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Ultrasound-responsive theranostic platform for real-time monitoring and efficient thrombolysis in tPA-resistant thrombi

ABSTRACT: There is no noninvasive solution for tPA-resistant thrombi while endovascular thrombectomy is the last option. Here, we proposed neutrophil extracellular traps (NETs), ε-(γ-glutamyl)lysine isopeptide bonds and fibrin scaffold as keychain in tPA-resistant thrombus, which was confirmed in the thrombi retrieved from stroke patients. A theranostic platform was designed for the combination of sonodynamic and mechanical thrombolysis under the guidance of ultrasonic imaging. Three rounds of 10 min noninvasive treatment led to the breakdown of the keychain, achieving great recanalization rate of 90% in rat occlusion model while tPA only made 10% improvement. RNA sequencing results and endothelium functional tests jointly indicated that the vascular homeostasis can be effectively reconstructed. The noninvasive theranostic capability presented in pig’s lengthy thrombi (>8mm) and thrombosis-susceptible tissue engineered vascular grafts (TEVGs) indicated its clinical transformation prospects. Taken together, this non-invasive theranostic platform provides a new strategy for tPA-resistant thrombi.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE254810 | GEO | 2024/05/26

REPOSITORIES: GEO

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Project description:The diterpene ester PEP005 is a novel anticancer agent that activates PKC and cures subcutaneous murine melanoma by topical application. We now describe the in vitro cytostatic effects of PEP005 and the diterpene ester TPA, observed in 20% of human melanoma cell lines. Primary cultures of normal human neonatal fibroblasts were uniformly resistant to growth arrest, indicating a potential for tumor selectivity. Sensitive cells were induced to senesce and exhibited a G1 and G2/M arrest. There was sustained expression of p21WAF1/CIP1, irreversible dephosphorylation of the retinoblastoma gene product (Rb) and transcriptional silencing of E2F-responsive genes in sensitive cell lines. Activation of MEK1/2 by PKC was required for diterpene ester-induced senescence. Expression profiling revealed that the MAPK inhibitor HREV107 was expressed at a higher transcript level in resistant compared to sensitive cell lines. We propose that activation of PKC over-stimulates the Ras/Raf/MEK/ERK pathway, resulting in sustained induction of p21WAF1/CIP1, dephosphorylation of Rb and transcriptional silencing of E2F-responsive genes required for DNA synthesis and mitosis. To investigate the molecular changes associated with the senescent phenotype, we examined the unique transcriptional changes occurring in sensitive melanoma cell lines treated with TPA or PEP005. Initially a time-course cDNA microarray analysis was conducted on one sensitive and one resistant cell line treated with 1 Âµg/ml of TPA for 6, 24 h and 24 h recovery following 24 h treatment, to determine the earliest time point at which the most significant changes in transcription occurred. The results provided support for conducting array experiments with 24 h treatment, in which three sensitive and four resistant melanoma cell lines were treated with 1 Âµg/ml of either diterpene ester. Our primary objective was to identify those genes which were uniquely up or down-regulated in sensitive or resistant cell lines in response to treatment, which could reflect the phenotypic outcome. Through applying a series of stringent selective criteria (see Material and Methods) we found that the most significant changes occurred in the transcriptional repression of genes required for DNA synthesis and mitosis in cell lines sensitive to treatment (Table 1). To confirm that these changes were reflected at the protein level, western blot analysis was conducted on three sensitive and three resistant cell lines following 6 and 24 h treatment with TPA or PEP005. We also included a 24 h recovery time point to determine the irreversibility of the change.

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Ultrasound-responsive theranostic platform for real-time monitoring and efficient thrombolysis in tPA-resistant thrombi

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