Induction of Non-Canonical Ferroptosis by Targeting Clusters Suppresses Glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor. There is a pressing need to develop novel treatment strategies due to the poor targeting effect of current therapeutics. Here, a gold cluster coated with optimized GBM-targeting peptide is engineered, namely NA. NA can efficiently target GBM both in vitro and in vivo. Interestingly, the uptake of NA significantly sensitizes GBM cells to ferroptosis, a form of programmed cell death that can bypass the tumor resistance to apoptosis. This effect is exerted through regulating the HO-1-dependent iron ion metabolism, which is the non-canonical pathway of ferroptosis. The combined treatment of a ferroptosis inducer and NA profoundly inhibited tumor growth in both the GBM spheroid model and a syngeneic mouse model with enhanced ferroptosis levels and excellent biosafety. Importantly, the infiltration of tumoricidal lymphocytes is also significantly increased within tumor. Therefore, NA presents a potential novel nanomaterial-based strategy for GBM treatment.

Targeted Gold Nanoclusters for Synergistic High-Risk Neuroblastoma Therapy through Noncanonical Ferroptosis.

Children with extracranial high-risk neuroblastoma (NB) have a poor prognosis due to resistance against apoptosis. Recently, ferroptosis, another form of programmed cell death, has been tested in clinical trials for high-risk NB; however, drug resistance and side effects have also been observed. Here, we find that the gold element in gold nanoclusters can significantly affect iron metabolism and sensitize high-risk NB cells to ferroptosis. Accordingly, we developed a gold nanocluster conjugated with a modified NB-targeting peptide. This gold nanocluster, namely, NANT, shows excellent NB targeting efficiency and dramatically promotes ferroptosis. Surprisingly, this effect is exerted by elevating the noncanonical ferroptosis pathway, which is dependent on heme oxygenase-1-regulated Fe(II) accumulation. Furthermore, NANT dramatically inhibits the growth of high-risk NB in both tumor spheroid and xenograft models by promoting noncanonical ferroptosis evidenced by enhanced intratumoral Fe(II) and heme oxygenase-1. Importantly, this strategy shows excellent cardiosafety, offering a promising strategy to overcome ferroptosis resistance for the efficient and safe treatment of children with high-risk neuroblastoma.

Colon-Accumulated Gold Nanoclusters Alleviate Intestinal Inflammation and Prevent Secondary Colorectal Carcinogenesis via Nrf2-Dependent Macrophage Reprogramming.

Inflammatory bowel disease (IBD) is one of the main factors leading to colitis-associated colorectal cancer (CAC). Therefore, it is critical to develop an effective treatment for IBD to prevent secondary colorectal carcinogenesis. M2 macrophages play crucial roles in the resolution phase of intestinal inflammation. However, traditional drugs rarely target intestinal M2 macrophages, and they are not easily cleared. Gold nanoclusters are known for their in vivo safety and intrinsic biomedical activities. In this study, a glutathione-protected gold nanocluster is synthesized and evaluated, namely, GA. Interestingly, GA specifically accumulates in the colon during IBD. Furthermore, GA not only promotes M2 differentiation of IL-4-treated peritoneal macrophages but also reprograms macrophage polarization from M1 to M2 in a pro-inflammatory environment. Mechanistically, this regulatory effect is exerted through activating the antioxidant Nrf2 signaling pathway, but not traditional STAT6. When applied in IBD mice, we found that GA elevates M2 macrophages and alleviates IBD in an Nrf2-dependent manner, evidenced by the abolished therapeutic effect upon Nrf2 inhibitor treatment. Most importantly, GA administration significantly suppresses AOM/DSS-induced CAC, without causing obvious tissue damage, providing critical evidence for the potential application of gold nanoclusters as nanomedicine for the treatment of IBD and CAC.

Propofol Ameliorates the Proliferation and Epithelial-Mesenchymal Transition of Hepatoma Carcinoma Cells via Non-Coding RNA Activated by DNA Damage (NORAD)/microRNA (miR)-556-3p/Migration and Invasion Enhancer 1 (MIEN1) Axis.

Propofol has been previously demonstrated to relieve hepatocellular carcinoma (HCC). However, the specific molecular mechanisms mediated by propofol remain to be explored. mRNA or miRNA expression was detected by real-time quantitative polymerase chain reaction (RT-qPCR). Protein expression was determined by Western blot. The interaction between microRNA (miR)-556-3p and long coding RNA non-coding RNA activated by DNA damage (NORAD) or migration and invasion enhancer 1 (MIEN1) was verified by luciferase reporter gene and RNA pull-down assays. Cellular functions were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetra-zolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), and Transwell assays. Propofol notably suppressed the proliferation and EMT of Hep3B and SNU449 cell lines. NORAD was overexpressed in the HCC tissues and cells, while propofol decreased NORAD levels in the HCC cells. Conversely, overexpression of NORAD partially restored malignant behaviors of the HCC cells and abolished the effects of propofol. Additionally, NORAD sponged miR-556-3p to upregulate MIEN1. However, the knockdown of MIEN1 suppressed the proliferation and EMT of HCC cells. Propofol inhibited HCC cell proliferation and EMT progress via NORAD/miR-556-3p/MIEN1 axis. These data provided a potent prognosis and diagnostic marker for HCC and supplemented the underlying mechanism of propofol-induced anti-tumor effects.

Distinguishing Microvasculature Features of Vogt-Koyanagi-Harada in Patients in Acute and Convalescent Phases Using Optical Coherence Tomography Angiography.

Purpose: To evaluate retinal and choroidal microvascular features of VKH patients in acute and convalescent phases after treatment using OCTA.Methods: A prospective, observational study was conducted in patients with initial VKH at the acute stage (n = 15) and healthy participants (n = 15) served as controls. After 3-month systemic corticosteroid treatment, patients' vascular parameters were recorded by OCTA before and after treatment and compared with results observed in healthy participants.Results: Our findings first uncovered that there are two types of abnormalities in the choriocapillary layer of patients with VKH in the acute stage: one is characterized as multiple dark spots of choriocapillary flow void and the other involves highly reflective areas surrounded by light spots with an increased flow area. During the convalescent stage, all eyes showed multifocal dark spots in the choriocapillary layer, leading to a reduced choroidal flow area.Conclusions: OCTA provides a better display of the microvascular appearance of the choroid to noninvasively evaluate choriocapillaris abnormalities in VKH disease.