"Golgi-customized Trojan horse" nanodiamonds impair GLUT1 plasma membrane localization and inhibit tumor glycolysis.

Nutrient or energy deprivation, especially glucose restriction, is a promising anticancer therapeutic approach. However, establishing a precise and potent deprivation strategy remains a formidable task. The Golgi morphology is crucial in maintaining the function of transport proteins (such as GLUT1) driving glycolysis. Thus, in this study, we present a "Golgi-customized Trojan horse" based on tellurium loaded with apigenin (4',5,7-trihydroxyflavone) and human serum albumin, which was able to induce GLUT1 plasma membrane localization disturbance via Golgi dispersal leading to the inhibition of tumor glycolysis. Diamond-shaped delivery system can efficiently penetrate into cells as a gift like Trojan horse, which decomposes into tellurite induced by intrinsically high H2O2 and GSH levels. Consequently, tellurite acts as released warriors causing up to 3.8-fold increase in Golgi apparatus area due to the down-regulation of GOLPH3. Further, this affects GLUT1 membrane localization and glucose transport disturbance. Simultaneously, apigenin hinders ongoing glycolysis and causes significant decrease in ATP level. Collectively, our "Golgi-customized Trojan horse" demonstrates a potent antitumor activity because of its capability to deprive energy resources of cancer cells. This study not only expands the applications of tellurium-based nanomaterials in the biomedicine but also provides insights into glycolysis restriction for anticancer therapy.

UcTCRdb: An unconventional T cell receptor sequence database with online analysis functions.

Unlike conventional major histocompatibility complex (MHC) class I and II molecules reactive T cells, the unconventional T cell subpopulations recognize various non-polymorphic antigen-presenting molecules and are typically characterized by simplified patterns of T cell receptors (TCRs), rapid effector responses and 'public' antigen specificities. Dissecting the recognition patterns of the non-MHC antigens by unconventional TCRs can help us further our understanding of the unconventional T cell immunity. The small size and irregularities of the released unconventional TCR sequences are far from high-quality to support systemic analysis of unconventional TCR repertoire. Here we present UcTCRdb, a database that contains 669,900 unconventional TCRs collected from 34 corresponding studies in humans, mice, and cattle. In UcTCRdb, users can interactively browse TCR features of different unconventional T cell subsets in different species, search and download sequences under different conditions. Additionally, basic and advanced online TCR analysis tools have been integrated into the database, which will facilitate the study of unconventional TCR patterns for users with different backgrounds. UcTCRdb is freely available at http://uctcrdb.cn/.

Orally Administrable H2 S-Scavenging Metal-Organic Framework Prepared by Co-Flow Microfluidics for Comprehensive Restoration of Intestinal Milieu.

Intestinal milieu disorders are strongly related to the occurrence of inflammatory bowel diseases (IBDs), which results from mucosa destruction, epithelium disruption, and tight junction (TJ) proteins loss. Excess of H2 S in the intestinal milieu produced by the sulfate-reducing bacteria metabolism contributes to development of IBDs via epithelial barrier breakdown. Conventional interventions, such as surgery and anti-inflammatory medications, are considered not completely effective because of frequent recurrence and other complications. Herein, a novel oral delivery system, a hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based polymer-coated Zr-based metal-organic framework (UiO-66) with a Cux -rhodamine B (CR) probe (hereinafter referred to as HUR), is produced via a co-flow microfluidic approach with the ability to reduce H2 S levels, thus restoring the intestinal lumen milieu. HPMCAS serves as an enteric coating that exposes UiO-66@CR at the pH of the intestine but not the acidic pH of the stomach. The synthesized HUR exhibits notable therapeutic efficacy, including mucosa recovery, epithelium integrity restoration, and TJ proteins upregulation via H2 S scavenging to protect against intestinal barrier damage and microbiome dysbiosis. Thus, HUR is verified to be a promising theranostic platform able to decrease the H2 S content for intestinal milieu disorder treatment. The presented study therefore opens the door for further exploitation for IBDs therapy.

Triangular-shaped homologous heterostructure as photocatalytic H2S scavenger and macrophage modulator for rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a chronic arthropathy causing cartilage destruction, bone erosion, and even disability. Although some advances in RA treatment have been made based on inflammatory cytokine inhibition, long-term treatment and drug effect have been restrained by severe side effects. Herein, we developed a resveratrol (RSV)-loaded Ag/Ag2S triangular-shaped homologous heterostructure with polyethylene glycol/folic acid (PEG/FA) modification (Ag/Ag2S-PEG-FA/RSV NTs) to simultaneously suppress inflammatory cytokine over-expression through photocatalytic H2S scavenging and macrophage polarization stimulation. On one hand, the over-expressed H2S, which acted as a pro-inflammatory mediator to activate the MAPK/ICAM-1 pathway and exacerbate inflammation, was eliminated through photocatalysis. The homologous Ag and Ag2S of the heterostructure enhanced electron separation and transfer by acting as a charge acceptor and electron generator, respectively, which restrained electron/hole recombination and promoted photocatalysis efficiency. Additionally, the intrinsic superoxide dismutase (SOD) and catalase (CAT) activity of Ag decomposed the reactive oxygen species (ROS) over-expressed in the RA microenvironment, which supplied O2 for the photocatalytic H2S scavenging progress. On the other hand, RSV, a natural product with anti-inflammatory activity, could be delivered to the inflammatory joint by the targeting effect of PEG-FA, thus inhibiting the IκB/NF-κB pro-inflammatory pathway to induce macrophage interconversion balance from M1 to M2. As expected, the Ag/Ag2S-PEG-FA/RSV NTs exhibited H2S scavenging capacity and modulated macrophage polarization to reduce the inflammatory cytokine level and halt RA progression in vitro and in vivo. Overall, this study revealed a therapeutic strategy with high efficacy, which opens broad prospects for RA treatment.

Effect of neoadjuvant chemotherapy on the immune microenvironment in gastric cancer as determined by multiplex immunofluorescence and T cell receptor repertoire analysis.

BACKGROUND: The combination of immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced gastric cancer (GC). It is crucial to unravel chemotherapy-induced tumor microenvironment (TME) modulation and identify which immunotherapy would improve antitumor effect. METHODS: In this study, tumor-associated immune cells (TAICs) infiltration in residual tumor after neoadjuvant chemotherapy (NAC) together with 1075 cases of treatment-naïve GC patients was analyzed first. Then we performed multiplex fluorescence staining of a panel of immune markers (CD3, CD4, CD8, FOXP3 and PDL1) and T cell receptor ß-chain sequencing to phenotype and enumerate T cell subpopulations and clonal expansion in paired GC samples (prechemotherapy and postchemotherapy) from another cohort of 30 cases of stage II/III GC patients. RESULTS: Infiltration of CD68+ macrophages in residual tumors after NAC was significantly decreased compared with treatment-naïve GC patients, while no significant difference observed with respect to other immune markers. In residual tumors, post-NAC CD8 +T cells and CD68+ macrophages levels were significantly associated with chemotherapy response. Post-NAC CD8+ T cell levels remained as an independent predictor for favorable prognosis. Furthermore, when comparing the paired samples before and after NAC from 30 cases of stage II/III GC patients, we found FOXP3+ regulatory T cells proportion significantly decreased after chemotherapy. Pre-NAC FOXP3+ T reg cells level was much richer in the response group and decreased more significantly in the stromal compartment. CD8+ cytotoxic T lymphocytes levels were elevated after chemotherapy, which was more significant in the group treated with XELOX regimen and in patients with better response, consistent with the TCR diversity elevation. CONCLUSIONS: These findings have deepened our understanding of the immune modulating effect of chemotherapy and suggest that the immune profile of specimens after standard chemotherapy should be considered for the personalized immunotherapy to ultimately improve clinical outcome in patients with GC.