Frontiers in Cell and Developmental Biology最新文献

The high mortality rate of lung cancer primarily results from its late-stage diagnosis, at which point metastasis has usually occurred and therapeutic options are limited, leading to an overall 5-year survival rate below 20% in most countries. The current screening method, low-dose computed tomography (LDCT), faces challenges such as high false-positive rates, which can result in overdiagnosis and unnecessary surgeries, as well as the risk of cancer due to repeated exposure to ionizing radiation. Although tumor tissue detection remains the gold standard for cancer diagnosis, it is limited by invasive sampling procedures that may cause patient trauma, as well as by tumor heterogeneity and inconsistent tissue quality, which can compromise diagnostic accuracy. Due to these challenges among others, researchers have been exploring better diagnostic methods that are not only sensitive and specific but also non-invasive, utilizing easily available samples with good reproducibility. In recent years, studies have revealed that humoral-derived materials, such as exosomal RNAs and proteins are considered the most promising biomarkers for the early diagnosis of lung cancer in body fluids owing to their stability, accessibility, and specificity. This study reviews current research on the exploration of exosomes as early diagnostic markers for lung cancer. Both established methods and emerging technologies, such as surface-enhanced Raman spectroscopy (SERS), lateral flow immunoassays (LFIA), microfluidics, and electric field-induced release and measurement (EFIRM), as well as commercial products, are discussed.

Background: Hepatocellular carcinoma (HCC), the predominant pathological subtype of primary liver cancer, remains a major global health burden with poorly defined molecular mechanisms. Cell growth regulator 11 (CGR11), a novel secreted protein characterized by EF-hand motifs, has recently emerged as a potential extracellular signaling modulator in tumor biology. Although implicated in cancer cell proliferation and metastasis, its precise role and regulatory mechanisms in HCC progression have not been elucidated.

Methods: We integrated bioinformatics analysis with single-cell transcriptomic profiling and CellChat-based intercellular communication mapping. CGR11 expression and localization were validated in tissue microarrays, HCC cell lines, and tumor specimens using immunohistochemical staining, qRT-PCR, and Western blotting. In vitro experiments and both subcutaneous and orthotopic xenograft models were established to evaluate the biological effects of CGR11 overexpression and knockdown. RNA sequencing, LC3 fluorescence assay, and transmission electron microscopy were conducted to elucidate the underlying molecular mechanism.

Results: CGR11 expression was markedly increased in HCC tissues relative to adjacent non-tumorous liver tissues and correlated with poor patient prognosis. Functional and mechanistic analyses demonstrated that CGR11 promotes HCC cell proliferation, invasion and tumor growth by inhibiting autophagy levels through activation of the PI3K/AKT signaling. Conversely, CGR11 knockdown restored autophagy and significantly suppressed tumor progression in both cellular and animal models.

Conclusion: Our findings establish CGR11 as a novel oncogenic regulator that contributes to HCC progression by suppressing autophagy via PI3K/AKT activation. Targeting the CGR11-PI3K/AKT axis may therefore provide a promising avenue for precision therapeutic intervention in HCC.

Introduction: Drug toxicity poses a significant threat to male fertility, and its mechanism is often associated with redox imbalance and mitochondrial dysfunction. Ivermectin (IVM), an anthelmintic increasingly explored for new therapeutic applications, induces apoptosis and impairs proliferation in spermatogonia via mitochondria-associated cellular injury at high concentrations in vitro. This study evaluated the protective effects of melatonin, agomelatine, and pinoline, as mitochondria-directed cytoprotectants.

Methods: Cultured type B spermatogonia were pretreated with 1 μM melatonin, agomelatine, or pinoline for 24 h under low-serum conditions, followed by exposure to 16 μM IVM. Cell proliferation was assessed by cell counting and Ki67 immunocytochemistry. Mechanistic analyses included fluorescence imaging of reactive oxygen species (ROS) using 2',7'-dichlorodihydrofluorescein diacetate, cytosolic Ca²⁺ using Fluo-4, AM, and mitochondrial membrane potential (ΔΨm) using tetramethyl rhodamine ethyl ester. Mitochondrial function was evaluated using Seahorse assays, and apoptosis was evaluated by caspase cleavage, the BAX/BCL-2 ratio, and Cytochrome c levels by Western blotting.

Results: Unlike pinoline, melatonin and agomelatine effectively suppressed IVM-induced oxidative stress and Ca²⁺ overload, while restoring mitochondrial membrane potential (ΔΨm), mitochondrial mass, and oxidative phosphorylation. These protective effects led to reduced apoptosis and enhanced cell proliferation. Structural differences among the three compounds indicate that the methoxy group and N-acetyl side chain are critical determinants of mitochondrial protection under redox stress.

Conclusion: Melatonin and agomelatine protect the male reproductive system from drug-induced toxicity by restoring redox homeostasis and mitochondrial function. These findings provide mechanistic insight into melatonin-based therapeutic strategies and the development of fertility preserving agents targeting mitochondria-mediated cellular injury.

Objective: The autogenous tooth transplantation and tooth replantation disrupt the original dental pulp and periodontal blood supply. Pulp necrosis post-reimplantation triggered inflammatory mediator leakage through the apical foramen, which stimulated periapical osteoclast activity and subsequent resorption of cementum, dentin, and alveolar bone. Successful outcomes thus depended critically on periodontal tissue regeneration. This review evaluated the therapeutic potential of enamel matrix derivatives (EMD) therein.

Methods: A comprehensive search was conducted across multiple electronic databases, including PubMed, EMBASE (Ovid), Web of Science, EBSCO, Springer Link, Oxford Journals, and Science Direct. Following a comprehensive review of the literature, the authors subsequently summarized and evaluated: 1. Molecular mechanisms of EMD-mediated periodontal regeneration, 2. Preclinical and clinical validation in tooth transplantation/replantation models, and 3. Current limitations and future translational directions. EMD-key regulators of tooth root development-were known to mediate acellular cementum formation through conserved developmental pathways.

Results: Emerging evidence confirmed that EMD promoted periodontal regeneration, particularly within the compromised healing microenvironment of transplanted/replanted teeth. EMD critically facilitated acellular cementum formation via established developmental pathways, thereby countering inflammatory resorption.

Conclusion: EMD-based therapies showed potential to improve outcomes in autogenous tooth transplantation and replantation and replantation by mitigating inflammatory resorption and promoting functional periodontal regeneration.

Background: Periplaneta americana L. is one of the most famous traditional Chinese medicines (TCMs), and CII-3 is the major bioactive extract of Periplaneta americana L. In recent years, CII-3 has gradually attracted the attention of researchers for its powerful capacity for treating immunocompromised diseases. However, systematical chemical composition investigation and mechanisms on immunomodulation of CII-3 have not been thoroughly scrutinized.

Methods: The chemical ingredients of CII-3 were determined by ultra-performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), and immune-enhancing mechanisms and active constituents were investigated by integration of metabolomics with network pharmacology and molecular docking.

Results: A total of 25 components were identified in the aqueous extract of CII-3, among which 10 were unambiguously confirmed by comparison with reference standards. In immunosuppressed rats, oral administration of CII-3 normalized biochemical profiles by promoting the secretion of immune-related cytokines (IL-2, IL-6) and immunoglobulins (IgG, IgM), significantly improving immune organ indices, and alleviating pathological lesions in the thymus and spleen. Furthermore, CII-3 stimulation attenuated CTX-induced upregulation of IL-6 mRNA levels and concurrently enhanced IL-2 mRNA expression in these two immune organs. Based on metabolomics analysis, 27 differential metabolites along with 7 crucial metabolic pathways including starch and sucrose metabolism, arginine biosynthesis, porphyrin and chlorophyll metabolism, nicotinate and nicotinamide metabolism, steroid biosynthesis, pyrimidine metabolism and tryptophan metabolism were regulated after CII-3 treatment, suggesting that CII-3 has the potential to target these metabolites and key pathways to improve immunosuppression. Nitric oxide synthase 1 (NOS1), nitric oxide synthase 3 (NOS3), acetylcholinesterase (ACHE), cluster of differentiation 38 (CD38) and poly (ADP-ribose) polymerase 1 (PARP1) were considered as the pivotal targets, and ginsenine, cyclo (Tyr-Asp), guanosine, tryptophan and inosine were deemed potential active components of CII-3 in alleviating immunosuppression.

Conclusion: The proposed approach provides a valuable evidence for demonstrating the material basis of CII-3. The results obtained in the present study elucidated that the potential immunomodulatory activity of CII-3 might be closely associated with these crucial targets, which can modulate the levels of major metabolites through multiple metabolic pathways, thus ameliorating immunosuppression.

X-prolyl aminopeptidase 2 (XPNPEP2), which is abundantly expressed in vascular endothelial cells (ECs), has been reported to be associated with cardiovascular disease and angiogenesis. However, its function in ECs and its involvement in the pathogenesis of angiogenesis remain unclear. In this study, we revealed that XPNPEP2 is essential for EC function and angiogenesis via modulation of mitochondrial function. In vivo, XPNPEP2 deletion led to pathological changes in the pulmonary artery wall and renal tissue, decreased venous blood vessel density in the proximal region of superficial retinal vessels, and significantly slowed wound healing and tumor growth in mice. In vitro, XPNPEP2 deficiency impaired EC proliferation, migration, and tubulogenesis, which was accompanied by diminished mitochondria-associated membranes and dysfunctional mitochondria, including insufficient ATP, excessive mitochondrial reactive oxygen species (mROS), and disrupted respiration chain function. XPNPEP2 was found to interact with SLC25A6. The overexpression of XPNPEP2 restored impaired EC angiogenesis and the reduction in SLC25A6 caused by XPNPEP2 ablation. Moreover, inhibition of XPNPEP2 downregulated SLC25A6 via Siah E3 ubiquitin protein ligase 1 (SIAH1)-mediated degradation. Additionally, attenuated EC angiogenesis was achieved solely by silencing SLC25A6. Our findings highlight that XPNPEP2 regulates angiogenesis via modulation of mitochondrial function, which may represent a new strategy for the treatment of angiogenesis-related diseases.

Here, we systematically investigated the effects of EDA1 variants on apoptosis, migration, and adhesion in ameloblast-like LS8 cells and identified downstream effectors of the EDA-NF-κB pathway through RNA sequencing (RNA-seq) combined with in vivo and in vitro validation. LS8 cells were transiently transfected with four constructs: wild-type (Wt) EDA1, nonsyndromic tooth agenesis-associated EDA1 variant (EDA1-A259E), X-linked hypohidrotic ectodermal dysplasia-associated EDA1 variant (EDA1-H252L), or empty vector control (pCMV-C-FLAG). We used flow cytometry, wound-healing assay, and cell counting kit 8 assay to assess cell apoptosis, migration, and adhesion, respectively. High-throughput RNA-seq was used to identify differentially expressed genes, which were subsequently validated through quantitative polymerase chain reaction and immunoblotting. Spatiotemporal Fosb expression patterns were comparatively analyzed in Wt and Tabby mouse tooth germs through in situ hybridization by using RNAscope. Wt EDA1 transiently enhances cellular migratory capacity, a function compromised in the pathogenic EDA1 variants. The EDA-NF-κB pathway operates through FOSB-mediated transcriptional regulation, as evidenced by coordinated suppression of Fosb expression at transcriptional and translational levels in the mutant models. Therefore, FOSB is a candidate downstream effector in EDA1-mediated odontogenesis. These results provide mechanistic insights into ectodermal dysplasia pathogenesis.

Background: Gastric cancer (GC) remains one of the most lethal malignancies worldwide due to its substantial heterogeneity, necessitating improved therapeutic strategies and prognostic tools. Recent studies have implicated dysregulated arginine metabolism in GC pathogenesis; however, its metabolic characteristics and clinical prognostic value are not fully understood.

Methods: GC samples were classified into three molecular subtypes based on the expression profiles of arginine metabolism-related genes (ArMGs). Prognostic ArMGs were identified within each subtype, and a cross-dataset prognostic model was developed to assess its predictive value. The associations of the model with anti-tumor immunotherapy, tumor immune microenvironment, signaling pathways, and gene expression patterns were further explored. Key candidate genes were validated using quantitative polymerase chain reaction (qPCR) in GC tissues and cell lines, and their biological functions were investigated through functional assays.

Results: Consensus clustering of nine ArMGs stratified GC into three molecular subtypes: C1, C2, and C3. A prognostic prediction model for GC was constructed using differentially expressed genes among the subtypes and seven key prognostic genes: TMEM171, SLC5A1, DEGS2, MGP, C7, HMGCS2, and CREB3L3. The model demonstrated varying sensitivities to anti-tumor immunotherapy and showed strong correlations with immune-related tumor markers, the tumor immune microenvironment, and multiple signaling pathways. Among the ArMGs, ODC1 and ALDH18A1 were identified as critical contributors to GC. qPCR confirmed their elevated expression in GC tissues and cell lines. Silencing these genes significantly reduced GC cell proliferation, colony formation, and invasion.

Conclusion: This study comprehensively characterized the molecular features of ArMGs in GC and developed a robust, validated prognostic prediction model. The findings offer new molecular insights for predicting patient outcomes and guiding personalized therapeutic strategies in GC.

Tumor neoantigens, a class of entirely novel antigens generated by somatic mutations, can be specifically recognized by T cells and serve as a central bridge connecting tumor genomic variation with anti-tumor immune responses. This review systematically elaborates on the dual role of neoantigens in the dynamic process of immunoediting: they act as targets for immune attack that are "sculpted" and as drivers of tumor evolution that are "selected." It further explores their immense potential as targets for personalized immunotherapy. By delving into the mechanisms of neoantigen generation, identification strategies, and their pivotal role within the cancer-immunity cycle, the review focuses on the latest advances in neoantigen-based DNA, RNA, and synthetic peptide vaccines. Notably, drawing on a first-in-human clinical trial of a neoantigen DNA vaccine in triple-negative breast cancer (TNBC), it validates the safety, clinical feasibility, and potent immunogenicity of this therapeutic strategy. Finally, the article discusses how to address core challenges such as tumor heterogeneity and immune escape by integrating cutting-edge strategies including artificial intelligence prediction, rational multi-epitope design, and combination therapies. This provides a solid theoretical foundation and promising clinical translation prospects for personalized immunotherapy in breast cancer and other solid tumors.

Background: Endometriosis is a common estrogen-dependent disease marked by ectopic endometrial growth. Although the PI3K/AKT and kisspeptin pathways are known to regulate endometrial homeostasis, their interplay in disease progression remains unclear. This study investigated the relationship between nuclear Kisspeptin (KiSS-1) localization and PI3K/AKT pathway activity in endometriotic tissues, focusing on stage-specific cellular alterations.

Methods: In this prospective study, control, eutopic and ectopic endometrial biopsies were collected from 27 women (18 controls, 9 with ovarian endometriosis). Histopathological assessments were performed using JB4 embedding, immunofluorescence, and transmission electron microscopy. Morphometric analyses were used to quantify structural alterations.

Results: In both eutopic and ectopic endometrium from patients with endometriosis, PI3K and AKT expression levels were significantly increased, whereas KiSS-1 expression was reduced and showed nuclear localization in a subset of cells. TEM analysis revealed features consistent with cellular stress, including autophagy-related vesicles, mitochondrial structural disruption, and alterations in nuclear architecture. Morphometric evaluation demonstrated a fibrotic remodeling in ectopic tissue. Specifically, glandular volume decreased, while stromal matrix content increased (p < 0.05).

Conclusion: These findings suggest a mechanistic link between PI3K/AKT signaling and nuclear KiSS-1 translocation as an adaptive response to chronic hypoxia and inflammation in endometrial cells. This interaction may regulate survival, proliferation, and fibrotic remodeling processes characteristic of endometriosis. This integrated ultrastructural and molecular analysis provides novel insights into the pathophysiological role of nuclear KiSS-1 and its potential as a diagnostic and therapeutic target in endometriosis.