Search Results (4)

Apart from HER2-positive, triple-negative breast cancer (TNBC) is the second most highly invasive type of breast cancer. Although TNBC does not overexpress HER2 receptors, it has been observed that EGFR protein expression is present in this specific type of tumor, making it an attractive target for immune and radiopharmaceutical treatments. In our current study, we used ¹⁰⁹Pd (T_1/2 = 13.7 h) in the form of a ¹⁰⁹Pd/^109mAg in vivo generator as a source of β⁻ particles and Auger electrons in targeted radionuclide therapy for TNBC. ¹⁰⁹Pd, obtained through neutron irradiation of the ¹⁰⁸Pd target, was deposited onto 15 nm gold nanoparticles to form Au@¹⁰⁹Pd core–shell nanoparticles, which were then conjugated to the panitumumab antibody. Au@¹⁰⁹Pd-PEG-panitumumab nanoparticles were bound, internalized, and partially routed to the nucleus in MDA-MB-231 human breast cancer cells overexpressing EGFR receptors. The Au@¹⁰⁹Pd-panitumumab radioconjugate significantly reduced the metabolic activity of MDA-MB-231 cells in a dose-dependent manner. In conclusion, we have found that Au@¹⁰⁹Pd-PEG-panitumumab nanoparticles show potential as a therapeutic agent for combined β⁻–Auger electron targeted radionuclide therapy of TNBC. The simultaneous emission of β⁻, conversion, and Auger electrons from the ¹⁰⁹Pd/^109mAg generator, similar to ¹⁶¹Tb conjugates, significantly enhances the therapeutic effect. The partial localization of these nanoparticles into the cell nucleus, provided by the panitumumab vector, ensures effective therapy with Auger electrons. This is particularly important for the treatment of drug-resistant TNBC cells. Full article

Parkinson’s disease (PD) is a widespread age-related neurodegenerative disorder characterized by the presence of an aggregated protein, α-synuclein (α-syn), which is encoded by the SNCA gene and localized to presynaptic terminals in a normal human brain. The α-syn aggregation is induced by the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mitochondrial neurotoxin and is therefore used to mimic PD-like pathology in various in vitro and in vivo models. However, in vitro PD-like pathology using α-syn and MPTP in human microglial cells has not yet been reported. Malvidin-3-O-glucoside (M3G) is a major anthocyanin primarily responsible for pigmentation in various fruits and beverages and has been reported to possess various bioactivities. However, the neuroprotective effects of M3G in humanized in vitro PD-like pathologies have not been reported. Therefore, individual and co-treatments of α-syn and MPTP in a human microglial (HMC3) cell line were used to establish a humanized PD-like pathology model in vitro. The individual treatments were significantly less cytotoxic when compared to the α-syn and MPTP co-treatment. This study examined the neuroprotective effects of M3G by treating HMC3 cells with α-syn (8 μg/mL) and MPTP (2 mM) individually or in a co-treatment in the presence or absence of M3G (50 μM). M3G demonstrated anti-apoptotic, anti-inflammatory, and antioxidative properties against the α-syn- and MPTP-generated humanized in vitro PD-like pathology. This study determined that the cytoprotective effects of M3G are mediated by nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase (HO)-1 signaling. Full article

Parkinson’s disease (PD) is an age-dependent neurodegenerative condition. Leucine-rich repeat kinase 2 (LRRK2) mutations are the most frequent cause of sporadic and autosomal dominant PD. The exact role of LRRK2 protective variants (R1398H, N551K) together with a pathogenic mutant (G2019S) in aging and neurodegeneration is unknown. We generated the following myc-tagged UAS-LRRK2 transgenic Drosophila: LRRK2 (WT), N551K, R1398H, G2019S single allele, and double-mutants (N551K/G2019S or R1398H/G2019S). The protective variants alone were able to suppress the phenotypic effects caused by the pathogenic LRRK2 mutation. Next, we conducted RNA-sequencing using mRNA isolated from dopaminergic neurons of these different groups of transgenic Drosophila. Using pathway enrichment analysis, we identified the top 10 modules (p < 0.05), with “LRRK2 in neurons in Parkinson’s disease” among the candidates. Further dissection of this pathway identified the most significantly modulated gene nodes such as eEF1A2, ACTB, eEF1A, and actin cytoskeleton reorganization. The induction of the pathway was successfully restored by the R1398H protective variant and R1398H-G2019S or N551K-G2019S rescue experiments. The oxidoreductase family of genes was also active in the pathogenic mutant and restored in protective and rescue variants. In summary, we provide in vivo evidence supporting the neuroprotective effects of LRRK2 variants. RNA sequencing of dopaminergic neurons identified upregulation of specific gene pathways in the Drosophila carrying the pathogenic variant, and this was restored in the rescue phenotypes. Using protective gene variants, our study identifies potential new targets and provides proof of principle of a new therapeutic approach that will further our understanding of aging and neurodegeneration in PD. Full article

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting people over age 55. Oxidative stress actively participates in the dopaminergic (DA) neuron degeneration of PD. Xyloketals are a series of natural compounds from marine mangrove fungus strain No. 2508 that have been reported to protect against neurotoxicity through their antioxidant properties. However, their protection versus 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity is only modest, and appropriate structural modifications are necessary to discover better candidates for treating PD. In this work, we designed and synthesized 39 novel xyloketal derivatives (1–39) in addition to the previously reported compound, xyloketal B. The neuroprotective activities of all 40 compounds were evaluated in vivo via respiratory burst assays and longevity-extending assays. During the zebrafish respiratory burst assay, compounds 1, 9, 23, 24, 36 and 39 strongly attenuated reactive oxygen species (ROS) generation at 50 μM. In the Caenorhabditis elegans longevity-extending assay, compounds 1, 8, 15, 16 and 36 significantly extended the survival rates (p < 0.005 vs. dimethyl sulfoxide (DMSO)). A total of 15 compounds were tested for the treatment of Parkinson’s disease using the MPP+-induced C. elegans model, and compounds 1 and 8 exhibited the highest activities (p < 0.005 vs. MPP⁺). In the MPP+-induced C57BL/6 mouse PD model, 40 mg/kg of 1 and 8 protected against MPP+-induced dopaminergic neurodegeneration and increased the number of DA neurons from 53% for the MPP+ group to 78% and 74%, respectively (p < 0.001 vs. MPP+ group). Thus, these derivatives are novel candidates for the treatment of PD. Full article