Cell and Bioscience最新文献

Background: Lysophosphatidic acid (LPA) is a bioactive phospholipid that affects hippocampal excitatory synaptic transmission.

Results: Here we provide in vitro evidence that LPA elicits intracellular calcium concentration ([Ca²⁺]_i) transients by LPA₂ receptor activation in primary cultured hippocampal mouse neurons. Downstream and via G_i-coupling, this led to phospholipase C (PLC) activation, inositol (1,4,5) trisphosphate (IP₃)-induced Ca²⁺ release (IICR) and voltage gated Ca²⁺ channel activation. In addition, we found that LPA elevated [Ca²⁺]_i, not only in the soma but also in presynaptic terminals. This altered the frequency of spontaneous vesicle release specifically in excitatory synapses. However, against our expectations, LPA reduced the frequency of miniature excitatory postsynaptic currents. This was due to a depletion of releasable vesicles resulting from a slowed recycling. SynaptopHluorin based measurements indicated a transient augmentation of release followed by prolonged persistence of vesicles at the membrane. Concordant to our previous findings on ex vivo brain slices, LPA increased spontaneous glutamatergic vesicle release in Banker style astrocytic co-cultures. Our results indicate that pro-excitatory LPA effects critically depend on stable vesicle pools.

Conclusions: Taken together, our data further support membrane derived phospholipids as active modulators of excitatory synaptic transmission.

Background: Although aerobic glycolysis contributes to malignancy and drug resistance in human cancers, the vital regulators of glycolysis in lung adenocarcinoma (LUAD) remain largely unknown. Transcription factor AF4/FMR2 family member 4 (AFF4) is the scaffolding protein of the super elongation complex (SEC) and regulates the transcription of cancer-related genes. However, the role of AFF4 in glycolysis and LUAD development remains unidentified.

Methods: AFF4 expression was assessed in LUAD cells and tissues using bioinformatics analysis, western blotting, and immunohistochemical staining. Changes in cell proliferation, migration, and invasion were determined using in vitro and in vivo loss- and gain-of-function assays. Additionally, glycolysis levels were assessed using metabolite determination assays of glucose and lactate. The underlying mechanisms were elucidated via transcriptome sequencing, cleavage under targets (CUT) &Tag, dual-luciferase reporting assay, and a series of rescue experiments.

Results: AFF4 was overexpressed in wild-type and cisplatin-resistant LUAD cells and acted as a prognostic indicator in patients with LUAD. AFF4 enhanced the tumorigenic characteristics and cisplatin resistance of LUAD cells by accelerating glycolysis. Meanwhile, glycolysis inhibition restored the AFF4 overexpression-induced increase in cell proliferation and migration and rendered AFF4-overexpressing LUAD cells sensitive to cisplatin. Mechanistically, AFF4 promoted glycolysis by modulating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/ signaling pathway. AFF4 downregulated phosphatase and tensin homolog (PTEN) expression by directly targeting its promoter, activating the PI3K/AKT/mTOR pathway. Additionally, transcription factor Yin Yang 1 (YY1) upregulated AFF4 by binding to its promoter, further influencing glycolysis and oncogenesis.

Conclusion: AFF4 drives metabolic reprogramming, tumor progression, and cisplatin resistance through PTEN-mediated activation of the PI3K/AKT/mTOR signaling pathway, highlighting AFF4 inhibition as a potential therapeutic strategy in LUAD.

Background: Insulin regulates blood sugar levels and several physiological processes, but many aspects of the relationship between insulin regulation and genes still require further discussion. Thus, this study aimed to explore the genetic variations associated with changes in fasting insulin level in Taiwanese Han individuals through genome-wide association studies (GWAS) and polygenic risk score (PRS) analysis.

Results: Through GWAS in the primary group and replication in the Follow-up group, no genome-wide significant loci were identified; however, three genes or SNPs, PIP4K2A, FTO, and rs3846601, approached significance. Among them, PIP4K2A and rs3846601 represent novel prominent fasting insulin susceptibility loci identified in this study. Consistency was noted among the target, validation, and Follow-up groups by PRS analysis. Significant associations were observed between fasting insulin level-derived PRS and type 2 diabetes (T2D) and BMI susceptibility. Strong and positive associations traits were found between various diseases/traits in PheWAS, they were morbid obesity, T2D, polycystic ovaries, chronic nonalcoholic liver disease, and hypertension.

Conclusions: This study identified fasting insulin-related loci and developed a PRS model, offering insights into genetic regulation and potential early risk assessment for metabolic diseases in Taiwanese Han population.

The integrity and stability of DNA, an essential genetic material, need to be maintained for normal cellular function, growth, and development. The DNA damage response (DDR) constitutes a complex, sophisticated, and extensive signaling network that preserves genomic stability under stress. It can be divided into the DNA damage surveillance system and DNA damage repair system, which work in concert to ensure genomic integrity. When DNA damage surpasses the repair capacity of the DDR, unrepaired DNA damage accumulates, inducing cellular senescence and altering the fate of alveolar epithelial cells; this process is intricately linked to the onset, progression, and management of developmental and chronic lung diseases. In this review, recent research on the pathogenic mechanisms of DDR in respiratory diseases across the lifespan, including bronchopulmonary dysplasia, bronchial asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis, as well as progress in the development of associated targeted therapeutic strategies, is synthesized.

Male genital lichen sclerosus (LS), a chronic inflammatory dermatological condition, has been recognized for its profound implications on the quality of life among males. The exact etiological factors behind this prevalent condition remained largely enigmatic. In this research, we employed a multi-omics strategy to identify and elucidate the underlying histological biomarkers and the fundamental pathogenesis associated with male genital LS. A comprehensive cell atlas of male genital LS disease was constructed, highlighting a pronounced increase in T cells and a remarkable reduction in keratinocytes within the male genital LS samples. Further insights elucidated the enhanced crosstalk between fibroblasts and T cells via the collagen-CD44 axis, and between fibroblasts and keratinocytes through the APP-CD74 signaling pathway. This molecular dialogue was implicated in the immune infiltration and hyperkeratosis observed in the dermal-epidermal layer of male genital LS. Subsequently, we integrated single-cell RNA sequencing data with genome-wide association study findings to explore the cell-type-specific genes predisposing to the development of male genital LS. The analysis underscored the pivotal role of GAS1, which was enriched in fibroblasts and implicated in the pathogenesis of male genital LS progression. Collectively, we highlighted the critical role of fibroblasts in initiating male genital LS onset, generating interactions with T cells and keratinocytes, and eliciting the classical histological features of male genital LS.

CTP synthase (CTPS) is a key enzyme in de novo CTP synthesis, playing a critical role in nucleotide metabolism and cellular proliferation. Human CTPS1 (hCTPS1), one of the two CTPS isoforms, is essential for immune responses and is highly expressed in proliferating cells, making it a promising therapeutic target for immune-related diseases and cancer. Despite its importance, the regulatory mechanisms governing hCTPS1 activity remain poorly understood. Here, we reveal that CTP, the product of CTPS, acts as a key regulator for hCTPS1 filamentation. Using cryo-electron microscopy (cryo-EM), we resolve the high-resolution structure of CTP-bound hCTPS1 filaments, uncovering the molecular details of CTP binding and its role in filament assembly. Importantly, we demonstrate that CTP generated from the enzymatic reaction does not trigger filament disassembly, suggesting a conserved regulatory pattern. Furthermore, by analyzing the binding modes of two distinct CTP-binding pockets, we provide evidence that this filamentation mechanism is evolutionarily conserved across species, particularly in eukaryotic CTPS. Our findings not only elucidate a novel regulatory mechanism of hCTPS1 activity but also deepen the understanding of how metabolic enzymes utilize filamentation as a conserved strategy for functional regulation. This study opens new avenues for targeting hCTPS1 in therapeutic interventions.

SATB2 is an AT-rich DNA-binding protein with a highly restricted expression pattern, primarily found in the brain, digestive tract, bone, and immune system, making it a promising target for medical research and clinical applications. Dysregulation or mutations in SATB2 have been implicated in various conditions, including cancers, isolated cleft palate, and SATB2-associated syndrome (SAS). This review aims to provide a comprehensive summary of the structure, biological functions, and potential role of SATB2 in tumor development. SATB2 influences gene regulation through epigenetic modulation, impacting various biological activities, including cell differentiation and immune responses. Recent studies have increasingly recognized its roles in tumorigenesis, including its contributions to cancer progression and metastasis. Moreover, SATB2 shows promise as a diagnostic marker and therapeutic target in oncology and bone-related disorders. Understanding its precise mechanisms in these contexts can pave the way for future advancements in therapeutic strategies. This review highlights the current state of knowledge on the roles of SATB2 and discusses its structural characteristics, biological functions, and potential implications in tumor development.

Brain injury following cardiac arrest (CA) is a significant cause of mortality and poor prognosis in patients, and effective treatment strategies remain limited. Stem cell-derived extracellular vesicles (EVs), a novel cell-free therapeutic approach, have recently demonstrated significant potential in the field of brain injury repair. EVs, key mediators of stem cell paracrine and autocrine signaling, are enriched with bioactive molecules such as non-coding RNAs and proteins. These EVs have the capacity to traverse the bloodstream, reach injury sites, and modulate various biological processes, including neuronal survival, oxidative stress, inflammatory responses, blood-brain barrier integrity, and neurovascular regeneration.This review aims to provide a comprehensive overview of the research history, structural characteristics, and in vivo distribution and metabolism of stem cell-derived EVs. The review further explores their therapeutic potential and underlying mechanisms in post-CA brain injury, including the inhibition of neuronal apoptosis, alleviation of oxidative stress and inflammation, promotion of blood-brain barrier repair, and enhancement of neurovascular regeneration. Additionally, the review highlights emerging directions and challenges in the clinical application of stem cell-derived EVs, offering theoretical insights and perspectives for future research and translational development. The potential of stem cell-derived EVs as a breakthrough strategy for treating post-CA brain injury is underscored, offering renewed optimism for enhancing patient outcomes.

Background: Both obesity and DNA methylation (DNAm) are influenced by genetic factors. Despite more than a thousand of obesity-related DNAm sites (CpGs) being identified, studies that account for genetic influences in these associations are limited.

Results: Using data from 1,074 twins in the Chinese National Twin Registry and bivariate structural equation models (SEMs), we investigated the phenotypic (Rph), genetic (Ra), and environmental (Re) correlations between genome-wide DNAm and three obesity indices: BMI, waist circumference (WC), and waist-to-hip ratio (WHR). Genome-wide, correlations between DNAm and obesity were small (Rph = 0.04, Ra = 0.08-0.09, Re = 0.02-0.03). For CpGs with high phenotypic correlation (Rph > 0.1), the mean genetic and environmental correlations were 0.23-0.24 and 0.03-0.05, respectively, indicating significant genetic influence on the DNAm-obesity associations. To further investigate the role of genetic influences, we then categorized the CpGs into different groups: high phenotypic correlation (Rph ≥ 0.2); high phenotypic and genetic correlations (Rph > 0.1 and Ra > 0.5); high phenotypic and low genetic correlations (Rph > 0.1 and Ra < 0.5). Association studies were conducted in the full population and in the monozygotic (MZ) twin-paired design, where genetic influences were controlled. For CpGs with Rph ≥ 0.2, 9, 8, and 22 were associated with BMI, WC, and WHR in the full population, but only 6, 1, and 1 CpGs remained significant after controlling for genetic effects in MZ twin-pair analyses. For CpGs with Rph > 0.1 and Ra > 0.5, genetic factors predominantly drove the association, and none of the 155/155/189 CpGs associated with BMI/WC/WHR in the full population were significant in MZ-paired analyses. For CpGs with Rph > 0.1 and Ra < 0.1, genetic effects were minimal or confounding, with 89, 4, and 17 significant in both full population and MZ-paired analyses.

Conclusions: Our results highlight the significant genetic influences on the DNAm-obesity relationships, which may explain the low replicability of obesity-related DNAm markers. This indicates that genetic influences should be carefully considered in DNAm-related studies.