Cell-mediated drug-delivery systems have received considerable attention for their enhanced therapeutic specificity and efficacy in cancer treatment. Neutrophils (NEs), the most abundant type of immune cells, are known to penetrate inflamed brain tumours. Here we show that NEs carrying liposomes that contain paclitaxel (PTX) can penetrate the brain and suppress the recurrence of glioma in mice whose tumour has been resected surgically. Inflammatory factors released after tumour resection guide the movement of the NEs into the inflamed brain. The highly concentrated inflammatory signals in the brain trigger the release of liposomal PTX from the NEs, which allows delivery of PTX into the remaining invading tumour cells. We show that this NE-mediated delivery of drugs efficiently slows the recurrent growth of tumours, with significantly improved survival rates, but does not completely inhibit the regrowth of tumours.
In this article, we first designed and synthesized curcumin-based near infrared (NIR) fluorescence imaging probes for detecting both soluble and insoluble amyloid beta (Aβ) species, and then an inhibitor that could attenuate crosslinking of Aβ induced by copper. According to our previous results and the possible structural stereo-hindrance compatibility of the Aβ peptide and the hydrophobic/hydrophilic property of the Aβ13–20 (HHQKLVFF) fragment, NIR imaging probe CRANAD-58 was designed and synthesized. As expected CRANAD-58 showed significant fluorescence property changes upon mixing with both soluble and insoluble Aβ species in vitro. In vivo NIR imaging revealed that CRANAD-58 was capable of differentiating transgenic and wild type mice as young as 4-months old, the age that lacks apparently visible Aβ plaques and Aβ is likely in its soluble forms. In this report, according to our limited studies on the interaction mechanism between CRANAD-58 and Aβ, we also designed CRANAD-17 to attenuate the crosslinking of Aβ42 induced by copper. It is well known that the coordination of copper with imidazoles on Histidine-13 and 14 (H13, H14) of Aβ peptides could initialize covalent crosslinking of Aβ. In CRANAD-17, a curcumin scaffold was used as an anchoring moiety to usher the designed compound to the vicinity of H13 and H14 of Aβ, and imidazole rings were incorporated to compete with H13/H14 for copper binding. The results of SDS-PAGE gel and Western blot indicated that CRANAD-17 was capable of inhibiting Aβ42 cross-linking induced by copper. This raises a potential for CRANAD-17 to be considered for AD therapy.
Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer's disease (AD). Although several NIRF probes for detecting amyloid beta (Aβ) species of AD have been reported, none of these probes has been used to monitor changes of Aβs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aβ species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aβ-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aβs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aβ cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17-treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aβ plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development.Alzheimer's | amyloid | imaging | fluorescence | curcumin
This review (with 335 references cited) is devoted to pentacyclic triterpenes. The total synthesis, semi-synthesis, structural modification, and metabolic behavior of naturally occurring pentacyclic triterpenes are described. We also cover the in vivo evidence, mechanistic studies, and clinical significance of pentacyclic triterpenes as multi-target therapeutic agents for the prevention and treatment of metabolic and vascular diseases.
The MYCN protooncogene is amplified in a number of advanced-stage human tumors such as neuroblastomas. Like other members of Myc family proteins, N-Myc is a transcription factor and its stability and activity are tightly controlled by ubiquitination-dependent proteasome degradation1-4. Although numerous studies demonstrate that N-Myc acts as a driver of neuroblastoma tumorigenesis, therapies that directly suppress N-Myc activity in human tumors are limited. Here, we have identified the herpesvirus-associated ubiquitin-specific protease (HAUSP or USP75-7) as a regulator of N-Myc in neuroblastoma. HAUSP interacts with N-Myc, and HAUSP expression induces deubiquitination and subsequent stabilization of N-Myc. Conversely, RNAi-mediated knockdown of HAUSP in neuroblastoma cancer cell lines, or genetic ablation of Hausp in the mouse brain destabilizes N-Myc, which leads to inhibition of N-Myc function. Notably, HAUSP is more abundant in neuroblastoma patients with poorer prognosis and HAUSP expression significantly correlates with N-Myc transcriptional activity. Furthermore, small molecule inhibitors against HAUSP deubiquitinase activity significantly suppress the growth of MYCN-amplified human neuroblastoma cell lines in xenograft mouse models. Together, our findings demonstrate a crucial role of HAUSP in regulating N-Myc function in vivo and suggest that HAUSP inhibition is a potential therapy for MYCN-amplified tumors.
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