Biomedicines最新文献

{"title":"The Role of Cytokines in Traumatic Brain Injury.","authors":"Lamprini Vlachodimitropoulou, Marios Lampros, George A Alexiou, Anastasia K Zikou, Spyridon Voulgaris, Paraskevi V Voulgari","doi":"10.3390/biomedicines14040879","DOIUrl":"10.3390/biomedicines14040879","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) is a major cause of death and disability, mainly in persons under 45 years of age and it remains clinically challenging due to its heterogeneous pathophysiology and unpredictable course. Except from the initial mechanical damage, secondary injury -largely driven by neuroinflammation-plays a critical role in outcome and extent of recovery. Cytokines are central mediators of this immune response and have therefore been extensively studied as potential biomarkers for TBI diagnosis, need of imaging and prognosis. Among pro-inflammatory cytokines, IL-1β is rapidly upregulated after TBI and contributes to blood-brain barrier disruption and secondary damage. Furthermore, experimental studies suggest that IL-1 inhibition could be neuroprotective. IL-6 is up to date the most extensively studied cytokine and shows strong associations with injury severity, neuroimaging abnormalities, mortality and long-term functional outcomes across multiple adult and pediatric studies. Nevertheless, results vary depending on the biological compartment and timing. Anti-inflammatory IL-10 levels correlate with injury severity and has shown promise in distinguishing CT-positive from CT-negative mild TBI patients, potentially reducing unnecessary imaging, though findings are inconsistent. Other cytokines, including IL-17, TNF-α, IL-8, IL-9, and IL-15, have been correlated to post-traumatic neuroinflammation and may have diagnostic or prognostic value. Overall, IL-6 and IL-10 currently appear to be the most promising cytokine as biomarkers, however future research should focus on standardized cytokines assessment methods and possible use of multimarker panels.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810606","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":"Explainable Machine Learning Reveals Time-Dependent Cognitive Risk in Minor Neurocognitive Disorder: Implications for Health Promotion and Early Risk Stratification.","authors":"Anna Tsiakiri, Christos Kokkotis, Dimitrios Tsiptsios, Leonidas Panos, Nikolaos Aggelousis, Konstantinos Vadikolias, Foteini Christidi","doi":"10.3390/biomedicines14040880","DOIUrl":"10.3390/biomedicines14040880","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Minor neurocognitive disorder (minor NCD) represents a heterogeneous and potentially modifiable stage along the continuum from normal aging to dementia, offering a critical window for targeted health promotion interventions. Early identification of individuals at increased risk of progression is essential for implementing preventive strategies that may delay functional decline. This study developed a transparent machine learning (ML) framework to predict diagnostic change from minor to major NCD at 12 and 24 months using baseline demographic, clinical, and multidomain neuropsychological data. <b>Methods</b>: A retrospective cohort of 162 memory clinic patients was analyzed using a rigorously controlled pipeline incorporating nested stratified cross-validation, SMOTE-based imbalance correction, and sequential forward feature selection. Logistic regression, support vector machines (SVMs), and XGBoost were evaluated, with SHapley Additive exPlanations (SHAPs) applied to ensure interpretability. <b>Results</b>: SVM achieved the most balanced predictive performance at both 12 months (accuracy = 0.90) and 24 months (accuracy = 0.81). Short-term progression was primarily driven by subtle multidomain cognitive inefficiencies, while longer-term risk reflected continued cognitive vulnerability modulated by metabolic factors such as diabetes. <b>Conclusions</b>: These findings highlight the potential of explainable ML as a health promotion tool and suggest that explainable ML can uncover clinically meaningful cognitive risk signatures at the earliest stages of NCD. By identifying modifiable systemic contributors alongside cognitive risk profiles, this framework supports precision-oriented preventive strategies and proactive longitudinal monitoring in minor NCD.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810258","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":"Hepatocellular Carcinoma Bridging and Downstaging: Advances in Locoregional Therapy.","authors":"Elliott L Fite, Nikhil Sekar, Jenish S Venancius, Mina S Makary","doi":"10.3390/biomedicines14040877","DOIUrl":"10.3390/biomedicines14040877","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) remains a major contributor to global cancer mortality, with many patients presenting beyond the bounds of upfront curative therapy (resection/transplant). Locoregional therapies, particularly transarterial chemoembolization (TACE), transarterial embolization (TAE), and transarterial radioembolization (TARE), therefore play an essential role in bridging and downstaging strategies designed to enable curative intent in otherwise ineligible patients. Bridging therapy aims to maintain transplant eligibility and reduce waitlist dropout, whereas downstaging seeks to reduce tumor burden to meet accepted criteria for resection or transplantation. This review synthesizes current evidence on TACE, TAE, and TARE for bridging to resection and transplantation, as well as for downstaging to surgical eligibility, drawing from systematic reviews and cohort studies in the recent literature. We examine modality-specific outcomes, contextualized by tumor biology, liver function, and treatment selection criteria. Comparative effectiveness and the need for standardized outcome measures will be highlighted, reflecting heterogeneity in study endpoints and patient populations. Finally, future directions in personalized locoregional therapy, integration with systemic therapies, and refined conversion strategies will be discussed, with emphasis on the need for consensus in defining treatment success. By integrating evolving clinical evidence with practical application, this review will help clarify the expanding role of locoregional therapies in enabling curative-intent strategies for HCC.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810532","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":"Exploring the Association Between Pulmonary Hypertension and Cancer: A Systematic Review and Meta-Analysis.","authors":"Filippo Catalani, Arianna Pannunzio, Emanuele Valeriani, Walter Ageno, Pasquale Pignatelli, Sandor Györik","doi":"10.3390/biomedicines14040876","DOIUrl":"10.3390/biomedicines14040876","url":null,"abstract":"<p><p><b>Background:</b> Cancer and pulmonary circulation disorders represent increasingly intersecting clinical entities. The prevalence of malignancy in patients with pulmonary hypertension (PH), particularly those with chronic thromboembolic pulmonary hypertension (CTEPH), is higher than in the general population. Moreover, cancer and antineoplastic therapies have been implicated in the development of PH through multiple mechanisms. <b>Methods:</b> We performed a systematic review and meta-analysis of the literature focusing on the prevalence of cancer in patients with PH. Mortality incidence and mortality risk were also evaluated for patients with PH with or without cancer. Specific sub-analyses for patients with CTEPH were also performed. Finally, we evaluated the prevalence of PH and its risk of mortality in patients with cancer. <b>Results:</b> Overall, 12 studies including 4402 patients were selected in the quantitative analysis. All the included studies had an observational design. The prevalence of cancer in patients with any PH group was 13% (95% CI: 11-16%); mortality incidence in patients with any PH group and cancer was 41% (95% CI: 26-58%), compared to 10% (95% CI: 1-48%) in those without cancer. The association was even stronger when considering only patients with CTEPH, with a mortality incidence of 4% (95% CI: 2-9%) in those without cancer compared to 19% (95% CI: 8-37%) in patients with cancer (<i>p</i> for difference: <0.01). Finally, prevalence of any PH group in patients with cancer was 22% (95% CI: 15-31%). <b>Conclusions:</b> We observed a possible correlation between PH and cancer, with a significant impact on mortality in patients with PH, particularly those with CTEPH. This association suggests the need for a close clinical surveillance for early detection of cancer and PH.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13114216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810254","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":"Exercise, Cellular Senescence, and Cancer: Novel Perspectives on Functional Aging Through Block Strength Training in Older Adults-A Narrative Review.","authors":"Rodrigo L Castillo, Emilio Jofré-Saldía, Daniela Cáceres-Vergara, Georgina M Renard, Esteban G Figueroa","doi":"10.3390/biomedicines14040875","DOIUrl":"10.3390/biomedicines14040875","url":null,"abstract":"<p><p>Population aging has markedly increased the burden of cancer in older adults, in whom frailty, sarcopenia, and reduced physiological reserve limit tolerance to treatment and worsen clinical outcomes. Aging is accompanied by progressive functional decline and by biological processes such as cellular senescence, characterized by irreversible cell cycle arrest, chronic low-grade inflammation, and impaired immune surveillance. The accumulation of senescent cells and the persistence of a senescence-associated secretory phenotype contribute to tissue dysfunction and generate a microenvironment that favors tumor initiation and progression. Physical exercise has been associated with attenuation of inflammation, improvements in metabolic and immune function, and with lower levels of senescence-related biomarkers. Although aerobic exercise has been extensively studied in this setting, resistance training holds relevance for older adults due to its capacity to counteract sarcopenia, preserve muscle strength and power, and sustain functional independence. Structured and periodized approaches to resistance exercise may further enhance these benefits by delivering targeted stimuli aligned with age-related physiological deficits. Block strength training (BST), a periodized model that concentrates training adaptations into sequential phases of maximal strength, power, and muscular endurance, has demonstrated consistent improvements in functional performance and reductions in frailty risk in community-dwelling older adults. BST improves physical function. It may also influence biological processes related to aging and cancer; however, mechanistic evidence specific to BST remains to be established. We hypothesized that the exercise in block as a targeted, a structured and physiologically grounded resistance training intervention highlights the potential of BST to promote functional aging and healthy. In the case of cancer biology, and the environment near to tumour, the relationship between aging mechanisms in older adults and controlled exercise effects are currently in advance, but mechanistic trials are still lacking. Finally, we propose a novel training method, structured and personalized, that could impact different clinical outcomes in older patients with cancer.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810216","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":"Protein C Levels in Human Immunodeficiency Virus-Infected Women with and Without Pre-Eclampsia in South Africa.","authors":"Wendy N Phoswa, Lawrence Chauke, Kabelo Mokgalaboni, Gaynor Balie, Sidney Hanser, Olive P Khaliq","doi":"10.3390/biomedicines14040866","DOIUrl":"10.3390/biomedicines14040866","url":null,"abstract":"<p><p><b>Background:</b> Pre-eclampsia (PE) is a significant cause of maternal and perinatal morbidity and mortality globally and is characterized by impaired endothelial function and disturbances in coagulation pathways. The effects of Human Immunodeficiency Virus (HIV) on the immune and coagulation systems have been investigated during pregnancy, but there are few reports on anticoagulant factors in pregnant women who are infected with HIV and develop PE. This investigation compares plasma protein C levels in pregnant women with pre-eclampsia and those without pre-eclampsia, and compares the results based on their HIV status. <b>Methods:</b> A hospital-based cross-sectional study design was used for the current research, which was carried out at Charlotte Maxeke Johannesburg Academic Hospital, South Africa. A total of 83 pregnant women participated in the study and were categorized into one of four groups: normotensive HIV-negative (<i>n</i> = 36); normotensive HIV-positive (<i>n</i> = 18); pre-eclamptic HIV-negative (<i>n</i> = 21); and pre-eclamptic HIV-positive (<i>n</i> = 8). Data collected included demographic information and clinical characteristics that were abstracted from maternity records. Plasma protein C concentrations were determined by ELISA (enzyme-linked immunosorbent assay). Nonparametric statistical methods were used to compare the mean values of plasma protein C between each of the four groups, and significance was set at <i>p</i> < 0.05. Subgroup analyses, particularly for the pre-eclamptic HIV-positive group (<i>n</i> = 8), were considered exploratory due to small sample sizes. <b>Results:</b> As would be anticipated, both systolic and diastolic blood pressure values were significantly elevated in the pre-eclamptic group when compared to the normotensive control subjects (<i>p</i> < 0.0001). There were no statistically significant differences in plasma protein C concentration between the normotensive and pre-eclamptic groups, nor between the HIV-negative and HIV-positive groups. Similarly, there were no significant differences in plasma protein C concentration when comparing all four study groups (Kruskal-Wallis test <i>p</i> = 0.2295). <b>Conclusions:</b> Plasma protein C concentrations did not vary significantly according to the presence of pre-eclampsia or HIV status in this cohort. These findings suggest that protein C concentrations were not measurably altered between groups within this study population. However, due to the small sample size in key subgroups, these findings should be considered preliminary and interpreted with caution. Larger, adequately powered studies are required to further investigate potential associations between HIV infection, pre-eclampsia, and anticoagulant pathways during pregnancy.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13114029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810461","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":"Molecular Mechanisms of Zhizhu Kuanzhong Capsule in the Treatment of Co-Morbid Anxiety and Depression of Functional Dyspepsia: Network Pharmacology, Molecular Docking and In Vivo Validation.","authors":"Jing He, Ruiyun Wang, Pengcheng Yang, Zhuanglong Xiao, Tao Bai, Xiaohua Hou, Lei Zhang","doi":"10.3390/biomedicines14040867","DOIUrl":"10.3390/biomedicines14040867","url":null,"abstract":"<p><p><b>Objective</b>: ZhiZhu Kuanzhong (ZZKZ) capsule, a Chinese herbal extract, is extensively employed for the clinical management of functional dyspepsia (FD) in China. This study aimed to elucidate the therapeutic efficacy and underlying mechanisms of ZZKZ on the co-morbidity of anxiety and depression of FD. <b>Methods</b>: The FD model was established in Sprague-Dawley rats via neonatal gastric irritation with 0.1% iodoacetamide. Subsequently, FD rats were gavaged with ZZKZ or fluoxetine. Depression-like behaviors were evaluated using the sucrose preference test (SPT) and forced swimming test (FST), while anxiety-like behaviors were assessed via light-dark box (LDB) and open field tests (OFTs). Network pharmacology and molecular docking were conducted to explore the mechanisms of ZZKZ's action. Hippocampal levels of monoamine neurotransmitters and monoaminergic system components were evaluated by HPLC and RT-qPCR, respectively. Serum concentrations of HPA axis hormones were determined by ELISA. <b>Results</b>: ZZKZ administration reversed the deficits in body weight gain and food intake in FD rats. Behaviorally, ZZKZ increased sucrose consumption in SPT and prolonged swimming duration in FST, and it increased duration and entries into the central zone in OFT. According to the prediction of network pharmacology, ZZKZ treatment elevated hippocampal levels of 5-HT/NE/DA, increased expression of TPH2/TH, and decreased expression of MAO_A/SERT in FD rats. Molecular docking further confirmed high-affinity binding between core ingredients of ZZKZ and TPH2/TH/MAO_A/SERT. Moreover, ZZKZ administration attenuated the stress-induced elevation of serum CRH/ACTH/CORT. <b>Conclusions</b>: ZZKZ effectively ameliorates the disordered gut-brain interaction and mitigates anxiety-like and depression-like behaviors, which might be modulated by the hippocampal monoaminergic system and hypothalamic-pituitary-adrenal axis response.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810705","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 Role of Endometrial Microbiota in the Pathogenesis of Chronic Endometritis: A Systematic Review and Meta-Analysis.","authors":"Angela Vidal, Anaïs Y Kilian, Vithusha Vinayahalingam, Branislav Zagrapan, Janna Pape, Tanya Karrer, Michael von Wolff","doi":"10.3390/biomedicines14040871","DOIUrl":"10.3390/biomedicines14040871","url":null,"abstract":"<p><p><b>Background:</b> Chronic endometritis (CE) is a subtle, often asymptomatic endometrial inflammation marked by CD138⁺ plasma cell infiltration and linked to recurrent implantation failure (RIF), recurrent pregnancy loss (RPL), and unexplained infertility. Emerging evidence implicates endometrial microbiome dysbiosis in CE. <b>Objective:</b> To systematically review and conduct meta-analysis on the association between CE and endometrial microbiome alterations and their reproductive implications. <b>Methods:</b> We searched MEDLINE, Embase, Web of Science, Scopus, Cochrane CENTRAL, and Google Scholar for studies diagnosing CE via CD138 immunostaining, assessing microbiota with molecular techniques. Data extraction, quality assessment, and meta-analysis were performed. <b>Results:</b> Twenty-two studies including 4022 women were analyzed. CE was associated with reduced prevalence of <i>Lactobacillus</i>-dominated microbiota and increased detection of non-<i>Lactobacillus</i> species, particularly <i>Streptococcus</i> spp., <i>Enterococcus</i> spp., <i>Escherichia coli</i>, <i>Staphylococcus</i> spp., <i>Ureaplasma</i> spp., and <i>Gardnerella vaginalis</i>. In the meta-analysis (2947 women), <i>Enterococcus</i> spp. and <i>Ureaplasma</i> spp. were significantly more prevalent in women with CE, whereas <i>Streptococcus</i> spp., <i>E. coli</i>, <i>Staphylococcus</i> spp. and <i>G. vaginalis</i> showed non-significant trends. Only <i>E. coli</i> and <i>Streptococcus</i> spp. showed significant heterogeneity between-studies. <b>Conclusions:</b> CE is linked to microbial dysbiosis with reduced <i>Lactobacillus</i> dominance and enrichment of potentially pathogenic taxa, notably <i>Enterococcus</i> and <i>Ureaplasma</i> spp. These findings suggest that the endometrial microbiome contributes to chronic inflammation and adverse reproductive outcomes, yet heterogeneity and limited evidence call for standardized diagnostics and robust trials before clinical implementation.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810559","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":"Intravenous and Subcutaneous Pharmacokinetic Modeling to Support the Development of Long-Acting Multipurpose Prevention Technology for HIV and Pregnancy.","authors":"Nathan Engel, Daniel Oliveira, Craig Sykes, Amanda P Schauer, Jasmine L King, Thy Le, Soumya Rahima Benhabbour, Mackenzie Cottrell","doi":"10.3390/biomedicines14040873","DOIUrl":"10.3390/biomedicines14040873","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Women and girls, particularly in sub-Saharan Africa, face high risks for both HIV and unintended pregnancy. Inconsistent condom use underscores the need for new multipurpose prevention technologies (MPTs) that combine HIV pre-exposure prophylaxis (PrEP) and contraception. Long-acting (LA) injectables are especially promising. To this end, an LA cabotegravir (CAB)/medroxyprogesterone acetate (MPA) in situ-forming implant (ISFI) has been developed. We report pharmacokinetic (PK) modeling to characterize CAB and MPA disposition and absorption to support the development of the MPT ISFI. <b>Methods</b>: Female BALB/c mice received single intravenous (IV) or subcutaneous (SQ) bolus doses of CAB or MPA. Sparse plasma samples were collected (~3 mice/timepoint) for PK analysis by LC-MS/MS. Noncompartmental analysis assessed SQ bioavailability. Macroparameterized compartmental PK models were fit to IV data to derive unit impulse responses (UIRs) for each drug. <b>Results</b>: CAB and MPA exhibited 61% and 42% bioavailability, respectively. CAB IV PK was best described by a two-compartment model with macroconstant parameters: A = 16,621 ng/mL, α = 4.52 h^-1, B = 30,206 ng/mL, and β = 0.053 h^-1. MPA IV PK was also best described by a two-compartment model, with A = 2506 ng/mL, α = 10.5 h^-1, B = 439 ng/mL, and β = 0.65 h^-1. These values define the UIR for CAB and MPA. <b>Conclusions</b>: Our IV PK modeling framework fully characterizes CAB/MPA disposition in mouse, enabling downstream deconvolution-based estimation of absorption from controlled-release formulations. This provides a foundation for in vitro-in vivo correlation, facilitating preclinical evaluation of long-acting formulations such as ISFIs.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13114243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810706","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":"Prophylactic Nebulized hUC-MSC-EVs Attenuate Hypobaric Hypoxia-Induced Lung Injury via Alveolar-Capillary Barrier Stabilization and TEK/Tie2 Preservation.","authors":"Peixin Wu, Yue Yin, Jinxia Liu, Zhenfei Mo, Jiabo Ren, Xiuqing Ma, Zhixin Liang, Miaoyu Wang, Chunsun Li, Liangan Chen","doi":"10.3390/biomedicines14040874","DOIUrl":"10.3390/biomedicines14040874","url":null,"abstract":"<p><p><b>Background/Objectives</b>: High-altitude pulmonary edema (HAPE) remains a serious condition with limited preventive options. This study evaluated the prophylactic protective effects of nebulized human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSC-EVs) in a rat model of hypobaric hypoxia-induced lung injury and explored potential mechanistic clues, with a focus on oxidative stress and TEK/Tie2 signaling. <b>Methods</b>: Rats were exposed to hypobaric hypoxia (47 kPa; 9.7% O₂) for 72 h and received prophylactic nebulized hUC-MSC-EVs (300 μg/rat). Lung injury was evaluated by histopathology, wet-to-dry ratio, and bronchoalveolar lavage fluid (BALF) protein concentration. Invasive pulmonary function indices were measured using a forced oscillation system. BALF cytokines (TNF-α, IL-6, and IL-10), reactive oxygen species (ROS), and TEK/Tie2 expression in lung tissue were assessed. In addition, transcriptome sequencing (RNA-seq) was performed to characterize global transcriptional changes. N-acetylcysteine (NAC), a classical antioxidant, was included as an auxiliary mechanistic intervention to assess the association of ROS with TEK/Tie2 changes. <b>Results</b>: Compared with hypoxia controls, prophylactic nebulized hUC-MSC-EVs reduced histopathological injury, pulmonary edema, and barrier leakage, and improved pulmonary function indices. hUC-MSC-EV intervention also attenuated inflammatory responses in BALF, with decreased TNF-α and IL-6 and increased IL-10. Hypobaric hypoxia increased ROS accumulation and decreased TEK/Tie2 expression, whereas nebulized hUC-MSC-EVs reduced ROS and partially preserved TEK/Tie2 expression. NAC pretreatment similarly reduced ROS and was accompanied by Tie2 preservation. <b>Conclusions</b>: Prophylactic nebulized hUC-MSC-EVs mitigated hypobaric hypoxia-induced lung injury, accompanied by reduced oxidative stress, improved vascular barrier integrity, and preservation of TEK/Tie2 expression. These findings support nebulized hUC-MSC-EVs as a potential lung-targeted prophylactic strategy for hypobaric hypoxia-induced lung injury and suggest that ROS imbalance may be associated with Tie2 preservation.</p>","PeriodicalId":8937,"journal":{"name":"Biomedicines","volume":"14 4","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810371","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}