The impact of polystyrene microplastics on cardiomyocytes pyroptosis through NLRP3/Caspase-1 signaling pathway and oxidative stress in Wistar rats.

The extensive existing of microplastics (MPs) in the ecosystem have increased considerable attention concerning their potential adverse effects, the toxicities and the underlying mechanism of MPs are still scarce. To explore the effect of MPs on cardiac tissue in Wistar rats and unravel the mechanism of pyroptosis and oxidative stress in the process of cardiomyocytes injury, 32 male Wister rats were divided into control group and three model groups, which were exposed to 0.5 mm PS MPs at 0.5, 5 and 50 mg/L for 90 days. Results revealed that MPs could damage cardiac structure and function with impaired mitochondria integrity, as well as increased levels of creatine kinase-MB and cardiac troponinI (cTnI). Moreover, MPs administration triggered oxidative stress as indicated by increased levels of malondialdehyde and decreased activity of superoxide dismutase, glutathione peroxidase and catalase. Treatment with MPs resulted in apoptosis and pyroptosis as evidenced by increasing expressions of interleukin (IL)-1ß, IL-18. Additionally, MPs were shown to induce the NOD-like receptor protein 3 inflammasomes activation in cardiac tissue, enabling activation of Caspase-1-dependent signaling pathway induced by inflammatory stimuli resulting from oxidative stress. In summary, these results illustrated that pyroptosis played a vital role in polystyrene MPs-induced cardiotoxicity, which might be helpful to understand the mechanism of cardiac dysfunction and induced by MPs.

pH-responsive CuS/DSF/EL/PVP nanoplatform alleviates inflammatory bowel disease in mice via regulating gut immunity and microbiota.

The clinical treatment of inflammatory bowel disease (IBD) is challenging. We developed copper sulfate (CuS)/disulfiram (DSF)/methacrylic acid-ethyl acrylate copolymer (EL)/polyvinylpyrrolidone (PVP) nanoplatform (CuS/DSF/EL/PVP) and evaluated its efficiency for treating IBD. After oral administration, the pH-sensitive EL protected the CuS/DSF/EL/PVP against degradation by acidic gastric juices. Once the colon was reached, EL was dissolved, releasing DSF and Cu2+. Further, the main in vivo metabolite of DSF can bind to Cu2+ and form copper (II) N, N-diethyldithiocarbamate (CuET), which significantly alleviated acute colitis in mice. Notably, CuS/DSF/EL/PVP outperformed CuS/EL/PVP and DSF/EL/PVP nanoplatforms in reducing colonic pathology and improving the secretion of inflammation-related cytokines (such as IL-4 and IL-10) in the colonic mucosa. RNA-seq analysis revealed that the nanoplatform reduced colonic inflammation and promoted intestinal mucosal repair by upregulating C-type lectin receptor (CLR)-related genes and signaling pathways. Furthermore, CuS/DSF/EL/PVP showed potential for improving colitis Th1/Th17 cells through innate immunity stimulation, down-regulation of inflammatory cytokines, and upregulation of anti-inflammatory cytokines. Additionally, the intervention with CuS/DSF/EL/PVP led to increased intestinal flora diversity, decreased Escherichia-Shigella abundance, and elevated levels of short-chain fatty acid (SCFA)-producing bacteria Prevotella, Lactobacillus, and Bifidobacterium, indicating their potential to modulate the dysregulated intestinal flora and suppress inflammation. STATEMENT OF SIGNIFICANCE: Our study introduces the CuS/DSF/EL/PVP nanoplatform as a therapeutic strategy for treating inflammatory bowel disease (IBD). This approach demonstrates significant efficacy in targeting the colon and alleviating acute colitis in mice. It uniquely modulates gut immunity and microbiota, exhibiting a notable impact on inflammation-related cytokines and promoting intestinal mucosal repair. The nanoplatform's ability to regulate gut flora diversity, combined with its cost-effective and scalable production, positions it as a potentially transformative treatment for IBD, offering new avenues for personalized medical interventions.

Liquid-solid phase-inversion PLGA implant for the treatment of residual tumor tissue after HIFU ablation.

BACKGROUND: HIFU has been shown to be a more suitable alternative for the treatment of primary solid tumors and metastatic diseases than other focal heat ablation techniques due to its noninvasive and extracorporeal nature. However, similar to other focal heat ablation techniques, HIFU is still in need of refinements due to tumor recurrence. METHODS: In this work, we investigated the effectiveness of an adjunct treatment regimen using doxorubicin (DOX)-loaded, injectable, in situ-forming, and phase-inverting PLGA as the second line of defense after HIFU ablation to destroy detrimental residual tumors and to prevent tumor recurrence. All of the statistical analyses were performed using the Statistical Package for the Social Sciences 18.0 (SPSS, Inc., Chicago, IL, USA), and p<0.05 was considered statistically significant. All of the results are presented as the means ± STDEV (standard deviation). For multiple comparisons, ANOVA (differences in tumor volumes, growth rates, apoptosis, proliferation indexes, and Bcl-2 and Bax protein levels) was used when the data were normally distributed with homogenous variance, and rank sum tests were used otherwise. Once significant differences were detected, Student-t tests were used for comparisons between two groups. RESULTS: Our results revealed that DOX diffused beyond the ablated tissue regions and entered tumor cells that were not affected by the HIFU ablation. Our results also show that HIFU in concert with DOX-loaded PLGA led to a significantly higher rate of tumor cell apoptosis and a lower rate of tumor cell proliferation in the areas beyond the HIFU-ablated tissues and consequently caused significant tumor volume shrinkage (tumor volumes:0.26±0.1,1.09±0.76, and 1.42±0.9 cm3 for treatment, sham, and no treatment control, respectively). CONCLUSIONS: From these results, we concluded that the intralesional injection of DOX-loaded PLGA after HIFU ablation is significantly more effective than HIFU alone for the treatment of solid tumors.