Macrophage-Derived Nanosponges Adsorb Cytokines and Modulate Macrophage Polarization for Renal Cell Carcinoma Immunotherapy.

Renal cell carcinoma (RCC) is a hot tumor infiltrated by large numbers of CD8+ T cells and is highly sensitive to immunotherapy. However, tumor-associated macrophages (TAMs), mainly M2 macrophages, tend to undermine the efficacy of immunotherapy and promote the progression of RCC. Here, macrophage-derived nanosponges are fabricated by M2 macrophage membrane-coated poly（lactic-co-glycolic acid）（PLGA）, which could chemotaxis to the CXC and CC chemokine subfamily-enriched RCC microenvironment via corresponding membrane chemokine receptors. Subsequently, the nanosponges act like cytokine decoys to adsorb and neutralize broad-spectrum immunosuppressive cytokines such as colony stimulating factor-1(CSF-1), transforming growth factor-ß（TGF-ß）, and Lnterleukin-10（IL-10）, thereby reversing the polarization of M2-TAMs toward the pro-inflammatory M1 phenotype, and enhancing the anti-tumor effect of CD8+ T cells. To further enhance the polarization reprogramming efficiency of TAMs, DSPE-PEG-M2pep is conjugated on the surface of macrophage-derived nanosponges for specific recognition of M2-TAMs, and the toll like receptors 7/8（TLR7/8） agonist, R848, is encapsulated in these nanosponges to induce M1 polarization, which result in significant efficacy against RCC. In addition, these nanosponges exhibit undetectable biotoxicity, making them suitable for clinical applications. In summary, a promising and facile strategy is provided for immunomodulatory therapies, which are expected to be used in the treatment of tumors, autoimmune diseases, and inflammatory diseases.

Metagenomic analysis reveals gut plasmids as diagnosis markers for colorectal cancer.

Background: Colorectal cancer (CRC) is linked to distinct gut microbiome patterns. The efficacy of gut bacteria as diagnostic biomarkers for CRC has been confirmed. Despite the potential to influence microbiome physiology and evolution, the set of plasmids in the gut microbiome remains understudied. Methods: We investigated the essential features of gut plasmid using metagenomic data of 1,242 samples from eight distinct geographic cohorts. We identified 198 plasmid-related sequences that differed in abundance between CRC patients and controls and screened 21 markers for the CRC diagnosis model. We utilize these plasmid markers combined with bacteria to construct a random forest classifier model to diagnose CRC. Results: The plasmid markers were able to distinguish between the CRC patients and controls [mean area under the receiver operating characteristic curve (AUC = 0.70)] and maintained accuracy in two independent cohorts. In comparison to the bacteria-only model, the performance of the composite panel created by combining plasmid and bacteria features was significantly improved in all training cohorts (mean AUCcomposite = 0.804 and mean AUCbacteria = 0.787) and maintained high accuracy in all independent cohorts (mean AUCcomposite = 0.839 and mean AUCbacteria = 0.821). In comparison to controls, we found that the bacteria-plasmid correlation strength was weaker in CRC patients. Additionally, the KEGG orthology (KO) genes in plasmids that are independent of bacteria or plasmids significantly correlated with CRC. Conclusion: We identified plasmid features associated with CRC and showed how plasmid and bacterial markers could be combined to further enhance CRC diagnosis accuracy.

Development of a 135K SNP genotyping array for Actinidia arguta and its applications for genetic mapping and QTL analysis in kiwifruit.

Kiwifruit (Actinidia spp) is a woody, perennial and deciduous vine. In this genus, there are multiple ploidy levels but the main cultivated cultivars are polyploid. Despite the availability of many genomic resources in kiwifruit, SNP genotyping is still a challenge given these different levels of polyploidy. Recent advances in SNP array technologies have offered a high-throughput genotyping platform for genome-wide DNA polymorphisms. In this study, we developed a high-density SNP genotyping array to facilitate genetic studies and breeding applications in kiwifruit. SNP discovery was performed by genome-wide DNA sequencing of 40 kiwifruit genotypes. The identified SNPs were stringently filtered for sequence quality, predicted conversion performance and distribution over the available Actinidia chinensis genome. A total of 134 729 unique SNPs were put on the array. The array was evaluated by genotyping 400 kiwifruit individuals. We performed a multidimensional scaling analysis to assess the diversity of kiwifruit germplasm, showing that the array was effective to distinguish kiwifruit accessions. Using a tetraploid F1 population, we constructed an integrated linkage map covering 3060.9 cM across 29 linkage groups and performed QTL analysis for the sex locus that has been identified on Linkage Group 3 (LG3) in Actinidia arguta. Finally, our dataset presented evidence of tetrasomic inheritance with partial preferential pairing in A. arguta. In conclusion, we developed and evaluated a 135K SNP genotyping array for kiwifruit. It has the advantage of a comprehensive design that can be an effective tool in genetic studies and breeding applications in this high-value crop.

Antioxidant, Anti-Inflammatory, and Antidiabetic Activities of Bioactive Compounds from the Fruits of Livistona chinensis Based on Network Pharmacology Prediction.

In this study, a chemical investigation on the fruits of Livistona chinensis (FLC) led to the isolation and identification of 45 polyphenols and 5 alkaloids, including two new compounds (Livischinol (1) and Livischinine A (46)), an undescribed compound (47) and 47 known compounds. FLC was predicted with novel potential antidiabetic function by collecting and analyzing the potential targets of the ingredients. Compound 32 exhibited significant α-glucosidase inhibitory activity (IC50 = 5.71 µM) and 1, 6, and 44 showed the PTP1B inhibitory activity with IC50 values of 9.41-22.19 µM, while that of oleanolic acid was 28.58 µM. The competitive inhibitors of PTP1B (compounds 1 and 44) formed strong binding affinity, with catalytic active sites, proved by kinetic analysis, fluorescence spectra measurements, and computational simulations, and stimulated glucose uptake in the insulin-resistant HepG2 cells at the dose of 50 µM. In addition, FLC was rich in antioxidant and anti-inflammatory bioactive compounds so that they could be developed as nutraceuticals against diabetes.

Characterization of antioxidant, α-glucosidase and tyrosinase inhibitors from the rhizomes of Potentilla anserina L. and their structure-activity relationship.

Five new flavonoids (1-5), along with 25 known compounds, were isolated from the rhizomes of Potentilla anserina L. and their structures were identified using spectroscopic and chemical evidence. The extract, all fractions, and all isolated compounds were evaluated for their antioxidant, α-glucosidase, and tyrosinase inhibitory activities, and their structure-activity relationship was interpreted. The biflavanols and quercetin-3-O-α-l-rhamnopyranoside-2″-gallate (14) exhibited significant antioxidant and α-glucosidase inhibition activities. In this study, anti-tyrosinase activity and its mechanism of active compounds (potenserin C (4), potenserin D (5), and quercetin-3-O-α-l-rhamnopyranoside-2″-gallate (14)) were explored by a combination of computational simulations and kinetic studies. Kinetic studies indicated that potenserin C (4) and quercetin-3-O-α-l-rhamnopyranoside-2″-gallate (14) inhibited tyrosinase in a competitive manner, whereas potenserin D (5) acted in a reversible noncompetitive manner. The molecular docking result indicated that the substitution of the glucose moiety with galloyl and the presence of 3', 4', 5'-OH in flavonoid aglycones played a crucial role for the tyrosinase inhibiting effect. Moreover, the presence of biflavanols increased the activity against tyrosinase because of strong hydrogen binding, π-alkyl binding, and electrostatic interaction. Thus, the presented experiments developed several new lead compounds that could act as antioxidants and α-glucosidase inhibitors. Furthermore, biflavanols and quercetin-3-O-α-l-rhamnopyranoside-2″-gallate played important roles in the anti-browning activity during food processing.

Antioxidant and α-Glucosidase Inhibitory Activities Guided Isolation and Identification of Components from Mango Seed Kernel.

In the present study, petroleum ether, dichloromethane, ethyl acetate, and n-butanol fractions of mango seed kernel exhibited different degrees of antioxidant and α-glucosidase inhibitory activity. Thus, quantitative and qualitative analysis of the petroleum ether fraction was conducted by GC-MS. Among identified components, four unsaturated fatty acids had never been reported in natural products before, together with 19 known components. In addition, 17 compounds were isolated and elucidated from other active fractions. Compounds 2, 9, 15, and 17 were isolated for the first time from Mangifera genus. Compounds 1 and 2 exhibited prominent DPPH radical scavenging and α-glucosidase inhibitory effects. In order to further explore their mechanism of α-glucosidase inhibition, their enzyme kinetics and in silico modeling experiments were performed. The results indicated that 1 inhibited α-glucosidase in a noncompetitive manner, whereas 2 acted in a competitive manner. In molecular docking, the stability of binding was enhanced by π-π T-shaped, π-alkyl, π-π stacked, hydrogen bond, and electrostatic interactions. Thus, compounds 1 and 2 were determined to be new potent antioxidant and α-glucosidase inhibitors for preventing food oxidation and enhancing hypoglycemic activity.