Background Central nervous system tuberculosis (CNS-TB) is the most devastating form of extrapulmonary tuberculosis. Rifampin (RIF) is a first-line antimicrobial agent with potent bactericidal action. Nonetheless, the blood-brain barrier (BBB) limits the therapeutic effects on CNS-TB. Exosomes, however, can facilitate drug movements across the BBB. In addition, exosomes show high biocompatibility and drug-loading capacity. They can also be modified to increase drug delivery efficacy. In this study, we loaded RIF into exosomes and modified the exosomes with a brain-targeting peptide to improve BBB permeability of RIF; we named these exosomes ANG-Exo-RIF. Methods Exosomes were isolated from the culture medium of BMSCs by differential ultracentrifugation and loaded RIF by electroporation and modified ANG by chemical reaction. To characterize ANG-Exo-RIF, Western blot (WB), nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM) were performed. Bend.3 cells were incubated with DiI labeled ANG-Exo-RIF and then fluorescent microscopy and flow cytometry were used to evaluate the targeting ability of ANG-Exo-RIF in vitro. Fluorescence imaging and frozen section were used to evaluate the targeting ability of ANG-Exo-RIF in vivo. MIC and MBC were determined through microplate alamar blue assay (MABA). Results A novel exosome-based nanoparticle was developed. Compared with untargeted exosomes, the targeted exosomes exhibited high targeting capacity and permeability in vitro and in vivo. The MIC and MBC of ANG-Exo-RIF were 0.25 μg/mL, which were sufficient to meet the clinical needs. Conclusion In summary, excellent targeting ability, high antitubercular activity and biocompatibility endow ANG-Exo-RIF with potential for use in future translation-aimed research and provide hope for an effective CNS-TB treatment.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the coronavirus disease (COVID-19), which poses a major threat to humans worldwide. With the continuous progress of the pandemic, a growing number of people are infected with SARS-CoV-2, including hepatocellular carcinoma (HCC) patients. However, the relationship between COVID-19 and HCC has not been fully elucidated. In order to provide better treatment for HCC patients infected with SARS-CoV-2, it’s urgently needed to identify common targets and find effective drugs for both. In our study, transcriptomic analysis was performed on both selected lung epithelial cell datasets of COVID-19 patients and the datasets of HCC patients to identify the synergistic effect of COVID-19 in HCC patients. What’s more, common differentially expressed genes were identified, and a protein-protein interactions network was designed. Then, hub genes and basic modules were detected based on the protein-protein interactions network. Next, functional analysis was performed using gene ontology terminology and the Kyoto Encyclopedia of Genes and Genomes pathway. Finally, protein-protein interactions revealed COVID-19 interaction with key proteins associated with HCC and further identified transcription factor (TF) genes and microRNAs (miRNA) with differentially expressed gene interactions and transcription factor activity. This study reveals that COVID-19 and HCC are closely linked at the molecular level and proposes drugs that may play an important role in HCC patients with COVID-19. More importantly, according to the results of our research, two critical drugs, Ilomastat and Palmatine, may be effective for HCC patients with COVID-19, which provides clinicians with a novel therapeutic idea when facing possible complications in HCC patients with COVID-19.
Hepatocellular carcinoma (HCC) is common worldwide, and novel therapeutic targets and biomarkers are needed to improve outcomes. In this study, bioinformatics analyses combined with in vitro and in vivo assays were used to identify the potential therapeutic targets. Differentially expressed genes (DEG) in HCC were identified by the intersection between The Cancer Genome Atlas and International Cancer Genome Consortium data. The DEGs were evaluated by a gene set enrichment analysis as well as Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. A protein interaction network, univariate Cox regression, and Lasso regression were used to screen out hub genes correlated with survival. Increased expression of the long noncoding RNA GBAP1 in HCC was confirmed in additional datasets and its biological function was evaluated in HCC cell lines and nude mice. Among 121 DEGs, GBAP1 and PRC1 were identified as hub genes with significant prognostic value. Overexpression of GBAP1 in HCC was confirmed in 21 paired clinical tissues and liver cancer or normal cell lines. The inhibition of GBAP1 expression reduced HCC cell proliferation and promoted apoptosis by inactivating the PI3K/AKT pathway in vitro and in vivo. Therefore, GBAP1 has a pro-oncogenic function in HCC and is a candidate prognostic biomarker and therapeutic target.
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