Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “metalloproteinase”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed2026

Influence of FAM13A gene polymorphism and serum matrix metalloproteinases 9 and 12 on the phenotypes of chronic obstructive pulmonary disease.

PURPOSE: FAM13A as a susceptibility gene for chronic obstructive pulmonary disease(COPD).Many studies verified that FAM13A involved epithelial‒mesenchymal transition (EMT) via the TGF-β1 pathway, some accompanied by an increase in MMP levels. The present study aimed to explore the disease susceptibility of the FAM13A gene, with clinical phenotypes, and investigate the relationships between FAM13A SNP loci and the serum levels of MMP-9 and MMP-12. PATIENTS AND METHODS: We recurited 497 patients with stable COPD patients and 303 healthy controls. Data on blood tests, pulmonary function, and HRCT imaging were collected. Serum MMP-9 and MMP-12 levels were measured by ELISA. Genomic DNA was extracted, and SNPs in the FAM13A gene were detected using targeted region genotyping chips. Logistic regression analysis was performed to assess the associations between SNP loci and COPD susceptibility. Differences in pulmonary function, haematological indicators, bronchial wall thickness, and emphysema parameters among different genotypes were evaluated. Multiple linear regression analysis was used to explore the relationship between genotypes and serum MMP-12 level. RESULTS: We screened a total of 476 SNPs and identified the rs2869947 polymorphism in the FAM13A gene as significantly associated with an increased risk of COPD,Stratified analyses further revealed that this association was particularly in males and individual with BMI ≥ 24.Serum levels of MMP-9 and MMP-12 were significantly higher in COPD patients compared with healthy controls. Genotype(AA vs.GG) showed no significant association with pulmonary function severity,bronchial wall indices,hematological marker,and serum MMP-9 levels in COPD patients(P > 0.05).Compared with GG genotype, AA genotype presented significantly higher LAA-950% and serum MMP-12 levels (P = 0.049 and P = 0.023). CONCLUSION: Our findings suggest that the FAM13A SNP rs2869947 may be associated with COPD susceptibility in the Han Chinese population. The FAM13A AA genotype increased serum MMP-12 levels and correlated with emphysema phenotype.

Humans↗
PubMed1975

Properties and specificity of a second metal chelator-sensitive proteinase in the keratinolytic larvae of the webbing clothes moth.

The properties of a second metal chelator-sensitive proteinase (metalloproteinase 2) from the larvae of the webbing clothes moth, Tineola bisselliella, have been studied. The pH optimum for casein digestion was 9-4 and the enzyme showed high stability between pH 8 and 11, but very poor stability at acid pH. The proteinase was inhibited by EDTA, but not by an EDTA-calcium complex. EDTA inhibition could be reversed by addition of a slight excess of calcium or zinc ions. The cleavage specificity of metalloproteinase 2 against the A and B chains of S-carboxymethyl insulin was almost identical to that found previously for metalloproteinase 1.

Animals↗
PubMed2026

Effects of Acute Low- and Moderate-Dose Alcohol on Chronic Disease-Related Biomarkers in Healthy Light and Heavy Drinkers.

BACKGROUND: Alcohol consumption is a major contributor to global chronic disease, with growing evidence indicating health risks even at low levels of intake. However, mechanistic understanding of these risks relies heavily on preclinical models and observational data, leaving a critical gap in controlled experimental evidence regarding how alcohol perturbs human biological systems in vivo. METHODS: The present study utilized plasma samples from a randomized, placebo-controlled trial to evaluate the effects of low-dose (0.35 g/kg) and moderate-dose (0.60 g/kg) alcohol on disease-relevant biomarkers in 32 healthy adults (mean age = 25.0 ± 3.8 years; 21 female/11 male), characterized by light (n = 15) or heavy (n = 17) drinking. This design enabled evaluation of effects across dose, timescale, and drinking history, as well as assessment of their interactions. Plasma was collected at prebeverage baseline and hourly for 4 h afterward. Immunoassays quantified 10 disease-related biomarkers: adiponectin, angiogenin, D-dimer, high-sensitivity C-reactive protein (hsCRP), Intercellular Adhesion Molecule-1 (ICAM-1), Lipocalin-2 (LCN2), Matrix Metalloproteinase-7 (MMP-7), Matrix Metalloproteinase-9 (MMP-9), soluble Receptor for Advanced Glycation End-products (sRAGE), and Triggering Receptor Expressed on Myeloid cells 2 (TREM2). RESULTS: Main effects of group indicated that even in this young healthy sample, heavy drinking status was associated with higher levels of adiponectin, angiogenin, ICAM-1, LCN2, and sRAGE, a profile suggesting altered vascular and metabolic activity. Acute alcohol administration induced changes in sRAGE and hsCRP. Specifically, moderate-dose alcohol triggered an increase in the immunoglobulin sRAGE, which may reflect an acute compensatory response to inflammation and/or oxidative stress. Compared to placebo, hsCRP was lower in the low-dose alcohol condition; however, this finding should be interpreted in light of CRP biology. MMP-7, MMP-9, and LCN2 showed time-dependent fluctuations that were independent of experimental condition, highlighting the critical importance of placebo-controlled designs to account for diurnal/postprandial variation in immune biomarkers. CONCLUSION: Findings provide translational evidence that alcohol is associated with multisystem biomarker changes relevant to chronic disease and that alcohol-related biomarker perturbations vary by dose and chronicity.

Humans↗
PubMed2025

A clinically applicable method for early interstitial lung disease detection in incident rheumatoid arthritis cases: integration of protein biomarkers and clinical factors.

BACKGROUND: This study aimed to develop an early diagnostic method integrating proteomic biomarkers and clinical parameters for screening interstitial lung disease (ILD) in patients with newly diagnosed rheumatoid arthritis (RA) through a multi-phase research strategy. METHODS: A three-phase study was conducted: (1) Discovery: Tandem mass tag (TMT)-labeled quantitative proteomics with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyzed serum protein profiles in 5 RA-ILD and 5 RA-non-ILD patients, identifying candidates via bioinformatics. (2) Verification: Enzyme-linked immunosorbent assay (ELISA) validated candidates in an independent cohort (13 RA-ILD vs 14 RA-non-ILD). (3) Application: Biomarkers combined with clinical indicators (Krebs von den Lungen-6 [KL-6], age, sex) were evaluated in 110 patients (51 RA-ILD vs 59 RA-non-ILD) to build a predictive model. RESULTS: Proteomic analysis identified matrix metalloproteinase-3 (MMP3), von Willebrand factor (VWF), and other significantly differentially expressed proteins. ELISA validation confirmed that serum MMP3 and VWF levels were significantly higher in the RA-ILD group than in the RA-non-ILD group (p = 0.025 and 0.027, respectively). Expanded validation demonstrated superior diagnostic performance when combining MMP3 and VWF with KL-6 (area under the curve [AUC] = 0.90). The nomogram prediction model based on univariate analysis exhibited excellent discrimination (AUC = 0.89) and calibration. CONCLUSION: This systematic study from discovery to validation identified MMP3 and VWF as potential biomarkers for RA-ILD. The integrated predictive model combining these biomarkers with clinical parameters (KL-6, age, sex) provides a potential tool for early ILD screening in RA patients, offering novel strategies for early diagnosis and intervention of RA-ILD.

Humans↗
PubMed2025

Invadopodia in cancer metastasis: dynamics, regulation, and targeted therapies.

Pseudopodia and invadopodia are dynamic, actin-rich membrane structures extending from the cell surface. While pseudopodia are found in various cell types, invadopodia are exclusive to tumor cells and play a key role in cancer progression. These specialized structures enable tumor cells to degrade the extracellular matrix, breach tissue barriers, and invade surrounding tissues and blood vessels, thus facilitating metastasis. Extensive research has elucidated the distinct structure of invadopodia, the signaling pathways driving their formation, and their interaction with the tumor microenvironment. Integrin- and Src kinase-mediated signaling pathways regulate invadopodia dynamics. This review explores the mechanisms underlying invadopodia stabilization and highlights recent insights into their regulation by the tumor microenvironment. Particular emphasis is placed on the role of cell surface signaling in modulating invadopodia activity and the intracellular targeting of matrix metalloproteinases (MMPs) in enhancing invasive potential. A deeper understanding of invadopodia-driven cancer cell migration and metastasis provides valuable implications for therapeutic development. These findings support the potential for receptor-mediated and molecularly targeted therapies to inhibit tumor metastasis, improve clinical outcomes, and enhance the efficacy of existing cancer treatments.

Humans↗
PubMed2026

MMP-2 rs243865 Polymorphism as a Risk Modifier of Hepatocellular Carcinoma in Taiwanese Males, Smokers and Alcohol Consumers.

BACKGROUND/AIM: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Matrix metalloproteinase-2 (MMP-2) plays an important role in extracellular matrix remodeling and HCC progression. This study investigated the associations of two functional MMP-2 promoter polymorphisms, rs243865 and rs2285053, with HCC susceptibility in a Taiwanese population and explored their potential interactions with environmental risk factors. MATERIALS AND METHODS: A hospital-based case-control study was conducted at China Medical University Hospital (Taichung, Taiwan), involving 298 HCC patients and 889 age- and sex-matched cancer-free controls recruited in Taiwan. MMP-2 rs243865 and rs2285053 genotypes were determined utilizing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Stratified analyses were used to explore their potential interactions between MMP-2 genotypes and environmental factors including sex, smoking and alcohol drinking status. RESULTS: No significant association was observed between HCC susceptibility and either rs243865 (CT+TT versus CC: odds ratio (OR)=1.20, 95% confidence interval (CI)=0.87-1.66, p=0.2944] or rs2285053 (CT+TT versus CC: OR=1.12, 95% CI=0.86-1.46, p=0.4219). Similarly, allelic analyses revealed no significant effects. Interestingly, stratified analyses demonstrated significant gene-environment interactions for rs243865. Male carriers of the TT genotype exhibited an increased HCC risk (OR=3.24, 95% CI=1.12-9.37, p=0.0488). Among smokers, the TT genotype was associated with a markedly elevated risk (OR=6.46, 95% CI=1.65-25.29, p=0.0055), while alcohol drinkers carrying the TT genotype showed the highest susceptibility (OR=9.69, 95% CI=1.99-47.13, p=0.0022). No significant association was found for rs2285053 genotype in any genetic variant and subgroup. CONCLUSION: Although MMP-2 rs243865 and rs2285053 do not independently determine HCC susceptibility, rs243865 T allele may serve as a genetic biomarker for identifying Taiwanese males, smokers, and alcohol drinkers at elevated risk of HCC. These findings highlight the importance of gene-environment interactions in hepatocarcinogenesis and support the incorporation of genetic information into personalized HCC risk assessment and prediction strategies.

Humans↗
PubMed2026

Dealcoholized muscadine wine improved skin elasticity and oxidative stress biomarkers without affecting gut microbiome in women over 40 in a randomized controlled trial.

Muscadine wine has a unique polyphenol profile distinct from that of common wine, and limited research exists on its health benefits. This study aimed to investigate the effects of intake of dealcoholized muscadine wine (DMW) on skin health, oxidative stress, inflammatory biomarkers, and the gut microbiome. Seventeen healthy women were randomly assigned to consume 300 mL of DMW or a placebo daily for 6 weeks, separated by a 3-week washout period, in a randomized, single-blinded, crossover design. Skin health parameters were measured on the face and forearm. Oxidative stress and inflammatory biomarkers were assessed in plasma. Fecal bacterial DNA was sequenced using shotgun sequencing. DMW did not affect UVB-induced erythema compared to placebo. However, it significantly decreased transepidermal water loss and increased facial gross elasticity. Skin elasticity significantly improved on the forearm, whereas other skin parameters were not affected. DMW significantly decreased plasma levels of matrix metalloproteinase-9 and advanced glycation end products compared with placebo. However, the abundance, diversity, and functions of the gut microbiome were not affected. Polyphenol-rich DMW administered for six weeks improved certain skin health parameters and reduced oxidative and inflammatory stress, without affecting the gut microbiome in healthy women.

Humans↗
PubMed2026

Platelet triggering receptor expressed on myeloid cells-like transcript 1 regulation in healthy donors and patients at risk of bleeding and thrombosis.

BACKGROUND: Triggering receptor expressed on myeloid cells-like transcript 1 (TLT-1), a platelet-specific &#x3b1;-granule protein, is implicated in hemostasis, but its regulation remains unclear. Platelet dysfunction contributes to trauma-induced coagulopathy (TIC) and thrombotic complications in trauma or mechanical circulatory support (MCS); however, underlying mechanisms remain poorly understood. OBJECTIVES: This study investigated the molecular mechanisms underlying soluble TLT (sTLT)-1 release and its role as a biomarker of platelet dysfunction in patients with severe trauma or receiving MCS. METHODS: TLT-1 dynamics on platelets exposed to glycoprotein (GP)VI ligand, coagulation, or shear stress in vitro were evaluated by ELISA and immunoblotting. sTLT-1 was measured in plasma from trauma or MCS-treated patients and healthy donors. Associations with TIC, injury severity, and mortality were assessed. RESULTS: Proteolysis of TLT-1 to release a 10- to 17-kDa fragment was metalloproteinase dependent and blocked by ADAM10 and ADAM17 inhibition. Unlike GPVI, platelet TLT-1 exposure increased following PAR-1 activation. sTLT-1 was elevated in trauma patients compared with controls and correlated with TIC (P < .05) and injury severity (P < .01). Receiver-operating characteristic analysis demonstrated discriminatory performance for TIC (area under the curve, 0.78; P = .011), with a Youden cutoff of 1.180 ng/mL yielding 89% sensitivity and 73% specificity. Platelet TLT-1 was basally expressed, mobilized 2.5-fold with activation, and shed in response to GPVI ligation and plasma recalcification. Shear-exposed platelets and plasma from MCS-treated patients exhibited elevated sTLT-1 levels. CONCLUSION: Unlike GPVI, TLT-1 increased on activated platelets and was regulated by ADAM10 and ADAM17. TLT-1 release is triggered by shear stress, GPVI ligands or activated factor X. Plasma sTLT-1 was associated with trauma severity and TIC.

Humans↗
PubMed2024

S100A9 induces tissue remodeling of human nasal epithelium in chronic rhinosinusitis with nasal polyp.

BACKGROUND: Chronic inflammation triggers tissue remodeling in human nasal epithelial (HNE) cells. S100A9, a protein secreted by inflammatory cells, exhibits potent proinflammatory activity. However, its effect on HNE cell remodeling, such as squamous metaplasia, remains unclear. Therefore, this study aimed to determine the effects and underlying pathways of S100A9 on HNE cell remodeling and investigate its clinical implications in chronic rhinosinusitis (CRS). METHODS: Cultured HNE cells were treated with S100A9. Bulk RNA sequencing was performed to analyze gene ontology (GO). Ingenuity pathway analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were also analyzed. Additionally, immunohistochemistry and multiplex immunofluorescence were performed on tissue samples obtained from 60 patients, whose clinical informations were also reviewed. RESULTS: GO enrichment analysis indicated that S100A9 induced tissue remodeling in HNE cells toward squamous metaplasia. IPA and KEGG commonly showed that S100A9 affected HNE cells associated with the IL-17 signaling pathway, including target molecules such as matrix metalloproteinase 1 (MMP1) and small proline-rich protein 2A (SPRR2A). Squamous metaplasia with a marked expression of S100A9 was observed in 50% of CRS with nasal polyps (CRSwNPs). In addition, in multiplex immunofluorescence, the S100A9 in sub-epithelium was co-expressed with myeloperoxidase, a neutrophil marker, and MMP1 and SPRR2A were strongly expressed in epithelial remodeling. Clinically, the expression of S100A9 correlated with sino-nasal outcome test-22 (r&#xa0;=&#xa0;0.294, p&#xa0;=&#xa0;0.022) and Lund-Mackay scores (r&#xa0;=&#xa0;0.348, p&#xa0;=&#xa0;0.006). CONCLUSION: S100A9 induces tissue remodeling in HNE cells. Its increased expression in CRSwNP, particularly squamous epithelium, correlates with disease severity. This suggests the clinical potential of S100A9 as a biomarker for CRS severity.

Humans↗
PubMed2026

Plasma Proteomics Identifies Thousand-and-One-Amino Acid Kinase 3 as a Potential Biomarker of Rheumatoid Arthritis Activity and a Novel Therapeutic Target.

OBJECTIVE: Bone destruction associated with active rheumatoid arthritis (RA) remains a major therapeutic challenge, with a lack of reliable molecular markers reflecting bone injury. This study aims to identify novel biomarkers linked to bone destruction in active RA through proteomic analysis, providing new strategies for precise monitoring and targeted therapy. METHODS: Data-independent acquisition mass spectrometry was used for proteomic quantification and bioinformatic analysis on plasma samples from 160 patients with RA and 40 healthy controls. Key proteins associated with bone destruction were screened by integrating Sharp scores with synovial single-cell RNA sequencing data and subsequently validated in two independent cohorts (N1 = 50 and N2 = 10) using enzyme-linked immunosorbent assay and multiplex immunohistochemistry. Functional studies were conducted using fibroblast-like synoviocytes (FLSs) in vitro and a collagen-induced arthritis (CIA) mouse model in vivo. RESULTS: A total of 4,998 plasma proteins were identified, with 506 showing significant differential expression between active and remitted RA. Thousand-and-one-amino acid kinase 3 (TAOK3) levels were positively associated with Sharp scores and markedly elevated in patients with active RA. Combining TAOK3 with C-reactive protein improved diagnostic accuracy for active RA (area under the curve = 0.915). High TAOK3 expression was also associated with increased relapse frequency. Functional studies showed that TAOK3 knockdown suppressed the tumor-like phenotype of FLSs and down-regulated matrix metalloproteinase 1/2/3 and cathepsin K, whereas TAOK3 overexpression promoted pannus cell-mediated bone erosion, mitigated by TAOK3-targeted inhibitor. In vivo, its inhibition showed therapeutic effects in CIA mice. CONCLUSION: TAOK3 serves as a potential biomarker for bone destruction in active RA and as a therapeutic target for precision monitoring and intervention.

Arthritis, Rheumatoid↗
PubMed2026

Hypoxia-Induced ADAM23 Drives Neuron-Tumor Crosstalk and Therapeutic Resistance in Hepatocellular Carcinoma.

Hypoxia and nutrient deprivation are fundamental drivers of tumor aggressiveness and therapeutic resistance in hepatocellular carcinoma (HCC). While the involvement of neural components in the tumor microenvironment (TME) is increasingly recognized, the molecular transducers linking metabolic stress to neuron-tumor crosstalk remain elusive. Here, we identify ADAM23 (A disintegrin and metalloproteinase 23) as a hypoxia-responsive mediator that mediates communication between HCC cells and neuronal cells. ADAM23 expression was markedly upregulated in HCC cells under both chemical (CoCl2) and physical hypoxia (1% O2), a process further amplified by glucose deprivation and directly modulated by HIF-1&#x3b1;. Functional assays revealed that ADAM23 overexpression promotes epithelial-mesenchymal transition (EMT) and enhances cell viability under metabolic stress. Notably, sorafenib-resistant HCC cells (Huh7SR) exhibited high levels of ADAM23 secretion, which triggered proliferative and metabolic activation in neuronal SH-SY5Y cells. In 3D co-culture spheroid models, Huh7SR cells mixed with SH-SY5Y cells displayed significantly larger spheroid volumes and enhanced neuronal fluorescence compared with parental controls, suggesting that ADAM23-mediated interactions facilitate a supportive neural niche. Analysis of The Cancer Genome Atlas (TCGA) datasets and patient microarrays confirmed that ADAM23 is significantly overexpressed in HCC and positively correlates with HIF-1&#x3b1; expression. Moreover, elevated expression of ADAM23 was significantly correlated with poor overall survival. Collectively, our findings underscore ADAM23 as a critical metabolic-neural linker that promotes HCC progression and drug resistance. These findings suggest that the ADAM23-mediated neuron-tumor axis may represent a potential therapeutic target in aggressive HCC.

ADAM23↗
PubMed2025

Comprehensive evaluation of differential expression of piRNAs in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a prevalent and fatal cardiovascular condition characterized by a high incidence rate and nonspecific clinical manifestations, with no effective preventive or therapeutic measures currently available. Piwi-interacting RNAs (piRNAs) have been identified as significant biomarkers for disease diagnosis due to their essential functions in transposon suppression, maintenance of genomic stability, immune response, and epigenetic modulation. The piRNA is intimately associated with various diseases such as cardiac hypertrophy, tumors, and neurodegeneration, yet its role in AAA is unclear. In this study, we employed gene sequencing to analyze the piRNA expression profiles in AAA vascular tissues and predicted variations in their target genes. Our findings revealed a total of 1368 piRNAs with abnormal expression in the AAA group relative to the control group, including 1240 up-regulated and 128 down-regulated piRNAs (|log2(fold change)|&#xa0;&#x2265;&#xa0;1.0), with 82 demonstrating significant differences (P&#xa0;<&#xa0;0.05). Through bioinformatics analysis, it was determined that the Wnt signaling pathway, calcium signaling, TNF-&#x3b1; and the p53 pathway are crucial mechanisms by which piRNAs contribute to the development of AAA. RT-qPCR confirmed that hsa_piR_011324 was the most significantly up-regulated piRNA in AAA (P&#xa0;<&#xa0;0.0001), corroborating RNA sequencing results. Further results indicate that hsa_piR_011324 promotes phenotypic transformation of human aortic vascular smooth muscle cells (HAVSMCs), enhances the activity of matrix metalloproteinases (MMPs), increased up-regulation of inflammation-related markers IL-1&#x3b2; and TNF-&#x3b1;, and induces apoptotic processes. In conclusion, the present study emphasizes the important regulatory role of hsa_piR_011324 in AAA, suggesting that it holds promise as a prospective target for diagnostic and therapeutic intervention.

Aortic Aneurysm, Abdominal↗
PubMed2025

Causal association between 91 circulating inflammatory proteins and primary open-angle glaucoma: a bidirectional Mendelian randomization study.

BACKGROUND: Glaucoma, especially primary open-angle glaucoma (POAG), is a leading cause of irreversible vision loss. While elevated intraocular pressure is a major risk factor, the pathogenesis of POAG also involves genetics, oxidative stress, abnormal hemodynamics, and inflammatory factors. The role of systemic inflammation in POAG remains a subject of debate. This study aimed to investigate the causal relationships between circulating inflammatory proteins and POAG using a bidirectional Mendelian randomization (MR) approach. METHODS: A bidirectional two-sample MR analysis was conducted using genome-wide association study summary statistics. The primary stage involved 91 circulating inflammatory proteins and POAG, followed by a replication stage to verify significant findings using independent data and meta-analysis. The random-effects inverse-variance weighted model was employed as the primary method, complemented by multiple sensitivity analyses employed to ensure robustness, including multivariable MR to adjust for potential confounders. RESULTS: In the primary stage, 9 circulating inflammatory proteins were found to have significant causal effects on POAG. Specifically, the higher levels of Delta and Notch-like epidermal growth factor-related receptor (DNER) (OR: 1.12, 95&#xa0;% CI: 1.04-1.21, P&#xa0;=&#xa0;0.004), leukemia inhibitory factor (LIF) (OR: 1.20, 95&#xa0;% CI: 1.06-1.36, P&#xa0;=&#xa0;0.003), matrix metalloproteinase-10 (MMP-10) (OR: 1.08, 95&#xa0;% CI: 1.02-1.16, P&#xa0;=&#xa0;0.013), and stem cell factor (SCF) (OR: 1.09, 95&#xa0;% CI: 1.03-1.15, P&#xa0;=&#xa0;0.005) were positively associated with the risk of POAG. Conversely, the levels of fibroblast growth factor 19 (FGF-19) (OR: 0.88, 95&#xa0;% CI: 0.82-0.95, P&#xa0;=&#xa0;0.002), interleukin-18 (IL-18) (OR: 0.92, 95&#xa0;% CI: 0.86-0.99, P&#xa0;=&#xa0;0.019), IL-18 receptor 1 (IL-18R1) (OR: 0.96, 95&#xa0;% CI: 0.92-1.00, P&#xa0;=&#xa0;0.037), tumor necrosis factor ligand superfamily member 14 (TNFSF14) (OR: 0.91, 95&#xa0;% CI: 0.86-0.97, P&#xa0;=&#xa0;0.004), and tumor necrosis factor-related activation-induced cytokine (TRANCE) (OR: 0.94, 95&#xa0;% CI: 0.88-1.00, P&#xa0;=&#xa0;0.041) exhibited inverse associations with the risk of POAG. Multivariable MR analysis adjusting for confounders supported the roles of DNER, FGF-19, IL-18, IL18R1, LIF, and SCF. The replication stage confirmed the significant associations for FGF-19 (OR: 0.89, 95&#xa0;% CI: 0.84-0.95, P&#xa0;=&#xa0;4.63&#xa0;&#xd7;&#xa0;10-4), IL-18 (OR: 0.93, 95&#xa0;% CI: 0.89-0.97, P&#xa0;=&#xa0;0.002), IL-18R1 (OR: 0.96, 95&#xa0;% CI: 0.93-0.99, P&#xa0;=&#xa0;0.023), and LIF (OR: 1.18, 95&#xa0;% CI: 1.04-1.34, P&#xa0;=&#xa0;0.013). Sensitivity analyses further supported the robustness of these findings. CONCLUSION: This study elucidated the causal relationships between circulating inflammatory proteins and POAG, highlighting FGF-19, IL-18, IL-18R1, and LIF as potential therapeutic targets. These findings provide new insights for the prevention and management of POAG, although further studies are needed to understand the precise biological mechanisms.

Humans↗
PubMed2026

Diurnal differences in the effects of heat exposure on renal function: A randomized controlled crossover trial.

High temperature is a major risk factor for kidney injury, and population exposure to nighttime heat is increasing as the climate warms. However, whether renal responses to heat exposure differ between daytime and nighttime remains unclear. Forty-one healthy adults participated in a randomized crossover experiment conducted in a controlled laboratory setting. Participants were exposed to heat (32&#xb0;C during daytime; 30&#xb0;C during nighttime) and thermoneutral conditions (26&#xb0;C) for 8&#x202f;h. Blood and urine samples were collected before and after each exposure to examine various renal biomarkers reflecting glomerular filtration function, tubular injury, and early kidney stress. Heat exposure affected both blood and urinary biomarkers of kidney function, with notable diurnal differences in renal responses. Daytime heat exposure primarily affected blood markers of glomerular filtration, increasing creatinine by 7.67% (95% CI: 4.73%-10.61%) and cystatin C by 3.05% (95% CI: 0.17%-5.93%), while reducing estimated glomerular filtration rate by 0.05% (95% CI: 0.02%-0.08%). In contrast, nighttime heat exposure predominantly elevated urinary biomarkers of early kidney stress, including insulin-like growth factor-binding protein 7 (58.40%, 95% CI: 27.66%-89.14%), kidney injury molecule-1 (47.25%, 95% CI: 18.91%-75.59%), and tissue inhibitor of metalloproteinases-2 (51.88%, 95% CI: 22.26%-81.51%). Moreover, increases in insulin-like growth factor-binding protein 7 were significantly greater at night than during the day. Sleep-related parameters, including sleep quality, duration, and heart rate variability, partially mediated nighttime heat effects on renal responses. These results indicated that heat exposure induced different diurnal patterns in renal responses.

Humans↗
PubMed2026

Mechanistic characterization and inhibition of PAD4-dependent NETosis following experimental neonatal hypoxic-ischemic brain injury.

Neonatal hypoxia-ischemia (HI) remains a major global cause of neonatal morbidity and mortality. To develop effective therapeutic strategies, a deeper understanding of the acute inflammatory processes following HI is required. As the role of peripheral immune cell infiltration is poorly understood we used single nuclei RNA sequencing to investigate acute sequalae post-HI. This revealed a distinct neutrophil population characterized by increased expression of markers associated with neutrophil extracellular trap (NET) formation. The study evaluated the therapeutic potential of inhibiting NETosis formation using the peptidylarginine-deiminase-4 (PAD4) inhibitor Cl-amidine. We demonstrated that while oxygen-glucose deprivation (OGD) induces NET-formation and matrix-metalloproteinase-9 release in neutrophils, this is significantly reduced by the PAD4 inhibitor Cl-amidine. Second, in a co-culture model, inhibition of NETosis during OGD conditions improved neuronal survival. Third, Cl-amidine treatment reduced brain tissue loss and decreased expression levels of NETosis-related proteins 48&#xa0;h post-HI in vivo. Moreover, behavioral testing performed six weeks after HI revealed improved motor function in the treatment group. This study highlights the detrimental role of neutrophil activation and NETosis in exacerbating brain injury following neonatal HI. Targeting NET formation in the acute phase after HI may represent a promising therapeutic approach to improve both immediate and long-term neurological outcomes.

Animals↗
PubMed2026

Elevated Triggering Receptor Expressed on Myeloid Cells 2 Expression in Tumor-Associated Macrophages Suppresses Cytotoxic T Cell Infiltration and Facilitates Immune Escape in Colorectal Cancer.

BACKGROUND & AIMS: Emerging evidence supports a crucial role for tumor-associated macrophages in shaping the immunosuppressive tumor microenvironment. Furthermore, research has identified that the triggering receptor expressed on myeloid cells 2 has immunomodulatory functions. The present investigated the potential effect of triggering receptor expressed on myeloid cells 2 expression in tumor-associated macrophages on facilitating immune evasion in colorectal cancer. METHODS: Immunohistochemical analysis of clinical specimens, complemented by extensive data mining from The Cancer Genome Atlas, revealed a significant upregulation of triggering receptor expressed on myeloid cells 2 in colorectal cancer-associated tumor-associated macrophages, with this upregulation exhibiting a correlation with poor patient prognosis. RESULTS: Mechanistically, triggering receptor expressed on myeloid cells 2+ tumor-associated macrophages were found to drive fibroblast activation through transforming growth factor-&#x3b2; signaling, inducing fibroblast-activated protein-positive cancer-associated fibroblasts that secrete collagen I/III to establish dense peritumoral barriers. Spatial profiling revealed that these fibrous structures physically impede CD8+ T-cell infiltration, restricting cytotoxic lymphocytes to stromal compartments. Intriguingly, triggering receptor expressed on myeloid cells 2 deficiency enhanced the secretion of matrix metalloproteinase 13 by macrophages, thereby promoting extracellular matrix degradation and improving T-cell penetration. In vivo, Trem2-knockout mice showed a reduction in tumor growth with enhanced intratumoral CD8+ T-cell infiltration compared with wild-type controls. CONCLUSIONS: Our findings establish triggering receptor expressed on myeloid cells 2+ tumor-associated macrophages as central regulators of stromal remodeling and suggest that therapeutic targeting of the triggering receptor expressed on myeloid cells 2/transforming growth factor-&#x3b2;/fibroblast-activated protein pathway may overcome immune resistance in patients with colorectal cancer.

Colorectal Neoplasms↗
PubMed2025

Self-organization of mouse embryonic stem cells into reproducible pre-gastrulation embryo models via CRISPRa programming.

Embryonic stem cells (ESCs) can self-organize into structures with spatial and molecular similarities to natural embryos. During development, embryonic and extraembryonic cells differentiate through activation of endogenous regulatory elements while co-developing via cell-cell interactions. However, engineering regulatory elements to self-organize ESCs into embryo models remains underexplored. Here, we demonstrate that CRISPR activation (CRISPRa) of two regulatory elements near Gata6 and Cdx2 generates embryonic patterns resembling pre-gastrulation mouse embryos. Live single-cell imaging revealed that self-patterning occurs through orchestrated collective movement driven by cell-intrinsic fate induction. In 3D, CRISPRa-programmed embryo models (CPEMs) exhibit morphological and transcriptomic similarity to pre-gastrulation mouse embryos. CPEMs allow versatile perturbations, including dual Cdx2-Elf5 activation to enhance trophoblast differentiation and lineage-specific activation of laminin and matrix metalloproteinases, uncovering their roles in basement membrane remodeling and embryo model morphology. Our findings demonstrate that minimal intrinsic epigenome editing can self-organize ESCs into programmable pre-gastrulation embryo models with robust lineage-specific perturbation capabilities.

Animals↗