The People's Liberation Army Naval Medical University (中国人民解放军海军军医大学), also known as the PLA Second Military Medical University (SMMU) (中国人民解放军第二军医大学), is a public university in Shanghai, China. It was founded in September 1949 and named in July 1951. It is a national key university supported by the state Project 211. It is a Chinese state Double First Class University, included in the national Double First Class University Plan. As of 2021, the Second Military Medical University is ranked between top 701-800 among world universities according to the Academic Ranking of World Universities.It was previously called People's Medical College of the East China Military Commanding Region. The building is adjacent to Fudan University and Tongji University and covers an area of nearly 1.1 square kilometres (270 acres). The premises have a total floor space of over 670,000 square metres (7,211,820 sq ft), including a complex of modern teaching buildings, a library, an experiment building and teaching hospitals of the first rate in China. The library itself covers an area over 11,000 square metres (118,403 sq ft) with a collection of over 500,000 book volumes..
Intervertebral disc degeneration (IVDD) has been a major contributor to chronic low back pain, yet effective disease-modifying therapies remain limited. Here, we identified a NOX4-associated ferro-aging program linking iron overload, oxidative stress, lipid peroxidation, and cellular senescence in degenerative NPCs. Clinical imaging, transcriptomic analyses, human disc specimens, iron-overloaded NPCs, and naturally aged rats consistently revealed ferro-aging-associated changes during IVDD. Mechanistically, gain- and loss-of-function, genetic rescue, and temporal analyses positioned NOX4 as an upstream oxidative regulator of ROS-dependent ACSL4 activation, lipid peroxidation, mitochondrial dysfunction, and NPC senescence. Natural-product screening identified amentoflavone (Amen) as a candidate NOX4-interacting compound that suppresses membrane-associated NADPH oxidase activity in a NOX4-dependent manner. Single-cell transcriptomic analyses showed that ferro-aging NPCs exhibited increased NKG2D ligand-related stress signals, reduced endocytic activity, and enhanced membrane-fusion features. Guided by these characteristics, we engineered SenoFAN, an Amen-loaded, iron-chelating phenolic nanozyme coated with NKG2D-engineered NPC membranes. SenoFAN integrates iron sequestration, nanozyme-mediated redox remodeling, Amen-mediated NOX4-dependent suppression of NADPH oxidase activity, and ferro-aging-cell-adapted delivery through NKG2D–ligand recognition and membrane fusion. In vitro, SenoFAN reduced labile iron and oxidative stress, restored mitochondrial and lipid homeostasis, and suppressed lipid peroxidation and senescence. In a rat puncture-induced IVDD model, SenoFAN showed preferential association with ferro-aging-associated NPCs, prolonged intradiscal retention, reduced iron deposition and senescence, preserved disc structure, and showed favorable biosafety. Collectively, our findings identify NOX4-associated ferro-aging as a therapeutically actionable pathological program in IVDD, while establishing an upstream regulatory role for NOX4 in the FAC-induced ferro-aging model.
Diabetes aggravates postoperative tumor recurrence and impairs wound healing due to divergent metabolic adaptations to hyperglycemia in tumor versus normal cells. Current therapeutics fail due to the incapabilities in adaptively modulating the metabolic bifurcation across the contradictory pathological contexts. Here, we address this challenge by developing a platinum (Pt) single-atom nanocatalyst (PtSNC) with microenvironments-selective multienzyme-mimicking activities to pioneer a bi-polar bioenergetic intervention strategy. In acidic and reduced nicotinamide adenine dinucleotide (NADH)-overexpressed tumor niches, it exhibits NADH oxidase (NOX)-, oxidase-, and peroxidase-like activities, depleting NADH reserves and generating highly reactive Pt = O species to disrupt energy metabolism and induce both apoptosis/ferroptosis. While it shows NOX-, catalase-, and superoxide dismutase-like activities in neutral diabetic wounds, rectifying hyperglycemia-induced cellular NAD+/NADH abnormity and bioenergetic disorder to revitalize the cells and tissues, with promoting angiogenesis and mitigating local inflammation to accelerate regeneration. Murine diabetic melanoma resection models demonstrate its extensive capacity in effectively eradicating residual tumor tissues and suppressing the recurrence, and promoting diabetic wound healing concurrently without systemic toxicity, making PtSNC a safe and potent nanotherapeutic for diabetic tumor postoperative therapy. This study holds promise for the application of single-atom catalytic medicines in precision therapy for intractable diseases featuring pathological metabolic bifurcation.
Conversion therapy remains an uncommon strategy for managing unresectable hepatocellular carcinoma (uHCC) due to limited evidence supporting its efficacy. To address this gap, we initiated a prospective phase 2 multicenter trial (NCT04997850) comparing the LEN-TAP regimen, combining lenvatinib, transarterial chemoembolization (TACE), and PD-1 inhibitors, against TACE alone in uHCC patients. The study’s primary outcome was salvage liver resection (SLR) rate; secondary measures included objective response rate (ORR), overall survival (OS), event-free survival (EFS), recurrence-free survival (RFS), and safety profile. From October 2020 to November 2021, 142 eligible participants were assigned to LEN-TAP (n = 71) or TACE monotherapy (n = 71). At a median follow-up of 24.2 months, the LEN-TAP cohort exhibited a significantly higher SLR rate (59.2% vs. 18.3%, P < 0.001) and ORR (78.9% vs. 16.9%, P < 0.001). Median OS, EFS, and RFS were also substantially prolonged in the LEN-TAP cohort (not reached vs. 23.0 months, P < 0.001; 20.03 vs. 6.52 months, P < 0.001; 36.6 vs. 19.0 months, P = 0.048). Although grade 3 treatment-related AEs occurred more frequently with LEN-TAP (60.6% vs. 21.1%, P < 0.001), no grade 4 or higher toxicities were observed. Exploratory biomarker assessments via single-cell sequencing and flow cytometry linked elevated levels of circulating HLA-DR+CD38+CD8+ T cells with improved treatment response. These T cells appear to mediate antitumor activity potentially through the CXCR6–PI3K–AKT signaling axis. In summary, the LEN-TAP protocol demonstrates promising efficacy and acceptable tolerability as a conversion therapy in uHCC, with peripheral HLA-DR+CD38+CD8+ T cell abundance serving as a potential predictor of therapeutic benefit.
Tumour-associated macrophages (TAMs) contribute to immune checkpoint blockade resistance, but their impact on intratumoural CD8⁺ T cell distribution remains unclear. Here we show that the expression of the glucose transporter SLC2A1 is spatially negatively correlated with CD8⁺ T cell distribution in both non-small-cell lung cancer (NSCLC) biopsies and murine tumour models. Tumour cell-specific Slc2a1 knockdown fails to reproduce the therapeutic benefit of SLC2A1 inhibition, whereas TAM-specific deletion of Slc2a1 suppresses tumour growth by enhancing the spatial homogeneity and effector function of intratumoural CD8⁺ T cells, thereby improving αPD-L1 efficacy. Spatial profiling of NSCLC specimens further revealed that SLC2A1⁺ TAM-enriched regions exhibit reduced CD8⁺ T cell density, and spatial proximity between these populations predicts resistance to αPD-(L)1 therapy. These findings identify SLC2A1⁺ TAMs as drivers of spatial CD8⁺ T cell exclusion and highlight TAM-specific SLC2A1 as a therapeutic target to overcome immune checkpoint blockade resistance in NSCLC. Wang, Chu, Chen, Wei and colleagues discover a subset of tumour-associated macrophages expressing SLC2A1 whose spatial proximity to CD8+ T cells drives resistance to anti-PD-L1 treatment in non-small-cell lung cancer.
According to statistics, more than 70% of drugs that are available on the market contain heterocyclic units. Among them, five-membered heteroaromatics bearing nitrogen, oxygen, and sulfur have served as the most important structural motifs found in diverse pharmaceuticals. Emerging toolboxes, such as photocatalysis, biocatalysis, electrocatalysis and skeletal editing have showcased unprecedented avenues to access them. In fact, >300 publications on the topic of synthesis of five-membered heteroaromatics by using emerging toolboxes have been recorded in the last ten years, clearly indicating the significance of this field. In this study, a conceptual overview and discussions are presented to showcase the advancement of this field. Moreover, the related drugs and bioactive compounds obtained by these approaches are highlighted.
