DNA and cell biology最新文献

Mechanical forces are fundamental drivers of morphogenesis, yet the molecular mechanisms that convert these physical cues into transcriptional responses remain incompletely understood. This review synthesizes current evidence identifying the mechanosensitive ion channel Piezo1 as a master regulator of developmental processes. The structural and biophysical principles underlying Piezo1 function are highlighted, focusing on its trimeric architecture and force-from-lipids gating mechanism that directly couples membrane tension to Ca²⁺ influx. Its spatiotemporal expression during embryogenesis is reviewed, and the downstream pathways it activates are examined, including mitogen-activated protein kinase (MAPK) and yes-associated protein/transcriptional co-activator with PDZ-binding moti (YAP/TAZ), alongside crucial crosstalk with canonical morphogen signaling cascades such as Notch, Wntwingless/integrated signaling pathway (Wnt)/beta-catenin (β-catenin), and bone morphogenetic protein/transforming growth factor-beta (BMP/TGF-β). Functional studies across diverse model systems demonstrate that Piezo1 orchestrates conserved morphogenetic events, including vascular and lymphatic patterning, neurogenesis, epithelial morphogenesis, myoblast fusion, and osteogenesis. Human genetic data further underscore its nonredundant role, linking gain-of-function mutations to dehydrated hereditary stomatocytosis and loss-of-function mutations to primary lymphatic dysplasia. Collectively, these findings establish Piezo1 as an essential integrator of mechanical and biochemical signals, central to tissue patterning and organ formation. The review concludes by emphasizing Piezo1's therapeutic potential in regenerative medicine and developmental disorders, while also underscoring the challenges of targeting such a broadly influential mechanosensor.

The long noncoding RNA (lncRNA) antisense noncoding RNA in the INK4 locus (ANRIL) expression is upregulated in hepatocellular carcinoma (HCC) tissues, and decreased ANRIL expression inhibits cell proliferation, metastasis, and invasion and induces apoptosis in HCC cells. However, the molecular mechanism by which ANRIL is involved in HCC tumorigenesis is unclear. In this study, ANRIL was found to be a significantly upregulated lncRNA in HCC and was associated with the metastasis and poor prognosis of HCC. p53 plays an important role in the mechanism of carcinogenesis. Therefore, we hypothesized that ANRIL plays a biological role by regulating the p53 signaling pathway. To comprehensively evaluate the biological function of ANRIL, bioinformatics analysis, quantitative real-time polymerase chain reaction, Western blotting, wound healing, Transwell, cell colonization assay, cell counting kit-8, reactive oxygen species, JC-1, EdU, and terminal deoxynucleotidyl transferase-mediated dUTP Nick end labeling were performed. The results showed that the knockdown of ANRIL inhibited HCC cell viability, colony forming ability, functions such as metastasis and invasion, and epithelial-mesenchymal transition. Meanwhile, the knockdown of ANRIL also resulted in the decreased expression of the p53 protein. All these effects are tightly intertwined with the regulation of the p53 signaling pathway. Thus, ANRIL may contribute to the development of new drugs for the treatment of human HCC.

Ferroptosis plays a crucial role in regulating tumor growth and represents a promising therapeutic target for nonsmall cell lung cancer (NSCLC). RNA-binding protein with serine-rich domain 1 (RNPS1) has been closely associated with the development of various cancer types, but its role in NSCLC remains unclear. In this study, we used lentiviral vectors to silence or overexpress RNPS1 in NSCLC cells and then assessed cell proliferation along with ferroptosis markers, such as lipid reactive oxygen species (ROS). Bioinformatics analysis revealed that RNPS1 was upregulated in clinical NSCLC samples. Consistently, functional experiments showed that overexpression of RNPS1 promoted cell proliferation, while RNPS1 knockdown inhibited cell proliferation. Furthermore, RNPS1 overexpression attenuated erastin-triggered ferroptosis by suppressing the accumulation of lipid ROS and malondialdehyde, as well as by preventing the depletion of glutathione. Mechanistic investigations identified that RNPS1 stabilized ETS variant transcription factor 4 (ETV4) mRNA. Importantly, blocking ETV4 expression partially reversed RNPS1 overexpression-mediated suppression of ferroptosis. Collectively, these results support the notion that RNPS1 acts as a novel suppressor of ferroptosis in NSCLC progression.

This essay focuses on a key host factor, the protein BIK (Bcl-2-interacting killer), that influences the severity of influenza A virus (IAV) infections. Our recent research published in Proceedings of the National Academy of Sciences describes a novel IAV-BIK-β5 axis that is critical for viral replication. The study demonstrates that BIK is essential for efficient IAV replication, and its overexpression leads to increased viral loads, lung inflammation, and heightened mortality in mouse models. We also identified a single nucleotide polymorphism (SNP), rs738276, in the BIK gene's promoter. This SNP influences the basal expression of BIK, and individuals with the high-expression AA genotype are at a higher risk for severe influenza. The molecular mechanism involves the viral nucleoprotein (NP) suppressing the proteasome's β5 subunit, which leads to BIK accumulation and promotes viral replication. These findings identify BIK as a potential therapeutic target and the rs738276 SNP as a biomarker for personalized medicine.

Dengue is the most important mosquito-borne viral infection of humans worldwide. Genetic ancestry of the host is a significant risk factor for severe dengue, but the mechanisms are not known. Recent findings using human skin explants from genetically defined donors reveal that dengue virus (DENV) replication and spread in skin increases with increasing proportion of European ancestry of the donor, associated with a strong inflammatory response and local myeloid cell infiltration, infection, and migration. In contrast, African ancestry is associated with substantially reduced cutaneous inflammation and cell infiltration following virus inoculation, resulting in reduced infection and migration of infected cells. These findings help explain the long-standing observation that individuals of African descent are relatively protected against severe dengue, while individuals of European descent are not. In this essay, we review DENV infection, focusing on human skin and the influence of genetic ancestry on the cutaneous innate response and virus spread.

Gastric cancer is one of the leading causes of cancer mortality worldwide, but the underlying molecular mechanisms by which gastric cancer progresses are not fully understood. While deubiquitinases have emerged as promising therapeutic targets in various cancers, a suitable target deubiquitinase for the treatment of gastric cancer has not yet been identified. Using bioinformatics analyses, we identified that upregulation of ubiquitin-specific peptidase 26 (USP26) was associated with poor patient survival in patients with gastric cancer; moreover, depletion of endogenous USP26 with short hairpin RNAs significantly suppressed the aerobic glycolysis and proliferation in tumor cells. In mechanism, USP26 was revealed to interact with and stabilize c-Myc, which is a key driver of tumor metabolism and carcinogenesis, via suppressing its polyubiquitination and degradation. In summary, these findings suggest that USP26 plays a novel oncogenic role of USP26 by forming a USP26-c-Myc regulatory axis, and that targeting USP26 may be a potential therapeutic strategy for gastric cancer.

Arrestin beta 1 (ARRB1) and ARRB2, which are multifunctional adapters in G protein-coupled receptor signaling, are highly involved in liver-related diseases. ARRB1 plays a protective role against ischemia-reperfusion injury, acute liver injury, and nonalcoholic fatty liver disease by inhibiting apoptosis and improving metabolic disorders. ARRB1 has been reported to be protective in mouse liver fibrosis models; however, it has also been shown to have pathogenic effects in human liver fibrosis. This discrepancy may be due to limitations in mouse models and species differences. In contrast, ARRB2 has dual functions in liver-related diseases. On the contrary, it reduces acute hepatitis and ischemic injury by inhibiting the NF-κB/c-Jun N-terminal kinase pathway. On the contrary, it accelerates disease progression by activating macrophages and promoting oxidative stress and collagen deposition in autoimmune hepatitis, alcoholic steatohepatitis, and fibrosis. Furthermore, the structural differences between ARRB1 and ARRB2 may determine their signal bias through nuclear output capability, nuclear input capability, and phosphorylation. In-depth analysis of the interaction between ARRBs and their signaling mechanisms is expected to provide accurate therapeutic targets for liver disease.

Copper plays an essential role in numerous biological functions, requiring tight regulation to prevent toxicity and health complications. Cuproptosis is a recently discovered form of regulated cell death that occurs due to intracellular copper accumulation, with a unique mechanism distinct from other known cell death pathways. It is initiated when copper binds to lipoylated enzymes within the tricarboxylic acid (TCA) cycle, leading to enzyme aggregation, proteotoxic stress, and, ultimately, cell death. Since its identification, cuproptosis has drawn significant attention for its potential application in cancer therapy. Copper-based treatments have shown promise in suppressing tumor growth and may offer therapeutic strategies for tumors resistant to conventional chemotherapy. This article explores the underlying mechanisms of cuproptosis and the involvement of copper in various malignancies, aiming to advance targeted cancer therapies and inspire the development of novel anticancer agents that harness this pathway. Finally, important concepts of cuproptosis and issues to focus on in future studies are discussed.

The development of effective therapeutic strategies for chronic kidney disease (CKD) remains a central focus of contemporary medical research. Mesenchymal stem cells (MSCs) have emerged as a highly promising therapeutic modality for CKD, primarily due to their inherent regenerative and immunomodulatory capabilities. MSCs exert their therapeutic effects predominantly through the transfer of miRNAs via extracellular vesicles (EVs), which orchestrate key cellular pathways involved in renal repair and regeneration. However, critical challenges-including limited differentiation potential, suboptimal survival rates, and inefficient homing capacity-have significantly constrained their clinical translation. As such, enhancing the therapeutic efficacy of MSCs has become a paramount research priority. Recent investigations have demonstrated that preconditioning MSCs can markedly augment their therapeutic performance. Notably, emerging evidence has established a compelling association between herbs and the regulation of miRNA expression in MSC-derived EVs, suggesting novel synergistic interactions between herbs and MSC-based therapies. This review systematically dissects the mechanistic frameworks through which herbs and their bioactive constituents enhance the therapeutic effects of preconditioned MSCs, with a particular emphasis on EV-mediated miRNA cross-talk. The overarching goal is to provide innovative perspectives and translational strategies to facilitate the clinical implementation of preconditioned MSCs in CKD management.

Mesenchymal stromal cells (MSCs) have been widely used in clinical trials for various diseases, due to their broad differentiation potential and effective immunomodulatory effects. However, the cell death profiles of MSC subsets remain inadequately characterized. In this study, we unexpectedly identified unique differentially expressed ferroptotic genes in MSC subsets from four different tissues (adipose, bone marrow, dermis, and umbilical cord) and revealed a critical role of ferroptosis in umbilical cord derived MSCs (UC-MSCs). Furthermore, increased ferroptosis level and ferroptosis sensitivity were detected in the C1 subset of UC-MSCs, and the upregulation in the ferroptosis level and sensitivity was examined during an expansion of UC-MSCs with the treatment with an ferroptosis inducer. In addition, we detected an increase in the proportion of C1 UC-MSCs after treatment with a ferroptosis inducer (Erastin) or inhibitor (Fer-1). Overall, this study further revealed the intricate nature of MSCs and will help facilitate the use of optimal subtypes to improve their clinical efficacy in the future.