Various oncolytic viruses (OVs) have been adopted as therapeutic tools to increase the efficacy of chimeric antigen receptor (CAR)-T cells against solid tumors. However, the therapeutic effect of OVs has been limited by pre-existing neutralizing antibodies and poor targeting delivery for systemic administration. Herein, we propose using bioorthogonal OV nanovesicles to boost the antitumor effects of CAR-T cells in solid tumors by reshaping the tumor microenvironment. Using a cell-membrane nanomimetic technique, we embedded artificial chemical ligands on cancer cell surfaces and then encapsulated lysoviral particles to obtain dual-targeted OV nanovesicles with bioorthogonal targeting and homologous recognition. OVs can be directly encapsulated into cancer cell nanovesicles and exhibit a liposome-like nanostructure, efficient loading, and excellent tumor-targeting capability. Encouragingly, OV nanovesicles efficiently induced tumor-cell apoptosis while sparing normal tissues and cells, thereby inhibiting tumor growth. Administration of viral nanovesicles effectively increased the secretion of anti-tumor cytokines such as IL-2, TNF-α and IFN-γ, and significantly promoted the infiltration and activation of CD8
Oral squamous cell carcinoma (OSCC) is the most widespread malignant oral cavity neoplasm, with even higher proportion of deaths than breast cancer and cervical cancer. Although advances were made in conventional treatment for OSCC such as surgery and radiation therapy, there has not been significant increase in the 5-year survival rate in the past four decades, and chemotherapeutic drug resistance and side-effects are still main obstacles for chemotherapy. Thus, improvement in the treatment of OSCC is strongly expected. In this study, nanosecond pulsed electric fields, known as nsPEFs, were applied in the treatment of OSCC in combination with gemcitabine, a clinical-used anti-cancer drug. Synergistic effects of nsPEFs and gemcitabine were observed and investigated. Cal-27 cells were exposed to 20 pulses with duration of 100ns at electric field intensity of 10, 30 and 60 kV/cm, and then cultured in the medium with 0.01ug/mL gemcitabine. Cell inhibition was increased by 5 fold after the combined treatment compared to gemcitabine or nsPEFs alone, verified with MTT test, and remarkable synergistic effects were obtained with synergistic quotient over 3. Cell proliferation and invasion ability decreased significantly, determined by clonogenic assay and transwell invasion assay. Cell apoptosis was evaluated by flow cytometry and morphological changes were observed by TEM. It is indicated that the combined treatment has significant advances over either gemcitabine or nsPEFs, and synergistic inhibition in cell line cal-27 was demonstrated. The combined therapy may reduce the dose of both chemotherapeutic drug and nsPEF, and thus may avoid side-effects or drug resistances as well as provide a better treatment for oral cancer.
Highly pathogenic avian influenza A viruses are emerging pandemic threats in human beings. Monitoring the in vivo dynamics of avian influenza viruses is extremely important for understanding viral pathogenesis and developing antiviral drugs. Although a number of technologies have been applied for tracking viral infection in vivo, most of them are laborious with unsatisfactory detection sensitivity. Herein we labeled avian influenza H5N1 pseudotype virus (H5N1p) with near-infrared (NIR)-emitting QDs by bioorthogonal chemistry. The conjugation of QDs onto H5N1p was highly efficient with superior stability both in vitro and in vivo. Furthermore, QD-labeled H5N1p (QD-H5N1p) demonstrated bright and sustained fluorescent signals in mouse lung tissues, allowing us to visualize respiratory viral infection in a noninvasive and real-time manner. The fluorescence signals of QD-H5N1p in lung were correlated with the severity of virus infection and significantly attenuated by antiviral agents, such as oseltamivir carboxylate and mouse antiserum against H5N1p. The biodistribution of QD-H5N1p in lungs and other organs could be easily quantified by measuring fluorescent signals and cadmium concentration of virus-conjugated QDs in tissues. Hence, virus labeling with NIR QDs provides a simple, reliable, and quantitative strategy for tracking respiratory viral infection and for antiviral drug screening.
Small interference RNA (siRNA)-based therapy holds great potential for cancer treatment. However, its clinical application remains unsatisfied due to the lack of a safe and effective RNA delivery system. Aberrantly elevated sialyation on cell membrane has been reported as an attractive target for cancer diagnosis and therapy. In this study, phenylboronic acid (PBA) was conjugated onto low molecular weight polyethylenimine (PEI1.8k) to generate amphiphilic PBA-grafted PEI1.8k (PEI-PBA) nanovector, which was designed to facilitate cancer-targeted RNA delivery through the recognition of sialic structures on a cancer cell membrane. PEI-PBA simultaneously encapsulated siRNA to form PEI-PBA/siRNA nanocomplexes with great biocompatibility, serum stability and RNase resistance. The cell culture study showed that PEI-PBA/siRNA dramatically increased siRNA uptake up to 70–90% in several cancer cell lines, which relied on the interaction between PBA and sialic acid on cell membrane. Moreover, the PEI-PBA nanovector effectively promoted the lysosome escape of siRNA, decreasing the expression of target gene Polo-like kinase 1 (PLK-1) in cancer cells. The systemic administration of PEI-PBA/PLK-1 siRNA (PEI-PBA/siPLK1) nanocomplexes not only facilitated tumor-targeted siRNA delivery but also significantly decreased PLK-1 expression in tumors, thereby robustly inducing tumor apoptosis and cell cycle arrest. Additionally, the administration of PEI-PBA/siPLK1 did not cause significant systemic toxicity or immunotoxicity. Hence, sialic acid-targeted PEI-PBA could be a highly efficient and safe nanovector to improve the efficacy of cancer siRNA therapy.
To develop liposomes containing doxorubicin with different salts and to investigate their influence on the stability of liposomal doxorubicin in vitro and in vivo.Liposomes were prepared by the film method, treated further by extruded through nuclear membrane. The entrapment efficiency was determined by column chromatography. In vitro drug release experiments were carried out with a dialysis bag (Mw cut-off 12000 - 14000). Reverse-phase HPLC was used to study the pharmacokinetics of liposomal doxorubicin.The particle size of liposomes with glycinate buffer, citrate buffer and ammonium sulfate as the inner water phase were (103 +/- 8), (102 +/- 12) and (97 +/- 8) nm. The zeta potential and the encapsulation ratio were (-21.3 +/- 0.5), (-21.7 +/- 0.4), (-20.9 +/- 0.7) mV and 47.8%, 96.7%, 98.6%, respectively. The leaking rate of doxorubicin from liposomes was related to the pH value of the release medium. The leaking rate increased at lowered pH. Pharmacokinetic study showed that the MRT (mean retention time) of liposomes with glycinate buffer, citrate buffer and ammonium sulfate as the inner water phase were 12.13, 23.31 and 29.79 h, respectively.Doxorubicin showed different stability in liposomes with different inner water phases, the weaker the acid in the inner water phase, the stabler the liposome.
In article number 2008262, Mingbin Zheng, Lintao Cai, and co-workers develop biohybrid AI microrobots based on sequential magneto/optics-driven marine magnetic bacteria. The AI microrobots tracked with NIRF/MRI imaging could be accurately manipulated via a magnetic field for hard-to-access diseases at the microscale level. An on-demand photothermal excitation method to eradicate tumors without side effects is engineered.
Lung cancer (the 5-year survival rate is only about 16%) has a low survival rate, and more-effective drugs are urgently needed. Our team discovered that cortex Periplocae Radicis has obvious toxic effects on various cancer cells, including lung cancer cells. However, the mechanism is not clear. Therefore, we used the PubChem database to obtain periplogenin as the target of therapeutic drugs and the TCGA database to obtain differential genes of lung cancer. The results showed that MMP9, PPARG, BMP2, and TGFB2 were the core proteins of periplogenin acting on lung adenocarcinoma (LUAD), and MMP9, angiotensin-converting enzyme (ACE), BMP2, PPARG, MMP13, MMP3, and TGFB2 were the core proteins of periplogenin acting on lung squamous cell carcinoma (LUCS). Through gene ontology (GO) enrichment analysis, it was found that periplogenin mainly acted on LUAD via fatty acid binding, metallopeptidase activity, and monocarboxylic acid binding, and mainly acted on lung squamous carcinoma (LUSC) via endopeptidase activity, metallopeptidase activity, and serine-type peptidase activity. Kyoto Encyclopedia of Genes, and Genomes (KEGG) analysis revealed that the IL-17 signaling pathway, fluid shear stress, atherosclerosis, hepatocellular carcinoma, and so on, were the main signaling pathways of periplogenin acting on LUSC, whereas glycolysis/gluconeogenesis, and the peroxisome proliferator-activated receptor (PPAR) signaling pathway were major signaling pathways of periplogenin acting on LUAD. This shows that treatment of lung cancer can be achieved through multi-targeted, and multi-channel periplogenin activity.
Abstract Recent studies indicated that the dysregulation of mitochondria‐associated endoplasmic reticulum membrane (MAM) could be a significant hub in the pathogenesis of Parkinson's disease (PD). However, little has been known about how MAM altered in PD. This study was aimed to observe morphological changes and analyze proteomic profiles of MAM in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced PD mouse models. In MPTP‐treated mice, transmission electron microscopy was applied for MAM ultrastructural visualization. Nano ultra‐high performance liquid chromatography‐tandem mass spectrum and bioinformatic analysis were adopted to obtain underlying molecular data of MAM fractions. The loosened, shortened and reduced MAM tethering was found in substantia nigral neurons from MPTP‐treated mice. In midbrain MAM proteomics, 158 differentially expressed proteins (DEPs) were identified between two groups. Specific DEPs were validated by western blot and exhibited significantly statistical changes, aligning with proteomic results. Bioinformatic analysis indicated that membrane, cytoplasm and cell projection were three major localizations for DEPs. Biological processes including metabolism, lipid transport, and immunological and apoptotic signaling pathways were greatly affected. For consensus MAM proteins, the enriched pathway analysis revealed the potential relationship between neurodegenerative diseases and MAM. Several biological processes such as peroxisome function and clathrin‐mediated endocytosis, were clustered, which provided additional insights into the fundamental molecular pathways associated with MAM. In our study, we demonstrated disrupted ER‐mitochondria contacts in an MPTP‐induced PD mouse model. The underlying signatures of MAM were revealed by proteomics and bioinformatic analysis, providing valuable insights into its potential role in PD pathogenesis.
Environment abstraction enriches predicate abstraction by idea from counter abstraction to develop a framework for verification of parameterized systems. However, despite various effects, the constructed abstractions still go beyond the capability of the usual model checkers for many realistic systems. In this paper, a new technique, called state clustering, is proposed to group local states into a small number of clusters, by purely syntactic analysis. The size of array variables in the resulting abstractions are further reduced using parameter abstraction technique. By combining different abstraction techniques, real-life cache coherence protocols such as FLASH have been successfully verified.
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