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关键词： HIV-1 reservoir   IL-15   thymosin alpha 1   human virtual memory CD8+T cells   immunological nonresponders  

摘要： Viral reservoir presents a significant challenge in HIV-1 cure. We previously observed that Thymosin alpha 1 (T alpha 1) may restrict the reservoir through the IL-15 pathway. However, the precise mechanism remains to be fully elucidated. Peripheral blood mononuclear cells (PBMCs) were obtained from people living with HIV-1 (PLWH). In vitro, THP-1 cells were differentiated into mature monocyte-derived dendritic cells (MoDCs) and co-cultured with PBMCs under various conditions. Intracellular HIV-1 p24 levels, CD8+ T and NK cell functionality, and reservoir size were evaluated. In vitro, T alpha 1 stimulation of MoDCs resulted in significant immune response and secretion of IL-15/RA complex (p < 0.001). This interaction with IL-2 R beta/gamma receptors on T cells enhanced the intracellular secretion of CCL3/5, IFN-gamma, and TNF-alpha in CD8+ T cells (p < 0.05 which inhibited p24 levels in CD4+ T cells (p = 0.002 and reduced HIV-1 integrated DNA levels (p = 0.012). Furthermore, the secretion levels of IFN-gamma, TNF-alpha, and GZMB in NK cells and proportion of CD8+ T-VM cells significantly increased following co-culture. These alterations were found to be markedly inversely associated with reservoir size and reactivation. However, these effects were observed in PBMCs from immunological responders (CD4+ T cell count > 350 cells/& micro;L) rather than nonresponders. T alpha 1 enhances CD8+ T cell function, promotes T-VM proliferation, and suppresses reservoir size and reactivation via IL-15 pathway activation in dendritic cells, which warrants testing in functional cure trials in the future.

关键词： Combined training   fisetin   inflammation   Maresin-1   obesity  

摘要： Background: Obesity is characterized by low-grade chronic inflammation and impaired insulin sensitivity. Maresin-1 (MaR1 a specialized pro-resolving mediator, plays a critical role in terminating inflammation and supporting metabolic homeostasis;however, interventional data in humans remain scarce. This study examined whether fisetin supplementation augments the effects of concurrent interval resistance-aerobic training on Maresin-1, pro-inflammatory markers, and insulin resistance in obese men. Methods: In a 12-week parallel-group randomized controlled trial, 44 obese adult males (BMI > 30 kg/m & sup2 completed one of four interventions: control-placebo (CP fisetin (F 200 mg/day training-placebo (TP or training-fisetin (TF). Training comprised eight resistance exercises at 60% 1RM with active rest followed by progressive aerobic bouts (50%-70% HRmax). Anthropometric and biochemical parameters, including plasma Maresin-1, interleukin-6 (IL-6 tumor necrosis factor-alpha (TNF-alpha fasting blood glucose (FBS insulin, and HOMA-IR, were assessed pre- and post-intervention. Results: Significant group & times;time interactions were observed for Maresin-1 (p = 0.034 IL-6 (p = 0.001 TNF-alpha (p = 0.001 FBS (p = 0.001 insulin (p = 0.001 and HOMA-IR (p = 0.001). Maresin-1 increased in the TP (p = 0.001) and TF (p = 0.001) groups. IL-6 decreased in T (p = 0.006 TF (p = 0.001 and F (p = 0.013) groups. TNF-alpha decreased in all intervention groups (F, TP, and TF p = 0.002). FBS, insulin, and HOMA-IR decreased significantly in all active arms (p = 0.003 with the greatest reductions in the TF group. Conclusion: Twelve weeks of concurrent interval resistance-aerobic training, especially when combined with fisetin, improved inflammatory resolution (up arrow Maresin-1, down arrow IL-6, and down arrow TNF-alpha) and metabolic control (down arrow FBS, down arrow insulin, and down arrow HOMA-IR) in obese men. The synergy between exercise-induced adaptations and fisetin's anti-inflamma

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 lines.MethodsTwo 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 analyses.ResultsOur 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 responses.ConclusionTramadol 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： Tubulointerstitial fibrosis   HIF-1 alpha   BNIP3   mitophagy   pyroptosis  

摘要： Tubulointerstitial fibrosis (TIF) is a key pathological hallmark and a major determinant of end-stage renal disease (ESRD). The mechanisms of TIF remain unclear, and there are currently no specific drugs to slow or reverse its progression. Notably, due to the kidney's unique structure, the course of renal dysfunction is intimately connected with hypoxia. The signaling pathway formed by hypoxia-inducible factor 1 alpha (HIF-1 alpha) and its downstream target gene, B-cell lymphoma-2/adenovirus E1B 19-kDa interacting protein (BNIP3 exerts a pivotal effect during renal hypoxia. This pathway mediates mitophagy, inhibits apoptosis and inflammatory responses, maintains cellular energy balance, and thus profoundly influences the progression of TIF. This article focuses on the molecular mechanism by which the HIF-1 alpha/BNIP3 pathway regulates mitophagy and affects TIF, and delves into its mechanisms in pyroptosis, oxidative stress, and ischemia-reperfusion injury, This work endeavors to establish a theoretical foundation and potential intervention targets for developing novel treatment strategies for TIF.

关键词： Esophageal cancer   radiotherapy   anti-PD-1 antibody   chemotherapy   elderly patients  

摘要： Background and purposeThe benefit of adding anti-PD-1 antibodies to definitive chemoradiotherapy (dCRT) in elderly patients with esophageal squamous cell carcinoma (ESCC) remains uncertain. This study evaluated its efficacy and safety versus dCRT alone.Materials and methodsWe retrospectively analyzed the patients aged >= 70 years with ESCC treated at three academic centers from 2009 to 2023. All patients received first-line dCRT and the study group additionally received anti-PD-1 antibodies (IO group). Propensity score matching (PSM) was applied to balance baseline factors.ResultsA total of 241 patients were enrolled, including 130 in the IO group and 111 in the dCRT group. After 1:1 PSM (110 patients per group no significant differences in overall survival (OS) or progression-free survival (PFS) were observed. The median OS was 34.5 vs 33.7 months (HR = 0.86, 95%CI: 0.58-1.28, p = 0.467) and median PFS was 29.8 vs 17.8 months (HR = 0.79, 95%CI: 0.55-1.13, p = 0.194). Multivariate Cox analysis identified high nutritional risk as an independent predictor of worse OS (p = 0.014 while both advanced TNM stage (p = 0.030) and high nutritional risk (p = 0.016) were independently associated with shorter PFS. Subgroup analyses suggested that patients with good performance, better nutritional status or lower comorbidity burden may benefit from combination therapy. Grade 3-4 adverse events were comparable between two groups.ConclusionAdding anti-PD-1 antibodies to dCRT did not result in a significant improvement in OS or PFS in the ESCC patients aged >= 70 years;however exploratory findings indicate a potential PFS signal in selected patients with favorable baseline conditions, which requires confirmation in prospective studies.

关键词： EGCG-NPs   SAH   heme oxygenase-1   reactive astrocyte   white matter injury   iron overload   oxidative stress  

摘要： ObjectiveSubarachnoid hemorrhage (SAH) is associated with high mortality and poor outcomes, which are closely related to white matter injury (WMI). (-)-Epigallocatechin-3-gallate (EGCG) exerts neuroprotective effects by inhibiting oxidative stress-related ferroptosis in astrocytes and improving neurological function. However, the role and mechanism of EGCG in regulating reactive astrocytes (RAs) to alleviate WMI after SAH remain unclear.MethodsA mouse model of SAH was used to evaluate the effects of EGCG-loaded nanoparticles (EGCG-NPs). Western blot, qPCR, and immunofluorescence were performed for biochemical analysis. Neurological function was assessed using neurological deficit scores and the Morris water maze test.ResultsFollowing SAH, HO-1-mediated iron accumulation and ROS production promoted A1/A2 reactive astrocyte polarization, resulting in myelination damage and aggravated WMI. Knockdown of S100A10 inhibited iron-dependent oxidative stress in RAs and attenuated WMI. EGCG-NPs significantly suppressed HO-1/S100A10-mediated iron overload and oxidative stress in both A1 and A2 RAs, thereby alleviating WMI after SAH.ConclusionEGCG-NPs attenuate SAH-induced WMI by inhibiting the iron overload-activated HO-1/S100A10 axis in RAs, representing a promising therapeutic strategy.

关键词： HIF-1 alpha   VEGF   lung   liver   roiler ascites syndrome  

摘要： Broiler ascites syndrome (BAS a hypoxia-driven metabolic disorder, causes significant economic losses in poultry production. This study aimed to evaluate the pathological changes in the lungs and liver of broiler chickens and the expression of HIF-1 alpha and VEGF. HE, Masson and Van Gieson staining were used to observe histopathological changes in the lungs and liver, and molecular biology methods such as qPCR, Western blotting and immunohistochemistry were used to detect the expression of HIF-1 alpha and VEGF in the lungs and liver. The histopathological results revealed significant thickening and remodelling of the pulmonary artery wall in BAS broiler chickens;the boundaries of the vascular intima, media and adventitia were unclear;and there was a significant increase in the collagen fibre content around the arteries. Additionally, the hepatic cords were loosely arranged liver cords. The molecular biology results revealed that both the mRNA and protein expression levels of HIF-1 alpha and VEGF were significantly increased (p < 0.05) in the lungs and liver of AS broiler chickens. These findings establish an association between HIF-1 alpha/VEGF dysregulation and BAS pathogenesis, providing a foundation for mechanistic investigation.

关键词： Intracranial atherosclerotic stenosis (ICAS)   cognitive impairment (CI)   cerebral small vessel disease (CSVD)   extracranial carotid artery stenosis (ECAS)   acute ischemic stroke (AIS)   transient ischemic attack (TIA)  

摘要： Background and purpose Intracranial atherosclerotic stenosis (ICAS) is common in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA but its relationship with long-term cognitive impairment remains unclear. This study examined whether ICAS was associated with 1-year cognitive impairment after AIS/TIA independently of cerebral small vessel disease (CSVD) and extracranial carotid artery stenosis (ECAS). Methods Data were obtained from the impairment of cognition and sleep after AIS or TIA in Chinese patients (ICONS a subgroup of the China National Stroke Registry III. Patients with AIS or TIA within 7 days of onset who had baseline vascular imaging and 12-month cognitive assessment were included. ICAS was defined as intracranial arterial stenosis >= 50%. The primary outcome was cognitive impairment at 12 months, defined as a Montreal Cognitive Assessment (MoCA) score <23. Multivariable logistic regression and domain-specific linear regression analyses were performed after adjustment for demographic characteristics, vascular risk factors, CSVD markers, ECAS, stroke severity, and baseline cognitive status. Results A total of 1261 patients were included. Patients with ICAS had a significantly higher rate of cognitive impairment at 1 year than those without ICAS. After full adjustment, ICAS remained independently associated with 1-year cognitive impairment (odds ratio 1.524, 95% confidence interval 1.068-2.176;p = 0.020). ICAS was also significantly associated with poorer recall performance (beta = -0.182, 95% confidence interval -0.293 to -0.071;p = 0.001 but not with other cognitive domains. Conclusions ICAS was independently associated with an increased risk of 1-year cognitive impairment after AIS/TIA, particularly in memory performance.

关键词： postbiotic   prediabetes   metabolic syndrome   glycemic control   intestinal microbiota   metagenome   weight control   responder analysis   Akkermansia muciniphila MucT  

摘要： Pasteurized Akkermansia muciniphila MucT was found to improve barrier function in preclinical models and a proof-of-concept study in obese and prediabetic adults. Here, we describe the results of a double-blind placebo-controlled multicenter (Ireland and Germany) trial in 142 adults with metabolic syndrome, with or without prediabetes. The primary endpoint of whole-body insulin sensitivity (Matsuda index) did not differ after 4-months of daily administration of capsules containing 30 billion cells of pasteurized A. muciniphila MucT compared to placebo in the intention-to-treat subjects. Subsequent exploratory analyses showed that 3-months intake of pasteurized A. muciniphila MucT already improved HOMA-based hepatic insulin sensitivity in prediabetic (12%;p = 0.05) and 63-y-or-older-age subgroups (p = 0.05) while increasing post-OGTT excursion of the insulinotropic hormone glucagon-like peptide 1 (GLP-1) over placebo (p < 0.01). Further analysis of the gut microbiota by deep metagenomic analysis showed minor effects of the intervention but revealed that the baseline microbial composition differed from that in matched healthy adults. We found that participants with low baseline Akkermansia gene counts experienced significant health improvements and GLP-1 excursion after 3-months of treatment with pasteurized A. muciniphila MucT over the placebo. These benefits included improved insulin sensitivity (as shown by Matsuda and HOMA-S indices) and GLP-1 excursion (post-OGTT p < 0.05 reductions in body weight (p = 0.06) and decreased trunk fat (p < 0.05). In conclusion, daily supplementation with pasteurized A. muciniphila MucT has the potential to improve health markers in overweight or obese normo- or dysglycemic adults with the most significant improvements in subjects with low baseline intestinal Akkermansia levels, who are apparently truly in need of this intervention.

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.