Network pharmacology combined with molecular docking and experimental verification to elucidate functional mechanism of Fufang Zhenzhu Tiaozhi against type 2 diabetes mellitus.

Fufang Zhenzhu Tiaozhi (FTZ) capsules have been prescribed for treating glucose and lipid metabolism disorders such as type 2 diabetes mellitus (T2DM). However, the underlying mechanism remains unknown. In this study, network pharmacology and experimental verification were combined to investigate the mechanisms of FTZ in treating T2DM. A total of 176 active ingredients and 1169 corresponding targets were screened using biological databases. 598 potential targets of T2DM were retrieved from GeneCards, PharmGKB, OMIM, Drugbank, and TTD. The Venn diagram was employed to identify the 194 intersection targets, which were employed to construct the "Herb-Compound-Target" interacting networks. These common targets were also used to prepare a protein-protein interaction (PPI) network to uncover potential targets. The four core targets were docked to their corresponding targets for binding analysis. Additionally, the top-ranked poses of ingredients and the positive compounds from each protein were evaluated for stability using molecular dynamics. Our results suggest that core active ingredients such as kaempferol, luteolin, and baicalein have high binding affinity and stability with AKT1, PTGS2 (also known as COX-2), DPP4, and PAPRG. GO and KEGG analyses indicated that the treatment T2DM by FTZ might be related to different pathway like AMPK and EGFR pathways. The experimental validation results proved that kaempferol, luteolin, and baicalein could significantly inhibit the activity of DPP4 and COX-2, kaempferol and luteolin were also able to activate AKT and AMPK signaling pathway. This study further validated previous findings and enhanced our understanding of the potential effects of FTZ on T2DM.Communicated by Ramaswamy H. Sarma.

Genetically engineered PD-1 displaying nanovesicles for synergistic checkpoint blockades and chemo-metabolic therapy against non-small cell lung cancer.

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.

The prevalence of primary angle closure glaucoma in adult Asians: a systematic review and meta-analysis.

BACKGROUND: Primary angle closure glaucoma (PACG) is higher in Asians than Europeans and Africans, with over 80% of PACG worldwide in Asia. Previous estimates of PACG were based largely on early studies, mostly using inappropriate case definitions. Therefore, we did a systematic review and meta-analysis to estimate the prevalence of PACG in adult Asian populations and to quantify its association with age, gender, and region. METHODS: All primary reports of population-based studies that reported the prevalence of PACG in adult Asian populations were identified. PACG case definition was compatible with the ISGEO definition. Twenty-nine population-based studies were included. The overall pooled prevalence estimates were calculated using a random effect model, and ethnicity-, age- and gender-specific pooled prevalence estimates were also calculated. RESULTS: The overall pooled prevalence of PACG in those of adult Asians was 0.75% (95% CI, 0.58, 0.96). Ethnicity-specific pooled prevalence estimates were 0.97% (0.22, 4.27) in Middle East group, 0.66% (0.23, 1.86) in South East Asia group, 0.46% (0.32, 0.64) in India group, 1.10% (0.85, 1.44) in China group, and 1.19% (0.35, 3.98) in Japan group, respectively. Age-specific prevalence was 0.21% (0.12, 0.37) for those 40-49 years, 0.54% (0.34, 0.85) for those 50-59 years, 1.26% (0.93, 1.71) for those 60-69 years, and 2.32% (1.74, 3.08) for those 70 years or above. The overall female to male ratio of the PACG prevalence was 1.51∶1 (95% CI 1.01, 2.28). CONCLUSIONS: PACG affects approximately 0.75% adult Asians, increasing double per decade, and 60% of cases being female. The prevalence rates vary greatly by ethnic region.