Alpha-fetoprotein acts as a key regulator of cancer stemness in hepatocellular carcinoma via PI3K/Akt pathway.

Enhancing hydrological regulation and nitrogen removal capacity of bioretention cells using Portland cement-modified sludge fillers.

Th2 cells were originally described as a homogeneous population capable of simultaneously producing interleukin (IL)-4, IL-5, and IL-13, thereby playing a central role in allergic asthma and related conditions. Subsequent studies have revealed substantial heterogeneity within the Th2 lineage, with distinct subpopulations defined by unique surface markers and cytokine profiles. Of particular interest are pathogenic Th2 subsets, referred to as peTh2, Tpath2, or Th2A, that exhibit specialised effector functions and actively drive allergic disease. These pathogenic Th2 (pTh2) cells have been identified across a wide range of human allergic conditions, including conjunctivitis, allergic rhinitis, chronic rhinosinusitis, atopic dermatitis, IgE-mediated food allergy, and eosinophilic gastrointestinal disorders such as eosinophilic esophagitis, underscoring their broad clinical relevance. The molecular requirements for early pTh2 differentiation, as well as the transcriptional networks and epigenetic mechanisms that regulate their maturation, remain incompletely understood. Moreover, pTh2 cells themselves display considerable heterogeneity, circulating in the blood, and residing in secondary lymphoid organs, and peripheral tissues. This review highlights recent advances in the heterogeneity, differentiation, and molecular regulation of pTh2 cells, with a particular focus on their roles in eosinophilic asthma. We review the signalling pathways that drive pTh2 differentiation, their transcriptional and epigenetic regulation, and the diverse subpopulations they encompass. These insights offer a foundation for developing targeted therapies to mitigate type 2-driven allergic inflammation.

Mesenchymal stem cell‑derived extracellular vesicles (MSC‑EVs) have garnered research attention due to their unique biological functionalities and therapeutic potential. Compared with the parent MSCs from which they originate, MSC‑EVs are typically free from systemic allergic reactions, hemolysis, pyrogenic reactions, abnormal hematological changes, and vascular and muscle irritation problems, and thus, exhibit therapeutic potential. The present review provides a comprehensive analysis of numerous isolation methodologies for MSC‑EVs, with each method being evaluated based on key parameters, including principles, advantages, limitations and applications. Notably, the therapeutic potential of MSC‑EVs in the treatment of tuberculosis (TB) has been emphasized. MSC‑EVs have demonstrated unique capacities to modulate the T helper cell (Th)1/Th2/T regulatory cell balance, promote M2 macrophage polarization, alleviate inflammation through microRNA‑mediated mechanisms and enhance host defense through antimicrobial peptide responses. The integration of MSC‑EVs with anti‑TB therapy can improve lung, kidney and bladder health by reducing TNF‑α levels and increasing IL‑10/TGF‑β ratios. Notably, functional discrepancies between EVs derived from distinct MSC sources, such as umbilical cord vs. bone marrow cells, underscore the need for targeted optimization strategies. Adequate risk assessment is important before clinical trials, particularly concerning immunogenicity, potential pro‑inflammatory effects and promotion of TB latency. The present review explores the potential clinical applications of MSC‑EVs in TB and other infectious diseases, offering key insights into their therapeutic potential, with the aim of guiding future research.

Colorectal cancer (CRC) is caused by a complex interaction between genetic, environmental, and microbial risk factors, and intestinal microbiota has critical roles in inflammation, immunology, and epithelial integrity. Pathobionts from the intestines (Fusobacterium nucleatum, Bacteroides fragilis, and E. coli that produce colibactin) promote DNA damage, immunity protection from cancer therapy, and resistance to chemotherapy treatments. The beneficial commensals and metabolites of intestinal microbes (namely butyrate) increase the mucosal immune response and inhibit tumor-specific signaling mechanisms. Microbe controlled changes of populations of myeloid, lymphoid, and regulatory cells dictate the state of the tumor-immune system and provide actionable checkpoints and biomarkers for cancer therapy. An enormous variety of clinical interventions based on the gut microbiota (probiotics, prebiotics, and fecal microbiota transfer) and diagnostic approaches is currently being developed. Translational issues are difficult due to the interindividual variability and regulatory complexity of tumors. Research needs include standardizing multi-omics data from multidisciplinary teams and mechanistic validation in organoid and gnotobiotic models as well as prediction algorithms to optimize the microbiome-based medicine for individual patients. Targeting the immune-microbiota axis may provide new therapeutic strategies in the diagnosis, prognosis, and therapy of CRC.

Radioulnar synostosis with amegakaryocytic thrombocytopenia type 2 (RUSAT-2) is a rare inherited bone marrow failure syndrome characterized by congenital or progressive thrombocytopenia, frequent radioulnar synostosis, and variable multisystem involvement. It is caused by heterozygous germline pathogenic variants in the MDS1 and EVI1 Complex Locus (MECOM) gene, which encodes transcription factors essential for hematopoietic stem cell regulation and embryonic development. Disruption of highly conserved zinc finger domains within MECOM impairs long-term hematopoietic stem cell maintenance, leading to amegakaryocytic thrombocytopenia and, in many cases, progression to pancytopenia. Although MECOM is also implicated in leukemogenesis through somatic dysregulation, germline variants associated with RUSAT-2 result in a distinct developmental and hematologic phenotype with highly variable penetrance and age of onset. As of 2025, there were approximately 66 reported cases of RUSAT-2 reported in the literature, with clinical severity ranging from isolated thrombocytopenia to early-onset bone marrow failure requiring hematopoietic stem cell transplantation. This review summarizes the current understanding of the genetic basis, clinical manifestations, differential diagnosis, clinical course, management considerations, and outstanding mechanistic questions surrounding RUSAT-2.

Multifunctional composite microgels: From structural design to biomedical applications.

Vasorin (VASN), a transmembrane glycoprotein, plays a pivotal role in hepatocellular carcinoma (HCC) progression by regulating cell proliferation and migration. However, its subcellular localization and organelle-specific functional mechanisms remain inadequately defined, mainly due to the limitations of ultrastructural resolution and quantitative analytical techniques. In this study, an optimized immunoelectron microscopy protocol (IEM-VASN) was developed, combining 4% paraformaldehyde-0.5% glutaraldehyde fixation and a 1:200 anti-VASN antibody dilution, achieving an optimal balance between structural preservation and antigenicity. This method enabled the precise detection of VASN depletion in Huh7-KD cells (p < 0.0001) and Vasn-/- mice (p < 0.0001). IEM-VASN revealed VASN's organelle-specific distribution, showing significant enrichment in mitochondria in both HCC cells and liver tissues (p < 0.001 and p < 0.0001). Furthermore, murine HCC tissues displayed elevated VASN levels (p < 0.001) alongside reduced mitochondrial counts (p < 0.01). In a chronic aflatoxin B1 (AFB1) exposure model, VASN upregulation correlated with ROS accumulation, mitochondrial membrane potential dissipation, and mitophagy induction. The IEM-VASN method demonstrated high precision and applicability across cellular, animal, and pathological models, providing a powerful tool for elucidating the functional roles of VASN in HCC. These findings establish a highly sensitive and specific IEM technique for characterizing VASN's ultrastructural distribution, highlighting its predominant mitochondrial localization and functional involvement in HCC progression and chemically-induced mitophagy, thus positioning VASN as a critical molecular mediator in liver cancer and mitochondrial homeostasis.

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by chronic inflammation and dysregulated interferon (IFN) signaling. Many patients remain refractory to existing treatments, underscoring the need for novel therapeutic approaches achievable through drug repurposing. Fluvoxamine, an antidepressant with anti-inflammatory and immunomodulatory properties, has not been systematically studied in SLE. Differentially expressed genes (|Z| ≥ 2) were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Gene Set Enrichment Analysis (GSEA) was applied to assess pathway-level modulation of six hallmark SLE-related signatures. Fluvoxamine induced cell line-specific transcriptomic changes. Jurkat and THP-1 cells showed strong enrichment of TNF-α/NF-κB signaling and regulation of apoptosis-related genes, while HEK293 and A549 cells displayed modulation of cytokine and fibrotic pathways, including NOS3 upregulation. U2OS cells exhibited prominent apoptotic signatures. Although hallmark interferon-α/γ responses were modestly altered at the pathway level, canonical interferon-stimulated genes (e.g. IFI44L, ISG15, MX1) were not significantly downregulated in immune-derived lines. Overall, TNF-α/NF-κB activation and apoptosis emerged as the most consistently affected pathways across models. This integrative transcriptomic study supports fluvoxamine as a candidate immunomodulator with potential relevance for SLE, particularly through modulation of NF-κB and apoptotic pathways. These findings provide a mechanistic rationale for further investigation of sigma-1 receptor-targeting agents in autoimmune diseases.

Cell-free mesenchymal stem cell products have shown promise in reducing inflammation, alleviating tissue degeneration, and regulating immune responses. A recent study has reported that adipose tissue-derived stem cell (ADSC) extract possesses immunomodulatory capacity. However, its comparative efficacy against other cell-free products is not well documented. Nevertheless, the underlying mechanism of ADSC extract is under intense investigation. We determined the immunosuppressive efficiency of ADSC extract and ADSC-concentrated conditioned medium (CCM) on T cell proliferation, T regulatory cell expansion, and T cell cycle progression. In addition, the comparative cytokine profiles of ADSC extract and ADSC-CCM were investigated by cytokine array analysis. The ADSC extracts were superior in inhibiting T cell proliferation, promoting T regulatory cell expansion, and inducing activated T cell arrest at G0/G1 phase compared with ADSC-CCM. The inhibitory effect of ADSC extract on T cell proliferation was partly associated with control of cell cycle progression but not apoptosis induction. A halt in cell cycle progression of activated T lymphocyte after ADSC extract exposure was mediated via p21 and p27 activation. The cytokine profiling demonstrated that there were distinct patterns of immunoregulatory components in ADSC extract and ADSC-CCM, likely associated with their differing in immunoregulatory actions. The marked expression of TGF-β1 and IL-10 in the composition of ADSC extract implied their key roles in mediating immunosuppressive actions. IL-10 and TGF-β1 neutralization partly abrogated immunosuppressive capacities of ADSC extract. Together, ADSC extract may serve as an alternative source of immunomodulatory mediators with potential for development as cell-free products for therapeutic use.

The maintenance of stem cell identity, as well as the differentiation of stem cells into any lineage, requires precise regulation of gene expression. Despite intensive research, our understanding of these regulatory processes remains incomplete. Here, we focus on the understudied paralogs of the U1 small nuclear RNA gene known as variant U1 snRNAs. By generating isogenic knockout lines of human induced pluripotent stem cells for different variant U1s, we show that their loss profoundly changes both gene expression and cell cycle profiles. These effects manifest alongside alternative splicing patterns, including those involving recursive splicing sites, and lead to differential availability of stem cell regulators. Together, our results shed new light on the functional roles of variant U1 snRNAs and further our understanding of the programs controlling human pluripotency.

Bone regeneration, particularly in critical-sized defects, remains a significant clinical challenge. Hydroxyapatite (HA) is widely used due to its similarity to bone mineral, yet its biological activity often requires improvement. Incorporation of therapeutic metal ions has shown promise, but the combined and mechanistically distinct effects of copper (Cu) and strontium (Sr) remain underexplored. Cu and Sr influenced stem cells via different signaling pathways: Cu enhanced angiogenesis and modulated differentiation, while Sr promoted osteogenesis and bone remodeling. Importantly, these differences extended beyond stem cell regulation; Cu and Sr activated distinct mechanisms in both osteogenesis and angiogenesis. When combined, this dual action resulted in a true synergistic effect, independently enhancing osteogenic and angiogenic outcomes beyond what either ion can achieve alone. To exploit this, we developed an injectable dual-network hydrogel composed of polyvinyl alcohol (PVA) and sodium alginate (SA), incorporating Cu/Sr co-doped HA synthesized via hydrothermal methods. By varying synthesis temperature (80, 120, 160 °C), we revealed the dependence of HA crystallinity on bioactivity and identified 120 °C as optimal for coupling mechanical stability with biological performance. Cytotoxicity assays established the safe Cu threshold and defined the single-ion optima for Cu and Sr. Strikingly, co-doping at these optima yielded a composite with excellent injectability, robust in vitro and ex vivo biocompatibility, and, most importantly, synergistic promotion of both osteogenesis and angiogenesis through complementary mechanisms. This dual-ion strategy provides a novel route for synchronizing bone and vascular regeneration in bone repair.

The airway epithelium is the first site of injury from cigarette smoke (CS), a major risk factor for chronic lung disease including idiopathic pulmonary fibrosis (IPF). Here, we report the first intracellular proteomic analysis of CS exposure in fully differentiated primary human bronchial epithelial cells (phBECs). Following pathway enrichment analysis, we identified nuclear protein 1 (NUPR1) as a candidate regulator of epithelial stress responses. In contrast to the prediction by pathway enrichment analysis, NUPR1 activity was not altered by CS in vitro. Nevertheless, inhibition of its nuclear translocation using ZZW-115 revealed a cytoprotective and anti-apoptotic role in phBECs, as demonstrated by increased apoptosis and impaired epithelial integrity. NUPR1 expression was markedly reduced in IPF whole lung tissue and bronchial epithelium. IPF-derived basal cells differentiated into an epithelium exhibiting fewer ciliated and more secretory cells which exhibited significantly higher sensitivity to NUPR1 inhibition. Our findings underscore cell type- and tissue-specific variation in NUPR1-dependent pathways. Collectively, this study positions NUPR1 as a context-dependent epithelial stress regulator whose loss may contribute to epithelial vulnerability in IPF.

Testosterone-TGF-β crosstalk modulates cell migration in human glioblastoma-derived cell lines.

Allogeneic islet transplantation is an effective treatment for type 1 diabetes, but its clinical use is limited by rejection involving innate and adaptive immune responses, requiring lifelong immunosuppression. We herein engineered islets that transiently display 2 immunomodulators chimeric with streptavidin (SA), thrombomodulin (SA-TM) and CD47 (SA-CD47), for localized modulation of both innate and adaptive immune responses. The engineering process did not impact islet viability, glucose responsiveness, and metabolic activity. Intraportal transplantation into allogeneic recipients achieved sustained survival, with 8 out of 11 grafts surviving 120-330 days without immunosuppression. In contrast, non-engineered islets were acutely rejected (median survival time [MST] = 12 days), while islets engineered with SA-TM showed delayed rejection (MST = 13.5 days) and those with SA-CD47 exhibited prolonged survival (MST = 24 days). Double-engineered islets generated a localized tolerogenic immune environment characterized by low frequencies of inflammatory innate immune cells and increased frequencies of M2 macrophages, myeloid-derived suppressor cells, and CD4+FoxP3+ T regulatory cells. The transcriptomic analysis showed downregulation of proinflammatory and upregulation of immune regulatory pathways. Our results demonstrate that transient co-display of immunomodulatory molecules on the islet surface is a versatile platform with significant translational potential for islet transplantation.

Early lymph node (LN) metastasis often precedes systemic metastasis and corresponds with significantly inferior survival for patients diagnosed with early-stage breast cancer (EBC). To understand the biological pathways involved in early LN metastasis, differential gene expression (DGE) analysis compared large tumors without evidence of LN metastasis (pT2-3pN0) to small tumors with LN metastasis (pT1pN+). This study included 2,349 patients with EBC who underwent MammaPrint and BluePrint testing as part of the FLEX (NCT03053193). DGE was performed between pT2-3pN0/pT1pN + and across their MP/BP subtypes. Immune deconvolution was assessed using gene-signature-based methods, complemented by conventional tumor-infiltrating lymphocyte (TIL) analyses on a representative subset of patients. Greater DGE was observed within the MammaPrint High Risk and BluePrint Luminal B subgroups compared to pathological stages. MammaPrint High Risk tumors saw 73 differentially expressed genes (DEGs), while 34 were found for Luminal B tumors. Gene set enrichment analysis (GSEA) of MammaPrint High Risk/Luminal B tumors showed upregulated proliferation pathways and downregulated epithelial-to-mesenchymal transition (EMT) and immune profiles in pT2-3pN0 vs. pT1pN+, respectively. Immune deconvolution analyses showed a higher abundance of T gamma delta cells and CD4 + Th1 cells and a lower abundance of T regulatory cells, M2 macrophages, and cancer-associated fibroblasts within pT2-3pN0 tumors. Conventional histological assessment revealed no significant differences in TILs. This study lays the groundwork for exploring mechanisms of LN metastasis in EBC and their relation to MammaPrint High Risk and Luminal B subtypes. These data support previous studies' association of LN metastasis with EMT and immune dysregulation.

CD72 downregulation is associated with increased CD5+ B cell proliferation and IL-10 production via ERK/Syk signaling in chronic HBV infection-associated liver disease.

The first protein kinases and their role in cell regulation were identified in the mid-1950s, but it was not until the 1980s that the first inhibitors of these enzymes were developed. More specific inhibitors that suppressed kinase activity at low nanomolar concentrations were described in the mid-1990s and their potential to treat cancers caused by kinase mutation became clear during the late 1990s. Over 100 protein and lipid kinase inhibitors have now been approved for clinical use during the 21st century with combined annual sales of over US$ 65 billion in 2024. They have not only transformed the clinical care of multiple malignancies but have also been exploited widely to identify physiological substrates and cellular functions of these enzymes. Here, I present some personal reflections on the early days of kinases and their inhibitors, give a few examples of how they were first exploited to dissect signal transduction pathways and explain how the first panels of protein kinases came to be established to facilitate the development of more specific kinase inhibitors.

Oligodendrocyte lineage cell-specific GPR17/Gelsolin signaling regulates remyelination and cognitive recovery after subarachnoid hemorrhage.

How developmental progenitors navigate divergent trajectories to either establish adult stem cell pools or undergo terminal differentiation remains a fundamental gap in stem cell biology. Here, we identify the well conserved Tet protein as an essential transcriptional regulator of intestinal stem cell (ISC) establishment. Developmental Tet depletion causes region-specific ISC loss and compromises adult lifespan, while adult-specific loss drives progressive stem cell exhaustion. Overexpression of Tet leads to ISC expansion in both developing and adult guts. Utilizing a comprehensive single-nucleus transcriptomic atlas spanning gut development, we demonstrate that Tet stabilizes progenitor identity by maintaining epithelial integrity, niche signaling, and fate maintenance. By defining this developmental trajectory, we reveal Tet as a critical factor that drives proper ISC maturation and maintains long-term adult epithelial homeostasis.