BMB Reports最新文献

Bowel syndrome is a prevalent and debilitating symptom in patients with multiple sclerosis (MS), substantially impairing their quality of life. However, the underlying mechanisms of MS development remain poorly understood. In this study, we demonstrated that intestinal epithelial cells (IECs) and the mucosal barrier were disrupted during experimental autoimmune encephalomyelitis (EAE) induction, driven by the inhibition of mitochondrial oxidative phosphorylation (OXPHOS). Proteomic analysis confirmed alterations in OXPHOS complexes, with a pronounced decrease in the expression of cytochrome c oxidase and ATP synthase subunits in small intestinal epithelial cells (sIECs). We identified a gut microbiota-derived metabolite that induces IEC dysfunction by downregulating OXPHOS protein complexes. Specifically, metabolomic analysis revealed an enrichment of phenyllactic acid (PLA), a phenolic acid typically produced by Lactobacillus murinus, in the cecal contents of EAE mice. Our findings indicate that PLA actively downregulates OXPHOS complexes and restrains maximal mitochondrial respiration. Using a multi-omics approach, this study elucidated a potential mechanism by which gut microbiota dysbiosis observed in EAE mice compromises IEC integrity and disrupts the mucosal barrier.

Microglial activation driving neuroinflammation is a key factor in secondary brain injury after intracerebral hemorrhage (ICH); however, the regulatory mechanisms remain unknown. This study investigates how corin influences microglial inflammatory activation and its underlying mechanisms. Corin expression in rat ICH brain tissue was assessed at multiple time points. To assess corin's effect on neurological function and microglial inflammation, ICH rats and oxygen-glucose deprivation plus hemin (OGD/H)-stimulated HAPI microglia were treated with corin-encoding lentivirus. Neurobehavioral performance was evaluated using the Morris water maze (MWM). Microglial activation was assessed via Iba-1, iNOS, and Arg-1 expression, cytokine secretion, and migration assays. To determine whether AMPK mediates corin's effects, cells were co-treated with Compound C (an AMPK inhibitor) and corin lentivirus. Corin expression decreased in ICH rat brain tissue, reaching its lowest level on day 3 post-ICH. Corin overexpression protected against ICH-induced neuronal apoptosis and improved neurological deficits as confirmed by MWM. Moreover, corin overexpression reduced microglial activation and inflammation in both ICH rats and OGD/H-stimulated microglial cells, ameliorated mitochondrial dysfunction, and increased the p-AMPK/AMPK ratio. The protective effects of corin on cell migration, inflammation, and mitochondrial function were reversed by Compound C, indicating AMPK is a downstream mediator of corin. Targeting corin offers a promising therapeutic strategy for ICH by reducing neuroinflammation and mitochondrial damage through AMPK activation and modulation of microglial inflammatory phenotype polarization.

DNA, a large molecule located in the nucleus, carries essential genetic information, including gene loci and cis-regulatory elements. Despite its extensive length, DNA is compactly stored within the limited space of the nucleus due to its hierarchical three-dimensional (3D) organization. In this structure, DNA is organized into territories known as topologically associated domains (TADs). Within each TAD, numerous chromatin loops link promoters and enhancers across the genome. These loops and the interactions between promoters and enhancers are dynamically regulated, thereby controlling gene transcription activities. With the rapid advancements in single-cell genomics technologies, TAD boundaries and chromatin loops can now be observed at the level of individual cells, allowing researchers to explore cellular heterogeneity in tissues. This review will summarize the state-of-the-art bioinformatics methods recently developed to analyze single-cell Hi-C and epigenomics datasets, which infer higher-order chromatin interactions within the 3D genome. Additionally, we will discuss the biological applications of these tools and future directions for comprehensively investigating epigenomic heterogeneity across different species, developmental stages, and disease states. [BMB Reports 2025; 58(12): 485-493].

Several individual bioactive compounds isolated from Hericium erinaceus exhibit various physiological and biochemical activities, including neuroprotective, neurotrophic, gastrointestinal protective, immunoregulatory, and anti-inflammatory effects. However, the specific anti-inflammatory effects of H. erinaceus extracts, which can vary significantly depending on the extraction solvent, require further investigation. In this study, we aimed to investigate the anti-inflammatory effects of H. erinaceus hot water extract (HWE). Therefore, we evaluated nitric oxide (NO) production, the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), the expression and release of pro- and anti-inflammatory cytokines, and changes in inflammation-related signaling pathways in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. HWE effectively suppressed NO production and iNOS expression; however, COX-2 expression exhibited a biphasic response, increasing at 1.25 mg/ml and decreasing at 2.5 mg/ml. Additionally, HWE reduced the expression and release of the proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and increased the expression and release of the anti-inflammatory cytokine IL-10. Furthermore, HWE attenuated the phosphorylation of IKK-α/β and NF-κB p65 and ameliorated LPS-induced inflammation by inhibiting the phosphorylation of JAK1 and STAT3. These findings suggest that HWE may serve as a valuable source for anti-inflammatory agents or health functional food ingredients. [BMB Reports 2025; 58(12): 494-500].

Senescence of mesenchymal stem cells in bone tissue (BMSCs), the primary progenitors of osteoblasts, is a key contributor to age-related osteopenia and osteoporosis. Aged cells exhibit elevated cellular stress and abnormal accumulation of stress granules (SGs), which contain G-quadruplex (G4) structured nucleic acids and G4-binding proteins. Dhx36, a helicase that unwinds G4 structure, may play a protective role in this context. In this study, we investigated the function of Dhx36 in BMSCs and bone homeostasis by silencing Dhx36 expression in vitro and in vivo. Dhx36 deficiency increased SG formation and impaired their resolution in BMSCs. This was accompanied by reduced expression of G4-containing autophagyrelated genes and diminished autophagic activity. Loss of Dhx36 also enhanced senescence features and impaired BMSC osteogenic differentiation. Dhx36 expression was significantly lower in bone tissue and BMSCs from aged mice, compared to young mice. Moreover, 8-week-old mice with BMSC-specific Dhx36 knockout exhibited reduced bone volume and trabecular number, indicating premature bone loss. Analysis of public singlecell RNA sequencing data further showed that stress induced by 5-fluorouracil in mice suppressed Dhx36 expression in BMSCs, and downregulated genes related to ossification and osteoblast differentiation. Collectively, our findings identify Dhx36 as a regulator of BMSC aging, linking SG dynamics and autophagy to bone homeostasis, and suggest Dhx36 as a potential therapeutic target to prevent age-related bone loss. [BMB Reports 2025; 58(12): 501-510].

This study examined therapeutic potential of mitochondrial transplantation using PN-101, a mitochondria preparation derived from human umbilical cord mesenchymal stem cells (UCMSCs), to address SSBP1-related mitochondrial DNA (mtDNA) depletion syndrome. Patient-derived fibroblasts harboring a heterozygous SSBP1 mutation (c.272G＞A:p.Arg91Gln) were treated with PN-101. Its successful uptake and integration into these cells were confirmed. Subsequent analyses revealed that PN-101 treatment significantly increased mtDNA copy numbers in a time- and dose-dependent manner, elevated the expression of key oxidative phosphorylation proteins, and enhanced overall mitochondrial bioenergetics. Taken together, these results provide strong evidence that mitochondrial transplantation holds promise as a therapeutic strategy for primary mitochondrial diseases, including those involving SSBP1 mutations.

Excessive generation of reactive oxygen species (ROS) and proinflammatory cytokines is a pivotal mechanism causing sensorineural hearing loss (SNHL) through damage to auditory hair cells. In particular, high expression levels of tumor necrosis factoralpha (TNF-α) were observed in SNHL. Alpha-lipoic acid (ALA) has demonstrated protective effects against cochlear hair cell damage and hearing deterioration. This study investigated the protective effect of ALA against TNF-α-triggered ototoxicity in auditory hair cells and in a noise-induced hearing loss mouse model. Cells were pretreated with ALA prior to TNF-α treatment, after which cell viability, ROS generation, and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant activity were assessed. In addition, we observed the hearing levels, the number of outer hair cells (OHCs), and Nrf2-related protein expression in ALA-pretreated mice before noise exposure. ALA pretreatment significantly enhanced cell viability, suppressed ROS production, and activated Nrf2-mediated antioxidant activity compared with TNF-α treatment alone. In the animal model, noise-exposed mice exhibited elevated TNF-α expression in cochlear tissues. ALA pretreatment decreased the auditory brainstem response threshold and reduced OHCs damage. Furthermore, ALA administration upregulated Nrf2-related antioxidant protein expression in cochlear tissues. Taken together, these findings suggest that ALA pretreatment confers cytoprotective effects against TNF-α-triggered auditory hair cell damage through activation of the Nrf2 signaling- mediated antioxidant activity.

Colorectal cancer (CRC) is a major health concern and understanding its molecular characteristics is crucial for improving its diagnosis and treatment. Here, we present a comprehensive analysis utilizing RNA-sequencing (RNA-seq) data and clinical information from Korean patients with CRC. Differential gene expression analysis identified significant changes in gene expression between tumor and normal tissues. Gene Set Enrichment Analysis (GSEA) revealed dysregulated pathways associated with tumor progression. Furthermore, using CMScaller, we successfully stratified CRC tissues into distinct molecular subtypes. Upon reviewing the public consensus molecular subtype (CMS) signature, it was confirmed that it shares similar biological characteristics with the existing CRC. Additionally, biological characteristics of the group that could not be classified using CMScaller were found to resemble those of CMS2. Finally, distinguishing characteristics were observed between the tumor and normal groups when analyzed from an immunological perspective. Patients with CRC were checked for immunotherapy responsiveness, and those who clinically responded to immunotherapy were identified. Survival analysis confirmed that certain microsatellite stable (MSS) samples were responsive to immunotherapy and showed a relatively better prognosis. Furthermore, analysis of various immune cell types to identify genes involved in the response to immunotherapy revealed that RORC, NOS2, and KLRK1 are potential candidate genes. Our findings provide valuable insights into the molecular landscape of CRC in the Korean population and underscore the potential for integrating RNA-seq data with clinical information to improve cancer research and patient care. Immunotherapy was found to be effective in Korean patients with CRC.

As a disease with a high mortality rate, colorectal cancer (CRC) highlights the importance of comprehending its molecular mechanisms to develop effective therapies. In this study, we conducted RNA sequencing (RNA-seq) analysis on 476 samples consisting of fresh-frozen CRC tissues and adjacent normal tissues obtained from Samsung Medical Center (SMC) in South Korea. By analyzing gene expression differences, we identified that upregulated genes in tumor samples were significantly associated with pathways related to the cell cycle, extracellular matrix (ECM)-receptor interaction, and DNA damage response (DDR). Conversely, genes exhibiting high expression in normal samples were primarily related to metabolic pathways. Tumor samples were found to be enriched in various DDR pathways, prompting an investigation into the enrichment of related genes. Additionally, the analysis focused on the Homologous recombination (HR) pathway, for which the Homologous recombination deficiency (HRD) score was calculated. Furthermore, we categorized colorectal tumor samples into four subgroups using in silico methods to identify the biological and clinical characteristics of each subgroup and compared our results with those of the widely used existing subgrouping methods. Majority of our fibroblast and immune enriched/fibroblast samples aligned with CMS4, characterized by stromal invasion and mesenchymal differentiation, whereas the immune enriched subtype aligned with CMS1, known for its immune-centric profile. To investigate the clinical implications, the composition of the tumor microenvironment (TME) by cell type was examined across four subgroups, along with an immunological analysis. In particular, the calculated HRD score and the expression levels of immune-related genes associated with CRC were analyzed to provide evidence for personalized therapeutic strategies for each subgroup. Our findings provide valuable insights into the molecular mechanisms underlying CRC in Korean patients, particularly in the SMC patient group, and offer opportunities for personalized therapeutic strategies.

The human genome contains sequences derived from endogenous retroviruses (HERVs), which constitute approximately 8% of chromosomal DNA. Most HERVs are currently inactive and noninfectious due to recombination, deletion, and mutation after integration into the host genome. However, recent studies have implicated HERVs as mutagens of intracellular genes, contributing to autoimmune diseases and tumors. Several studies have shown a significant association between HERVs and certain cancers. We focused on knocking out the HERV-R (ERV3-1) env gene in the DLD1 colon cancer cell line. A 208-bp deletion was confirmed by genomic PCR and DNA sequencing. As a result, HERV-R env gene expression was significantly lower in DLD1 HERV-R knockout (HERV-R KO) cells compared to control cells at both RNA and protein levels. Additionally, the invasion and migration abilities of HERV-R KO cells were significantly reduced. In vivo experiments on mice injected with HERV-R KO cells showed smaller tumor sizes compared to mice injected with control cells, suggesting that HERV-R env plays an important role in tumor growth. Further mRNA-seq analysis identified genes associated with cell invasion and migration. The STRING tool, which analyzes gene correlations, confirmed that HERV-R is linked to genes involved in cancer proliferation, migration, and invasion in colon cancer. This study suggests that the expression of the HERV-R env gene influences the tumorigenic properties of colon cancer, providing valuable evidence for potential clinical studies in colon cancer patients.