Non-small cell lung cancer (NSCLC) remains the most frequently diagnosed lung cancer and the leading cause of cancer-related mortality worldwide. PD-1/PD-L1 axis inhibitors have changed the treatment paradigm for various cancer types, including NSCLC. However, success of these inhibitors in lung cancer clinic is severely limited by their inability to inhibit the PD-1/PD-L1 signaling axis due to heavy glycosylation and heterogeneity expression of PD-L1 in NSCLC tumor tissue. Taking advantage of the facts that tumor cell derived nanovesicles could efficiently accumulate in the homotypic tumor sites due to their innate targeting abilities and that specific and high affinity existed between PD-1 and PD-L1, we developed NSCLC targeting biomimetic nanovesicles (NV) cargos from genetically engineered NSCLC cell lines that overexpressed PD-1 (P-NV). We showed that P-NVs efficiently bound NSCLC cells in vitro and targeted tumor nodules in vivo. We further loaded P-NVs with 2-deoxy-D-glucose (2-DG) and doxorubicin (DOX), and found that these drugs co-loaded P-NVs efficiently shrank lung cancers in mouse models for both allograft and autochthonous tumor. Mechanistically, drug-loaded P-NVs efficiently caused cytotoxicity to tumor cells and simultaneously activated anti-tumor immunity function of tumor-infiltrating T cells. Our data therefore strongly argue that 2-DG and DOX co-loaded, PD-1-displaying nanovesicles is a highly promising therapy for treatment of NSCLC in clinic. STATEMENT OF SIGNIFICANCE: Lung cancer cells overexpressing PD-1 are developed for preparing nanoparticles (P-NV). PD-1s displayed on NVs enhance their homologous targeting abilities to tumor cells expressing PD-L1s. Chemotherapeutics such as DOX and 2-DG, are packaged in such nanovesicles (PDG-NV). These nanovesicles efficiently delivered chemotherapeutics to tumor nodules specifically. The synergy between DOX and 2-DG is observed in inhibiting lung cancer cells in vitro and in vivo. Importantly, 2-DG causes deglycosylation and downregulation of PD-L1 on tumor cells while PD-1 displayed on nanovesicles' membrane blocks PD-L1 on tumor cells. 2-DG loaded nanoparticles thus activate anti-tumor activities of T cells in the tumor microenvironment. Our work thus highlights the promising antitumor activity of PDG-NVs, which warrants further clinical evaluation.

Aberrant activation of the WNT/β-catenin signaling pathway is implicated in various types of cancers. Inhibitors targeting the Wnt signaling pathway are intensively studied in the current cancer research field, the outcomes of which remain to be determined. In this study, we have attempted to discover novel potent WNT/β-catenin pathway inhibitors through tankyrase 1/2 structure-based virtual screening. After screening more than 13.4 million compounds through molecular docking, we experimentally verified one compound, LZZ-02, as the most potent inhibitor out of 11 structurally representative top hits. LiCl-induced HEK293 cells containing TOPFlash reporter showed that LZZ-02 inhibited the transcriptional activity of β-catenin with an IC₅₀ of 10 ± 1.2 μM. Mechanistically, LZZ-02 degrades the expression of β-catenin by stabilizing axin 2, thereby diminishing downstream proteins levels, including c-Myc and cyclin D1. LZZ-02 also inhibits the growth of colonic carcinoma cell harboring constitutively active β-catenin. More importantly, LZZ-02 effectively shrinks tumor xenograft derived from colonic cell lines. Our study successfully identified a novel tankyrase 1/2 inhibitor and shed light on a novel strategy for developing inhibitors targeting the WNT/β-catenin signaling axis.

Mahonia bealeiis one of the important members of the genus Mahonia and Traditional Chinese Medicine (TCM). Several compounds isolated from this plant have exhibited useful biological activities. Polysaccharides, an important biomacromolecule have been underexplored in case ofM. bealei. In this study, hot water extraction and ethanol precipitation were used for the extraction of polysaccharides from the stem ofM. bealei, and then extract was purified using ultrafiltration membrane at 50,000 Da cut off value. Characterization of the purifiedM. bealeipolysaccharide (MBP) was performed using Fourier Transform Infrared Spectroscopy (FT-IR), along with Scanning Electron Microscopy (SEM), X-ray crystallography XRD analysis and Thermal gravimetric analysis (TGA). The purified polysaccharide MBP was tested for antioxidant potential by determining its reducing power, besides determining the DPPH, ABTS, superoxide radical, and hydroxyl radical scavenging along with ferrous ion chelating activities. An increased antioxidant activity of the polysaccharide was reported with increase in concentration (0.5 to 5 mg/ml) for all the parameters. Antimicrobial potential was determined against gram positive and gram-negative bacteria. 20 µg/ml MBP was found appropriate with 12 h incubation period againstEscherichia coliandBacillus subtilisbacteria. We conclude that polysaccharides fromM. bealeipossess potential ability of biological importance; however, more studies are required for elucidation of their structure and useful activities.

Diabetic wounds present significant clinical challenges owing to their impaired healing. It is evident that current therapeutic strategies are ineffective, underscoring the need for more efficient approaches. Atractylodes macrocephala Koidz. (AM) has been shown to exhibit hypoglycemic, anti-inflammatory, and antioxidant properties, which make it a potential therapeutic agent for diabetic wounds. However, the bioactive components and efficacy mechanism remain unclear. The purpose of this study is to extract polysaccharides from AM (AMP) and construct AMP-loaded composite hydrogels, characterize their chemical and structural properties, then investigate their efficacy and potential mechanism of action for diabetic wound care. AMP was extracted and purified from AM via water decoction and the Sevag method. The composition and structure of AMP were characterized using UV-Vis spectroscopy, FT-IR, HPGPC, ion chromatography, and SEM. A high-glucose-induced HUVEC model was established to study the properties of AMP in terms of its pro-proliferative, promigratory, and tubule formation abilities. The effect of AMP on macrophage inflammatory responses was evaluated via qPCR and ELISA. The structural and mechanical characteristics of the AMP-loaded composite hydrogels were investigated by SEM, FT-IR and rheological analysis. Meanwhile, a full-thickness excisional diabetic mouse model was established to investigate the therapeutic effect. Hematoxylin and Eosin staining and other immunohistochemical analyses were further conducted to explore the potential mechanism. AMP was identified as a homogeneous heteropolysaccharide with an average molecular weight of 3454 Da. It promoted the proliferation, migration, and tubule formation of HUVECs in a high-glucose environment. Meanwhile, AMP decreased the inflammatory response of M1-type macrophages induced by LPS and promoted macrophage polarization toward the M2 phenotype. Moreover, the composite hydrogel composed of AMP and CBM940/CMC-Na showed more stable networks, high porosity, good rheological properties, and biocompatibility. Such composite hydrogels significantly accelerated the healing of diabetic wounds by upregulating CD31 expression and reducing TNF-α and NF-κB levels in the wound area. The AMP and AMP-loaded composite hydrogels could serve as promising candidates for diabetic wound healing treatment in the future.

Diabetes wounds represent a significant clinical challenge, primarily attributed to their complex microenvironment characterized by persistent inflammation