Unlocking PD-1 antibody resistance: The MUC1 DNA vaccine augments CD8+ T cell infiltration and attenuates tumour suppression.

In light of increasing resistance to PD1 antibody therapy among certain patient populations, there is a critical need for in-depth research. Our study assesses the synergistic effects of a MUC1 DNA vaccine and PD1 antibody for surmounting PD1 resistance, employing a murine CT26/MUC1 colon carcinoma model for this purpose. When given as a standalone treatment, PD1 antibodies showed no impact on tumour growth. Additionally, there was no change observed in the intra-tumoural T-cell ratios or in the functionality of T-cells. In contrast, the sole administration of a MUC1 DNA vaccine markedly boosted the cytotoxicity of CD8+ T cells by elevating IFN-γ and granzyme B production. Our compelling evidence highlights that combination therapy more effectively inhibited tumour growth and prolonged survival compared to either monotherapy, thus mitigating the limitations intrinsic to single-agent therapies. This enhanced efficacy was driven by a significant alteration in the tumour microenvironment, skewing it towards pro-immunogenic conditions. This assertion is backed by a raised CD8+/CD4+ T-cell ratio and a decrease in immunosuppressive MDSC and Treg cell populations. On the mechanistic front, the synergistic therapy amplified expression levels of CXCL13 in tumours, subsequently facilitating T-cell ingress into the tumour setting. In summary, our findings advocate for integrated therapy as a potent mechanism for surmounting PD1 antibody resistance, capitalizing on improved T-cell functionality and infiltration. This investigation affords critical perspectives on enhancing anti-tumour immunity through the application of innovative therapeutic strategies.

Effective improvements to the live-attenuated Newcastle disease virus vaccine by polyethylenimine-based biomimetic silicification.

Live and killed vaccines impart a significant role in preventing of Newcastle disease (ND) in China. Vaccine efficacy could be ameliorated by improving vaccine-induced cellular immunity and antibody persistency. Previous studies substantiated the potency of silicon dioxide (SiO2) in the control-release of drugs and as a vaccine adjuvant, and polyethylenimine (PEI) merits as a mucosal adjuvanticity with electro-positivity. The present study employed SiO2 and PEI to prepare biomimetic silicon mineralized nanoparticle G7M@SiO2-PEI and microparticle (SiO2 + PEI)@G7M vaccines of G7M, a candidate for live attenuated vaccine of genotype VII Newcastle disease virus (NDV). The zeta potential experiment confirmed the significant increase in the average zeta potential of the nanoparticle G7M@SiO2-PEI and microparticle (SiO2 + PEI)@G7M relative to G7M before mineralization. The results of RT-qPCR revealed more than 99% mineralization efficiency of the G7M@SiO2-PEI and (SiO2 + PEI)@G7M. The morphology detected by transmission electron microscopy reported that the diameters of G7M@SiO2-PEI were similar to those of G7M, while for (SiO2 + PEI)@G7M, it was about five times larger than that of G7M. Silicon was detected on the surface of both mineralization particles, except for G7M, as observed from the elemental distribution detected by elemental mapping and energy dispersive X-ray spectrogram. Indirect immunofluorescence assays validated that mineralization virus have replicated ability in BHK-21F cells. In vivo experiments revealed higher than 5.50 log2 of antibody in nanoparticles G7M@SiO2-PEI group until 10-week post-vaccination, and significant proliferation of antigen-specific CD3+CD4+ in nanoparticles G7M@SiO2-PEI immunized group corroborated improved cellular immune responses. Vaccines provided full protection to the immunized chickens, whereas all the chickens receiving mock immunizations succumbed to the disease. Overall, our study concluded the efficacy of biomimetic mineralization of live attenuated vaccine in nanoparticles to improve humoral and cellular immune responses.

Aloe-emodin-mediated antimicrobial photodynamic therapy against multidrug-resistant Acinetobacter baumannii: An in vivo study.

BACKGROUND AND AIM: Antimicrobial photodynamic therapy (aPDT) has shown great potential for treatment of superficial or localized multidrug-resistant (MDR) Acinetobacter baumannii infections. The purpose of this study was to investigate the cytotoxicity and in vivo safety of aloe-emodin (AE), and its photodynamic treatment efficacy against MDR A. baumannii infections. METHODS: The cytotoxicity (dark toxicity) and phototoxicity of AE to human immortalized keratinocytes and mice fibroblasts were detected by CCK-8 kit. Low and high doses of AE were intravenously injected into mice to evaluate the safety of AE in vivo. Bioluminescent MDR A. baumannii strain was employed to establish the infection model on BALB/c mice after skin scald, and infection status and therapeutic effect of AE-mediated aPDT were assessed by animal imaging system. The peripheral blood of mice was analyzed by flow cytometer. RESULTS: AE had low cytotoxicity to human immortalized keratinocytes and mice fibroblasts, and had certain phototoxicity to these cells under light irradiation. The in vivo experiments demonstrated that AE caused no obvious effects on the weight and pathological changes of mice. AE-mediated aPDT was effective in the treatment of MDR A. baumannii caused infections in mice after skin scald. CONCLUSIONS: AE has potential to be used in the photodynamic treatment of MDR A. baumannii caused superficial infections after scald.

The effects of aloe emodin-mediated antimicrobial photodynamic therapy on drug-sensitive and resistant Candida albicans.

The extensive and repetitive use of antifungal drugs has led to the development of drug-resistant Candida albicans. Antimicrobial photodynamic therapy (aPDT) has received considerable attention as an emerging and promising approach to combat drug-resistant microbes. This study evaluated the photodynamic effects mediated by aloe emodin (AE), a natural compound isolated from Aloe vera and Rheum palmatum, on azole-sensitive and azole-resistant C. albicans in vitro. AE exhibited no significant dark toxicity, but in the presence of light, effectively inactivated C. albicans cells in a concentration-dependent manner. The uptake of AE by fungal cells was investigated by confocal laser scanning microscopy (CLSM), and the results showed that AE possessed stronger ability to enter into C. albicans cells following light irradiation. Transmission electron microscopy analysis suggested that AE-mediated aPDT could induce damage to the cell wall, cytoplasm, and nucleus. Damage to the surface of C. albicans was observed by scanning electron microscopy. These results suggest that AE is a potential PS for use in aPDT of drug-resistant C. albicans strains, and AE-mediated aPDT shows promise as an antifungal treatment.

Antimicrobial photodynamic therapy against multidrug-resistant Acinetobacter baumannii clinical isolates mediated by aloe-emodin: An in vitro study.

BACKGROUND AND AIM: Antimicrobial photodynamic therapy (aPDT) has received considerable attention as an emerging and promising approach for treating superficial infections. The aim of this study was to investigate aPDT mediated by aloe emodin (AE), a natural compound isolated from Aloe vera and Rheum palmatum, against multidrug-resistant (MDR) Acinetobacter baumannii clinical isolates in vitro. METHODS: The photodynamic inactivation (PDI) efficacies of AE on three MDR A. baumannii isolates were assessed by colony forming units (CFU) assay. The aPDT effects mediated by AE on the genomic DNA, membrane integrity, and cellular structure of MDR A. baumannii were also investigated. RESULTS: AE showed no obvious dark toxicity, but inactivated the MDR A. baumannii isolates in an AE concentration and light energy dose-dependent manner. Agarose gel electrophoresis and LIVE/DEAD BacLight Bacterial Viability kit assay indicated that the genomic DNA and membrane integrity of MDR A. baumannii were damaged after AE-mediated aPDT treatment. Transmission electron microscopy (TEM) images demonstrated that AE-mediated aPDT could induce rupture of bacterial cell wall and membrane, and condensation of ribosomes in the cytoplasm. CONCLUSIONS: The results obtained in this study suggested that AE could serve as a potential antibacterial photosensitizer in the treatment of superficial infections caused by MDR A. baumannii.

Redox-responsive biodegradable PEGylated nanographene oxide for efficiently chemo-photothermal therapy: a comparative study with non-biodegradable PEGylated nanographene oxide.

Nanographene oxide (NGO) with a non-sheddable poly(ethylene glycol) (PEG) coating has been used for chemo-photothermal therapy. However, the drug release of PEGylated NGO (NGO-PEG) with an amine bond is adversely affected by the diffusion barrier effect of PEG shells. Here, we developed a simple new method for the preparation of biodegradable PEGylated NGO conjugates (NGO-SS-PEG) with cleavable disulfide bonds for rapid drug release and more efficiently chemo-photothermal therapy. The glutathione (GSH)-induced and photothermal-mediated intracellular release of doxorubicin (DOX) from NGO-SS-PEG was studied in A549 cells using confocal laser scanning microscopy and flow cytometry analysis. In vivo cytotoxicity experiments were performed on chemo-photothermal therapy. Furthermore, we presented a comparative study of intracellular drug release and biological efficacy between NGO-SS-PEG/DOX and NGO-PEG/DOX. The results demonstrated that the rapid drug release from the NGO-SS-PEG conjugates with sheddable PEG was triggered upon the stimulus of high GSH levels inside A549 cells. Interesting, the DOX release mediated by the photothermal effect from the NGO-SS-PEG conjugates was found to be more obvious than that for NGO-PEG. Additionally, NGO-SS-PEG showed a higher efficacy than NGO-PEG for anti-tumor therapy compared with NGO-PEG. Thus, NGO-SS-PEG can improve therapeutic efficacy and is an attractive drug nanocarrier.

[Construction of the subtracted cDNA library in hypothalamus of the seasickness adaptive rats].

OBJECTIVE: To construct subtracted cDNA library in hypothalamus of the seasickness adaptive rats for providing theoretical basis for effective adaptive training against seasickness. METHODS: Suppression subtract hybridization technique was used, and forward and reverse hybridization was performed on the hypothalamus of seasickness adaptive rats and that of normal rats so that to construct subtracted cDNA library. Dot blot was used for differential screening the subtracted library. RESULTS: 23 fragments of differentially expressed genes was obtained including 10 up-regulating and 13 down-regulating fragments. CONCLUSION: Many played role in adaptability formation to seasickness such as SAM, vasopressin, and heme oxygenase.