Cell and Bioscience最新文献

Background: Nicotine is known to influence metabolism and body weight, yet existing murine models of nicotine exposure often fail to replicate human smoking behaviors accurately. To address this gap, we designed a cost-effective, self-administered nicotine inhalation system that allows mice to voluntarily inhale nicotine vapor generated from e-liquid.

Results: Using this system, we investigated the metabolic effects of nicotine exposure in adult and adolescent mice. Adult mice exposed to nicotine vapor for 10 days exhibited significant weight loss, which was rapidly regained upon cessation, paralleling human smoking patterns. In contrast, adolescent mice did not lose weight during nicotine exposure but experienced increased fat mass accumulation after cessation. These results highlight critical age-dependent differences in nicotine's metabolic effects and challenge the common perception that nicotine aids in weight control among adolescents.

Conclusions: Our novel e-liquid-based inhalation model provides a valuable tool for studying nicotine's physiological and behavioral effects, with implications for understanding smoking-related health risks and addiction mechanisms.

Background: As a serine/threonine kinase, PINK1 (PTEN-induced putative kinase 1) is widely expressed in mammalian tissues and cells, especially in the female reproductive system. However, its role in meiotic oocytes remains obscure. Here, we report that murine oocytes overexpressing Pink1 are unable to completely progress through meiosis.

Results: In the present study, we found that PINK1 protein levels in aged oocytes showed a substantial increase. Importantly, we revealed that murine oocytes overexpressing Pink1 are unable to completely progress through meiosis. This leads to inadequate mitochondrial redistribution, an elevated reactive oxygen species (ROS) level, severely disrupted spindle/chromosome organization, and abnormal mitophagy. Furthermore, we noted that elevated Pink1 expression significantly compromises the developmental ability of the mouse early embryo. In addition, we revealed that RAB8A activity is a key factor for PINK1-mediated mitophagy in old oocytes and active guanosine triphosphate (GTP)-bound state RAB8A could partially rescue the quality of aged oocytes by promoting the formation of autolysosome.

Conclusions: Collectively, our data display critical functions for PINK1 in meiotic progression and mitochondrial homeostasis in murine oocytes, and RAB8A activity is required for PINK1-mediated mitophagy in senescent oocytes.

Cytidine/Uridine monophosphate kinase 2 (CMPK2) is a crucial enzyme responsible for the phosphorylation of nucleotides, specifically converting cytidine monophosphate (CMP) and uridine monophosphate (UMP) into their respective diphosphates, known as cytidine diphosphate (CDP) and uridine diphosphate (UDP). Recent studies have demonstrated that CMPK2 plays a pivotal role in multiple pathophysiological processes, such as cellular nucleotide metabolism, energy homeostasis, and inflammatory response. Dysregulation of CMPK2 has been implicated in a variety of pathologies, including viral infections, neurodegenerative diseases, and autoimmune disorders. Despite its biological significance and interventive potential, knowledge gaps remain with respect to CMPK2, in particular, the precise molecular mechanism and mechanical basis through which it contributes to the onset and progression of underlying diseases. In this regard, this narrative review aims to provide an overview concerning the biological functions of CMPK2, shed light on its involvement in disease pathogenesis alongside clinical relevance, and ultimately highlight potential therapeutic strategies to target CMPK2 across multisystemic disorders.

Background: Morphologic sex differences between males and females typically emerge after the primordial germ cell migration and gonad formation, although sex is determined at fertilization based on chromosome composition. A key debated sexual difference is the embryonic developmental rate, with in vitro produced male embryos often developing faster. However, the molecular mechanisms driving early embryonic sex differences remain unclear.

Results: To investigate the transcriptional sex difference during early development, in vitro produced bovine blastocysts were collected and sexed by PCR. A significant male-biased development is consistently observed in expanded blastocysts. Ultra-low input RNA-seq analysis identified 837 DEGs, 1555 significantly sex-biased differential alternative splicing (AS), and 1151 differentially expressed isoforms (DEIs). Among all of the DEGs, there were 231 upregulated and 606 downregulated in males. Functional enrichment analysis revealed male-biased DEGs were associated with metabolic regulation, whereas female-biased DEGs were related to female gonad development, sex differentiation, inflammatory pathways, and TGF-beta signaling. Comparing X chromosome and autosome expression ratio, we found that female-biased DEGs contributed to the higher X-linked gene dosage, a phenomenon not observed in male embryos. Moreover, we identified the sex-biased transcription factors and RNA-bind proteins, including pluripotent factors such as SOX21 and PRDM14, and splicing factors FMR1 and HNRNPH2. Additionally, we revealed that the significantly sex-biased differential AS were predominantly skipped exons, and they could be mapped to 906 genes, with 59 overlapping with DEGs enriched in metabolic and autophagy pathways. By incorporating novel isoforms from long reads sequencing, the sex-biased DEIs were associated with 1017 genes. Functional analysis showed that female-biased DEIs were involved in the negative regulation of transcriptional activity, while male-biased DEIs were related to energy metabolism. Furthermore, we identified sex-biased differential exon usage in DENND1B, DIS3L2, DOCK11, IL1RAPL2, and ZRSR2Y, indicating their sex-specific regulation in early embryo development.

Conclusion: This study provided a comprehensive analysis of transcriptome differences between male and female bovine blastocysts, integrating sex-biased gene expression, alternative splicing, and isoform dynamics. Our findings indicate that enriched metabolism processes in male embryos may contribute to the faster developmental pace, providing insights into sex-specific regulatory mechanisms during early embryogenesis.

Background: Spinal cord ischemia reperfusion injury (SCIRI) is a serious disease that can result in irreversible neuronal damage, leading to the loss of sensory and motor function. Cuproptosis, a novel form of regulated cell death, has been studied in various diseases. However, the role and mechanism of cuproptosis in SCIRI remain to be elucidated.

Results: The results of transcriptome analysis showed significant downregulation of ATP7B, which regulates copper ion efflux. Concurrently, another key cuproptosis-related gene, FDX1, was significantly altered. Thus, we performed qPCR and Western blot assays in vivo and in vitro to detect changes in cuproptosis-related genes. The results indicated that cuproptosis was indeed activated by SCIRI or OGD/R. Moreover, immunofluorescence/immunohistochemitry staining and neuronal activity tests were consistent with the above results. Furthermore, we also proved that ammonium tetrathiomolybdate, a copper chelator and cuproptosis inhibitor, could not only ameliorate neuronal damage and promote neuronal survival but also improve lower limb motor dysfunction.

Conclusions: SCIRI caused ATP7B downregulation, which blocked copper ion efflux, leading to copper ion accumulation, DLAT oligomerization, degradation of iron-sulfur cluster proteins and ultimately cuproptosis in neurons.

The striatin family proteins, striatin, SG2NA, and zinedin, belong to the calmodulin-binding WD-40 repeat protein group and are components of the striatin interacting phosphatase and kinase (STRIPAK) complex. These proteins are known for their roles as scaffold proteins, facilitating various cellular pathways, and regulating cell-cell interactions and signaling mechanisms. The observation that Striatin is expressed in cell junctions, suggests a potential role in maintaining cell integrity and communication. Here, we used shRNA technology to examine the biological significance of the striatin family proteins. This approach allowed us to modulate their expression levels and observe the effects on cellular processes. Our results suggest that the striatin family members affect the Hippo signaling pathway by protecting phosphorylated YAP (pYAP) from proteasomal degradation, thus decreasing the expression of Hippo target genes. This regulation impacts key cellular processes, such as cell migration and proliferation. RNA sequencing analyses of keratinocytes and fibroblasts depleted of striatin proteins enabled the identification of novel gene sets affected by the modulation of striatin expression and provided insights into the broader impact of striatin proteins and their roles in various cellular pathways.

Hepatocellular carcinoma (HCC), the most common primary liver cancer, remains a major global health burden due to its high recurrence, late diagnosis, and limited prognostic tools. While imaging and treatment modalities have advanced, there is an urgent need for reliable, noninvasive biomarkers to facilitate early detection, therapeutic monitoring, and outcome prediction. Circulating cell-free mitochondrial DNA (ccf-mtDNA) has emerged as a promising candidate biomarker, attributed to its unique biological properties, including high copy number, circular configuration, and resistance to degradation. Ccf-mtDNA enters the circulation via diverse mechanisms such as mitochondrial damage, extrusion through extracellular vesicles, and neutrophil extracellular traps, all of which are prevalent in the inflammatory and hypoxic tumor microenvironment of HCC. Accumulating evidence links alterations in ccf-mtDNA levels, sequence variants, and fragmentomic profiles with tumor burden, treatment response, and overall survival. Notably, its potential utility has been demonstrated in patients receiving locoregional therapies such as transarterial chemoembolization. However, variability in findings across studies, lack of methodological consensus, and confounding effects from liver inflammation or injury pose significant barriers to clinical translation. This review provides a comprehensive overview of the origins, biological significance, and clinical applicability of ccf-mtDNA in HCC, and explores emerging interest in mitochondrial DNA encapsulated in extracellular vesicles as a novel diagnostic tool. Addressing current challenges through assay standardization and validation in larger, stratified cohorts will be pivotal for its integration into precision oncology frameworks.