Serum exosomal miRNA promote glioma progression by targeting SOS1 via abscopal effect of radiation.

INTRODUCTION: Local exposure to ionizing radiation (IR) can induce changes in biological processes in distant tissues and organs. Exosomes are nanoscale vesicles that transport biomolecules, mediate communication between cells and tissues, and can affect the abscopal effects of radiotherapy. METHODS: Mice were treated with 8.0 Gy doses of chest and abdomen IR, after which serum samples were taken 24 h after exposure. Their serum exosomes were then isolated via ultracentrifugation and the small RNA portions were extracted for sequencing and bioinformatic analysis. Exosomes were injected intravenously into the mice to assess their ability to cross the blood-brain barrier (BBB). Glioma cells and glioma stem cells (GSCs) were examined for malignant biological behaviors, stemness, and tumorigenic capacity after co-culturing with different groups of exosomes. RESULTS: We found that serum exosomes crossed the BBB in mice after local IR exposure-which induced decreases in the expression of BBB tight-junction proteins and increased brain endothelial cell apoptosis. Exosomes from the exposed groups promoted malignant biological behaviors, stemness, and tumorigenic capacity in glioma cells and GSCs by upregulating the expression of SOS1. Phospho-MEK1/2 and Phospho-ERK1/2, of the MAPK signaling pathway, were found to be up-regulated in cells that were co-cultured with the exposing groups of the exosomes. Further analyses demonstrated that differentially expressed levels of miR-93-5p in mouse serum exosomes regulated the cellular expression of SOS1. CONCLUSION: Following local IR exposure, serum exosomes cross the BBB to promote the progression of distant gliomas. Exosomal microRNAs play an important role in this process.

Synthesis of Dioxo-Azabicyclo[3.2.1]octanes via Hypervalent Iodine-Mediated Domino Reaction.

Bicyclo[3.2.1]octane (BCO) skeleton widely exists in natural products and biologically active molecules, whereas the development of convenient approaches to construct this structure remains a challenge. Herein, we describe a cascade reaction to synthesize 6,8-dioxa-3-azabicycle[3.2.1]octane derivatives from ß-keto allylamines via an oxidation-cyclization reaction. A series of dioxo-azabicyclo[3.2.1]octanes bearing a quaternary carbon center were obtained in good yields under mild reaction conditions. Moreover, the mechanistic rationale for this novel domino reaction is supported by control experiments.

The COP9 signalosome stabilized MALT1 promotes Non-Small Cell Lung Cancer progression through activation of NF-κB pathway.

MALT1 has been implicated as an upstream regulator of NF-κB signaling in immune cells and tumors. This study determined the regulatory mechanisms and biological functions of MALT1 in non-small cell lung cancer (NSCLC). In cell culture and orthotopic xenograft models, MALT1 suppression via gene expression interference or protein activity inhibition significantly impaired malignant phenotypes and enhanced radiation sensitivity of NSCLC cells. CSN5, the core subunit of COP9 signalosome, was firstly verified to stabilize MALT1 via disturbing the interaction with E3 ligase FBXO3. Loss of FBXO3 in NSCLC cells reduced MALT1 ubiquitination and promoted its accumulation, which was reversed by CSN5 interference. An association between CSN5/FBXO3/MALT1 regulatory axis and poor prognosis in NSCLC patients was identified. Our findings revealed the detail mechanism of continuous MALT1 activation in NF-κB signaling, highlighting its significance as predictor and potential therapeutic target in NSCLC.

Synthesis of Oxazolidines and Dihydroxazines via Cyclization of α-Aminated Ketones.

A new approach to oxazolidines and dihydroxazines was developed by regioselective cyclization of α-aminated ketones under transition metal-free conditions. Oxazolidine derivatives were generated in the presence of chloro benziodoxole and TFA, while dihydroxazines were formed without a hypervalent iodine reagent. The reaction was performed under room temperature and gave the products in good to excellent yields.

Synthesis of Dihydroxazines and Fluorinated Oxazepanes Using a Hypervalent Fluoroiodine Reagent.

Application of a hypervalent fluoroiodane for the regiodivergent synthesis of dihydroxazines and fluorinated oxazepanes from allylaminoethanol was investigated. The reaction was carried out under mild conditions and gave the products in moderate to good yields. The selectivity of this transformation is controlled by the substituents of the allylaminoethanol.

Recent progress of 1,1-difunctionalization of olefins.

Olefins are a very important class of compounds and broadly used in the construction of various synthetic building blocks and practical industrial production. The difunctionalization of olefins provides one of the most powerful methods for the C-C or C-X bond formation with a rapid increase of the molecular complexity and synthetic value economically and effectively. Compared with the vigorous growth and abundant achievements of 1,2-difunctionalization of olefins, 1,1-difunctionalization is a relatively emerging and inadequately exploited research direction, despite being tremendously attractive from synthetic perspectives. In this minireview, we provide a brief overview of the advancements of 1,1-difunctionalization of olefins in the past twenty years, and prospects of future developments.

Divergent synthesis of oxazolidines and morpholines via PhI(OAc)2-mediated difunctionalization of alkenes.

Herein we describe the PhI(OAc)2-mediated 1,1- and 1,2-difunctionalization of alkenes with N-tosyl amino alcohols to form oxazolidine and morpholine derivatives. This transformation was realized under mild reaction conditions and allows application to various substrates furnishing the multi-substituted oxazolidines and morpholines with yields up to 98%. A deuterium-labeling experiment was carried out and the result indicated that a phenyl group migration occurred to generate oxazolidine products.

Electrocatalytically Active Fe-(O-C2 )4 Single-Atom Sites for Efficient Reduction of Nitrogen to Ammonia.

Single-atom catalysts have demonstrated their superiority over other types of catalysts for various reactions. However, the reported nitrogen reduction reaction single-atom electrocatalysts for the nitrogen reduction reaction exclusively utilize metal-nitrogen or metal-carbon coordination configurations as catalytic active sites. Here, we report a Fe single-atom electrocatalyst supported on low-cost, nitrogen-free lignocellulose-derived carbon. The extended X-ray absorption fine structure spectra confirm that Fe atoms are anchored to the support via the Fe-(O-C2 )4 coordination configuration. Density functional theory calculations identify Fe-(O-C2 )4 as the active site for the nitrogen reduction reaction. An electrode consisting of the electrocatalyst loaded on carbon cloth can afford a NH3 yield rate and faradaic efficiency of 32.1 µg h-1 mgcat. -1 (5350 µg h-1 mgFe -1 ) and 29.3 %, respectively. An exceptional NH3 yield rate of 307.7 µg h-1 mgcat. -1 (51 283 µg h-1 mgFe -1 ) with a near record faradaic efficiency of 51.0 % can be achieved with the electrocatalyst immobilized on a glassy carbon electrode.

Hypervalent iodane mediated reactions of N-acetyl enamines for the synthesis of oxazoles and imidazoles.

A hypervalent iodane reagent used for the intramolecular cyclization of N-acetyl enamines and intermolecular cyclocondensation of enamines and nitriles was investigated. The reaction was performed under mild conditions and gave oxazoles and imidazoles, respectively, in moderate to excellent yields. This transformation exhibits good reactivity, selectivity and functional group tolerance. The selectivity of the intra- or intermolecular reaction is dependent on the structure of N-acetyl enamines.

ZnCl2-Catalyzed [3 + 2] Cycloaddition of Benzimidates and 2 H-Azirines for the Synthesis of Imidazoles.

ZnCl2-catalyzed [3 + 2] cycloaddition reaction of benzimidates and 2 H-azirines has been developed. This convenient method allowed the efficient construction of a series of multisubstituted imidazoles in moderate to good yields under mild reaction conditions. This transformation exhibits good reactivity and high functional group tolerance.

Exosomal small RNA sequencing uncovers the microRNA dose markers for power frequency electromagnetic field exposure.

PURPOSE: The potential health risks caused by power frequency electromagnetic field (PFEMF) have led to increase public health concerns. However, the diagnosis and prognosis remain challenging in determination of exact dose of PFEMF exposure. MATERIALS AND METHODS: Mice were exposed to different magnetic doses of PFEMF for the following isolation of serum exosomes, microRNAs (miRNAs) extraction and small RNA sequencing. After small RNA sequencing, bioinformatic analysis, quantitative real-time PCR (qRT-PCR) validation and serum exosomal miRNA biomarkers were determined. RESULTS: Significantly changed serum exosomal miRNA as biomarkers of 0.1, 0.5, 2.5 mT and common PFEMF exposure were confirmed. Gene ontology (GO) and Kyoto encyclopaedia of genes and genomes (KEGG) pathway analysis of the downstream target genes of the above-identified exosomal miRNA markers indicated that, exosomal miRNA markers were predicted to be involved in critical pathophysiological processes of neural system and cancer- or other disease-related signalling pathways. CONCLUSIONS: Aberrantly-expressed serum exosomal miRNAs, including miR-128-3p for 0.1 mT, miR-133a-3p for 0.5 mT, miR-142a-5p for 2.5 mT, miR-218-5p and miR-199a-3p for common PFEMF exposure, suggested a series of informative markers for not only identifying the exact dose of PFEMF exposure, also consolidating the base for future clinical intervention.

Synthesis of Isoquinolines from Benzimidates and Alkynes via Cobalt(III)-Catalyzed C-H Functionalization/Cyclization.

C-H alkenylation/annulation of benzimidates with alkynes has been realized by using a Cp*Co(III) catalyst under air. A series of substituted isoquinolines were obtained with moderate to good yields under mild reaction conditions.

Loss of BAX by miR-365 Promotes Cutaneous Squamous Cell Carcinoma Progression by Suppressing Apoptosis.

Pro-apoptotic BCL2 associated X (BAX) is traditionally thought to be regulated by anti-apoptotic BCL-2 family members, like BCL2-like 1 (BCL-XL), at the protein level. However, the posttranscriptional regulation of BAX is under explored. In this study, we identified BAX as the novel downstream target of miR-365, which is supported by gain- and loss-of-function studies of onco-miR-365. Loss of BAX by either RNA interference or highly-expressed miR-365 in cells of cutaneous squamous cell carcinoma (CSCC) enhanced the tumor resistance against apoptosis, while repressing cell proliferation, migration, and invasiveness. In vivo experiment confirmed that BAX knockdown promotes the growth of CSCC xenografts. Collectively, our results find a miR-365-BAX axis for alleviating the pro-apoptotic effects of BAX, which promotes CSCC development and may facilitate the generation of novel therapeutic regimens to the clinical treatment of CSCC.

Heavy metals in wild marine fish from South China Sea: levels, tissue- and species-specific accumulation and potential risk to humans.

Heavy metal pollution in marine fish has become an important worldwide concern, not only because of the threat to fish in general, but also due to human health risks associated with fish consumption. To investigate the occurrence of heavy metals in marine fish species from the South China Sea, 14 fish species were collected along the coastline of Hainan China during the spring of 2012 and examined for species- and tissue-specific accumulation. The median concentrations of Cd, Cr, Cu, Zn, Pb and As in muscle tissue of the examined fish species were not detectable (ND), 2.02, 0.24, 2.64, 0.025, and 1.13 mg kg(-1) wet weight, respectively. Levels of Cu, Zn, Cd and Cr were found to be higher in the liver and gills than in muscle, while Pb was preferentially accumulated in the gills. Differing from other heavy metals, As did not exhibit tissue-specific accumulation. Inter-species differences of heavy metal accumulation were attributed to the different habitat and diet characteristics of marine fish. Human dietary exposure assessment suggested that the amounts of both Cr and As in marine wild fish collected from the sites around Hainan, China were not compliant with the safety standard of less than 79.2 g d(-1) for wild marine fish set by the Joint FAO/WHO Expert Committee on Food Additives. Further research to identify the explicit sources of Cr and As in marine fish from South China Sea should be established.

Exploring the versatility of biodegradable biomass aerogels: In-depth evaluation of Firmiana simplex bark microfibers depolymerized by deep eutectic solvent.

In this study, we investigated the use of deep eutectic solvents (DESs) at different molar ratios and temperatures as a green and efficient approach for microfibers (MFs) extraction. Our approach entailed the utilization of Firmiana simplex bark (FSB) fibers, enabling the production of different dimensions of FSB microfibers (FSBMFs) by combining DES pretreatment and mechanical disintegration technique. The proposed practice demonstrates the simplicity and effectiveness of the method. The morphology of the prepared microfibers was studied using the Scanning electron microscopic (SEM) technique. Additionally, the results revealed that the chemical and mechanical treatments did not significantly alter the well-preserved cellulose structure of microfibers, and a crystallinity index of 56.6 % for FSB fibers and 63.8 % for FSBMFs was observed by X-ray diffraction (XRD) analysis. Furthermore, using the freeze-drying technique, FSBMFs in water solutions produced effective aerogels for air purification application. In comparison to commercial mask (CM), FSBMF aerogels' superior hierarchical cellular architectures allowed them to attain excellent filtration efficiencies of 94.48 % (PM10) and 91.51 % (PM2.5) as well as excellent degradation properties were analyzed. The findings show that FSBMFs can be extracted from Firmiana simplex bark, a natural cellulose-rich material, using DES for environmentally friendly aerogel preparation and applications.

KTN1 mediated unfolded protein response protects keratinocytes from ionizing radiation-induced DNA damage.

BACKGROUND: The unfolded protein response (UPR) is one of the cytoprotective mechanisms against various stresses and essential for the normal function of skin. Skin injury caused by ionizing radiation (IR) is a common side effect of radiotherapy and it is unclear how UPR affects IR-induced skin injury. OBJECTIVES: To verify the effect of UPR on IR-induced DNA damage in keratinocytes and the relation between an endoplasmic reticulum (ER) protein KTN1 and UPR. METHODS: All experiments were performed on keratinocytes models: HaCaT and HEK-A. ER lumen and the expression levels of KTN1 and UPR pathway proteins (PERK, IRE1α and ATF6) were examined by transmission electron microscopy and immunoblotting, respectively. 4-PBA, an UPR inhibitor, was used to detected its effects on DNA damage and cell proliferation. Subsequently, the effects of KTN1 deletion on UPR, DNA damage and cell proliferation after IR were detected. Tunicamycin was used to reactivate UPR and then we examined its effects on DNA damage. RESULTS: UPR was activated by IR in keratinocytes. Inhibition of UPR aggravated DNA damage and suppressed cell proliferation after IR. KTN1 expression was upregulated by IR and KTN1 depletion reduced ER expansion and the expression of UPR-related proteins. Moreover, KTN1 depletion aggravated DNA damage and suppressed cell proliferation after IR could reversed by reactivation of UPR. CONCLUSION: KTN1 deletion aggravates IR-induced keratinocyte DNA damage via inhibiting UPR. Our findings provide new insights into the mechanisms of keratinocytes in response to IR-induced damage.

Amodiaquine ameliorates stress-induced premature cellular senescence via promoting SIRT1-mediated HR repair.

DNA damage is considered to be a potentially unifying driver of ageing, and the stalling of DNA damage repair accelerates the cellular senescence. However, augmenting DNA repair has remained a great challenge due to the intricate repair mechanisms specific for multiple types of lesions. Herein, we miniaturized our modified detecting system for homologous recombination (HR) into a 96-well-based platform and performed a high-throughput chemical screen for FDA-approved drugs. We uncovered that amodiaquine could significantly augment HR repair at the noncytotoxic concentration. Further experiments demonstrated that amodiaquine remarkably suppressed stress-induced premature cellular senescence (SIPS), as evidenced by senescence-associated beta-galactosidase (SA-ß-gal) staining or senescence-related markers p21WAF1 and p16ink4a, and the expression of several cytokines. Mechanistic studies revealed that the stimulation of HR repair by amodiaquine might be mostly attributable to the promotion of SIRT1 at the transcriptional level. Additionally, SIRT1 depletion abolished the amodiaquine-mediated effects on DNA repair and cellular senescence, indicating that amodiaquine delayed the onset of SIPS via a SIRT1-dependent pathway. Taken together, this experimental approach paved the way for the identification of compounds that augment HR activity, which could help to underscore the therapeutic potential of targeting DNA repair for treating aging-related diseases.

Higher affinities of fibers with cell receptors increase the infection capacity and virulence of human adenovirus type 7 and type 55 compared to type 3.

IMPORTANCE: HAdV-3, -7, and -55 are the predominant types causing acute respiratory disease outbreaks and can lead to severe and fatal pneumonia in children and adults. In recent years, emerging or re-emerging strains of HAdV-7 and HAdV-55 have caused multiple outbreaks globally in both civilian and military populations, drawing increased attention. Clinical studies have reported that HAdV-7 and HAdV-55 cause more severe pneumonia than HAdV-3. This study aimed to investigate the mechanisms explaining the higher severity of HAdV-7 and HAdV-55 infection compared to HAdV-3 infection. Our findings provided evidence linking the receptor-binding protein fiber to stronger infectivity of the strains mentioned above by comparing several fiber-chimeric or fiber-replaced adenoviruses. Our study improves our understanding of adenovirus infection and highlights potential implications, including in novel vector and vaccine development.

Discovery of a Series of 4-Amide-thiophene-2-carboxyl Derivatives as Highly Potent P2Y14 Receptor Antagonists for Inflammatory Bowel Disease Treatment.

The P2Y14 receptor has been proven to be a potential target for IBD. Herein, we designed and synthesized a series of 4-amide-thiophene-2-carboxyl derivatives as novel potent P2Y14 receptor antagonists based on the scaffold hopping strategy. The optimized compound 39 (5-((5-fluoropyridin-2-yl)oxy)-4-(4-methylbenzamido)thiophene-2-carboxylic acid) exhibited subnanomolar antagonistic activity (IC50: 0.40 nM). Moreover, compound 39 demonstrated notably improved solubility, liver microsomal stability, and oral bioavailability. Fluorescent ligand binding assay confirmed that 39 has the binding ability to the P2Y14 receptor, and molecular dynamics (MD) simulations revealed the formation of a unique intramolecular hydrogen bond (IMHB) in the binding conformation. In the experimental colitis mouse model, compound 39 showed a remarkable anti-IBD effect even at low doses. Compound 39, with a potent anti-IBD effect and favorable druggability, can be a promising candidate for further research. In addition, this work lays a strong foundation for the development of P2Y14 receptor antagonists and the therapeutic strategy for IBD.

A novel onco-miR-365 induces cutaneous squamous cell carcinoma.

The expression levels of miR-365 vary in different malignancies. Herein, we found that miR-365 was overexpressed in both cells and clinical specimens of cutaneous squamous cell carcinoma (SCC). We demonstrated that the HaCaT(pre-miR-365-2) cell line, which overexpressed miR-365, could induce subcutaneous tumors in vivo. Antagomir-365, an anti-miR-365 oligonucleotide, inhibited cutaneous tumor formation in vivo, along with G1 phase arrest and apoptosis of cancer cells. These findings suggest that miR-365 may act as an onco-miR in cutaneous SCC both in vitro and in vivo. The present study provides valuable insight into the role of miR-365 in cutaneous SCC formation, which can help develop new drug and miR-365 target-based therapies for cutaneous SCC.