Cell and Bioscience最新文献

Diabetes mellitus (DM) represents a significant global public health challenge, as economic development and changes in modern dietary habits have contributed to a rising prevalence of DM patients. Pancreatic cancer (PC), a highly aggressive malignancy, exhibits a 5-year survival rate of approximately 10%. The intricate and perilous relationship between DM and the onset and progression of PC is increasingly being elucidated, revealing a complex underlying network that encompasses multiple dimensions, including molecular signaling, metabolism, endocrinology, immunity, microbiota, and tumor microenvironment formation. Consequently, this review aims to delineate the overarching framework of the extensive relational network between DM and PC, focusing on the aforementioned aspects. Specifically, this review highlights the promoting effects of DM on the carcinogenic process of PC, emphasizing the complexity of the DM-PC interaction and identifying potential therapeutic targets for intervention.

Background: Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease caused by the expanded GGC repeats in the NOTCH2NLC gene, yet its underlying pathogenic mechanisms remains to be fully elucidated. Previous study suggests that hnRNP M, an RNA-binding protein sequestered into the inclusions, may contribute to RNA processing defects in NIID.

Results: In this study, we investigated the role of hnRNP M in NIID pathogenesis by utilizing a NOTCH2NLC-98GGC transgenic mouse model that faithfully recapitulates key NIID phenotypes. We found that AAV-mediated hnRNP M expression partially alleviated neuropathological features, such as neuronal loss and gliosis, and improved motor deficits in NIID mice. Transcriptome analysis further revealed that hnRNP M expression restored transcriptional and splicing dysregulation in synapse- and neurodegeneration-related genes, such as Dlg and Smn.

Conclusions: Our study established hnRNP M as a key regulator of NIID pathogenesis by modulating RNA transcription and splicing, underscoring the potential of targeting RNA processing abnormalities as a therapeutic strategy.

Long non-coding RNAs (lncRNAs) play pivotal roles in diverse cellular processes ranging from gene regulation and chromatin remodeling to RNA stability and epigenetic modifications. Despite the identification of approximately 95,000 lncRNA genes in humans, our understanding of their structure-function relationships remains very limited. This review examines the current state of lncRNA structure determination. We briefly discuss the advantages and limitations of experimental approaches-including chemical probing methods such as SHAPE and DMS-as well as the challenges inherent to computational predictions, particularly given RNA's dynamic nature, structural heterogeneity, and the energy degeneracy of its building blocks. The review also highlights the difficulties in predicting long-range interactions, including pseudoknots, which are essential for global folding of large RNAs, and discusses how elevated, nonphysiologically Mg²⁺ concentrations used in many experiments can distort our perception of native RNA conformations. Recent advances in cryo-electron microscopy and atomic force microscopy, coupled with machine learning algorithms, offer promising strategies to capture the realistic conformational landscapes of RNAs, including lncRNAs, under near-physiological conditions. These advances have the potential to redefine our understanding of lncRNA architectures, their structural dynamics, and how they influence cellular functions, ultimately informing future directions of lncRNA research and opening new frontiers such as structure-based drug discovery and therapeutic interventions targeting lncRNAs.

Background: The presence of metabolic dysfunction-associated steatotic liver disease (MASLD) in lean patients challenges the traditional association between fatty liver and obesity. While genome-wide association studies (GWAS) have identified key genetic variants linked to hepatic steatosis, most have focused on Western obese populations and were based on the former non-alcoholic fatty liver disease (NAFLD) criteria. Genetic studies targeting lean MASLD, particularly among the Taiwan Han Chinese population, remain limited. This study addresses this knowledge gap by investigating the genetic architecture of lean MASLD in a Taiwan Han Chinese cohort.

Methods: We analyzed data from the Taiwan Biobank, integrating genomic data with abdominal ultrasound findings to define lean MASLD cases with BMI less than 23. A total of 1,720 lean MASLD individuals and 5,331 lean controls were included. A metabolic risk score ranging from 1 to 5 was calculated for each participant, reflecting the number of metabolic criteria met for MASLD classification. GWAS was conducted using logistic regression, adjusting for age, sex, and top 10 principal components. Conditional analyses were used to identify independent signals. Significant variants were replicated using data in the All of Us Research Program (1,017 lean MASLD and 1,553 lean healthy).

Results: Lean MASLD patients exhibited significantly worse metabolic profiles than lean controls. GWAS identified 47 genome-wide significant variants, predominantly in PNPLA3 and SAMM50, with rs9625962 in PNPLA3 emerging as the most significant and independent variant. These associations were replicated in the All of Us lean MASLD cohort, affirming their cross-population relevance. Notably, the C allele of rs9625962 increased the risk of MASLD in both lean and non-lean individuals. In the lean MASLD group, fibrosis risk scores (FIB-4 and NFS) positively correlated with the metabolic risk scores.

Conclusion: This study identified significant associations between genetic variants in PNPLA3 and SAMM50 and lean MASLD in the Taiwan Han Chinese population. The variant rs9625962 exhibited pleiotropic effects, contributing to MASLD regardless of BMI category, triglyceride levels, and liver function profiles. The replication of all significant variants in the All of Us dataset underscores the robustness and generalizability of our findings. These results highlight the importance of genetic factors in lean MASLD pathogenesis and support further investigation into gene-environment interactions.

Background: The oviduct (or fallopian tube) plays a functional role in the transportation of gametes and early-stage embryos, serving as a site for fertilization. Any aberrations from the normal functioning of fallopian tube epithelium may lead to diseases, including but not limited to infertility, ectopic pregnancy, and carcinoma. However, little is known about the mechanisms governing oviductal epithelial homeostasis between secretory cells and ciliated cells by miRNAs.

Results: In this study, we found that the expression levels of miR-34b/c and miR-449a/b/c were positively correlated with the number of ciliated cells. Using the miR-34b/c^-/-; miR-449 ^-/- double knockout (miR-dKO) mouse model, we found that adult female miR-dKO mice were infertile, owing to reduced ciliated cells and increased secretory cells, which hindered oocyte pickup. Transcriptomic analysis revealed Wnt/β-catenin signaling over-activation in the oviductal epithelium of the miR-dKO mice, with Dvl2 as a target of miR-34/449. The aberrant ciliated cell differentiation was completely rescued with the treatment of the Wnt/β-catenin signaling pathway inhibitors and partially rescued with the knockdown of Dvl2, using the oviductal epithelial organoid culture model.

Conclusions: In summary, we discovered that ablation of miR-34/449 led to hyperactivation of the Wnt/β-catenin signaling pathway, which resulted in the differentiation impairment of ciliated cells, thus resulting in infertility in the mice. This study revealed a novel mechanism describing how miR-34/449 affects oviductal ciliated cell differentiation and oviductal epithelial homeostasis through the Wnt/β-catenin signaling pathway and finally affects fertility.

Background: Turner syndrome is the most common sex chromosome abnormality in females and affects approximately 1-2 in 2500 girls and women. To date, no cure is available for the treatment of infertility in Turner syndrome patients with 45,XO.

Results: Here, we report an organoid approach for generating human germline stem cells and their somatic niche cells in the Turner syndrome. The niche provides an appropriate microenvironment for germline fate in the organoids. Single-cell transcriptomics reveals the dynamics of germline development from iPSCs to germline stem cells, together with their somatic niche. The germline stem cells follow a successive trajectory of four developmental states with featured molecular events, which determine the developmental fate of the germline stem cells. Notably, we have identified the key factor E2F1 from the germline trajectory to regulate the germline stemness fate. E2F1 knockout impairs the specification of the germline stem cells in 45,XO organoids. Remarkably, E2F1 acts as a key fate regulator by activating the transcription of germline factor TFAP2C through binding to and activating its promoter. Importantly, transcriptional regulation of E2F1 creates a positive-feedback loop of E2F1-TFAP2C-SOX17, which contributes to the fate of the germline stem cells, hPGCLCs.

Conclusion: This study revealed a successive development trajectory of germline stem cells and identified E2F1 and related positive-feedback loop of E2F1-TFAP2C-SOX17 to control the fate of germline stem cells, hPGCLCs, offering a foundation for understanding and reconstituting germline fate in vitro in Turner syndrome patients with 45,XO.

Background: Cholangiocarcinoma is a malignancy with poor prognosis and increasing incidence in recent years. Apart from early surgical resection, other treatments have shown limited efficacy. Lysine-specific demethylase 4A (KDM4A), a histone demethylase, is known to have a promotional effect on a variety of tumours. However, its impact on cholangiocarcinoma remains underexplored.

Methods: The expression differences of KDM4A in cholangiocarcinoma and adjacent tissues were analyzed by database and tissue microarray. The effects of KDM4A on the growth and proliferation ability of cholangiocarcinoma cells were explored through subcutaneous tumor formation experiments in nude mice and cholangiocarcinoma mouse models. The regulatory role of KDM4A on TGFβ pathway was analyzed by real-time quantitative PCR and Western blot experiments. Bioinformatics methods were employed to predict KDM4A binding, which was validated by chromatin immunoprecipitation.

Results: KDM4A was highly expressed in cholangiocarcinoma tissues compared with normal tissues, and KDM4A significantly promoted the proliferation and invasion ability of cholangiocarcinoma. KDM4A positively regulated SMAD5, upregulating its expression and subsequently promoting the expression of TGFβ pathway target genes ID1 and ID2. Knockdown of SMAD5 could reverse the biological effects caused by KDM4A. The expression of SMAD5 was regulated by the histone methylation mark H3K9me3. KDM4A was enriched at the SMAD5 gene promoter region, downregulated H3K9me3 marks, and thus promoted SMAD5 transcription. KDM4A inhibitor can inhibit the proliferation and invasive ability of cholangiocarcinoma through the aforementioned mechanisms. Treatment of cholangiocarcinoma model mice with a KDM4A inhibitor resulted in significantly reduced liver volume and lesion area in the treatment group compared to the control group.

Conclusion: In summary, KDM4A promotes the development of cholangiocarcinoma by regulating SMAD5 to activate the TGFβ pathway. The KDM4A inhibitor JIB-04 shows potential in inhibiting cholangiocarcinoma progression, providing a rationale for the epigenetic therapy of cholangiocarcinoma.

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.