BMB Reports最新文献

Tau, a microtubule-associated protein, is known for its significant involvement in neurodegenerative diseases. While various molecular and immunohistochemical techniques have confirmed the presence of Tau in podocytes, its precise function within these cells remains elusive. In this study, we investigate the role of Tau in kidney podocytes using Drosophila pericardial nephrocytes as a model. We found that knockdown of Drosophila Tau in nephrocytes resulted in apoptotic cell death and the disruption of nephrocyte structure. Furthermore, we observed that decreased Tau levels induced genomic damage and abnormal distribution of γ-H2Av, altering nuclei architecture in nephrocytes, and affecting the nuclear membrane structure by interfering with lamin with aging. Additionally, Tau knockdown led to a reduction in lipid droplets in Drosophila fat body tissues, suggesting a potential role of Tau in inter-organ communication. These findings underscore the importance of Tau in the nephrocytes of Drosophila, and advocate further research to broaden our understanding of podocyte biology in kidney diseases. [BMB Reports 2025; 58(4): 169-174].

Long noncoding RNAs (lncRNAs) are integral to epigenetic regulation during cardiogenesis; however, their role in aortic valve disease is not well characterized. Investigating lncRNAs present in the human embryonic heart and pinpointing their specific isoforms presents notable challenges due to both technical and ethical limitations. In our research, we identified GATA6- AS1 as a lncRNA predominantly found in the heart by analyzing publicly accessible RNA sequencing data derived from human embryonic tissues. Employing in vitro models along with CS17 embryonic heart tissue, we determined that isoforms 202 and 208 of GATA6-AS1 are uniquely expressed in cardiac neural crest lineage cells throughout the development of the aortic valve. We also identified Moshe, the murine ortholog of GATA6-AS1, whose expression occurs during aortic valve formation in mice. Notably, depletion of Moshe results in the development of bicuspid aortic valves (BAV), accompanied by a significant downregulation of genes associated with BAV, particularly those related to the Notch and TGF-β signaling pathways. These findings highlight the critical role of GATA6-AS1 in aortic valve development through the study of its mouse ortholog Moshe. They also suggest that lncRNAs, still underexplored in congenital heart disease research, may hold significant implications for BAV pathogenesis and potential therapeutic strategies. [BMB Reports 2025; 58(4): 175-182].

The reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) is a crucial development in regenerative medicine, providing patient-specific cells for therapeutic uses. Traditional methods often utilize viral vectors and transcription factors that pose tumorigenic risks, rendering them unsuitable for clinical applications. This study explored the use of chemicals as a non-tumorigenic alternative for cell reprogramming. Utilizing CRISPR/Cas9 technology, we previously created iPSCs expressing OCT4-EGFP and NANOG-tdTomato, and derived OCT4-EGFP and NANOG-tdTomato fibroblastic cells (ON-FCs). These cells were reprogrammed using episomal vectors, and their pluripotency was validated by fluorescence and FACS analyses. High-content screening was employed to assess small molecules that improve reprogramming efficiency, confirming the usefulness of ON-FCs as a dual reporter cell line for identifying small molecules effective in generating human iPSCs. This study underscores the utility of a dual reporter system and high-content screening in identifying effective reprogramming chemicals, establishing a scalable platform for high-throughput screening. Discovering new chemicals that can reprogram iPSCs would provide a non-tumorigenic method to advance the field of regenerative medicine. [BMB Reports 2025; 58(4): 183-189].

Spondyloarthritis (SpA) is a chronic inflammatory disease that leads to ankylosis of the axial skeleton. Celecoxib (cyclooxygenase-2 inhibitor, COX-2i) inhibited radiographic progression in a clinical study of SpA, but in the following study, diclofenac (COX-2 non-selective) failed to show that inhibition. Our study aimed to investigate whether nonsteroidal anti-inflammatory drugs (NSAIDs) inhibited bone progression in SpA, and whether celecoxib had a unique function (independent of the COX-inhibitor), compared with the other NSAIDs. We investigated the efficacy of various NSAIDs in curdlan-injected SKG mice (SKGc), an animal model of SpA, analyzed by bone micro-CT and immunohistochemistry. We also tested the effect of NSAIDs on osteoblast (OB) differentiation and bone mineralization in primary bone-derived cells (BdCs) from mice, and in ankylosing spondylitis (AS) patients and human osteosarcoma cell line (SaOS2). Celecoxib significantly inhibited clinical arthritis and bone progression in the joints of SKGc, but not etoricoxib (another COX-2i), nor naproxen (COX-2 nonselective). Both DM-celecoxib, not inhibiting COX-2, and celecoxib, inhibited OB differentiation and bone mineralization in the BdCs of mice and AS patients, and in SaOS2, but etoricoxib or naproxen did not. The in silico study indicated that celecoxib and 2,5-dimethyl-celecoxib (DM-celecoxib) would bind to cadherin-11 (CDH11) with higher affinity than etoricoxib and naproxen. Celecoxib suppressed CDH11-mediated β-catenin signaling in the joints of SKGc, primary mice cells, and SaOS2 cells. Of the NSAIDs, only celecoxib inhibited bone progression in SKGc and OB differentiation and bone mineralization in the BdCs of mice and AS patients via CDH11/WNT signaling, independent of the COX-2 inhibition. [BMB Reports 2025; 58(3): 140-145].

Limited efficacy and severe side effects often result in suboptimal outcomes to solid tumor therapies. In contrast, the reduced side effects and potential long-term benefits of tumor immunotherapy offer promise, notwithstanding the challenges of variable patient responses and immune-related adverse events hindering its widespread application. Recent advances in mRNA technology have revolutionized cancer immunotherapy. The versatility of mRNA as a vaccine and therapeutic agent is evident in it overcoming the limitations of traditional approaches by reducing in vivo toxicity and enhancing immune response activation. The synergy between mRNA technology and immunotherapy is increasingly being utilized to improve cancer treatment efficacy. One critical aspect of maximizing the therapeutic impact of mRNA-based treatments is the selection of an effective delivery system. Due to their size properties and material characteristics, nanoparticles offer a transformative solution, enabling the targeted and efficient delivery of mRNA to tumor tissues or immune cells. This precision delivery mechanism significantly enhances the effectiveness of immunotherapy, and represents a significant advance in cancer treatment. This review aims to explore how mRNA delivery via nanoparticles enhances tumor immunotherapy. Examination of its applications and challenges provides insights and strategic perspectives to advance this innovative therapeutic approach. [BMB Reports 2025; 58(3): 124-132].

Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) and its progressive form, Metabolic Dysfunction Associated Steatohepatitis (MASH), represent significant health concerns associated with the metabolic syndrome. These conditions are characterized by excessive hepatic fat accumulation, inflammation, and potential progression to cirrhosis and hepatocellular carcinoma. Neutrophils are innate immune cells that play a pivotal role in the development of MASLD and MASH. They can infiltrate the hepatic microenvironment in response to inflammatory cytokines and damage associated molecular patterns (DAMPs) derived from the liver and exacerbate tissue damage by releasing of reactive oxygen species (ROS), cytokines, and neutrophil extracellular traps (NETs). Moreover, neutrophils can disrupt the metabolism of hepatocytes through key factors such as neutrophil elastase (NE) and human neutrophil peptides-1 (HNP-1), leading to inflammation and fibrosis, while myeloperoxidase (MPO) and lipocalin (LCN2) are involved in inflammatory and fibrotic processes. In contrast, neutrophils contribute to liver protection and repair through mechanisms involving microRNA-223 and matrix metalloproteinase 9 (MMP9). This dual role of neutrophils highlights their significance in the pathogenesis of MASLD and MASH. This review summarizes current understanding from recent studies on the involvement of neutrophils in MASLD and MASH. Understanding complex roles of neutrophils within the liver's unique microenvironment offers insights into novel therapeutic strategies, emphasizing the need for further research to explore neutrophil-targeted interventions for managing MASLD and MASH. [BMB Reports 2025; 58(3): 116-123].

Ethical considerations surrounding the utilization of animals in scientific research have prompted a widespread search for alternative methodologies. This review explores the historical context and ethical dilemmas associated with traditional animal testing methods, before introducing the Monocyte Activation Test (MAT) as a promising alternative, and outlining its basic principles, historical development, and advantages over conventional animal testing. The role of monocytes in the immune system and the activation pathways utilized in MAT are elucidated, while regulatory acceptance and guidelines for MAT validation are introduced, alongside case studies proving its reliability and reproducibility. The applications of MAT in pharmaceutical and medical device testing are summarized, together with its potential future uses. Although the MAT faces limitations and challenges, the global perspective to reduce unnecessary animal tests has become a general concept in animal welfare and scientific research. [BMB Reports 2025; 58(3): 105-115].

G protein-coupled receptor 40 (GPR40) is gaining recognition as a potential therapeutic target for several metabolic disturbances, such as hyperglycemia and excessive inflammation. GPR40 is expressed in various tissues, including the heart; however, its specific roles in cardiomyocytes remain unknown. The objective of the present study was to investigate whether treatment with AM1638, a GPR40-full agonist, reduces palmitate-mediated cell damage in H9c2 rat cardiomyocytes. AM1638 treatment increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and expression levels of the antioxidant molecules heme oxygenase-1 (HO-1) and nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase-1 (NQO1). Palmitate-mediated superoxide production and levels of 4-hydroxynonenal, a biomarker of oxidative stress, decreased after treatment with AM1638. Notably, palmitate-mediated disruption of mitochondrial membrane potential, lower levels of mitochondrial complex protein, and failure of adenosine triphosphate production were all recovered by treatment with AM1638. Moreover, AM1638 blocked palmitate-mediated caspase-3 cleavage and nuclear fragmentation, thereby improving cell viability. However, these AM1638-mediated beneficial effects were abrogated by treatment with Compound C, an AMPK inhibitor. These results demonstrate that AM1638, a GPR40-full agonist, ameliorates palmitate-mediated oxidative stress in H9c2 cells in an AMPK-dependent manner. [BMB Reports 2025; 58(3): 133-139].

Programmed cell death 5 (PDCD5) regulates cell death and suppresses tumor progression. Since the stability and nuclear translocation of PDCD5 are regulated by TP53-dependent cell death stimuli, knowledge of the regulatory mechanism of PDCD5 function is required to better understand the TP53-signaling pathway. We identified Jumonji domain-containing protein 4 (JMJD4) to be a PDCD5-interacting protein using liquid chromatography- mass spectrometry (LC-MS). Interestingly, JMJD4 upregulates cell proliferation and chemo-resistance under genotoxic stress conditions by colony-formation assay and decreases TP53-related apoptotic genes (BAX, PUMA) by suppressing protein levels of PDCD5. Additionally, using the Cancer Genome Atlas and the Gene Expression Omnibus database to confirm the clinical correlation between JMJD4 and cancer patients, we verified that JMJD4 is associated with a poor prognosis in colon cancer and lung cancer patients. Therefore, this study demonstrates that JMJD4 directly interacts with PDCD5, regulates cancer cell death negatively, and could be a potential therapeutic target for cancer development. [BMB Reports 2025; 58(2): 64-69].

Prime editing is widely used in many organisms to introduce site-specific sequence modifications such as base substitutions, insertions, and deletions in genomic DNA without generating double-strand breaks. Despite wide-ranging applications of prime editing, prime editors (PEs) have low editing efficiencies, especially in dicot plants. Therefore, PEs are barely used for genome engineering in dicot plant species. Here, based on previous approaches used to improve prime editing efficiency, we generated different combinations of PE components and prime editing guide RNAs (pegRNAs) and examined their prime editing efficiencies in Arabidopsis thaliana protoplasts as a dicot model system. We found that v4e2, in which PE was fused to viral nucleocapsid (NC) protein, RNase Hdeleted M-MLV RT, and a dominant negative version of human mutL homolog 1 (hMLH1dn), showed the highest prime editing efficiency in Arabidopsis protoplasts when it was co-transfected with dual enhanced pegRNA. Our results suggest that the v4e2 PE system could be used for efficient prime editing in dicot plants. [BMB Reports 2025; 58(2): 70-74].