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关键词： Sepsis associated acute kidney injury   endothelial glycocalyx   renal resistive index   bedside doppler ultrasound   macro- microcirculatory dysfunction  

摘要： The interplay between macro-microcirculatory dysfunction and sepsis associated acute kidney injury (SA-AKI) remains elusive. This study aimed to explore the association between hemodynamics and endothelial damage in SA-AKI by evaluating the combined predictive value of renal resistive index (RRI) and plasma syndecan-1. This prospective observational study enrolled 80 septic patients admitted to the general intensive care unit (ICU) of a tertiary hospital from May to December 2024. Plasma syndecan-1 levels were measured at admission, and RRI was assessed within 24 h of ICU admission. Univariate and multivariate logistic regression models were applied to identify independent risk factors of SA-AKI. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis by calculating the area under the curve (AUC). Among 80 septic patients, 41(51.25%) developed AKI. Syndecan-1 levels were significantly higher in the AKI group [109.95 (73.67-221.40) vs.73.67 (54.59-109.95) ng/mL, p = 0.007], and RRI values were markedly elevated (0.69 +/- 0.08 vs. 0.60 +/- 0.06, p < 0.001) compared to non-AKI patients. Univariate analysis revealed syndecan-1 (OR = 2.68, 95%CI 1.29-5.59) and RRI (OR = 1.18, 95%CI 1.09-1.28) as predictors of AKI. In multivariate models adjusted for confounders, both plasma syndecan-1 (OR = 3.57, 95%CI 1.01-12.64, p = 0.048) and RRI (OR = 1.19, 95% CI 1.07-1.33, p = 0.002) retained significance. A predictive model using a combination of plasma syndecan-1 and RRI achieved superior diagnostic performance (AUC 0.859, sensitivity 87.8%, specificity 92.3%). In patients with SA-AKI, elevated plasma syndecan-1 and RRI were identified as independent risk factors. The combination of syndecan-1 and RRI can serve as synergistic biomarkers for the prediction of SA-AKI.

关键词： Androgenetic alopecia   minoxidil   finasteride   topical foam   phase 1   CG2001  

摘要： ObjectivesCompared with placebo, this phase I study evaluated the safety, tolerability, and pharmacokinetics of CG2001, a novel isopropyl alcohol-free minoxidil-finasteride combination topical foam, in Chinese males with androgenetic alopecia (AGA).MethodsIn this randomized, double-blind, placebo-controlled trial, 44 subjects received single and multiple doses across five cohorts with varying finasteride concentrations (0.025%-0.1%) and frequencies. Safety, tolerability, and pharmacokinetics were evaluated. The concentrations of minoxidil-finasteride were both *** result shows that CG2001 was safe and well-tolerated, with no serious adverse events. Systemic minoxidil exposure was consistent across most dosages, while finasteride exposure increased dose- and frequency-dependently, though it remained markedly lower than that reported with oral administration. Steady state was achieved for both drugs after 7 *** favorable safety profile and reduced systemic finasteride exposure position CG2001 as a promising alternative, supporting further clinical development in a phase IIa trial, and provide a pharmacokinetic foundation for subsequent efficacy trials in patients with AGA.

关键词： Influenza A virus   SARS-CoV-2   TMPRSS2   inhibitors   entry inhibitors   host-directed-antivirals   broad-spectrum antiviral drugs  

摘要： Human TMPRSS2 is a type II transmembrane serine protease and an essential host factor for SARS-CoV-2 and influenza A virus (IAV H1N1) infections. It facilitates the cleavage of viral surface glycoproteins, which are required for membrane fusion. This importance makes it an attractive target for host-directed antiviral therapies. We previously identified N-0385 and N-0920 as nanomolar TMPRSS2 inhibitors and demonstrated their antiviral potency against several SARS-CoV-2 variants. Here, we screened another twelve N-0385/N-0920 analogs with improved pharmacokinetics. Compounds 9 and 10 showed strong inhibition of TMPRSS2 activity and viral entry: they blocked pseudoviruses and authentic SARS-CoV-2 JN.1 and IAV H1N1 in Calu-3 cells. Compound 9 displayed a synergistic effect with baloxavir during IAV H1N1 infection. Both compounds highly reduced H1N1 infection in air-liquid interface cultures and mouse models, thus highlighting their broad antiviral potential. The discovery of broad-spectrum, host-directed antivirals against current and emerging human viruses is critical in preparing for future pandemics.

关键词： Moringa oleifera seeds   cyanoglycosides   structure elucidation   diabetic nephropathy   metabolic reprogramming  

摘要： ContextDiabetic nephropathy (DN) is a major complication of diabetes. Moringa oleifera seeds are recognized as a source of bioactive compounds with potential health benefits, prompting investigation into their specific components and effects on *** study aimed to isolate bioactive compounds from M. oleifera seeds and evaluate their renoprotective effects and underlying mechanisms of action against high-glucose-induced diabetic *** and methodsFour cyanoglycosides and one cyanoaglycone were isolated from M. oleifera seeds using chromatographic techniques. The renoprotective effects of these compounds were then evaluated using an in vitro model of high-glucose-induced diabetic nephropathy in HBZY-1 mesangial cells. Mechanistic studies further investigated the compounds' effects on oxidative stress, inflammation, mitochondrial function, expression of the glycolysis-related protein PFKFB3, and the TGF-beta 1/Smad signaling *** previously undescribed cyanoglycosides were isolated alongside three known compounds. All five compounds demonstrated significant renoprotective effects in the high-glucose-induced HBZY-1 cell model. Mechanistically, these effects were achieved by suppressing oxidative stress and inflammation, protecting mitochondrial function, modulating the expression of the glycolysis-related protein PFKFB3, and inhibiting the TGF-beta 1/Smad signaling pathway, collectively contributing to beneficial metabolic *** study isolated two novel cyanoglycosides from M. oleifera seeds. These compounds, alongside known ones, protect against high-glucose-induced renal injury. Their renoprotection involves metabolic reprogramming via suppressing oxidative stress/inflammation, preserving mitochondrial function, modulating PFKFB3, and inhibiting TGF-beta 1/Smad signaling. These findings offer insights for utilizing M. oleifera seeds and suggest these cyanoglycosides as potential diabetic nephropathy ther

摘要： Bovine alphaherpesvirus 1 (BoHV-1) is the causative agent of infectious bovine rhinotracheitis and reproductive disorders causing significant economic losses in the cattle industry. Both BoHV-1 glycoproteins B (gB) and D (gD) are targets of neutralizing antibodies and desirable antigens for subunit vaccine. In this study, a bivalent subunit vaccine was generated based on the ectodomain of gD and gB expressed by baculoviruses system. Compared with the inactivated vaccine, the bivalent subunit vaccine induced higher neutralizing antibody levels against both the BoHV-1 reference strain and the virulent BoHV-1 field strain. Following intranasally challenge with BoHV-1 J2303, the clinical signs and virus excretion were significantly reduced in rabbits vaccinated with this subunit vaccine whereas severe clinical symptoms appeared in the non-vaccinated rabbits, indicating that the bivalent subunit vaccine provides complete protection against virulent BoHV-1 infection. Considering that the respiratory symptoms caused by J2303 in rabbits is highly similar and even identical to those of cattle, our findings suggest that the bivalent subunit vaccine based on combination of gD with gB protein have promising application to BoHV-1control programs.

关键词： Tramadol   ER stress   HIF-1 alpha   reactive oxygen species   paraptosis   ATF4   CHOP   postoperative pain   cytoplasmic vacuolization  

摘要： ObjectivesTramadol, a clinically approved analgesic widely used for managing postoperative pain, has recently been shown to possess anticancer properties in several tumor models, especially in breast cancer. In this study, we explored the intricate molecular mechanisms by which tramadol induces cytotoxicity in breast cancer cell *** invasive ductal carcinoma lines MCF-7 and MDA-MB-231 were used to verify the molecular cytotoxicity of tramadol using cell viability analysis, flow cytometry analysis, real-time polymerase chain reaction, western blotting, Seahorse biogenetic, and transmission electron microscopy *** findings demonstrate that tramadol induces the normoxic stabilization and nuclear translocation of hypoxia-inducible factor- 1 alpha (HIF-1 alpha) to activate hypoxia responsive genes. Concurrently, tramadol triggers endoplasmic reticulum (ER) stress and activates the p-eIF2 alpha/ATF4/CHOP signaling axis, leading to the generation of reactive oxygen species, impaired autophagy, mitochondrial dysfunction, including mitochondrial membrane depolarization and the decline of ATP production, cytoplasmic vacuolization, and lipid droplet accumulation which is characteristics of paraptosis-like cell death. Notably, the knockout of HIF-1 alpha or ATF4 significantly reduced tramadol-induced cytotoxicity, highlighting their crucial roles in mediating these cellular *** induced breast cancer cell death via paraptosis which highlights its therapeutic potential in targeting resistant cancer subtypes such as triple-negative breast cancer.

关键词： PD-1 fate-mapping   PD-1 blockade   cytotoxic drug   combination therapy   TCR diversification   single cell analysis  

摘要： Combined cytotoxic chemotherapy and immune checkpoint inhibition (ICI) improves outcomes in PD-L1-low lung cancer, but transient and broad PD-1 expression across immune cells complicates the understanding of the underlying mechanisms. We generated Pdcd1-CreERT2 fate-mapping mice to trace PD-1-expressing cells via tdTomato during PD-1 blockade. PD-1-fate-mapped lymphocytes downregulated PD-1 in the spleen but largely retained it in tumors, except for NK cells, which lost PD-1 and regained function. Single-cell transcriptional profiling was performed on immune cells in PD-L1-low Lewis lung carcinoma (LLC) treated with cyclophosphamide (CTX) and/or anti-PD-1 antibodies. Anti-PD-1 monotherapy showed limited efficacy, whereas CTX plus anti-PD-1 markedly improved tumor control. Single-cell analysis identified 15 transcriptionally distinct immune clusters with treatment-dependent abundances. Combination therapy expanded cytotoxic CD8 T cells and a dysfunctional Treg cluster, enhancing CTL activity, including PD-1-fate-mapped CD8 T cells expressing Tpex1 markers. Single-cell TCR analysis revealed that clonotypes selectively expanded by combination therapy, mediating potent cytotoxicity against LLC tumors. PD-1 blockade synergizes with cytotoxic chemotherapy to diversify and expand PD-1 lineage-traced CTL clonotypes, driving robust antitumor immunity. Thus, our fate-mapping system is a valuable tool to search for immune cells responsive to ICI therapy.

关键词： Macrophages   Insulin-like growth factor-1   acute lung injury   efferocytosis   acute respiratory distress syndrome  

摘要： BackgroundNo effective treatment strategy for acute respiratory distress syndrome (ARDS) has been established. Conflicting reports on the effects of insulin-like growth factor (IGF)-1 stimulation and the inhibition of IGF-1 receptor (IGF-1R) signalling in tissue injury across several organs have led to hesitation in advancing IGF-1-based treatment strategies for tissue *** aim to examine whether IGF-1/IGF-1R signalling contributes to recovery from acute lung injury in mouse models and to further explore its potential *** (LPS) was intratracheally injected into mice to create acute lung injury models. Experiments were conducted to acquire or inhibit IGF-1 signalling through the intratracheal injection of recombinant IGF-1 or JB1, an IGF-1 receptor antagonist during the recovery phase of the models, starting on day 4 after LPS administration. Bone marrow monocyte-derived macrophages (MDMs) cocultured with IGF-1 and/or JB1 were intratracheally injected during the recovery *** cell counts and lung injury scores were significantly decreased when recombinant IGF-1 was administered in the later phase, while they increased with the administration of JB1. On day 4 after LPS injection, IGF-1 receptor (IGF-1R, also known as CD221) was strongly expressed on macrophages, particularly in CD11c+SiglecF+ alveolar macrophages (AMs). Intratracheal injection of MDMs cocultured with IGF-1 decreased lung neutrophil counts, whereas the addition of JB1 to MDMs cocultured with IGF-1 counteracted the effect of IGF-1. JB1 also reduced efferocytosis capacity of AMs in the later phase. In the phagocytosis assay, LPS decreased the efflux capacity of macrophages, but recombinant IGF-1 improved this capacity regardless of the presence or absence of ***-1/IGF-1R signalling in macrophage facilitates the recovery from acute lung injury via enhancing efferocytosis. IGF-1 delivery potentially offers a new treatment str

关键词： Random forest regression   soil moisture mapping   Sentinel-1 C-band SAR   SMOS-IC   NDVI   croplands and grasslands  

摘要： This study presents a methodology to retrieve surface soil moisture (SM) at 1-km scale over croplands and grasslands using Sentinel-1 radar backscatter, harmonized Landsat/Sentinel-2 NDVI, and ancillary environmental variables. A Random Forest (RF) model was trained on the coarse (25-km) SMOS-IC product (2017-2024) to learn relationships between predictors and SM and then applied to generate fine-scale estimates. Only SMOS-IC pixels dominated by cropland and grassland selected to improve the reliability of the estimation. The RF achieved good performance at the training scale (R = 0.79, RMSE = 5.68 vol.% and negligible bias). When transferred to 1-km grids, independent validation using International Soil Moisture Network observations (2015-2024) yielded an R value of 0.49, an RMSE of 11.2 vol.%, an unbiased RMSE of 9.55 vol.%, and a global bias of 5.8 vol.%. Spatial comparison with GLASS SM indicated generally strong correlations, especially in humid regions. However, limitations remain, including a systematic underestimation inherited from SMOS-IC and reduced performance over areas with fine-textured soils. Accuracy also decreases under very dense vegetation and following recent heavy rainfall events (>30 mm). Despite these challenges, the 1-km High-resolution SM dataset offers valuable spatial detail on soil moisture variability, supporting improved agricultural management and local-scale monitoring.