Near-Infrared-II Light Induced Mild Hyperthermia Activate Cisplatin-Artemisinin Nanoparticle for Enhanced Chemo/Chemodynamic Therapy and Immunotherapy.

Chemodynamic therapy (CDT) is an effective cancer treatment that uses Fenton reaction to induce cancer cell death. Current clinical applications of CDT are limited by the dependency of external supply of metal ions as well as low catalytic efficiency. Here, a highly efficient metal-free CDT by using endoperoxide bridge-containing artesunate as free radical-generating substance is developed. A Pt(IV) prodrug (A-Pt) containing two artesunate molecules in the axial direction is synthesized, which can be decomposed into cisplatin and artesunate under reducing intracellular environment in tumor cells. To improve the catalytic efficiency for Fenton reaction, a near-infrared-II (NIR-II) photothermal agent IR1048 is incorporated to achieve a mild hyperthermia effect. By encapsulating the A-Pt and IR1048 with human serum albumin, A-Pt-IR NP are formulated for efficient drug delivery in 4T1 tumor-bearing mice. NIR-II light irradiation of A-Pt-IR NP treated mice show accelerated Fenton reaction. In addition, A-Pt-IR NP could also induce strong immunogenic cell death, which effectively reverses the immunosuppressive tumor microenvironment, and augments antitumor immunity. This study demonstrates that A-Pt-IR NP are potent biodegradable NIR-II active chemotherapy/CDT nanomedicine for clinical translation.

AP3S1 is a Novel Prognostic Biomarker and Correlated With an Immunosuppressive Tumor Microenvironment in Pan-Cancer.

Background: Adaptor-related protein complex 3, sigma one subunit (AP3S1) is one of the encoding subunits of the adaptor complex AP-3. However, its role in various tumor types and relationship with the tumor immune microenvironment (TIME) remains unclear. Methods: AP3S1 expression was analyzed using datasets from The Cancer Genome Atlas, Genotype-Tissue Expression, UALCAN, and HPA databases. Then, we performed a systematic analysis of the genetic alterations, clinical features, and prognostic value of AP3S1 in pan-cancer. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to identify the signaling pathways associated with AP3S1. The correlation between immune cell infiltration and AP3S1 expression was analyzed using immune cell infiltration data from the ImmuCellAI, TIMER2, and a previous study. Finally, we analyzed the association of AP3S1 with tumor mutational burden (TMB), microsatellite instability (MSI), and immune-related genes. Results: We found AP3S1 overexpression in most tumors and a significant association with low survival rates. GSEA and GSVA results show that AP3S1 is involved in tumor progression and associated with immune pathways in different tumor types. We also found that AP3S1 expression was positively correlated with the level of infiltration of immunosuppressive cells (tumor-associated macrophages, cancer-associated fibroblasts, Tregs) and negatively correlated with immune killer cells, including NK cells and CD8+ T cells, in pan-cancer. The expression of AP3S1 could affect TMB and MSI in various cancers. In addition, AP3S1 was positively correlated with most immunosuppressive genes, including PD-1, PD-L1, CTLA4, LAG3 and TIGIT in most cancer types. Conclusion: Our study reveals that AP3S1 is a potential pan-cancer oncogene and plays an essential role in tumorigenesis and cancer immunity. Elevated expression of AP3S1 indicates an immunosuppressive microenvironment and can be used as a potential prognostic biomarker and a target for immunotherapy.

Huangqi-Danshen decoction alleviates diabetic nephropathy in db/db mice by inhibiting PINK1/Parkin-mediated mitophagy.

Huangqi-Danshen decoction (HDD) is composed of Astragali Radix (Huang-qi) and Salviae Miltiorrhizae Radix et Rhizoma (Dan-shen), both of which are the most commonly used herbs for the clinical treatment of diabetic nephropathy (DN) in traditional Chinese medicine and show good efficacy. However, the underlying mechanism of this effect is unclear. The aim of this study was to evaluate the effect and potential mechanism of HDD in the treatment of DN in a type 2 diabetic animal model, db/db mice. HDD extract was administered orally to db/db mice at a dose of 6.8 g/kg/day for 12 weeks. At the end of the study, serum, urine, and kidney samples were collected for biochemical and pathological examination. The expression of proteins associated with mitochondrial fission and mitophagy was determined by quantitative real-time PCR, Western blotting, and immunohistochemical analysis. The results showed that treatment with HDD substantially reduced urinary albumin excretion and improved renal injury in db/db mice. Moreover, mitochondrial fission was increased in the kidneys of the db/db mice, as evidenced by enhanced expression of dynamin-related protein 1 and mitochondrial morphological changes. Furthermore, PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy was activated in the db/db mice, which manifested as increased protein expression and obvious autophagic vacuole encapsulating mitochondria. HDD treatment significantly reversed the enhanced mitochondrial fission and PINK1/Parkin-mediated mitophagy in the db/db mice. In conclusion, this work suggested that HDD could protect against type 2 diabetes-induced kidney injury possibly by inhibiting PINK1/Parkin-mediated mitophagy.

Drug Resistance and Integron Genes in Escherichia coli Isolated from Urinary Tract Infection.

Escherichia coli (E. coli) is a major cause of urinary tract infections. Treatment of these infections with antibiotics is often not effective due to the acquisition of drug-resistance genes by the bacteria. This process is mediated by integrons which belong to bacterial mobile genetic elements. Therefore, the present study addressed the issue of the relation between antibiotic resistance and integron genes in E. coli isolated from patients affected by urinary tract infection. Multiplex PCR assay employed to detect the E. coli integrase gene demonstrated that out of 49 bacterial strains, 26 were carrying class 1 integron and there was no case of bacteria harboring class 2 or class 3 integrons. Correlation analysis documented that E. coli strains harboring class 1 integron exhibited higher resistance towards tobramycin. The variable region gene cassette contained combinations of four genes responsible for antibiotic resistance: dfr17, aadA2, aadA5, and aac(6')-Ib-cr, of which the latter conferred tobramycin resistance. Together, the collected data underscore the need for identification and analysis of integrons in E. coli-induced urinary infections.