Exosomal PD-L1 confers chemoresistance and promotes tumorigenic properties in esophageal cancer cells via upregulating STAT3/miR-21.

Chemotherapy resistance remains a major obstacle in the treatment of esophageal cancer. Previous researches have shown that an increase in exosomal PD-L1 expression was positively associated with a more advanced clinical stage, a poorer prognosis as well as drug resistance in patients with esophageal squamous cell carcinoma (ESCC). To explore the role of exosomal PD-L1 in ESCC, we performed bioinformatics analysis as well as several in vitro/in vivo functional experiments in a parental sensitive cell line EC-9706 and its derivative, a paclitaxel-resistant subline EC-9706R, and found that the exosomal PD-L1 from EC-9706R was higher than that from EC-9706. Moreover, exosomes from EC-9706R significantly increased invasion, migration and chemoresistance of EC-9706. Anti-PD-L1 treatment in combination with chemotherapy also led to reduced tumor burden in vivo. Inhibition of the release of exosomes by GW4869 or inhibition of STAT3 phosphorylation by stattic could effectively reverse the resistance to paclitaxel mediated by exosomal PD-L1. Furthermore, we found that PD-L1, miR-21, and multidrug resistance (MDR1) gene are involved in the process of exosomal transfer. Moreover, PD-L1 could enhance miR-21 expression by increasing the enrichment of STAT3 on miR-21 promoter. Our results suggested that exosomal PD-L1 may contribute to drug resistance to paclitaxel by regulating the STAT3/miR-21/PTEN/Akt axis and promote tumorigenic phenotype. This study provides a novel potential therapeutic approach to reverse chemoresistance and tumor progression through exosomal PD-L1 in ESCC patients.

Recent progress in the development of upconversion nanomaterials in bioimaging and disease treatment.

Multifunctional lanthanide-based upconversion nanoparticles (UCNPs), which feature efficiently convert low-energy photons into high-energy photons, have attracted considerable attention in the domain of materials science and biomedical applications. Due to their unique photophysical properties, including light-emitting stability, excellent upconversion luminescence efficiency, low autofluorescence, and high detection sensitivity, and high penetration depth in samples, UCNPs have been widely applied in biomedical applications, such as biosensing, imaging and theranostics. In this review, we briefly introduced the major components of UCNPs and the luminescence mechanism. Then, we compared several common design synthesis strategies and presented their advantages and disadvantages. Several examples of the functionalization of UCNPs were given. Next, we detailed their biological applications in bioimaging and disease treatment, particularly drug delivery and photodynamic therapy, including antibacterial photodynamic therapy. Finally, the future practical applications in materials science and biomedical fields, as well as the remaining challenges to UCNPs application, were described. This review provides useful practical information and insights for the research on and application of UCNPs in the field of cancer.

Behavior, remediation effect and toxicity of nanomaterials in water environments.

In recent years, nanotechnology has been developing continuously. Due to their advantageous huge specific surface areas, microinterface characteristics, remediation ability and potential environmental risks, nanomaterials have become a hot topic in the field of environmental research. With the mass production and use of nanomaterials, they will inevitably be discharged or leaked into the water environment. In this paper, we will describe some typical nanomaterials, such as nanoscale zero valent iron (nZVI), graphene nanomaterials (GNMs), TiO2 nanoparticles (NPs), ZnO NPs, Fe3O4 NPs, carbon nanotubes (CNTs), Ag NPs, and other nanomaterials in water environments, focusing on the positive and negative effects of some nanomaterials in water environments. The remediation function and the impact of nanomaterials in water environments, including behavior of nanomaterials and their toxicity to aquatic organisms will be discussed. This will be of great significance for our subsequent research on nanomaterials.

Enhanced Antibacterial and Anti-Biofilm Activities of Antimicrobial Peptides Modified Silver Nanoparticles.

BACKGROUND: The biofilms could protect bacteria from antibiotics and promote the production of drug-resistant strains, making the bacteria more difficult to be eradicated. Thus, we developed an AMP@PDA@AgNPs nanocomposite, which is formed by modifying silver nanoparticles (AgNPs) with antimicrobial peptides (AMP) modified nanocomposite to destroy biofilm in this study. METHODS: The AMP@PDA@AgNPs nanocomposite was prepared with polymerization method and characterized by using ultraviolet-visible (UV-vis) spectroscopy, dynamic light scattering (DLS), Fourier transform-infrared spectroscopy (FT-IR), and transmission electron microscope (TEM). The antibacterial effects of the nanocomposite were investigated by using agar diffusion method and minimum inhibitory concentration (MIC) test. The quantitative analysis of the biofilm formation by the nanocomposite was conducted using crystal violet staining and confocal laser scanning microscope (CLSM). RESULTS: The DLS and TEM analysis showed it was a spherical nanocomposite with 200 nm size and well dispersed . The results of UV-vis and FT-IR confirmed the presence of AMP and AgNPs. The nanocomposite had an excellent biocompatibility at 100 µg/mL. And the AMP@PDA@AgNPs nanocomposite showed superior antimicrobial activity against both Gram-negative (E. coli, P. aeruginosa) and Gram-positive (S. aureus) bacteria than AgNPs or AMP. Importantly, the mRNA expression of biofilm-related genes were decreased under the action of the nanocomposites. CONCLUSION: An AMP@PDA@AgNPs nanocomposite with good biocompatibility was successfully prepared. The nanocomposite could destruct bacterial biofilms by inhibiting the expression of biofilm-related genes. The synergistic strategy of AMPs and AgNPs could provide a new perspective for the treatment of bacterial infection.

Strategies for Engineering Exosomes and Their Applications in Drug Delivery.

Exosomes are representative of a promising vehicle for delivery of biomolecules. Despite their discovery nearly 40 years, knowledge of exosomes and extracellular vesicles (EVs) and the role they play in etiology of disease and normal cellular physiology remains in its infancy. EVs are produced in almost all cells, containing nucleic acids, lipids, and proteins delivered from donor cells to recipient cells. Consequently, they act as mediators of intercellular communication and molecular transfer. Recent studies have shown that, exosomes are associated with numerous physiological and pathological processes as a small subset of EVs, and they play a significant role in disease progression and treatment. In this review, we discuss several key questions: what are exosomes, why do they matter, and how do we repurpose them in their strategies and applications in drug delivery systems. In addition, opportunities and challenges of exosome-based theranostics are also described and directions for future research are presented.

Metformin attenuates cardiac remodeling in mice through the Nrf2/Keap1 signaling pathway.

Obesity results in a variety of metabolic alterations that may contribute to abnormalities in cardiac structure and function. Although metformin (Met) has been previously reported to exhibit beneficial effects against cardiomyopathy associated obesity, the mechanism underlying this observation remains unclear. The aim of the present study was to investigate the status of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/kelch-like ECH-associated protein 1 (Keap1) system underlying the protective effects of Met against cardiac remodeling. High-fat diet-induced obesity mouse models were first generated, which were subsequently treated with Met. Metabolic parameters, heart weight index and degree of cardiac fibrosis were examined. The expression levels of genes and proteins associated with the Nrf2/Keap1 signaling pathway were assessed using reverse transcription-quantitative PCR and western blotting. In obese mice, Met treatment significantly ameliorated the obesity phenotype, improved metabolic disorders, reduced the heart weight index and attenuated cardiac fibrosis. The cardioprotective effects of Met may be mediated through the promotion of Keap1 degradation whilst increasing the expression of Nrf2 and associated downstream antioxidant factors.

Porphyromonas gingivalis Promotes the Proliferation and Migration of Esophageal Squamous Cell Carcinoma through the miR-194/GRHL3/PTEN/Akt Axis.

Recent studies have revealed that Porphyromonas gingivalis is closely related to the occurrence and progression of esophageal squamous cell carcinoma (ESCC). However, the underlying mechanism of P. gingivalis in ESCC has not been well elucidated. To explore the mechanism of P. gingivalis infection in ESCC, cellular proliferation, invasion, and migration models of KYSE-30 and KYSE-150 cells infected by P. gingivalis at a multiplicity of infection (MOI) of 10 were established. The results showed that P. gingivalis infection could drastically increase the proliferation, invasion, and migration ability of ESCC. Furthermore, the results of high-throughput sequencing showed that miR-194 was considerably upregulated in infected cells compared with control cells, which was further verified by qRT-PCR. The inhibition or overexpression of miR-194 had a significant effect on KYSE-30 and KYSE-150 cell migration and invasion. Additionally, the levels of GRHL3 and PTEN were decreased in P. gingivalis-infected esophageal cancer cells compared with uninfected esophageal cancer cells. Furthermore, dual-luciferase experiments confirmed that GRHL3 is a direct target of miR-194. In addition, the GRHL3-related pathway was investigated, and the levels of GRHL3 and PTEN were downregulated while the level of p-Akt was upregulated after P. gingivalis infection. Taken together, these findings indicated that P. gingivalis might promote ESCC proliferation and migration via the miR-194/GRHL3/PTEN/Akt signaling axis.