Cell and Bioscience最新文献

Background & aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses various conditions, ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. MASLD is a significant risk factor for hepatocellular carcinoma (HCC) and is rapidly becoming the primary cause of liver transplantation. Dysregulated sphingolipid metabolism has been linked to the development of MASH-HCC. However, detailed insight into the sphingolipid profiles and cell type-specific changes in key genes involved in sphingolipid metabolism remains limited and forms the primary focus of this study.

Approaches & results: This study used the well-characterized diet-induced MASH-HCC mouse model (DIAMOND). Total RNA sequencing data, NanoString nCounter^® Gene profiling, and single-nucleus RNA sequencing (snRNA-seq) GEO data (GSE225381) were used in characterizing gene regulation in MASH-HCC progression. Sphingolipids in the serum and liver were profiled using targeted lipidomics. RNA data analysis showed dysregulation of key genes involved in sphingolipid metabolism, including ceramide synthase 6 (Cers6), serine palmitoyltransferase long chain base subunit 2 (Sptlc2), sphingosine kinase 2 (SphK2), and sphingosine-1-phosphate receptor 1-3 (S1pr1-3) which paralleled significant changes in sphingolipid composition and levels in both serum and liver. Furthermore, TCGA-LIHC patient data were analyzed and potential prognostic genes for MASH-HCC were identified using univariate and multivariate Cox analysis. The multivariate Cox analysis underscored the prognostic significance of several genes related to sphingolipid metabolism, including CERS6, SPTLC2, and S1PR1.

Conclusion: Our findings provided valuable insights into the role of sphingolipids in the progression of MASH to HCC. Specific serum and liver sphingolipid profiles may serve as valuable biomarkers for diagnosis and prognosis in MASH-HCC.

Background: Calcium-regulated heat-stable protein 1 (CARHSP1) has been identified as a cold shock domain (CSD) protein family member, participating in the regulation of ribosomal translation, mRNA degradation, and the rate of transcription termination. However, there is an extremely limited understanding of the function of CARHSP1 as an RNA binding protein (RBP) in prostate cancer (PCa).

Methods: The expression pattern of CARHSP1 and the correlation between the CARHSP1 expression and clinical prognosis in PCa patients were analyzed by using multiple public databases. In vitro and in vivo functional assays were conducted to assess the role of CARHSP1. The mechanisms of CARHSP1 function on IL-17RA were identified by RNA pull-down and RNA stability assays. A co-culture model of Jurkat cells and PCa cells was established to investigate the potential role of CARHSP1 in tumor immunity of PCa.

Results: CARHSP1 was highly expressed in PCa, and correlated with advanced characteristics of PCa and unfavorable prognosis in PCa patients. Moreover, knockdown of CARHSP1 significantly dampened the capacity of proliferation, migration, invasion, and immune evasion of PCa cells in vitro and in vivo. Mechanistically, the RNA-binding protein CARHSP1 selectively bound to the mRNA of IL-17RA, resulting in the increased expression of both IL-17RA mRNA and protein. Downregulating expression of CARHSP1 shortened the half-life of IL-17RA mRNA and reduced its expression. Subsequently, the downstream pathways of IL-17RA, JAK-STAT3 signaling pathway and NF-κB signaling pathway, were activated by CARHSP1 and contributed to the malignant phenotype of PCa cells.

Conclusions: In conclusion, our results demonstrated that the increased expression of CARHSP1 in PCa is correlated with advanced clinical characteristics and unfavorable prognosis, and CARHSP1 may promote the progression of PCa through enhancing the mRNA stability of IL-17RA and activating its downstream pathways. These results suggest that CARHSP1 is an important regulator of tumor microenvironment in PCa, and CARHSP1-IL-17RA axis could be potential novel therapeutic targets for PCa.

Objectives: Drug-induced liver injury (DILI) can be improved by modulating gut microbiota. We aimed to investigate a probiotic mixture comprising Bifidobacterium Longum, Streptococcus thermophilus, and Lactobacillus delbrueckii subspecies bulgaricus (BSL) in mitigating acetaminophen induced liver injury (AILI), and to elucidate the underlying mechanisms.

Methods: Gut bacterial communities were analyzed in fecal samples from patients with DILI and healthy controls. Mice were pretreated with BSL or PBS for 10 days, then subjected to a single dose of acetaminophen (300 mg/kg) gavage and euthanized 24 h later. Transcriptome sequencing, microbiome, and metabolome sequencing were performed on mouse samples, respectively.

Results: Gut bacterial dysbiosis existed in DILI patients, with a decrease in Gram-positive bacteria and an increase in Gram-negative bacteria. A similar situation occurred in AILI mice. Pretreatment of BSL significantly improved APAP-induced disorders of gut bacteria and alleviated hepatic inflammation and necrosis. Transcriptome sequencing showed that BSL inhibited the hepatic damage pathways, such as Hippo and TGF-β signaling pathway. Metabolomic profiling revealed an obvious increase in oligopeptides containing branched-chain amino acids (BCAAs) in AILI mice, whereas these metabolites were significantly negatively correlated with the abundance of BSL, but positively with key genes of Hippo pathway. In vitro experiments showed that leucine exerted a dose-related exacerbation pattern on APAP-mediated hepatocellular injury. Mice supplemented with leucine resulted in the further overexpression of Yes-associated protein, an increase in oxidative stress, and a worsening of AILI.

The telomerase complex consists of a protein component (TERT), which has reverse transcriptase activity, and an RNA component (TERC), which serves as a template for telomere synthesis. Evidence is rapidly accumulating regarding the non-canonical functions of these components in both normal or diseased cells. An oligonucleotide-based drug, the first telomerase inhibitor, secured FDA approval in June 2024. We recently summarized the non-canonical functions of TERT in viral infections and cancer. In this review, we expand on these non-canonical functions of TERC beyond telomere maintenance. Specifically, we explore TERC's roles in cellular aging and senescence, immune regulation, genetic diseases, human cancer, as well as involvement in viral infections and host interactions. Finally, we discuss a transcription product of telomere repeats, TERRA, and explore strategies for targeting TERC as a therapeutic approach.

Eukaryotic somatic cells undergo continuous telomere shortening because of end-replication problems. Approximately 10%~15% of human cancers rely on alternative lengthening of telomeres (ALT) to overcome telomere shortening. ALT cells are characterized by persistent telomere DNA replication stress and rely on recombination-based DNA repair pathways for telomere elongation. The Bloom syndrome (BLM) helicase is a member of the RecQ family, which has been implicated as a key regulator of the ALT mechanism as it is required for either telomere length maintenance or telomere clustering in ALT-associated promyelocytic leukemia bodies (APBs). Here, we summarize recent evidence detailing the role of BLM in the activation and maintenance of ALT. We propose that the role of BLM-dependent recombination and its interacting proteins remains a crucial question for future research in dissecting the molecular mechanisms of ALT.

Depression, a widespread psychiatric disorder, is characterized by a diverse array of symptoms such as melancholic mood and anhedonia, imposing a significant burden on both society and individuals. Despite extensive research into the neurobiological foundations of depression, a complete understanding of its complex mechanisms is yet to be attained, and targeted therapeutic interventions remain under development. Synaptic homeostasis, a compensatory feedback mechanism, involves neurons adjusting synaptic strength by regulating pre- or postsynaptic processes. Recent advancements in depression research reveal a crucial association between the disorder and disruptions in synaptic homeostasis within neural regions and circuits pivotal for emotional and cognitive functions. This paper explores the mechanisms governing synaptic homeostasis in depression, focusing on the role of ion channels, the regulation of presynaptic neurotransmitter release, synaptic scaling processes, and essential signaling molecules. By mapping new pathways in the study of synaptic homeostasis as it pertains to depression, this research aims to provide valuable insights for identifying novel therapeutic targets for more effective antidepressant treatments.

N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotes, plays a critical role in the development and progression of various diseases, including cancer, through its regulation of RNA degradation, stabilization, splicing, and cap-independent translation. Emerging evidence underscores the significant role of m6A modifications in both pro-tumorigenic and anti-tumorigenic immune responses. In this review, we provide a comprehensive overview of m6A modifications and examine the relationship between m6A regulators and cancer immune responses. Additionally, we summarize recent advances in understanding how m6A modifications influence tumor immune responses by directly modulating immune cells (e.g., dendritic cells, tumor-associated macrophages, and T cells) and indirectly affecting cancer cells via mechanisms such as cytokine and chemokine regulation, modulation of cell surface molecules, and metabolic reprogramming. Furthermore, we explore the potential synergistic effects of targeting m6A regulators in combination with immune checkpoint inhibitor (ICI) therapies. Together, this review consolidates current knowledge on the role of m6A-mediated regulation in tumor immunity, offering insights into how a deeper understanding of these modifications may identify patients who are most likely to benefit from immunotherapies.

Background: Pulpitis is a prevalent oral disease characterized by severe pain. The activation of microglia in the medullary dorsal horn (MDH) is reportedly essential for the central sensitization mechanism associated with pulpitis. The P2X7 receptor (P2X7R) on microglia can trigger the secretion of exosomes enriched with IL-1β, which is involved in inflammation. Thus, we hypothesized that the enhanced exosome secretion regulated by microglial P2X7R in the MDH contributes to pulpitis-induced pain.

Methods: An experimental pulpitis model was established in male SD rats to observe pain behaviors. Immunofluorescence staining, western blotting and quantitative real-time PCR were used to analyze the expression of IL-1β and Rab27a, a key protein secreted by exosomes during nociceptive processes. The effects of the exosome inhibitor GW4869 and the P2X7R antagonist Brilliant Blue G (BBG) on microglial P2X7R, exosome secretion and inflammation in the pulpitis model were analyzed. In vitro, microglial cells were cultured to collect exosomes, and stimulation with lipopolysaccharide (LPS), oxidized ATP (oxATP) and GW4869 altered the secretion of exosomes containing IL-1β.

Results: In the experimental pulpitis model, the microglial exosome secretion and inflammatory factor release in the MDH were both correlated with the extent of pulpitis-induced pain, with the highest expression occurring on the 7th day. GW4869 and BBG inhibited Rab27a and IL-1β expression, reducing pulpitis-induced pain. In addition, exosomes were successfully extracted by ultracentrifugation in vitro, wherein LPS treatment promoted exosome secretion but GW4869 had the opposite effects on the secretion of exosomes and the IL-1β. Moreover, P2X7R inhibition by oxATP diminished exosome secretion, leading to a reduction in inflammatory responses.

Conclusion: This study highlights the regulatory role of microglial P2X7R in increased exosome secretion, indicating the potential utility of P2X7R as a promising target for pulpitis therapy. Our research highlights a new pulpitis mechanism in which exosomes enriched with IL-1β contribute to pulpitis-induced pain, suggesting the crucial roles of exosomes as pain biomarkers and harmful signaling molecules during pulpitis.

Background: Cell-free DNA (cfDNA) in plasma carries epigenetic signatures specific to tissue or cell of origin. Aberrant methylation patterns in circulating cfDNA have emerged as valuable tools for noninvasive cancer detection, prenatal diagnostics, and organ transplant assessment. Such epigenetic changes also hold significant promise for the diagnosis of neurodegenerative diseases, which often progresses slowly and has a lengthy asymptomatic period. However, genome-wide cfDNA methylation changes in neurodegenerative diseases remain poorly understood.

Results: We used whole-genome bisulfite sequencing (WGBS) to profile age-dependent and ALS-associated methylation signatures in cfDNA from 30 individuals, including young and middle-aged controls, as well as ALS patients with matched controls. We identified 5,223 age-related differentially methylated loci (DMLs) (FDR < 0.05), with 51.6% showing hypomethylation in older individuals. Our results significantly overlapped with age-associated CpGs identified in a large blood-based epigenome-wide association study (EWAS). Comparing ALS patients to controls, we detected 1,045 differentially methylated regions (DMRs) in gene bodies, promoters, and intergenic regions. Notably, these DMRs were linked to key ALS-associated pathways, including endocytosis and cell adhesion. Integration with spinal cord transcriptomics revealed that 31% of DMR-associated genes exhibited differential expression in ALS patients compared to controls, with over 20 genes significantly correlating with disease duration. Furthermore, comparison with published single-nucleus RNA sequencing (snRNA-Seq) data of ALS demonstrated that cfDNA methylation changes reflects cell-type-specific gene dysregulation in the brain of ALS patients, particularly in excitatory neurons and astrocytes. Deconvolution of cfDNA methylation profiles suggested altered proportions of immune and liver-derived cfDNA in ALS patients.

Conclusions: cfDNA methylation is a powerful tool for assessing age-related changes and ALS-specific molecular dysregulation by revealing perturbed locus, genes, and the proportional contributions of different tissues/cells to the plasma. This technique holds promise for clinical application in biomarker discovery across a broad spectrum of neurodegenerative disorders.

Proteoglycans are an ample family of complex extracellular matrix/cell surface components known to impact on virtually all biological processes that take place during life of a human being, in its healthy and diseased conditions. They are consolidated multivalent regulators of the behaviour of normal and malignant hematopoietic cells because of being critical components of their membranes, because of their pivotal role as multifaceted factors of the hematopoietic niches and because of acting as pillars of the tumour microenvironment. Likewise, they act as promoters of the growth, spreading and therapeutic resistance of diseased hematopoietic cells, also by modulating intracellular processes through a dual utilization of core protein domains and their glycosaminoglycan side chains. The intricate pattern of expression of the myriads of proteoglycan isoforms generated by differential glycanations of the core proteins is differentiation- and cell activation-dependent and often associates with genomic aberrations and gene amplifications. Selected proteoglycans stand out as widely recognized, disease type-specific markers and as alluring but still unappreciated therapeutic targets. We therefore pose here a clinical-translational view on the hematopoietic proteoglycome to highlight its underestimated biological and pathological significance during normal and neoplastic hematopoiesis. We underscore the potential of several proteoglycans to be exploited as key markers for prognostication and therapeutic targeting of hematopoietic cancers.