Glioblastoma stem cell-specific histamine secretion drives pro-angiogenic tumor microenvironment remodeling.

The communication between glioblastoma stem cells (GSCs) and the surrounding microenvironment is a prominent feature accounting for the aggressive biology of glioblastoma multiforme (GBM). However, the mechanisms by which GSCs proactively drive interactions with microenvironment is not well understood. In this study, we interrogated metabolites that are preferentially secreted from GSCs and found that GSCs produce and secrete histamine to shape a pro-angiogenic tumor microenvironment. This histamine-producing ability is attributed to H3K4me3 modification-activated histidine decarboxylase (HDC) transcription via MYC. Notably, HDC is highly expressed in GBM, which is associated with poor survival of these patients. GSC-secreted histamine activates endothelial cells by triggering a histamine H1 receptor (H1R)-Ca2+-NF-κB axis, thereby promoting angiogenesis and GBM progression. Importantly, pharmacological blockage of H1R using antihistamines impedes the growth of GBM xenografts in mice. Our findings establish that GSC-specific metabolite secretion remodels the tumor microenvironment and highlight histamine targeting as a potential strategy for GBM therapy.

Rational construction of a robust metal-organic framework nanozyme with dual-metal active sites for colorimetric detection of organophosphorus pesticides.

While nanomaterials with enzyme-mimicking activities are emerging as promising candidates in the colorimetric detection of organophosphorus pesticides (OPs), the catalytic activities and recognition ability to analyte of most nanozymes are inherently deficient. In this work, we introduced manganese ions into a typical iron based MOF (Fe-MIL(53)) via a one-pot hydrothermal reaction strategy, which brought out a catalytically favorable bimetallic Mn/Fe-MIL(53) MOF nanozyme. The catalytic performance of Mn/Fe-MIL(53) is superior to that of pure Fe-MIL (53) and the mechanism for superior catalytic activity of material is revealed by active species scavenging experiments and X-ray photoelectron spectroscopy (XPS). Besides, the introduction of manganese endows the material with the characteristic of being specially destroyed by choline, which motivates the establishment of a simple, selective and sensitive colorimetric strategy for OPs detection. The proposed colorimetric strategy could quantify the methyl parathion and chlorpyrifos in the concentration range of 10-120 nM and 5-50 nM, respectively. The low detection limit of 2.8 nM for methyl parathion and 0.95 nM (3 S/N) for chlorpyrifos were achieved. Good recoveries were obtained when applied in the real sample detection. Our work paves the way to boost catalytic performance of MOF nanozymes, which will be useful in biosensing.

Hypoxia blocks ferroptosis of hepatocellular carcinoma via suppression of METTL14 triggered YTHDF2-dependent silencing of SLC7A11.

Residue hepatocellular carcinoma (HCC) cells enduring hypoxic environment triggered by interventional embolization obtain more malignant potential with little clarified mechanism. The N6 -methyladenosine (m6 A) biological activity plays essential roles in diverse physiological processes. However, its role under hypoxic condition remains largely unexplored. RT-qPCR and Western blot were used to evaluate METTL14 expression in hypoxic HCC cells. MDA assay and electronic microscopy photography were used to evaluate ferroptosis. The correlation between SLC7A11 and METTL14 was conducted by bioinformatical analysis. Flow cytometry was used to verify the effect of SLC7A11 on ROS production. Cell counting kit-8 assay was performed to detect cells proliferation ability. Hypoxia triggered suppression of METTL14 in a HIF-1α-dependent manner potently abrogated ferroptosis of HCC cells. Mechanistic investigation identified SLC7A11 was a direct target of METTL14. Both in vitro and in vivo assay demonstrated that METTL14 induced m6 A modification at 5'UTR of SLC7A11 mRNA, which in turn underwent degradation relied on the YTHDF2-dependent pathway. Importantly, ectopic expression of SLC7A11 strongly blocked METTL14-induced tumour-suppressive effect in hypoxic HCC. Our investigations lay the emphasis on the hypoxia-regulated ferroptosis in HCC cells and identify the HIF-1α /METTL14/YTHDF2/SLC7A11 axis as a potential therapeutic target for the HCC interventional embolization treatment.

Boosting the Ferroptotic Antitumor Efficacy via Site-Specific Amplification of Tailored Lipid Peroxidation.

Ferroptosis is an iron-dependent cell death pathway that can eradicate certain apoptosis-insensitive cancer cells. The ferroptosis-inducing molecules are tailored lipid peroxides whose efficacy is compromised in hypoxic solid tumor and lack of tumor selectivity. It has been demonstrated that ascorbate (Asc) in pharmacological concentrations can selectively kill cancer cells via accumulating hydrogen peroxide (H2O2) only in tumor extracellular fluids. It was hypothesized that Asc-induced, selective enrichment of H2O2 in tumor coupled with Fe3+ codelivery could simultaneously address the above two problems via boosting the levels of hydroxyl radicals and oxygen in the tumor site to ease peroxidation initiation and propagation, respectively. The aim of this work was to synergize the action of Asc with lipid-coated calcium phosphate (CaP) hybrid nanocarrier that can concurrently load polar Fe3+ and nonpolar RSL3, a ferroptosis inducer with the mechanism of inhibiting lipid peroxide repair enzyme (GPX4). The hybrid nanocarriers showed accelerated cargo release at acidic conditions (pH 5.0). The combinational approach (Asc plus nanocarrier) produced significantly elevated levels of hydroxyl radicals, lipid peroxides, and depleted glutathione under hypoxia, which was accompanied with the strong cytotoxicity (IC50 = 1.2 ± 0.2 µM) in the model 4 T1 cells. In the 4 T1 tumor-bearing xenograft mouse model, the intravenous nanocarrier delivery plus intraperitoneal Asc administration resulted in a superior antitumor performance in terms of tumor suppression, which did not produce supplementary adverse effects to the healthy organs. This work provides a novel approach to enhance the potency of ferroptotic nanomedicine against solid tumors without inducing additional side effects.

Hierarchical theranostic nanomedicine: MRI contrast agents as a physical vehicle anchor for high drug loading and triggered on-demand delivery.

The loading of drugs and imaging agents in theranostic nanomedicines by a physical approach is usually poor (<5%), which limits their therapeutic effect and translation potential. We report a hierachical hybrid nanocarrier made of a manganese phosphate core, an outermost lipid shell, and an electrostatically deposited campothecin phosphonate interfacial middle layer. The hydrophobic interactions between camptothecin and lipid layers maintained the integrity and stability of the hybrid nanocarrier. Such a nanoplatform could surprisingly load camptothecin over 15% (w/w) with decent serum stability. The nanocarrier displayed pH-dependent cargo release profiles due to particle collapse under acidic conditions under which the r1 relaxivity of magnetic resonance imaging (MRI) was 25.2 mM-1 s-1 (pH 5.0). The nanocarrier could efficiently transport camptothecin into 4T1 cells with a half maximal inhibitory concentration of 5.4 ± 0.3 µM. Both in vivo MRI and fluorescence imaging analysis revealed that the nanocarrier could competently deliver the cargo to the tumor site. The anticancer efficacy of camptothecin-loaded nanocarrier was proved using the same 4T1 tumor-bearing mice model coupled with the histological and apoptosis analysis. This work not only presented a novel drug encapsulation approach, but also provided a new theranostic hybrid nanoplatform which could realize MRI-guided delivery of hydrophobic agents.