Biomedicines最新文献

{"title":"Irritable Bowel Syndrome and Incident Hypertension: Epidemiologic and Genetic Insights.","authors":"Luyao Li, Changying Zhao, Feiyang Wang, Qian Zhao, Yan Zhao, Shouping Gong, Guoliang Li, Jing Li","doi":"10.3390/biomedicines14092057","DOIUrl":"10.3390/biomedicines14092057","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Irritable bowel syndrome (IBS) may have health implications beyond the gastrointestinal tract, but its association with incident hypertension remains unclear. <b>Methods</b>: We analyzed 355,404 UK Biobank participants without recorded hypertension at baseline using multivariable Cox regression, propensity score matching, and sensitivity analyses addressing early events, baseline medication use and blood pressure, and competing mortality. Bidirectional Mendelian randomization (MR), Bayesian colocalization, and intestinal transcriptomic analyses examined genetic and tissue-level evidence. <b>Results</b>: During a median follow-up of 14.09 years, IBS was associated with incident hypertension (HR, 1.26; 95% CI, 1.22-1.30). The association persisted after matching (HR, 1.22; 95% CI, 1.16-1.28) and across sensitivity analyses. Forward MR provided suggestive support: the primary inverse-variance weighted estimate was positive but imprecise (OR, 1.18; 95% CI, 0.78-1.77), while weighted median and outlier-corrected analyses showed positive associations. Reverse MR showed no clear association. SuSiE-based colocalization supported shared signals for IBS with diastolic and systolic blood pressure at the <i>NCAM1</i> locus (PP.H4, 0.903 and 0.890, respectively). Intestinal <i>NCAM1</i> expression was lower in IBS, and correlated transcriptional programs involved epithelial remodeling, adhesion, and mucosal immune processes. <b>Conclusions</b>: IBS was associated with increased long-term hypertension risk, with suggestive genetic support and shared susceptibility signals at <i>NCAM1</i>. These findings support a potential biological link and prioritize <i>NCAM1</i> for mechanistic investigation.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 9","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149057890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibiotic Resistance and the Return to a Pre-Antibiotic Era: A Critical Narrative Review of a Global Catastrophe.","authors":"Shaurya Prakash, Saloni Saini, Mahima Bharti, Saveg Yadav, Pravin Hivare, Neeraj Kumar Rai","doi":"10.3390/biomedicines14092053","DOIUrl":"10.3390/biomedicines14092053","url":null,"abstract":"<p><p>Antimicrobial resistance is a growing global crisis that threatens to return humanity to a pre-antibiotic era where common infections become deadly. This narrative review synthesizes evidence from 2000 to early 2026, including Global Research on Antimicrobial Resistance data and World Health Organization surveillance, to outline the problem's scale, drivers, and solutions. In 2019, bacterial resistance directly caused 1.27 million deaths and was linked to 4.95 million more. Low- and middle-income countries bear the heaviest burden. ESKAPE pathogens, especially carbapenem-resistant <i>Acinetobacter baumannii</i> and NDM-producing <i>Klebsiella pneumoniae</i>, drive intensive care unit mortality near 50% and cause untreatable neonatal sepsis. One Health drivers include antibiotic overuse in humans, with 30% of prescriptions unnecessary in high-income settings; agriculture, consuming 70% of global antibiotics; and environmental pollution, with resistance genes found in 72% of rivers. Bacteria spread resistance through horizontal gene transfer and mutations such as <i>gyrA</i> S83L, creating pan-drug-resistant strains that make surgeries, transplants, and cancer treatment risky. Economic modeling studies suggest that unchecked antimicrobial resistance could reduce annual global GDP by 1.1-3.8%, with some scenarios projecting losses of up to approximately 5% by 2050, depending on assumptions about healthcare costs, labor productivity, and livestock production. Solutions require subscription-based payment models, enforceable agricultural regulations, integrated genomic surveillance, and equity-focused diagnostics for low- and middle-income countries. Without binding 2030 targets, the post-antibiotic era would become a clinical reality within a decade.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 9","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149057937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Periodontal Dysbiosis and Premature Atherosclerosis: A Critical Appraisal of the Oral-Gut-Vascular Axis.","authors":"Larisa Anghel, Dan-Nicolae Bele, Radu Andy Sascău, Laura-Cătălina Benchea, Monica Mihaela Scutariu, Cristina Prisacariu, Rodica Radu, Mircea Ovanez Balasanian, Cristian Stătescu","doi":"10.3390/biomedicines14092051","DOIUrl":"10.3390/biomedicines14092051","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Premature coronary artery disease (PCAD) is not fully explained by conventional risk factors, particularly in younger adults with residual inflammatory risk. This review evaluates the oral-gut-vascular axis as a mechanistic framework linking periodontal dysbiosis to premature atherosclerosis. <b>Methods</b>: A structured narrative search of PubMed/MEDLINE, Scopus, Embase, and Web of Science was conducted for English-language publications issued between January 2015 and June 2026. Human observational and interventional studies, mechanistic studies, systematic reviews, meta-analyses, and major scientific statements addressing periodontal disease, gut dysbiosis, barrier dysfunction, microbial metabolites, and vascular outcomes were considered. <b>Results</b>: Current evidence supports the biological plausibility of interconnected pathways involving periodontal pathobionts, microbial translocation, intestinal dysbiosis, increased epithelial permeability, endotoxemia, TLR2/TLR4 signaling, TMAO metabolism, oxidative stress, immune dysregulation, endothelial dysfunction, and plaque development. Candidate translational markers include hsCRP, IL-6, LPS, LBP, TMAO, oxidized LDL, adhesion molecules, salivary microbial signatures, and vascular imaging indices. Periodontal treatment and microbiome-directed strategies may reduce inflammatory burden, although effects on major cardiovascular outcomes remain unproven. <b>Conclusions</b>: The oral-gut-vascular axis is biologically plausible but not yet causally established in humans, and its specific relevance to PCAD remains largely inferential. Prospective PCAD-specific cohorts, standardized multi-omics, validated biomarkers, vascular imaging, and externally validated artificial-intelligence models are required to establish clinical utility and inform integrated cardio-dental prevention in younger populations.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 9","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating Ghrelin, Nesfatin-1, and Vaspin Levels Across Glycemic Control Categories in Type 2 Diabetes Mellitus: A Cross-Sectional Study.","authors":"Suheda Akkus, Orkun Saricam, Murat Kavruk, Gulcin Turkmen Sariyildiz, Fatma Busra Benguboz, Berna Yilmaz Sirin, Elif Esra Altuner, Ali Dogan Dursun, Veli Cengiz Ozalp","doi":"10.3390/biomedicines14092055","DOIUrl":"10.3390/biomedicines14092055","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Diabetes mellitus is characterized by chronic hyperglycemia, insulin resistance, and low-grade inflammation, and adipose-tissue-derived adipokines are increasingly implicated as regulators of glucose homeostasis. This study compared circulating ghrelin, nesfatin-1, and vaspin levels across three glycemic-control categories defined by HbA1c and evaluated their association with glycemic status. <b>Methods:</b> In this cross-sectional comparative study, serum ghrelin, nesfatin-1, and vaspin were measured by enzyme-linked immunosorbent assay (ELISA) in 161 adults stratified into three groups: HbA1c 6.0-8.4% (<i>n</i> = 55), HbA1c ≥ 8.5% (n = 52), and non-diabetic controls with HbA1c < 6.0% (n = 54). Distributional assumptions were tested with the Kolmogorov-Smirnov and Shapiro-Wilk tests. Because all three adipokines deviated from normality, the primary omnibus comparison was the Kruskal-Wallis test, followed by Dunn's post hoc test with Bonferroni adjustment; effect sizes are reported with 95% confidence intervals. Group differences were additionally examined after adjustment for age and sex, and HbA1c was analysed as a continuous variable. <b>Results:</b> Ghrelin (Kruskal-Wallis <i>p</i> = 0.726) and vaspin (<i>p</i> = 0.364) did not differ among the three groups. Nesfatin-1 differed significantly (H = 15.16, <i>p</i> < 0.001, ε² = 0.095) and non-monotonically: concentrations were higher in the HbA1c 6.0-8.4% group than in controls (median 824 versus 650 pg/mL; Dunn <i>p</i> = 0.018) and than in the HbA1c ≥ 8.5% group (824 versus 600 pg/mL; <i>p</i> < 0.001), whereas the HbA1c ≥ 8.5% and control groups did not differ (<i>p</i> = 0.909). The nesfatin-1 difference persisted after adjustment for age and sex (<i>p</i> < 0.001) and after excluding controls with impaired fasting glucose (<i>p</i> < 0.001). Within the diabetic participants, nesfatin-1 correlated inversely with continuous HbA1c (ρ = -0.373, <i>p</i> < 0.001). <b>Conclusions:</b> Nesfatin-1, but not ghrelin or vaspin, differed significantly between HbA1c-defined glycemic-control categories in a non-monotonic manner, with the highest concentrations in the intermediate-HbA1c group. Because body mass index, diabetes duration, and antidiabetic medication were not available, and because the design is cross-sectional, these between-group differences cannot be interpreted as a within-person trajectory or attributed to glycemic status independently of adiposity. These exploratory findings require confirmation in larger, prospective, BMI- and medication-adjusted cohorts before nesfatin-1 can be considered a candidate biomarker.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 9","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149057910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Gut-Heart-Kidney Axis in Heart Failure: Trimethylamine N-Oxide and Beyond-A State-of-the-Art Review.","authors":"Ismaila Ajayi Yusuf, Solomon Anighoro, Abdullah Sultany, Sheeza Nawaz, Ayush Adhikari, Shubhendu Bajpai, Ashraf Ullah, Arundhati Sharma, Sahil Grover, Naga Sumanth Reddy Gopireddy, Amlish Gondal, Michelle Bernshteyn, Subash Ghimire","doi":"10.3390/biomedicines14092054","DOIUrl":"10.3390/biomedicines14092054","url":null,"abstract":"<p><p>Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite of dietary choline and L-carnitine, has emerged as a leading molecular mediator of the gut-heart-kidney axis in heart failure (HF). This state-of-the-art narrative review synthesizes evidence from 14 observational studies (13 prospective cohorts and one cross-sectional analysis), encompassing a heterogeneous range of HF settings, including established chronic HF, acute decompensated HF, incident HF in community cohorts, and subclinical myocardial injury. Across these populations, elevated circulating TMAO has been associated with adverse outcomes, including mortality, rehospitalization, and major adverse cardiovascular events, although the strength and consistency of associations vary by HF phenotype, renal function status, and population ancestry. The prognostic independence of TMAO is attenuated after adjusting for renal function in several cohorts, reflecting both obligatory renal clearance and a potentially bidirectional relationship with kidney injury. TMAO was not reduced during neurohormonal GDMT uptitration in the BIOSTAT-CHF study, suggesting that gut microbiota dysbiosis may represent a pathophysiological axis not reached by current HF treatment. The field has evolved through three thematic stages: TMAO as a single prognostic biomarker, TMAO within cardiorenal pathophysiology, and multimetabolite and multipathway risk profiling. Beyond the TMAO pathway, emerging evidence for phenylacetylglutamine (PAGln), short-chain fatty acids (SCFAs), and protein-bound uremic toxins as parallel gut-derived cardiovascular mediators supports a multidimensional metabolite profiling approach. Several cohorts suggest that selected multimetabolite panels may provide additional prognostic information beyond TMAO alone, although their composition, calibration, and external validity remain uncertain. Population-specific variation in TMAO levels and prognostic thresholds complicates universal clinical application. Without human interventional data demonstrating that lowering TMAO improves cardiovascular outcomes, TMAO remains a prognostic risk marker rather than a validated clinical target. Clinical translation requires resolving the renal confounding problem, validating multimetabolite panels across diverse populations, and conducting intervention trials targeting the gut-heart-kidney axis.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 9","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149057533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Responses to Nei-Xiao-Luo-Li-San in Toledo Diffuse Large B-Cell Lymphoma Cells: Potential Involvement of ATF5- and HDAC-Associated Epigenetic Changes.","authors":"Kaixuan Zou, Jong Hyuk Kim, Sahana Arunasalam, Betty Yangari, Deng-Shan Shiau","doi":"10.3390/biomedicines14092052","DOIUrl":"10.3390/biomedicines14092052","url":null,"abstract":"<p><p><b>Background</b>: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in adults and is characterized by aggressive progression and substantial molecular and clinical heterogeneity. Despite advances in immunochemotherapy, a considerable proportion of patients develop relapsed or refractory disease, highlighting the need to better understand the molecular mechanisms underlying DLBCL. Nei-Xiao-Luo-Li-San (NXLLS), a traditional herbal formulation historically used for nodules and tumor-like masses, provides a pharmacological model for investigating molecular responses and candidate regulatory mechanisms in DLBCL. <b>Methods:</b> NXLLS was chemically characterized to assess its compositional profile and compositional similarity among batches. Its biological effects were evaluated by assessing cell viability, migration, invasion, and cell-cycle progression in Toledo DLBCL cells. Molecular responses to NXLLS were investigated through an integrated approach combining transcriptomic analysis, network pharmacology, and molecular assays. The functional role of ATF5 was further evaluated using lentiviral overexpression and knockdown. <b>Results:</b> Chromatographic profiling provided an exploratory assessment of compositional similarity among NXLLS samples and supported the selection of eight representative compounds using liquid chromatography-mass spectrometry (LC-MS) annotation and high-performance liquid chromatography (HPLC) authentic-standard confirmation. NXLLS reduced cell viability, migration, and invasion in Toledo DLBCL cells within the tested concentration range. At the molecular level, NXLLS was associated with altered cell-cycle distribution and potential G1-phase accumulation at later time points, reduced vascular endothelial growth factor (VEGF)-associated enzyme-linked immunosorbent assay (ELISA) signal, and modulated stress-response genes. RNA sequencing (RNA-seq) revealed transcriptional changes involving stress-response and histone deacetylase (HDAC)-associated epigenetic pathways. Correspondingly, HDAC expression was reduced, whereas acetylated histone H3 lysine 9 (Ac-H3K9) and acetylated histone H3 lysine 27 (Ac-H3K27) levels were increased. <i>ATF5</i> knockdown recapitulated several cellular and epigenetic changes observed following NXLLS treatment, supporting ATF5 as a potential downstream mediator of the NXLLS response. <b>Conclusions:</b> This study identified potential molecular targets associated with the response to NXLLS in Toledo DLBCL cells, with ATF5 further investigated as a potential downstream mediator. The findings also suggest an association between the NXLLS response and HDAC-related epigenetic changes, providing a basis for further investigation of their mechanistic relationships.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 9","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149057990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine Learning for Identification of Cirrhosis in Autoimmune Hepatitis Using Routine Biomarkers and Liver Elastography: Development and External Validation of an Interpretable Classification Model.","authors":"Nazugum Ashimova, Symbat Abzaliyeva, Araylym Maldanova, Madina Suleimenova, Andreas Teufel, Alexander Nersesov","doi":"10.3390/biomedicines14092045","DOIUrl":"10.3390/biomedicines14092045","url":null,"abstract":"<p><p><b>Background:</b> Autoimmune hepatitis (AIH) is a chronic immune-mediated liver disease that may progress to cirrhosis. This study aimed to develop and externally validate interpretable machine-learning models for the classification of prevalent cirrhosis in patients with AIH. <b>Methods:</b> The development cohort included 55 patients with biopsy-confirmed AIH. Cirrhosis was defined histologically as F4, whereas F0-F3 was classified as non-cirrhosis. Logistic Regression with L2 regularization, Random Forest, and XGBoost were evaluated. The original stratified 70/30 hold-out analysis was retained, and repeated stratified five-fold cross-validation with 20 repeats was additionally performed to assess internal stability. Primary external validation was performed in an independent histology-matched cohort of 42 patients. Models were applied without refitting, recalibration, or threshold optimization. Discrimination, probabilistic accuracy, calibration, and threshold-dependent classification metrics were evaluated. <b>Results:</b> In the original held-out test set, AUROC was 0.900 for Logistic Regression with L2 regularization, 0.830 for Random Forest, and 0.890 for XGBoost. In repeated cross-validation, mean AUROC was 0.878 ± 0.021, 0.914 ± 0.015, and 0.896 ± 0.015, respectively. In the primary external validation cohort, Random Forest showed the highest numerical discrimination (AUROC 0.810; 95% CI, 0.653-0.933), followed by XGBoost (0.728; 95% CI, 0.566-0.878) and Logistic Regression with L2 regularization (0.716; 95% CI, 0.545-0.875). Random Forest also had the lowest Brier score (0.188). However, confidence intervals were wide and overlapping. Elastography stage alone achieved an AUROC of 0.745, and the numerical improvement of the full Random Forest model was not statistically clear. <b>Conclusions:</b> Machine-learning models integrating routinely available clinical, biochemical, immunological, and elastography-related variables showed preliminary external transportability for the classification of prevalent cirrhosis in AIH. However, the small development and validation cohorts, uncertainty in calibration, and lack of a clearly demonstrated incremental advantage over elastography alone indicate that larger prospective multicenter studies are required before clinical implementation.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 9","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149057970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms Underlying the Biphasic Effects of Hydrogen Sulfide in Rat Intrapulmonary Arteries.","authors":"Agilė Tunaitytė, Elif Alan, Arnas Aleknavičius, Silvijus Abramavičius, Ulf Simonsen, Edgaras Stankevičius","doi":"10.3390/biomedicines14092043","DOIUrl":"10.3390/biomedicines14092043","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Hydrogen sulfide (H₂S) is an important regulator of pulmonary vascular tone; however, the mechanisms underlying its biphasic contractile and relaxant effects, as well as the distinct contributions of endogenous and exogenous H₂S to nitric oxide (NO) signaling, remain incompletely understood. This study investigated the roles of endogenous and exogenous H₂S in regulating pulmonary vascular responses under physiological and oxidative stress conditions. <b>Methods</b>: Rat intrapulmonary arteries were studied using wire myography and simultaneous measurements of vascular force and intracellular Ca²⁺. Pharmacological inhibitors were used to examine the contribution of endogenous H₂S synthesis, NO synthase, soluble guanylate cyclase (sGC), K_ATP channels, and oxidative stress to vascular responses. <b>Results</b>: Sodium hydrogen sulfide (NaHS) produced biphasic concentration-dependent responses, with contraction at low concentrations followed by relaxation at higher concentrations. Simultaneous measurements of vascular force and intracellular Ca²⁺ showed that the initial contractile response to low concentrations of NaHS was not accompanied by a clear increase in intracellular Ca²⁺, whereas relaxation developed despite maintained or increasing intracellular Ca²⁺, indicating that NaHS-induced relaxation cannot be explained solely by reduced intracellular Ca²⁺ levels. Inhibition of endogenous H₂S synthesis reduced vascular responsiveness to the NO donor sodium nitroprusside, whereas relaxation induced by exogenous NaHS was largely preserved after inhibition of NO synthase or sGC, indicating distinct roles of endogenous and exogenous H₂S. Oxidative stress impaired acetylcholine- and riociguat-induced relaxation, while NaHS partially restored endothelial function. <b>Conclusions</b>: Endogenous and exogenous H₂S regulate pulmonary vascular tone through distinct mechanisms. Endogenous H₂S supports vascular responsiveness to NO, whereas exogenous H₂S induces relaxation largely independently of NO-sGC signaling. Furthermore, NaHS-induced relaxation occurs despite maintained intracellular Ca²⁺, suggesting an important contribution of Ca²⁺-independent mechanisms, and partially preserves endothelial function under oxidative stress.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 9","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149057982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Switching of Biological Drugs in Paediatric Severe Asthma: Experience of a Referral Centre.","authors":"Valentina Agnese Ferraro, Margherita Amadi, Veronica Ferasin, Stefania Zanconato, Silvia Carraro","doi":"10.3390/biomedicines14092050","DOIUrl":"10.3390/biomedicines14092050","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Biologic therapies are the cornerstone of severe asthma management. However, evidence regarding switching between biologics in children with severe asthma remains limited. <b>Methods</b>: Retrospective observational study including patients aged 6-17 years with severe asthma, followed at our tertiary referral center, who switched biologic therapy. Clinical, laboratory, and lung function data were collected at the initiation of the second biologic (T0) and after 4 (T1) and 12 months (T2). Changes in asthma control, exacerbation rate, inhaled corticosteroid dose, FeNO and lung function were evaluated. <b>Results</b>: Eight patients who switched and had been treated with a second biologic for at least 12 months were included. Switching occurred from omalizumab to dupilumab (<i>n</i> = 1), mepolizumab to dupilumab (<i>n</i> = 5), and mepolizumab to omalizumab (<i>n</i> = 2). The main reason for switching was inadequate asthma control, while one patient switched because of poorly controlled comorbidity. At T2, exacerbations significantly decreased (<i>p</i> = 0.03), with significant improvements in FEV₁ (<i>p</i> = 0.002) and FEV₁/FVC (<i>p</i> = 0.015). The daily fluticasone-equivalent dose decreased from a median of 500 μg to 425 μg. <b>Conclusions</b>: In this cohort, switching biologic therapy was associated with improved clinical and functional outcomes, with a significant response already detectable after 4 months. These findings highlight the importance of close clinical and functional monitoring to identify children who may benefit from a change in biologic therapy. Larger prospective studies are needed to define standardized criteria and optimal timing for biologic switching in pediatric severe asthma.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 9","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transforming Growth Factor-β1 Induces Concurrent Periostin and SLUG Expression in Normal Human Dermal Fibroblasts: Potential Implications for Extracellular Matrix Remodeling.","authors":"Patrycja Sputa-Grzegrzolka, Anna Socha-Banasiak, Natalia Glatzel-Plucinska, Mateusz Olbromski, Katarzyna Ratajczak-Wielgomas, Tomasz Gornicki, Elzbieta Czkwianianc, Piotr Dziegiel, Bartosz Kempisty","doi":"10.3390/biomedicines14092042","DOIUrl":"10.3390/biomedicines14092042","url":null,"abstract":"<p><p><b>Background</b>: Transforming growth factor beta 1 (TGF-β1) is a master regulator of fibrogenesis and extracellular matrix (ECM) remodeling. Among molecules involved in profibrotic signaling, periostin (<i>POSTN</i>) and the Snail family transcriptional repressor 2 (SLUG, <i>SNAI2</i>) have emerged as potential regulators of tissue remodeling and fibroblast activation. However, the temporal relationship between TGF-β1-induced expression of SLUG and periostin in human dermal fibroblasts remains poorly understood. <b>Objectives</b>: This study aimed to evaluate the effect of TGF-β1 stimulation on <i>SNAI2</i>/SLUG and <i>POSTN</i>/periostin expression dynamics in normal human dermal fibroblasts (NHDFs) and characterize their association with profibrotic responses. <b>Methods</b>: NHDFs were stimulated with recombinant human TGF-β1 (20 ng/mL) for 24, 48, and 72 h. <i>SNAI2</i> and <i>POSTN</i> mRNA expression was quantified by RT-qPCR, intracellular SLUG protein levels were assessed by Western blotting, and periostin accumulation in the culture medium was measured by enzyme-linked immunosorbent assay (ELISA). The RT-qPCR and ELISA data were analyzed using two-way ANOVA with Bonferroni correction; because of the small number of replicates (<i>n</i> = 2), the Western blot data are presented descriptively. <b>Results</b>: TGF-β1 significantly increased <i>POSTN</i> mRNA expression after 24 and 48 h (both <i>p</i> < 0.001); at 72 h, <i>POSTN</i> mRNA levels remained numerically elevated relative to the control, although this difference did not reach statistical significance. Periostin accumulation in the culture medium increased progressively and was significantly higher than in the control group after 48 and 72 h (<i>p</i> < 0.001). In contrast, <i>SNAI2</i>/SLUG exhibited transient expression kinetics, with increased <i>SNAI2</i> mRNA at 48 h (<i>p</i> < 0.05) and the highest SLUG protein levels also observed after 48 h of stimulation, followed by a decline at 72 h. <b>Conclusions</b>: TGF-β1 induced time-dependent changes in <i>SNAI2</i>/SLUG and <i>POSTN</i>/periostin expression in human dermal fibroblasts. As fibroblast activation and ECM remodeling were not directly assessed, the present conclusions are restricted to the expression changes in the two investigated molecules, whose concurrent yet temporally distinct regulation may indicate potential relevance in the fibroblast response to profibrotic signaling. Further studies are required to determine whether they participate in common regulatory mechanisms or independently contribute to fibrotic processes.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 9","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}