Cell and Bioscience最新文献

Brain organoids have emerged as transformative in vitro models for studying human neurodevelopment, neural disorders, and evolutionary brain complexity. This review systematically compares neural development in mice and humans, reflecting the limitations of traditional rodent models and highlights the importance of organoid technology. It synthesizes evolutionary, cellular, and molecular perspectives through comprehensive analysis of literature, detailing the evolution of brain organoid technologies, from early "unguided" whole-brain models to region-specific, vascularized, and assembloid systems that recapitulate inter-regional connectivity. The integration of multi-omics approaches including transcriptomics, epigenomics, and proteomics with organoids has enabled rigorous validation of their fidelity to in vivo development and uncovered novel disease mechanisms. We further explore applications of organoids in modeling cellular dynamics, elucidating gene functions, and replicating neurodevelopmental disorders such as autism, microcephaly, and Rett syndrome. Finally, we discuss their utility in high-throughput drug screening and personalized medicine, while addressing ongoing challenges including vascularization, functional maturation, and ethical considerations. Critically, these advances in organoid technology bridge translational gaps by enabling patient-specific disease modeling, accelerating therapeutic discovery, and providing human-relevant platforms to overcome precision neuroscience. By leveraging mouse and human brain organoids to transcend species limitations in neural research, this review offers unprecedented insights into brain development and pathology.

Sepsis-induced liver injury is associated with high morbidity and mortality, yet its underlying mechanisms remain elucidated. In this study, we observed a significant reduction in the E3 ubiquitin ligase TRIM16 in lipopolysaccharide (LPS)-injured hepatocytes; however, its functional role and regulatory mechanisms were unclear. Using in vitro LPS-induced hepatocyte injury and in vivo cecal ligation and puncture (CLP)-induced septic liver injury models, we investigated TRIM16's effects via small interfering RNA and AAV9-overexpression plasmids in hepatocytes. Results demonstrated that TRIM16 overexpression rescued LPS-induced suppression of hepatocyte viability, reduced cellular dysfunction (ALT, AST), and significantly suppressed pro-inflammatory cytokine expression (TNF-α, IL-6) and oxidative stress (SOD, MDA). Conversely, TRIM16 silencing exacerbated hepatocyte damage and dysfunction. In septic mice, TRIM16 overexpression alleviated liver injury and fibrosis by inhibiting oxidative stress and inflammatory responses. Mechanistically, TRIM16 directly bound to and stabilized YAP1 through K63-linked ubiquitination, facilitating its nuclear translocation. This process enhanced Nrf2 activation and subsequent expression of antioxidant genes. Collectively, our findings reveal that TRIM16 protects against septic liver injury by mitigating oxidative stress and inflammation via the YAP1/Nrf2 pathway, highlighting its potential as a therapeutic target for sepsis-induced acute liver injury.

The incidence of inflammatory bowel disease (IBD) has been increasing, and while the interaction between T cells and intestinal microorganisms is crucial in its pathogenesis, the related epigenetic mechanisms remain unclear. This study found that the expression of lysine acetyltransferase 6A (KAT6A) was increased in T cells of patients with acute colitis. Knocking out KAT6A in CD4⁺ T cells alleviated dextran sulfate sodium (DSS)-induced colitis in mice, as manifested in body weight, disease activity index, colon length, inflammation, and the expression of proinflammatory factors. Mechanistically, KAT6A deficiency upregulated the senescence of CD4⁺ T cells and affected the expression of related genes. Moreover, the regulation of colitis by CD4⁺ T cell KAT6A was dependent on the gut microbiota. Antibiotic treatment could reverse the protective effect in T cell KAT6A knockout (TK6AKO) mice, and fecal transplantation experiments confirmed that it was related to the change of the microbiota. 16S rRNA sequencing showed that the composition of the gut microbiota was changed, and specific bacteria such as Akkermansia muciniphila were enriched in TK6AKO mice. This study reveals that KAT6A affects colitis through the interaction between regulating T cell senescence and the gut microbiota, providing a new strategy for treatment.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is estimated to affect over 30% of the global population with a rising trend, posing significant healthcare burden due to its progression and increased risk of related metabolic diseases. Dietary intervention plays an important role in the prevention and management of MASLD. Ketogenic diets represent a range of high-fat, moderate-protein, very low-carbohydrate (< 20-50 g/day) diets that induce nutritional ketosis. These diets have been proposed to benefit patients with MASLD by promoting weight loss, reducing inflammation and insulin resistance through different pathways. This review summarized the current findings on the outcomes of ketogenic diets on patients with MASLD regarding the liver, plasma lipid profile, systemic inflammation and gut microbiota. Studies showed that short- to medium- term ketogenic diets, with or without calorie restriction, are able to lower plasma triglycerides and ameliorate hepatic steatosis, steatohepatitis and fibrosis in MASLD. In particular, studies found ketogenic diets may be more effective in alleviating hepatic steatosis in short time periods than calorie-matched, high-carbohydrate, low-fat diets. Evidence on the impact on plasma high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c) was mixed. Clinical trials investigating the effects on different markers of systemic inflammation and the composition of gut microbiota among patients with MASLD were scarce. To better understand the role of ketogenic diets in MASLD management, longer-term, well-controlled trials are warranted to clarify their potential benefits and risks, and whether they are varied by types of fats. Appropriate and sustainable formulations of ketogenic diets that maximize benefits and minimize side effects remain to be determined.

Mesenchymal stem cells (MSCs) have many uses in tissue engineering and clinical applications. However, maintaining their stemness during in vitro expansion is challenging. We previously found that Krüppel-like factor 2 (KLF2) plays a crucial role in maintaining the stemness of MSCs. In this study, KLF2 was revealed to be closely linked to mitochondrial oxidative phosphorylation (OXPHOS), and impaired KLF2 expression in MSCs led to mitochondrial dysfunction that ultimately resulted in the loss of stemness. Moreover, decreased KLF2 expression was associated with reduced expression of the mitochondrial electron transport chain components, particularly the accessory subunit of complex I, NDUFC1. Further study demonstrated that KLF2 transcriptionally regulates NDUFC1 expression by binding to its promoter region. In addition, NDUFC1 knockdown largely phenocopied KLF2 knockdown in mitochondrial dysfunction and loss of stemness, and these phenotypes were partially rescued by NDUFC1 overexpression. Taken together, we reveal that KLF2 critically maintains MSCs stemness by transcriptionally promoting the expression of mitochondrial electron transport chain components such as NDUFC1, and KLF2/NDUFC1 axis-regulated mitochondrial oxidative phosphorylation may serve as a novel therapeutic target for improving MSCs stemness.

Background: The aggregation of α-Synuclein (αS) into amyloid fibrils and their deposition in intraneuronal Lewy bodies are hallmark features of Parkinson's disease (PD) and other synucleinopathies. Among the molecular players implicated in αS toxicity, the cellular prion protein (PrP^C) has emerged as a potential modulator of αS-neuron interactions.

Results: Using confocal microscopy, colocalization analysis and both siRNA-induced PrP^C silencing and antibody-based blockade, we investigated the contribution of PrP^C to αS-induced neurotoxicity in human iPSC-derived dopaminergic neurons, primary rat cortical neurons and human SH-SY5Y neuroblastoma cells. We show that PrP^C facilitated the early recruitment of αS prefibrillar type B* oligomers (OB*) and short fibrils (SF) to neuronal membranes, enhancing αS-induced Ca²⁺ influx and membrane permeabilization. However, PrP^C levels remained unchanged following prolonged exposure with OB* and SF, suggesting no feedback modulation of PrP^C expression. While PrP^C blockade partially inhibited the release of toxic soluble oligomers from αS fibrils, downstream cell death was only marginally reduced, indicating a limited contribution of PrP^C to the final neurotoxic outcome. By contrast, extracellular Ca²⁺ emerged as a major driver of αS toxicity, directly promoting the membrane recruitment, internalization and cytotoxic effects of αS aggregates.

Conclusions: Collectively, our findings indicate that while PrP^C facilitates early events in αS aggregate interaction with neurons, the sustained neurotoxicity induced by αS prefibrillar oligomers and fibrils is predominantly mediated by extracellular Ca²⁺. This promotes aggregate-membrane interactions, membrane permeabilization, and intracellular Ca²⁺ dyshomeostasis, thereby establishing a vicious cycle of neuronal dysfunction and death.

Mitochondrial Antiviral Signaling Protein (MAVS), a key adaptor in the innate immune system, has traditionally been recognized for its role in defending against viral infections through activation of the interferon (IFN) and NF-κB signaling pathways. Recent studies, however, have expanded this view, revealing that MAVS also functions at the intersection of innate immunity, mitochondrial dynamics, and cellular metabolism. Located on the outer mitochondrial membrane, MAVS serves as a critical signaling hub, linking pathogen detection to inflammatory and stress responses. Beyond its canonical antiviral roles, MAVS is now implicated in diverse physiological and pathological processes, including regulation of apoptosis, NLRP3 inflammasome activation, metabolic reprogramming, and autophagy. Its dysregulation contributes to the onset and progression of a range of diseases, such as cancer, cardiovascular and autoimmune disorders, and neurological conditions. This review provides a comprehensive overview of MAVS activation, downstream signaling outputs, and regulatory mechanisms. We also discuss the emerging evidence on MAVS-related diseases and therapeutic strategies targeting MAVS, emphasizing its broader significance in human health beyond antiviral immunity.

Background and aims: RNF186, which encodes a ring-finger domain-containing E3 ubiquitin-protein ligase, has previously been implicated in the regulation of lipid metabolic disorders associated with metabolic dysfunction-related fatty liver disease (MAFLD). However, the precise mechanism by which RNF186 influences glucose metabolism in the context of MAFLD remains unclear. In this study, we aimed to elucidate the role of RNF186 in the regulation of glucose metabolism, with a particular focus on skeletal muscle.

Methods: In vitro, we treated skeletal myocytes and hepatocytes with high glucose concentrations to study the expression of RNF186 and its effects on glucose uptake and insulin signaling. In vivo, we developed a MAFLD model through long-term high-fat feeding and assessed the impact of RNF186 deficiency on glucose metabolism in skeletal muscle, liver and adipose tissue using Western blotting, quantitative PCR (qPCR), and immunofluorescence.

Results: Our findings demonstrate that RNF186 is regulated by glucose concentration in skeletal muscle cells and hepatocytes and is sensitive to insulin in a high-glucose environment. The deletion of RNF186 increases glucose metabolism and alleviates insulin signaling disruption in the MAFLD model, affecting skeletal muscle, liver, and adipose tissue. Furthermore, in skeletal muscle, RNF186 deficiency reduces the ER stress-mediated unfolded protein response (UPR) by preventing the ubiquitination of ATF6, leading to increased transcription of GLUT4. Additionally, RNF186 deficiency promotes the membrane translocation of GLUT4 via the AKT/TBC1D4 signaling pathway. In contrast, overexpression of RNF186 decreases AKT signaling and GLUT4 expression, resulting in exacerbated disruption of glucose metabolism in MAFLD.

Conclusions: RNF186 regulates glucose metabolism across multiple tissues in MAFLD, notably by playing a dual role in modulating the transcription and translocation of GLUT4 in skeletal muscle. These findings suggest that targeting the expression of RNF186 could be a potential therapeutic strategy for treating MAFLD and related metabolic disorders.

N4-acetylcytidine (ac4C) is a novel RNA modification that plays important biological roles in a variety of diseases, including tumors, by regulating gene expression at the posttranscriptional level. As a currently known ac4C-modified "writing" protein, N-acetyltransferase (NAT10) affects the stability and translation efficiency of target mRNAs by changing the chemical and spatial structure of RNA, thereby acting as an oncogene and tumor suppressor gene in different tumors, highlighting its potential role as a tumor prognostic marker and therapeutic target. Research on the molecular mechanism of ac4C modification and its function in tumors continues to expand, but its action network and clinical translational application still face many challenges. This review systematically explains the molecular mechanism of ac4C modification and its biological significance in tumors and its connection with relevant signaling pathways and the immune microenvironment, focuses on analyzing the research progress of ac4C modification enzymes, and discusses its potential as a tumor target. The purpose of this study was to provide a theoretical basis and new ideas for basic research and the clinical translation of the ac4C modification in the field of oncology.