Search Results (36,607)

NLRP6 is a member of the NOD-like receptor family that was initially characterized as an inflammasome-forming sensor in the intestine. However, accumulating evidence over the past decade has revealed that the functions of NLRP6 extend far beyond this canonical role. NLRP6 operates in a wide range of tissues, including the intestine, liver, lung, and immune system, where it exerts context-dependent effects that can be either protective or detrimental. In the intestine, NLRP6 is most consistently associated with host protection, contributing to antiviral defense, epithelial barrier integrity, and the maintenance of microbial and metabolic homeostasis through both inflammasome-dependent and -independent mechanisms. In contrast, in systemic infection models and in certain inflammatory settings, NLRP6 can also promote pathology by suppressing NF-κB signaling; inducing IL-18–mediated lymphocyte death, or enhancing inflammatory cell death pathways. Moreover, studies using both conventional and tissue-specific knockout models have highlighted the importance of the gut–organ axis; particularly the gut–liver axis, in shaping NLRP6-dependent disease outcomes. Here, we summarize recent advances in understanding the upstream regulation, downstream signaling, and tissue-specific functions of NLRP6. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide in both males and females. Despite recent advances in precision-targeted therapeutics, mortality rates remain high, largely due to delayed diagnoses when curative interventions are no longer feasible. Recent studies from our group demonstrated that the LINE-1 mRNA and associated miRNA cargo of plasma exosomes can be used as sensitive and specific diagnostic and prognostic biomarkers of non-small-cell lung cancer (NSCLC). Because exosomes from various cancer types can be detected in urine, we extended our investigation to examine these analytes in urine exosomes from NSCLC patients. LINE-1 ORF1 and ORF2 mRNA levels, along with miR-21-5p, miR-126-3p, miR-210-3p, miR-221-3p, Let-7b-5p, miR-146a-5p, miR-222-3p, miR-9-5p, and miR-1277-5p, were higher in urine exosomes from NSCLC patients compared to healthy controls. The cargo of urine-derived exosomes often mirrored that of plasma exosomes and correlated with several clinicopathologic characteristics. The strong predictive performance of urine exosomal RNAs distinguishing NSCLC patients from controls suggests these measurements may serve as a complementary and readily accessible source for noninvasive assessment of patients with NSCLC. Full article

This study aimed to measure mRNA and miRNA expression profile in corneal impression cytology (IC) samples from patients with congenital aniridia (CA) and healthy controls, and to elucidate the key genes and signaling pathways involved in aniridia-associated keratopathy (AAK). Corneal IC samples were collected from 14 patients with CA and 14 healthy controls. RNA sequencing was performed to identify differentially expressed genes (DEGs) and miRNAs. Correlations with age and AAK grade were analyzed, selected miRNAs were validated by RT-qPCR, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to characterize biological functions and pathways. A total of 695 DEGs and 19 differentially expressed miRNAs were identified. KRT24 expression was negatively associated with age, whereas LY6D expression positively correlated with AAK grade. Several miRNAs were linked to disease severity, including positive correlations for miR-224-5p, miR-224-3p, and miR-452-5p, and negative correlations for miR-204-3p, miR-181b-5p, and miR-181a-5p. RT-qPCR confirmed significant downregulation of miR-204-5p and miR-138-5p in aniridia samples. Functional enrichment analyses showed that DEGs were mainly involved in cell adhesion, extracellular matrix remodeling, inflammatory and immune responses, and neural-related processes. Target genes of dysregulated miRNAs were enriched in transcriptional regulation, cell proliferation, apoptosis, and migration, with significant involvement of PI3K-Akt, AGE-RAGE, and EGFR signaling pathways. Corneal epithelial cells from patients with CA exhibit coordinated mRNA and miRNA dysregulation associated with extracellular matrix disruption, inflammation, and altered signaling pathways. These findings improve understanding of AAK pathogenesis and identify potential biomarkers and therapeutic targets. Full article

Background: The dysregulation of the CDK1/Cyclin B1 complex drives tumor progression in breast cancer (BC). The natural flavonoid luteolin (LT) shows anti-cancer potential, but its mechanism targeting CDK1/CCNB1 remains unclear. Methods: CDK1, CCNB1, and CCNB2 expression were profiled in normal and BC cell lines. An engineered HEK293T GST-CDK1/CCNB1 cell model was used to evaluate LT’s effects on proliferation, ROS levels, and target gene transcription. Computational approaches (molecular docking, dynamics simulations, pharmacophore modeling, MM/GBSA, ADMET, and network pharmacology) assessed LT and its analogues. Results: CDK1/CCNB1 expression was lower in MCF7 BC cells than in normal cells, suggesting the loss of a growth barrier. In engineered HEK293T cells, LT suppressed CCNB1 transcription with minimal effect on CDK1 levels, correlating with anti-proliferative and ROS-modulating effects. Computational analyses confirmed stable LT binding to the CDK1/CCNB1 complex. Designed LT analogues showed improved binding and favorable ADMET profiles. Network pharmacology identified cell cycle regulation, particularly in BC stem cells, as the primary pathway targeted. Conclusions: LT and its analogues inhibit the CDK1/Cyclin B1 complex, revealing a dual mechanism that suppresses both tumor growth and BC stemness. Full article

More than 20 years after the discovery of lunasin, a clear shift in lunasin research is observable—from an initial focus on its direct in vitro anticancer effects toward strategies aimed at improving its bioavailability and repositioning it as a potential adjunct in cancer therapy. Lunasin, a soy-derived bioactive peptide, has been extensively studied for its antineoplastic properties. However, its limited oral bioavailability restrains its efficacy in clinical trials. Therefore, recent research on lunasin points towards the possibility of using it as an adjunct in cancer treatment, rather than as a stand-alone nutraceutical in humans. In preclinical models, in vitro and in vivo, lunasin can enhance the effects of standard anticancer drugs in breast and colon cancers. Research suggests that lunasin can potentiate the effects of drugs, such as tamoxifen, aspirin, cisplatin, and oxaliplatin, by sensitizing cancer cells to apoptosis, modulating cell cycle progression, reducing metastatic potential, and attenuating drug-resistance pathways, including PI3K/Akt, FAK/MAPK1/NF-κB, and integrin-mediated signaling. In combination with those drugs, lunasin exerts significant anticancer effects at concentrations substantially lower than those proven as effective in monotherapy, suggesting a potential role in dose reduction in conventional agents and, subsequently, mitigation of their adverse effects. Although the enhanced effect of those combinations has been shown in preclinical models, there is a distinct lack of human clinical trials in this matter. Available evidence supports a promising concept of lunasin as a molecular “priming” agent that might complement cytotoxic therapies rather than replace them. This combination-oriented paradigm may represent a shift in lunasin research and offer a novel direction for the use of bioactive peptides in precision oncology; however, further studies exploring this possibility, including human clinical trials, are needed to elucidate lunasin’s role in nutraceutical-assisted cancer therapy. Full article

Background: Bougainvillea species have been used in traditional Mexican medicine, but their bioactive compounds and mechanisms of action are insufficiently studied. This is the first comprehensive evaluation of fractions from the acetone extract of Bougainvillea × buttiana Holtum & Standl (var. Rose), combining phytochemical profiling with in vitro multitarget bioactivity assessment. Methods: Eleven fractions were analyzed for total phenolic (TPC) and flavonoid content (TFC) and antioxidant capacity using the DPPH assay. The most active fractions were further tested for nitric oxide (NO) scavenging, protection of erythrocytes and bovine serum albumin (BSA) from oxidative damage, inhibition of enzymes involved in inflammation (PLA₂, COX, LOX) and carbohydrate metabolism (α-glucosidase, α-amylase, tyrosinase), cytoprotective effects in L929 fibroblasts exposed to hydrogen peroxide, and their main metabolites were qualitatively identified by HPLC-UV-Vis. Results: All fractions showed significant TPC and TFC and concentration-dependent antioxidant activity. The fractions with the highest antioxidant indices were F5, F7, and F9. These effectively scavenged NO, protected erythrocytes and L929 cells (maintaining viability at 82.0%, 75.6%, and 72.0%, respectively), and inhibited key enzymes. Seven major compounds, mainly flavonoids, were identified. Conclusions: These findings showed that flavonoid-enriched fractions from B. × buttiana exhibit coordinated antioxidant, anti-inflammatory, antidiabetic, and cytoprotective effects, suggesting potential to treat oxidative stress-related disorders. Full article

Background: Although ERα-positive breast cancer represents approximately 70% of all breast cancer diagnoses worldwide, specific prognostic biomarkers for this subtype that are capable of stratifying patients remain limited. TRIM28 (KAP1/TIF1β), which is a multifunctional E3 ubiquitin ligase and transcriptional coregulator of ERα, has been shown to play oncogenic roles in multiple malignancies. However, its prognostic significance in ERα-positive breast cancer subtype has not been explored across independent patient cohorts. Methods: Multiple bioinformatics tools were employed to assess TRIM28 mRNA expression and prognostic significance across independent patient cohorts totaling over 4000 patients. The Kaplan–Meier plotter was used to examine associations between TRIM28 expression and survival outcomes in ERα-positive breast cancer. Multivariate Cox proportional hazards regression was performed in the METABRIC dataset (n = 1356) to confirm independent prognostic value, with sensitivity analyses using alternative TRIM28 expression cutoffs and PAM50 subtype-specific subgroup analyses. Independent validation was performed using multivariate Cox regression in the TCGA-BRCA Firehose Legacy ERα-positive cohort (n = 372). Gene Set Cancer Analysis (GSCA) was used to investigate pathways associated with TRIM28-correlated genes, and Breast Cancer Gene-Expression Miner (Bc-GenExminer) was used to assess immune cell infiltration. Results: TRIM28 expression is significantly elevated in ERα-positive breast cancer compared to normal breast tissue. High TRIM28 expression (defined as the upper quartile, ≥75th percentile, of TRIM28 expression) is independently associated with worse overall survival after adjustment for tumour size, tumour mutational burden (TMB), hormone therapy status, and age, with stratification on histologic grade (HR = 1.21, 95% CI: 1.03–1.41, p = 0.0194; METABRIC, n = 1356). This finding was independently validated using multivariate Cox proportional hazards regression in the TCGA-BRCA Firehose Legacy ERα-positive cohort (n = 372; events = 56), in which high TRIM28 expression remained independently associated with worse OS after adjustment for age, T-stage, and TMB (HR = 2.02, 95% CI: 1.10–3.71, p = 0.024). PAM50 subtype-specific analyses within METABRIC additionally confirmed an independent association of high TRIM28 with worse OS in Luminal A (HR = 1.37, 95% CI: 1.08–1.74, p = 0.009), with a directionally consistent but non-significant trend in Luminal B (HR = 1.21, 95% CI: 0.93–1.58, p = 0.155). The prognostic effect was robust across alternative TRIM28 expression cutoffs. TRIM28 expression positively correlates with tumour size, histologic grade, Nottingham Prognostic Index, and TMB, and negatively correlates with immune cell infiltration and is significantly lower in patients receiving hormone therapy. Genes co-expressed with TRIM28 are enriched in cell cycle and DNA damage response activation signatures and RAS/MAPK and RTK pathway inhibition signatures. Conclusions: TRIM28 is an independent prognostic biomarker in ERα-positive breast cancer, validated across multiple independent cohorts. These findings nominate TRIM28 as a priority candidate for prospective clinical validation and targeted experimental investigation in ERα-positive breast cancer. Full article

Alzheimer’s disease (AD) is the leading cause of dementia, affecting millions of individuals on a global scale. A fatal and incurable neurodegenerative disease, AD is defined by various molecular and cellular abnormalities, such as the formation of intracellular neurofibrillary tangles and extracellular amyloid plaque deposition, leading to increased neuroinflammation, parenchymal tissue breakdown, and cognitive deficiencies. These pathological conditions are associated with the disruption of the blood–brain barrier (BBB), which is the protective network of cells responsible for maintaining homeostasis at the borders of the central nervous system (CNS). The breakdown of the BBB results in a dysregulation of the neuroimmune axis. The induction of inflammatory and autoimmune responses has been a key topic of study in AD, particularly surrounding innate immune cell activation. Recent discoveries focusing on the adaptive immune branch in the diseased CNS show evidence of effector and memory T cell activation and expansion, highlighting the complex relationship of the neuroimmune axis. It is speculated that humoral immunity might play a significant role in pathology through the production of autoantibodies. However, the contribution of B cells and plasma cells is unclear. We aim to review the literature addressing the following questions: are B cells protective or pathogenic in the CNS during AD, and do their antibodies have specific antigenic targets within this niche? The characterization of humoral contributions to immune dysregulation in AD is critical to the development of novel therapeutic strategies to slow or prevent neurodegeneration and cognitive impairment. Full article

Small cell lung cancer (SCLC) has historically been treated as a single, uniformly aggressive disease defined by neuroendocrine differentiation, near-universal loss of TP53 and RB1, and the absence of classical druggable oncogene addictions. Two converging lines of evidence are now reshaping that view. First, transcriptomic profiling has resolved SCLC into molecular subtypes—SCLC-A (ASCL1-driven), SCLC-N (NEUROD1-driven), SCLC-P (POU2F3-driven), and SCLC-I (inflamed)—with distinct immune microenvironments, surface-antigen expression patterns, and emerging therapeutic vulnerabilities, although intratumoral heterogeneity and phenotypic plasticity complicate clean subtype assignment. Second, the development of delta-like ligand 3 (DLL3)-directed therapies provides a natural experiment: the same validated surface antigen failed as an antibody–drug conjugate (rovalpituzumab tesirine, three negative randomized trials) yet succeeded as a bispecific T-cell engager (tarlatamab, which received FDA accelerated approval in 2024 and subsequent traditional FDA approval in 2025 following positive confirmatory phase 3 data). In this review, we integrate the current first-line standard of care—chemoimmunotherapy with atezolizumab- or durvalumab-based regimens followed by maintenance intensification with lurbinectedin–atezolizumab (IMforte)—with the molecular framework of subtypes and biomarkers, and we use DLL3 as a case study to propose that delivery modality is an important determinant of therapeutic success in SCLC and should be considered alongside target biology and tumor heterogeneity. Rapid proliferation, antigen heterogeneity, subtype plasticity, and a relatively less immunogenic microenvironment systematically penalize modalities dependent on payload accumulation and cell-cycle progression and reward modalities that recruit catalytic, cell-cycle-independent cytotoxic effectors. The emerging B7-H3 and SEZ6 programs—including ifinatamab deruxtecan and ABBV-706—are the next test of this framework. We discuss implications for biomarker development, trial design, and the operational challenges of subtype-guided precision oncology in a disease where tissue is scarce and biology shifts under therapy. Full article

Despite advances in multimodal treatment, head and neck squamous cell carcinoma (HNSCC) remains a major clinical problem owing to its high recurrence rate and frequent development of treatment resistance. Abnormal histone modifications, particularly lysine methylation regulated by methyltransferases (KMTs) and demethylases (KDMs), have emerged as key drivers of HNSCC initiation, progression, and cellular plasticity. This review aims to comprehensively evaluate the role of selected KMTs and KDMs in HNSCC biology, with a focus on their contribution to resistance to immunotherapy, radiotherapy, and cytotoxic chemotherapy. We summarize and critically analyze preclinical and clinical studies investigating histone methylation dynamics in HNSCC, with particular emphasis on enzymes such as KMT2C/D, EZH2, NSD1/NSD2, SMYD3, G9a/EHMT2, LSD1, KDM2A/B, KDM3, KDM4, KDM5, KDM6, KDM7, and KDM8. Attention is given particularly to pharmacological approaches targeting these proteins: we discuss small-molecule inhibitors of EZH2, LSD1, KDM4/5/6, and other KMT/KDMs that are currently in preclinical development or in early clinical trials, and we highlight completed and ongoing studies testing EZH1/2 inhibitors and epigenetic combinations in patients with recurrent and metastatic HNSCC. The deregulation of specific KMTs and KDMs reshapes histone methylation at key residues, thereby controlling cell cycle progression, epithelial–mesenchymal transition (EMT), stem cell phenotypes, DNA damage responses, and multiple interactions with the immune system in HNSCC. Targeting disrupted histone methylation pathways may partially reverse the epigenetic reprogramming of HNSCC cells and represents a promising strategy to improve treatment efficacy in patients with advanced disease. We also summarize the preclinical evidence and the currently limited clinical data on targeting histone methylation dynamics in HNSCC and discuss their therapeutic implications. Full article

Background/Objective: Dysthyroid Optic Neuropathy (DON) is a severe complication of Thyroid Eye Disease (TED) leading to irreversible visual impairment. Its pathogenesis remains unclear, and early predictive tools are lacking. The study aims to investigate peripheral immune characteristics associated with DON, focusing on the IL-2⁺Th1/CD4⁺Tregs axis. Methods: A retrospective study was conducted in 37 TED patients, including DON (n = 22) and non-DON (n = 15) groups. Peripheral blood immune cell subsets were quantified using flow cytometry. Clinical data and peripheral blood immune indicators including T cell subsets, B cell subsets, T helper (Th) cell subsets, and regulatory T (Treg) cells populations were analyzed. Correlation and logistic regression analyses were applied to evaluate associations between immune indicators and DON. Receiver operating characteristic (ROC) analysis was used to assess the discriminatory performance of candidate variables and exploratory combined models. Results: Patients with DON showed higher IL-2⁺Th1 levels and lower CD4⁺Tregs levels compared with non-DON patients, along with an increased IL-2⁺Th1/CD4⁺Tregs ratio. Age and clinical activity score also differed significantly between groups. The IL-2⁺Th1/CD4⁺Tregs axis showed significant alterations associated with DON. The exploratory logistic regression model combining immune and clinical indicators showed potential discriminatory ability in differentiating DON from non-DON patients. Conclusions: This study identifies an imbalance between IL-2⁺Th1 and CD4⁺Tregs as a potential immune signature associated with DON. Integration of immune and clinical features may provide an exploratory framework for risk stratification in TED. Further prospective studies with larger cohorts are warranted to validate these findings. Full article

(-)-Epigallocatechin gallate (EGCG) possesses potent bioactivities but its applications in functional cosmetics is severely limited by its poor water solubility and chemical instability. To overcome these challenges, this study engineered a recombinant levansucrase from Vibrio natriegens to catalyze the transfructosylation of EGCG. The conversion rate of EGCG to fructoside reached 65.59%. The purified product was unequivocally identified as EGCG-1F, with a fructosyl group linked to the 3′-hydroxyl group. Compared to pristine EGCG, EGCG-1F exhibited remarkably enhanced water solubility (96.6-fold that of EGCG) and aqueous stability under acidic and thermal conditions. Biological evaluation revealed that EGCG-1F significantly enhanced HaCaT cell migration, upregulated the expression of basement membrane-associated collagens in ultraviolet B-damaged HaCaT cells, and modulated ultraviolet A-induced senescence in human dermal fibroblasts by type I collagen, type III collagen and matrix metalloproteinase-1 balance. This study demonstrates that enzymatic fructosylation is an effective approach to generate a stable and safe EGCG derivative with potential applications in skin barrier repair and anti-aging functional cosmetics. Full article

Composite environmental risks accumulate unevenly along urban–rural gradients, yet the conditional and nonlinear interaction between built environment quality (BEQ) and urban–rural functional connectivity (URFC) remains poorly quantified at fine resolution. This study aims to determine whether, and under what conditions, BEQ moderates the relationship between URFC and a population-weighted composite risk index (CRI), and to translate the result into spatia targeted green-infrastructure priorities. We use 744,714 grid cells at 100 m resolution over Guangzhou, China. The framework couples entropy-weighted BEQ from satellite and street-view imagery, gravity-model URFC computed on the real road network, and a two-stage population-weighted CRI of heat and air hazards. We apply nested ordinary least squares with incremental F-tests, spatial-lag and spatial-error models, generalised additive models with B-spline bases, gradient-boosted trees with SHAP interaction values, and Baron–Kenny mediation analysis. The main BEQ × URFC estimates are negative across the parametric and machine-learning specifications. The interaction is, however, small: a spatial-lag model on a 10,000-cell subsample returns β = −5.4 × 10⁻⁴, but a scalable generalised-method-of-moments spatial regression on the full grid—where the spatial autoregressive coefficient reaches ρ ≈ 0.99—shows the coefficient to be negative yet not statistically significant, and a five-seed re-estimation confirms that the subsample-based significance is draw-dependent. We therefore interpret the buffering as directionally supported but small and not robustly significant once spatial autocorrelation is fully modelled. The buffering response is nonlinear in the GAM main effects, and BEQ buffers across the entire observed connectivity range rather than switching sign at an interior threshold; URFC functions predominantly as a moderator rather than a mediator. Population-stratified estimation shows that the buffering is exposure-conditional: it is strongest where population exposure is high and weakens or reverses in sparsely populated cells, consistent with the risk = hazard × exposure structure of CRI. Sensitivity tests across values of the distance-decay parameter, 100 entropy perturbations and spatial scales corroborate the buffering direction. The framework provides an evidentiary basis for prioritising green infrastructure in functionally connected, populated but environmentally degraded transition zones. Full article

This study investigated lactic fermentation of green buckwheat beverages formulated at 8% (A, AA) and 10% (B, BB) solids using single- and multiple-strain cultures of Lactiplantibacillus plantarum, Lactobacillus acidophilus, Lacticaseibacillus paracasei and Lacticaseibacillus rhamnosus. Fermentation at 37 °C rapidly reduced pH from slightly alkaline values (7.44–7.57) to approximately 4.2–4.5 within 3–8 h, while viable counts increased from near-zero to 8–9 log₁₀CFU mL⁻¹, confirming efficient lactic acid bacteria (LAB) proliferation in all substrates. A general trend was observed in the sugar consumption strategy of studied LAB: sucrose (after hydrolysis) and glucose were almost completely depleted within 6–8 h, fructose was consumed more slowly, and raffinose remained largely unchanged, with the 10% substrate mainly accelerating early sugar turnover without altering final cell densities or the qualitative utilisation pattern. Dry matter changed little during fermentation, whereas total phenolic content (TPC) and total tannin content (TTC) were strongly affected in a matrix- and strain-dependent manner. At 8% solids, fermentation promoted substantial TTC reduction and, for several cultures, a net decrease in extractable phenolics. In contrast, 10% formulations, particularly those inoculated with L. acidophilus and L. paracasei (alone or in combination), partially preserved or increased TPC while achieving more moderate tannin losses. Overall, green buckwheat proved to be a promising substrate for developing fermented beverages in which solids level and starter composition can be tuned to combine rapid acidification and high LAB viability with tailored sugar depletion and favourable modulation of phenolic and tannin fractions. Full article

(1) Background: Large language models (LLMs) are increasingly used to generate morally distinct non-player characters in interactive fiction and tabletop role-playing games. However, prior work shows that reinforcement learning from human feedback (RLHF) safety training suppresses morally extreme expression. Hence, whether models can reliably generate and evaluate speech with a fixed moral–ethical alignment, within an assigned fictional persona, remains an open question. (2) Methods: To explore this issue, eight generator LLMs each produced three-turn role-play conversations for 37 Dungeons & Dragons 5th Edition deities spanning all nine cells of the 3 × 3 moral–ethical alignment grid (888 conversations by design, 885 obtained after one generator’s midexperiment deprecation). Next, eight evaluator LLMs classified each conversation on both alignment axes using structured output evaluation (6951 evaluation records), assessed across 17 analysis metrics. (3) Results: The obtained results can be summarised as follows. Moral-axis accuracy (Good/Neutral/Evil) exceeded ethical-axis accuracy (Lawful/Neutral/Chaotic) by approximately 10 percentage points on average across all 64 generator–evaluator pairs, with the pair-level gap ranging up to 32 points and reversing sign for one generator (nemotron-120b). Moreover, the alignment-cell hardness ranged 27.6-fold, from Lawful Good (0.910) to Neutral Neutral (0.033). Furthermore, a strong good-ward moral drift, consistent with RLHF suppression effects reported in prior work, was observed for nemotron-120b (0.931 of Evil-target outputs classified as Good) and was near-absent for grok-4.1-fast (0.024). Finally, deity wiki prominence did not predict per-deity accuracy after controlling for alignment cell (partial ρ < 0.20, p > 0.20). (4) Conclusions: In summary, good-ward drift, consistent with RLHF suppression of morally extreme expression, turned out to be graded and model-specific. Moreover, iconic characters override it (Cyric, Chaotic Evil: 0.947, nearly matching the top Lawful Good score). Finally, alignment-cell identity is the dominant accuracy predictor, not the deity familiarity, within the role-played persona setting studied here. Full article