课程文献中心 更多>>

关键词： COPD   Immune checkpoint   PD-1   PD-L1   Physical activity level   T-cells  

摘要： Chronic obstructive pulmonary disease (COPD) is characterized by systemic inflammation, immune dysregulation, and T-cell dysfunction. The PD-1/PD-L1 immune checkpoint axis is implicated in immune exhaustion and increased exacerbation risk in COPD. Physical activity (PA) is known to exert anti-inflammatory effects, yet its impact on immune checkpoint regulation remains unclear. We aimed to evaluate the association between PA and PD-1/PD-L1 expression in COPD and assess whether a structured PA intervention modulates this axis and improves T-cell function. Ninety-one patients with stable COPD were classified by baseline physical activity level (PAL) using a multiparametric accelerometer. Plasma PD-1/PD-L1 levels, peripheral blood mononuclear cell expression, and T-cell proliferation were assessed pre-and-post-intervention. Sedentary patients showed elevated plasma PD-1/PD-L1 and increased expression in CD4⁺ T cells and monocytes, correlating inversely with activity and CD4⁺ T-cell proliferation. Following the intervention, patients with improved PAL exhibited significant reductions in PD-1 and enhanced CD4⁺ T-cell proliferation. These effects were not observed in CD8⁺ cells, which responded primarily to PD-1 blockade. Physical activity is associated with lower PD-1/PD-L1 expression and improved CD4⁺ T-cell function in COPD. A structured PA intervention may modulate immune checkpoint pathways, offering a non-pharmacologic strategy to restore immune competence. © The Author(s) 2025.

关键词： Biomarkers   Hepatocellular carcinoma   Immune checkpoint inhibitors   Neutrophil-to-Lymphocyte Ratio  

摘要： Purpose: Immune checkpoint inhibitors (ICIs) are the preferred treatment for advanced hepatocellular carcinoma (HCC). However, most patients do not respond to initial immunotherapy alone, even when combined with other therapies. Our study aimed to profile ICI-based therapies for HCC patients in real-world clinical practice and to identify factors associated with survival and treatment efficacy. Methods: A retrospective cohort study was conducted to describe ICI-based therapies for HCC patients at our center, including combination modalities, effectiveness, and safety. Pre- and post-treatment indicators were collected to explore factors related to progression-free survival (PFS) and treatment efficacy in these patients. Results: All 110 patients received therapy based on immune checkpoint inhibitors (ICIs) using three strategies, with the majority (60.9%) undergoing triple combination therapy. The overall progression-free survival (PFS) was 7.0 months, and the objective response rate (ORR) was 26.4%. Analysis of PFS identified several independent risk factors: a history of hepatitis B virus (HBV) infection (hazard ratio [HR] = 1.78), a platelet-to-lymphocyte ratio (PLR) greater than 276.9 (HR = 2.19), and an international normalized ratio (INR) greater than 1.2 (HR = 3.49). Conversely, the use of PD-1 inhibitors was associated with a favorable outcome (HR = 0.44). The combination of a history of HBV infection with HBeAg positivity and TNM stage (III + IV) effectively distinguished responders from non-responders. Additionally, neutrophil count and the neutrophil-to-lymphocyte ratio (NLR) were significantly elevated in non-responders and exhibited dynamic changes during treatment. Conclusion: In HCC clinical practice, ICI-based systemic therapies are both effective and safe. Patient characteristics can serve as reliable predictors of progression-free survival (PFS) and treatment efficacy. Importantly, neutrophil count and the neutrophil-to-lymphocyte ratio (NLR) may al

关键词： Anti-fibrotic   M2 macrophages   Phytochemicals   Pulmonary fibrosis   Rubiadin-1-methyl ether  

摘要： To investigate the therapeutic effects of Rubiadin-1-methyl ether (RBM) on bleomycin (BLM)-induced pulmonary fibrosis in mice and the underlying mechanism by which it inhibits fibrosis through the modulation of macrophage polarization. A C57BL/6 mouse model of pulmonary fibrosis was established by intratracheal injection of BLM (3 mg/kg), followed by oral administration of RBM (3, 10, 30 mg/kg). Lung injury was assessed through histopathological examinations (HE and Masson staining), lung coefficient measurements, bronchoalveolar lavage fluid (BALF) inflammatory cell counts, and cytokine detection (TGF-β1, IL-6, etc.). Flow cytometry was employed to analyze M2 macrophages (F4/80⁺CD206⁺) in lung tissue, and qRT-PCR was used to measure the expression of fibrosis markers (Fn1, Col1a1, Acta2) and M2-related genes (Mrc1, Arg1, Tgfb1, Il10). RBM at 10 mg/kg exhibited the most potent therapeutic effect: it significantly ameliorated BLM-induced weight loss, reduced the elevated lung coefficient, and attenuated lung tissue pathological damage. In BALF, RBM reduced the total number of inflammatory cells by ~ 47.2%, with significant decreases in neutrophils (~ 59.4%) and lymphocytes (~ 25.6%) compared to the BLM group. Additionally, RBM downregulated the mRNA expression of fibrosis-associated genes: Fn1 (by ~ 52.4%), Col1a1 (by ~ 30.8%), and Acta2 (by ~ 44.3%). Flow cytometry analysis showed that RBM inhibited M2 macrophage polarization, reducing the proportion of F4/80⁺CD206⁺ cells from 28.4% ± 5.7% (BLM group) to 19.8% ± 1.8%. Correspondingly, the mRNA levels of M2 marker genes were significantly downregulated: Mrc1 (by ~ 48.3%), Arg1 (by ~ 46.1%), Tgfb1 (by ~ 59%), and Il10 (by ~ 38.7%). RBM also reduced the secretion of pro-inflammatory and pro-fibrotic factors in BALF: TGF-β1 (by ~ 28.7%), IL-6 (by ~ 26.5%), IL-1β (by ~ 55%), and TNF-α (by ~ 51%). RBM significantly attenuates pulmonary inflammation and collagen deposition, likely by inhibiting macrophage M2 polarization a

关键词： CD8 + T cell   CXCL10-CXCR3 axis   Mutant p53   Prostate cancer   Single-cell RNA sequencing  

摘要： Background: TP53 mutations are frequently linked to an immunosuppressive tumor microenvironment and resistance to immune checkpoint blockade (ICB). However, their mechanistic role in shaping antitumor immunity in advanced prostate cancer remains unclear. Methods: We generated CRISPR-Cas9-engineered murine prostate cancer models harboring the Trp53 p.R245Q knock-in mutation (orthologous to human TP53 p.R248Q). Tumor growth and response to anti-PD-1 therapy were evaluated in vivo. Single-cell RNA sequencing and integrated immune profiling were performed to characterize stromal and immune remodeling. Chromatin immunoprecipitation assays were used to assess mutant p53 binding and histone modifications at the Cxcl10 promoter. Statistical significance was assessed using Student’s t-test, Wilcoxon rank-sum test, and one-/two-way ANOVA, as appropriate. Results: Mutant p53 accelerated tumor progression yet unexpectedly enhanced responsiveness to anti-PD-1 therapy within an otherwise suppressive microenvironment. Single-cell transcriptomics revealed epithelial lineage and metabolic rewiring, accompanied by depletion of cancer-associated fibroblasts and a shift toward immune-permissive stromal states. Immune profiling demonstrated increased infiltration of cytotoxic CD8⁺ granzyme B⁺ T cells and augmented lymphoid and vascular features. Mechanistically, mutant p53 occupied the Cxcl10 promoter, remodeled local chromatin by enriching H3K4me3 while reducing repressive histone marks, and transcriptionally upregulated Cxcl10. This established a CXCL10–CXCR3 chemotactic axis that promoted recruitment of cytotoxic CD8⁺ T cells and sensitized tumors to PD-1 blockade. Consistently, cohort analysis further supported that high CXCL10 expression correlated with immune activation and clinical benefit from ICB. Conclusions: These findings indicate that mutant p53 can reprogram immune-cold prostate tumors into immune-hot ecosystems through coordinated epigenetic, metabolic, and stromal-immune

摘要： Achieving precise stereocontrol when forging two vicinal C(sp³)–C bonds on unsymmetrical internal alkenes remains a formidable challenge. The comparable reactivity of alkyl radicals often compromises chemo- and regioselectivity, while the concurrent induction of diastereo- and enantioselectivity has proven elusive. Here, we show a unified metallaphotoredox strategy that addresses these challenges through two complementary multicomponent difunctionalization protocols. First, a Ni/terpyridine catalyst system enables anti-selective 1,2-dialkylation of both cyclic and acyclic internal alkenes, delivering vicinal C(sp³)–C(sp³) linkages with high levels of chemo-, regio-, and diastereoselectivity. A switch to a chiral biimidazole ligand and replacement of the alkyl halide with a (hetero)aryl bromide unlocks enantioselective 1,2-alkylarylation of cyclic internal alkenes. This transformation affords β-aryl-α-alkylated lactones and related scaffolds bearing two contiguous stereocenters with excellent diastereo- and enantioselective control. This dual strategy offers a rapid and efficient access to drug-like molecular architectures. © The Author(s) 2026.

摘要： Renal fibrosis is a major driver of chronic kidney disease (CKD) progression, yet targeted therapies remain limited due to incomplete understanding of key molecular mechanisms. While IL-1-mediated inflammation and mitochondrial dysfunction are recognized contributors, the precise links between IL-1 signaling, fibrosis, and mitochondrial homeostasis are unclear. Here, we investigated the therapeutic effects of recombinant human IL-1 receptor antagonist (rhIL-1Ra) in both acute (UUO) and chronic (5/6Nx) mouse models of kidney injury, as well as in vitro TGF-β1-stimulated kidney cells. rhIL-1Ra significantly attenuated renal fibrosis, inflammation, and functional impairment in vivo. Mechanistically, rhIL-1Ra suppressed TGF-β1-induced expression of the E3 ubiquitin ligase RNF182, which we show mediates MFN2 ubiquitination and degradation, leading to mitochondrial dysfunction. Inhibition of RNF182 by rhIL-1Ra stabilized MFN2, preserved mitochondrial respiration and ATP production, and reduced oxidative stress. Rescue experiments confirmed the centrality of the RNF182-MFN2 axis in fibrotic and mitochondrial injury. Our findings reveal a novel IL-1R/RNF182/MFN2 pathway linking inflammation to mitochondrial and fibrotic pathology, supporting RNF182 as a promising target and rhIL-1Ra as a potential therapy for CKD. © The Author(s) 2025.

关键词： Carbon dots   Neuron protection   Neurotrophic factor   NTG   Stem cell  

摘要： Background: Normal tension glaucoma (NTG) causes progressive retinal ganglion cell (RGC) loss without elevated intraocular pressure, and currently lacks effective neuroprotective therapies. OPTN(E50K) mutation, a pathogenic gene of NTG, compromises paracrine trophic capacity in bone marrow (BM) stem cells. Allogeneic young BM stem cells can provide trophic support and exhibit therapeutic potential;however, their clinical application is limited by immunogenic rejection and tumorigenic risks, prompting a renewed interest in rejuvenate autologous BM stem cells strategy. Methods: To address these challenges, we developed a composite chitosan-rapamycin (RAPA) carbon dots (CRCD) to restore the reparative potential of autologous BM stem cells. BM stem cells from aged OPTN(E50K) mice were isolated, clustered and treated with CRCD before validated their changes of neurotrophic factors expression as well as oxidative stress and autophagy indicators. Then we assessed their impact on co-cultured retinas in vitro. Transplantation were performed into lethally irradiated age-matched OPTN(E50K) hosts with CRCD-pretreated autologous BM stem cells via tail vein injection, and generated stable chimeric models. Neurotrophic factors and neuron apoptosis analyses were performed, followed by the visual behavioral tests. Results: Our results demonstrated that CRCD pretreatment enhanced autophagy, reduced oxidative stress, and augmented paracrine neurotrophic release. In vitro, these cells reduced retinal ganglion cell apoptosis and promoted neurotrophic factor expression in co-cultured retinal explants. In vivo, comparative analysis revealed that CRCD intervention significantly elevated neurotrophic factor expression in retinal tissues compared to RAPA-treated and untreated chimeras. Functional assessments further confirmed superior visual performance in CRCD-Sca-1⁺ chimeras, correlating with improved RGC survival. Conclusion: These findings suggest that CRCD improved paracrine

关键词： Anticancer   Antimicrobial   Carboxamide   Nanoparticles   Triazole   Zinc oxide  

摘要： The rise of drug-resistant infections and cancer highlights the urgent need for new therapeutic agents. This study aimed to synthesize a novel triazole-based compound and its ZnO nanocomposite to evaluate their antimicrobial and anticancer potential. N-(4-nitrophenyl)-1-(4-(N-(pyridin-2-yl)sulfamoyl)phenyl)-1H-1,2,3-triazole-4-carboxamide (NPST) was prepared and combined with zinc oxide nanoparticles (NPST/ZnO NPs). The geometry and bonding type of the compounds were determined using various spectroscopic techniques, including FTIR, UV-visible, XRD, and ¹H NMR. The antibacterial activities of NPST and NPST/ZnO NPs were investigated against Bacillus cereus (Gram-positive), Escherichia coli (Gram-negative), and Candida albicans (yeast). The in vitro antimicrobial assay demonstrated minimal inhibitory concentration, minimum microbicidal concentration, and agar well diffusion methods. All the synthesized compounds exhibited a strong inhibitory effect against the yeast C. albicans compared to other antibacterial agents. This study evaluated the antioxidant and organ-protective effects of NPST and NPST/ZnO in Ehrlich Ascites Carcinoma (EAC)-bearing mice, in comparison to the standard chemotherapeutic agent cisplatin. Both treatments significantly enhanced antioxidant enzyme activities, indicating a reduction in oxidative stress. Histological analysis revealed preservation of liver architecture in NPST and NPST/ZnO groups. Additionally, both compounds improved liver, kidney, and lipid profiles. The novelty of this study lies in combining a triazole ligand with ZnO nanoparticles to create a dual-action system with enhanced antimicrobial, antioxidant, and anticancer efficacy. The results highlight the therapeutic potential of NPST and NPST/ZnO compounds in enhancing antioxidant status and preserving organ function during cancer progression. An IC₅₀ value of 80.21 ± 3.49 µg/mL was observed against MCF-7 breast cancer cell lines for the MTT method anticancer assay.

摘要： Medial unicompartmental knee arthroplasty (UKA) has been introduced in the fifties to treat patients with medial tibio-femoral osteoarthritis. Initial reports, showed encouraging functional outcomes, tempered by high loosening rates. With advances in the materials and prosthetic designs UKA has become common, representing more than 11% of all knee replacement surgeries and growing at a rate of 32.5% per year. This fast increase is the consequence of the new radiographic, clinical and patient-related indications. In the past, indications were strict although not universally accepted with several grey zones. More recently, indications have expanded, but there is consensus on the different aspects. The present fist-part comprehensive review focuses on the indications for medial UKA analyzing practical aspects such as patient activity and age, BMI, coronal alignment ligament competency, patella-femoral osteoarthritis, other compartments involvement with a comparison between historical approach and modern evidence. Hot topics and future directions will be discussed in the second-part of the review. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025.

关键词： Allele-specific targeting   Autosomal dominant retinal disorder   Best disease   BEST1   Bestrophin-1   BVMD   CRISPR/Cas9   Dominant-negative mutation  

摘要： Background: Treating autosomal dominant gene mutations remains challenging, particularly when mutations convey a gain-of-function or a dominant-negative effect, as standard gene supplementation strategies often fail to counteract the pathogenic allele. Methods: In this study, we employed human induced pluripotent stem cell-derived retinal pigment epithelium (hiPSC-RPE) to investigate allele-specific CRISPR/Cas9 genome editing as a potential treatment for Best disease (BD), an autosomal dominant macular dystrophy caused by over 250 distinct mutations in the bestrophin-1 (BEST1) gene. We designed and evaluated single guide RNAs (sgRNA) targeting three known BEST1 mutations (p.(R218C), p.(A243V), and p.(I295del)), assessing their impact on BD-associated hiPSC-RPE phenotypes and BEST1 channel function. Computationally predicted sgRNAs were rigorously tested for on-target efficiency, allele specificity and genome-wide off-target activities. Results: We found that shortening sgRNA length improved specificity in some cases, while introducing an additional mismatch generally compromised editing efficiency. Notably, only one of the three mutations yielded an sgRNA with both high cleavage efficiency and undetectable off-target effects in hiPSC-RPE cells. We then explored the consequences of allele-specific editing on BEST1 expression and function in clonal BD hiPSC-RPE lines. Eliminating the mutant BEST1 transcript led to enhanced BEST1 localization, improved protein stability and restoration of anion transport function. Conclusions: Taken together, our findings support allele-specific gene editing as a viable therapeutic strategy for selected BEST1 mutations, while underscoring the necessity for rigorous testing of computationally designed sgRNAs, given their mutation- and context-dependent variability. © The Author(s) 2026.