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.

A portable dual-mode colorimetric platform for sensitive detection of Hg2+ based on NiSe2 with Hg2+-Activated oxidase-like activity.

The nanozyme-based colorimetric strategy for heavy metal detection has broad application prospects nowadays. However, the inefficient recognition capabilities of nanozyme sensors for targets hinder its further application. Herein, the authors synthesize bare nickel selenide (NiSe2) via a one-step hydrothermal reaction, in which the Se element possesses a strong binding ability with mercury (Hg). As expected, NiSe2 exhibits oxidase-like activity in the presence of Hg2+, that is, Hg2+ can enhance the oxidase-like activity of NiSe2. The enhanced mechanism is the accelerated electron transfer between NiSe2-Hg2+ and substrate caused by the formation of Hg-Se bonds. Besides, the oxidase-like activity of NiSe2 exhibits excellent selectivity, sensitivity and stability in response to Hg2+, which enables NiSe2-Hg2+ to efficiently oxidize colorless TMB to blue TMB even in harsh environments. Based on this, a dual-mode colorimetric sensor integrating solution reaction and test paper is developed for the detection of Hg2+. In the Hg2+ concentration range of 10-700 nM, the colorimetric platform presents a liner response to Hg2+, which can reach a low LOD of 5.18 nM in solution reaction and 8.42 nM in the test paper. The proposed strategy can also be applied to real water samples with good recovery and excellent self-calibration capability.

The Detrimental Role of Intraluminal Thrombus Outweighs Protective Advantage in Abdominal Aortic Aneurysm Pathogenesis: The Implications for the Anti-Platelet Therapy.

Abdominal aortic aneurysm (AAA) is a common cardiovascular disease resulting in morbidity and mortality in older adults due to rupture. Currently, AAA treatment relies entirely on invasive surgical treatments, including open repair and endovascular, which carry risks for small aneurysms (diameter < 55 mm). There is an increasing need for the development of pharmacological intervention for early AAA. Over the last decade, it has been increasingly recognized that intraluminal thrombus (ILT) is involved in the growth, remodeling, and rupture of AAA. ILT has been described as having both biomechanically protective and biochemically destructive properties. Platelets are the second most abundant cells in blood circulation and play an integral role in the formation, expansion, and proteolytic activity of ILT. However, the role of platelets in the ILT-potentiated AAA progression/rupture remains unclear. Researchers are seeking pharmaceutical treatment strategies (e.g., anti-thrombotic/anti-platelet therapies) to prevent ILT formation or expansion in early AAA. In this review, we mainly focus on the following: (a) the formation/deposition of ILT in the progression of AAA; (b) the dual role of ILT in the progression of AAA (protective or detrimental); (c) the function of platelet activity in ILT formation; (d) the application of anti-platelet drugs in AAA. Herein, we present challenges and future work, which may motivate researchers to better explain the potential role of ILT in the pathogenesis of AAA and develop anti-platelet drugs for early AAA.

HCMV-miR-US33-5p promotes apoptosis of aortic vascular smooth muscle cells by targeting EPAS1/SLC3A2 pathway.

BACKGROUND: In patients with acute aortic dissection (AAD), increased vascular smooth muscle cell (VSMC) apoptosis has been found. Human cytomegalovirus (HCMV)-miR-US33-5p was significantly increased in the plasma of patients with AAD. However, the roles of miR-US33-5p in human aortic VSMC (HA-VSMC) apoptosis remain to be elucidated. METHODS: In the current study, cell apoptosis was analyzed by flow cytometry, cell proliferation by CCK-8 assay, and differentially expressed genes by RNA sequencing. Luciferase reporter assay was used for binding analysis between miR-US33-5p and endothelial PAS domain protein 1 (EPAS1), and EPAS1 and amino acid transporter heavy chain, member 2 (SLC3A2). The enrichment degree of SLC3A2 promoter DNA was analyzed by chromatin immunoprecipitation assay. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunoblotting were performed for measuring messenger RNA (mRNA) and protein levels, respectively. RESULTS: It was found that HCMV infection inhibited proliferation but promoted HA-VSMC apoptosis by upregulating HCMV-miR-US33-5p. Transfection of HCMV-miR-US33-5p mimics the significant effect on several signaling pathways including integrin signaling as shown in the RNA sequencing data. Western blotting analysis confirmed that HCMV-miR-US33-5p mimics suppression of the activity of key factors of the integrin signal pathway including FAK, AKT, CAS, and Rac. Mechanistic study showed that HCMV-miR-US33-5p bound to the 3'-untranslated region of EPAS1 to suppress its expression, leading to suppression of SLC3A2 expression, which ultimately promoted cell apoptosis and inhibited cell proliferation. This was confirmed by the findings that silencing EPAS1 significantly reduced the SLC3A2 expression and inhibited proliferation and key factors of integrin signal pathway. CONCLUSIONS: HCMV-miR-US33-5p suppressed proliferation, key factors of integrin signal pathway, and EPAS1/SLC3A2 expression, but promoted HA-VSMC apoptosis. These findings highlighted the importance of HCMV-miR-US33-5p/EPAS1/SCL3A2 signaling and may provide new insights into therapeutic strategies for AAD.

Kansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with Koolen-de Vries syndrome in mice.

Koolen-de Vries syndrome (KdVS) is a rare disorder caused by haploinsufficiency of KAT8 regulatory NSL complex subunit 1 (KANSL1), which is characterized by intellectual disability, heart failure, hypotonia, and congenital malformations. To date, no effective treatment has been found for KdVS, largely due to its unknown pathogenesis. Using siRNA screening, we identified KANSL1 as an essential gene for autophagy. Mechanistic study shows that KANSL1 modulates autophagosome-lysosome fusion for cargo degradation via transcriptional regulation of autophagosomal gene, STX17. Kansl1+/- mice exhibit impairment in the autophagic clearance of damaged mitochondria and accumulation of reactive oxygen species, thereby resulting in defective neuronal and cardiac functions. Moreover, we discovered that the FDA-approved drug 13-cis retinoic acid can reverse these mitophagic defects and neurobehavioral abnormalities in Kansl1+/- mice by promoting autophagosome-lysosome fusion. Hence, these findings demonstrate a critical role for KANSL1 in autophagy and indicate a potentially viable therapeutic strategy for KdVS.

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.

Peripheral Blood miR-451 May Serve as a Biomarker of Ischemic Stroke.

BACKGROUND: The current study aims to investigate the correlation between the expression level of miR-451 in peripheral blood and the risk of ischemic stroke, and its feasibility as a biomarker of ischemic stroke. METHODS: Three hundred and two cases of ischemic stroke diagnosed in Qianfoshan Hospital Affiliated to Shandong University from April 2017 to Dec 2017 and 302 cases matched for age and gender were selected from routine health examination subjects. Real-time quantitative PCR was used to detect the expression of microRNA in peripheral blood. Receiver operating curve (ROC) was used to analyze whether miR-451 could be used as a basis for judging ischemic stroke. RESULTS: The expression level of miR-451 in peripheral blood of patients with ischemic stroke was higher than that of the control group (p < 0.05). ROC analysis demonstrated that peripheral blood miR-451 could screen ischemic stroke patients from healthy controls, with the AUC of 0.912. In addition, the expression level of miR-451 was negatively correlated with the number of platelets and platelet hematocrit (p < 0.05). CONCLUSIONS: There is a significant correlation between the expression level of miR-451 in peripheral blood and the occurrence of ischemic stroke. miR-451 is expected to be a biomarker of ischemic stroke.

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.

Characterization and genome analysis of a novel bacteriophage vB_SpuP_Spp16 that infects Salmonella enterica serovar pullorum.

A novel virulent bacteriophage vB_SpuP_Spp16 (hereafter designated Spp16) that infects Salmonella enterica serovar pullorum was isolated. Transmission electron microscopy showed that Spp16 possessed an isometric polyhedral head (60 nm in diameter) and a short tail (10 nm in length) belonging to the family Podoviridae. Its complete genome was determined to be 41,832 bp, with a 39.46% GC content by next-generation sequencing. The genome contains 53 proposed open reading frames that are involved in DNA replication and modification, transcriptional regulation, phage structural and packaging proteins and bacterial lysis. No transfer RNA genes were identified. The termini of genome were determined using our previously proposed termini identification method, which suggests that this phage has redundant termini with 421 bp direct terminal repeats. BLASTn analysis revealed the highest sequence similarity with Yersinia phage phi80-18, with a genome coverage of 33% and highest sequence identity of 69%. The phylogenetic analysis indicated that Spp16 forms a distinct branch of the subfamily Autographivirinae. Comparative genomics analysis showed that the phage Spp16 should be regarded as a new subcluster within the GAP227-like cluster in the Autographivirinae subfamily. The phage Spp16 has an obligate lytic life cycle demonstrated by experimental data and genomic analysis. These results suggest that Spp16 may be a proper candidate to control diseases caused by Salmonella enterica serovar pullorum.

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.

When self-assembly meets topology: an enhanced micelle stability.

The topology of hydrophobic moieties can affect the stability of self-assembled micelles. Curved corannulene and flat perylene were selected as model hydrophobic molecules with poly(ethylene glycol) as the hydrophilic segment. The curvature can enhance the intermolecular π-π interaction, and hence the driving force of micelle formation.