. Our results showed that ghrelin concentration-dependently elicited a persistent enhancement of AMPA EPSCs. The ghrelin-induced augmentation of glutamatergic transmission was mediated by increasing presynaptic glutamate release because ghrelin decreased the coefficient of variation (C.V.) and paired-pulse ratio of AMPA EPSCs, increased NMDA EPSCs as well and enhanced the frequency with no effect on the amplitude of mEPSCs. Ghrelin enlarged the size of readily releasable pool and increased release probability. Ghrelin-elicited increases in glutamate release did not require the functions of Gαq-phospholipase C pathway and Gαi, but was dependent on Gαs and cAMP/EPAC/PI3K pathway. As GHSRs have been shown to activate cAMP signals via heterodimerization with dopamine D₁ receptors, we probed the roles of D₁ receptors in ghrelin-mediated facilitation of glutamate release. Our results indicated that ghrelin enhanced glutamate release via interaction with D₁ receptors. Our results may provide a novel cellular and molecular mechanism whereby ghrelin enhances glutamatergic transmission.