4,5-Dihydro-1,2,4-oxadiazole as a Single Nitrogen Transfer Reagent: Synthesis of Functionalized Isoxazoles Assisted by Sc(OTf)3 or Au(I)/Sc(OTf)3 Synergistic Catalysis.

A five-membered N-O heterocycle, 4,5-dihydro-1,2,4-oxadiazole, was found to act as a single nitrogen atom transfer reagent via elimination of a ketone/aldehyde and a nitrile. This reagent was successfully applied for the synthesis of isoxazoles from ynones promoted by Sc(OTf)3 or through Au(I)/Sc(OTf)3 synergistic catalysis. The efficiency of this protocol was also demonstrated by its application in modifications of structurally complex natural products and pharmaceuticals.

Photoredox/Nickel Dual-Catalyzed Regioselective Allylic Arylations of Allyl Trifluoroborates with Aryl Halides.

An efficient photoredox/nickel dual-catalyzed coupling of allyl trifluoroborates with aryl halides has been developed, which provides an attractive route to diverse-substituted allylic benzenes. The method offers several advantages, such as high efficiency and regioselectivity, mild reaction conditions, wide substrate scope, and functional group compatibility. Mechanistic studies suggest that a π-allyl nickel(III) intermediate generated via the addition of an allyl radical to nickel species is possibly formed as a key reaction intermediate.

Trimer structures formed by target-triggered AuNPs self-assembly inducing electromagnetic hot spots for SERS-fluorescence dual-signal detection of intracellular miRNAs.

Accurate quantitative, in situ and temporal tracking imaging of tumor-associated miRNAs in living cells could provide a basis for cancer diagnosis and prognosis. In this strategy, a surface-enhanced Raman scattering (SERS)-fluorescence (FL) dual-spectral sensor (DSS) was constructed based on the nanoscale photophysical properties of AuNPs, mediated by functionalized DNA, to achieve rapid imaging of FL and accurate SERS quantification of intracellular miRNAs. The dual-spectrum sensor in the strategy is highly sensitive, specific and reproducibly stable. The LOD values of the dual spectra were 3.58 pM (SERS) as well as 11.8 pM (FL) with RSD values less than 2.69%. The bispectral sensor self-assembled into a trimer by the lapidation of Y-type DNA under the excitation of the target, generating a stable enhanced electric field coupling; and selected adenine located in the enhanced electric field as the reporter molecule, simplifying the labeling process and variables of the Raman reporter molecule, distinguishing it from other traditional methods. This strategy successfully achieved accurate tracking and quantification of miR-21 in cancer cells and showed good stability in the cells. The reported probes are potential tools for reliable monitoring of biomolecular dynamics in living cells.

An NIR-Driven Upconversion/C3N4/CoP Photocatalyst for Efficient Hydrogen Production by Inhibiting Electron-Hole Pair Recombination for Alzheimer's Disease Therapy.

Redox imbalance and abnormal amyloid protein (Aß) buildup are key factors in the etiology of Alzheimer's disease (AD). As an antioxidant, the hydrogen molecule (H2) has the potential to cure AD by specifically scavenging highly harmful reactive oxygen species (ROS) such as •OH. However, due to the low solubility of H2 (1.6 ppm), the traditional H2 administration pathway cannot easily achieve long-term and effective accumulation of H2 in the foci. Therefore, how to achieve the continuous release of H2 in situ is the key to improve the therapeutic effect on AD. As a corollary, we designed a rare earth ion doped g-C3N4 upconversion photocatalyst, which can respond to NIR and realize the continuous production of H2 by photocatalytic decomposition of H2O in biological tissue, which avoids the problem of the poor penetration of visible light. The introduction of CoP cocatalyst accelerates the separation and transfer of photogenerated electrons in g-C3N4, thus improving the photocatalytic activity of hydrogen evolution reaction. The morphology of the composite photocatalyst was shown by transmission electron microscopy, and the crystal structure was studied by X-ray diffractometry and Raman analysis. In addition, the ability of g-C3N4 to chelate metal ions and the photothermal properties of CoP can inhibit Aß and reduce the deposition of Aß in the brain. Efficient in situ hydrogen production therapy combined with multitarget synergism solves the problem of a poor therapeutic effect of a single target. In vivo studies have shown that UCNP@CoP@g-C3N4 can reduce Aß deposition, improve memory impairment, and reduce neuroinflammation in AD mice.

Smart Programmable Scalable Dual-Mode Diagnostic Logic Nanoflare Strategy for Dual-Tumor Marker Detection.

Compared with the single-marker detection scheme, the detection of multiple targets in the complex cell and biological environment can obtain more reliable detection results. Herein, we detected miRNA-21 and APE1 in two modes, AND and OR, respectively, based on gold nanoflares and simple logic components. In both modes, DNAzyme and APE1 can get rich fluorescence recovery results by breaking the DNA strands from the gold nanorods (AuNRs) and unquenching under different conditions. In vivo and in vitro experiments suggest that both nanoflares exhibit excellent biocompatibility and make efficient and sensitive judgments on the two targets. This strategy emphasizes the reuse nature of enzymes, and a small amount of target can generate a large amount of fluorescent signal in the logic device, which greatly reduces the detection limit when monitoring low-abundance targets. Since the short-stranded DNA component of the detection device is simple in composition and easy to program its probe sequence, it can be expanded into a detection system for the detection of other sets of related markers, which increases its potential for clinical application.

KIF11 manipulates SREBP2-dependent mevalonate cross talk to promote tumor progression in pancreatic ductal adenocarcinoma.

Cholesterol metabolism is highly correlated with risks of pancreatic ductal adenocarcinoma (PDAC). Nevertheless, the underlying mechanisms of activation of cholesterol biogenesis remain inconclusive. KIF11 is a key component of the bipolar spindle and expresses highly in various malignancies. However, its functional role in PDAC tumorigenesis is still unclear. This study aims to elucidate the oncogenic functions of KIF11 in stimulating cholesterol metabolism, thereby driving PDAC progression. We utilized bioinformatics analysis to identify that KIF11 expressed highly in tumor samples versus paired normal tissues and high KIF11 correlated with high clinical stages of patients. Patients with high KIF11 had worse survival outcomes relative to those with low KIF11. Gene set enrichment analysis (GSEA) revealed that KIF11 correlated intensively with the mevalonate (MVA) metabolic pathway. Positive associations were observed between KIF11 and MVA-signature (HMGCR, FDFT1, SQLE, and MSMO1). KIF11 could elevate the free cholesterol content of PDAC cells and targeting MVA inhibited the in vitro growth of KIF11-overexpressing cells. Mechanistically, we found KIF11 could interact with SREBP2, the master regulator of MVA. High KIF11 could increase SREBP2 proteins, but not alter their mRNA levels. KIF11 could attenuate the ubiquitination-mediated degradation of SREBP2, thereby enhancing its stability and accumulation. Accordingly, KIF11 stimulated the expressions of MVA-signature and free cholesterol contents depending on SREBP2. In addition, KIF11 depended on SREBP2 to promote cell growth, migration, stemness, and colony formation abilities. The subcutaneous xenograft models indicated that targeting MVA biogenesis (atorvastatin) is effective to restrict the in vivo growth of KIF11high PDAC. Taken together, our study identified that KIF11 could activate the MVA cross talk to drive PDAC progression and inhibiting the KIF11/MVA axis provided a therapeutic vulnerability in the treatment of PDAC.

Gold(III) or Gold(I)/Lewis-Acid-Catalyzed Substitution/Cyclization/1,2-Migration Reactions of Propargyl Alcohols with 3-Amino-benzo[d]isoxazoles: Synthesis of Pyrimidine Derivatives.

A straightforward synthesis of pyrimidines via Au(III) or Au(I)/Lewis-acid-catalyzed cascade reactions of propargyl alcohols with 3-amino-benzo[d]isoxazoles is described. The propargyl amine intermediates are readily generated in situ via oxophilic activation of gold(III) or a Lewis acid, which undergo cyclization/1,2-group migration/aromatization to deliver the desired products. Highly selective 1,2-H or -R1 migrations are observed in most cases, and the migratory aptitude is dependent on the steric and electronic properties of the propargylic groups.

Gold-Catalyzed Cyclization of Ynones Involving cis-Hydrofunctionalizations: Rapid Assembly of C-, O-, or S-Functionalized Pyrroles by a Single Methodology.

A gold-catalyzed cyclization of conjugated ynones with various nucleophiles such as indoles, alcohols, and thiols has been developed. The reaction provides a new and efficient protocol for the synthesis of functionalized pyrroles with wide versatility and functional group compatibility. Remarkably, for indolyl, alkoxy, or sulfenyl pyrroles, all could be constructed efficiently by this single methodology. In addition, cis-hydrofunctionalizations of ynones are involved in these reactions.

Gold-Catalyzed Oxidative Cyclization Involving Nucleophilic Attack to the Keto Group of α,α'-Dioxo Gold Carbene and 1,2-Alkynyl Migration: Synthesis of Furan-3-carboxylates.

A multicomponent strategy for the synthesis of functionalized furan-3-carboxylates based on gold-catalyzed oxidative cyclization of diynones with alcohols or water has been developed. Mechanistic studies revealed that a rare nucleophilic attack to the carbonyl group of the α,α'-dioxo gold carbene instead of the carbene center and 1,2-alkynyl group migration were involved in this transformation. This method offers several advantages such as mild conditions, high regio- and chemoselectivity, and wide functional group compatibility.

New nitrogen-containing metabolites from cultures of rice false smut pathogen Villosiclava virens.

Two new nitrogen-containing metabolites methyl N-acetyl-O-(4-acetylphenyl)-L-homoserinate (1), dimethyl (1H-indole-3-carbonyl)-D-glutamate (2), and two new natural products, 1,2-O-isopropylidene-D-mannitol (3), N-acetyl-ß-methyl-L-phenylalanine (4), along with five known compounds (5-9) were isolated from the rice false smut pathogen Villosiclava virens UV-8b cultured in the solid rice medium. The structures were elucidated by spectroscopic analysis and by comparison of their physical and spectroscopic data with the literature. These metabolites were evaluated for their antibacterial and phytotoxic activities. Compounds 5-7 showed weak inhibition against the tested bacteria, while compounds 4-6 and 9 displayed inhibitory activity against the radicle elongation of rice seeds.

Development of an Autophagy Score Signature for Predicting Overall Survival in Papillary Renal Cell Carcinoma.

BACKGROUND: Autophagy is considered to be closely associated with cancer, functioning as either an anticancer or procancer mechanism depending on the cancer stage. However, the prognostic value of autophagy on papillary renal cell carcinoma (pRCC) remains unclear. In this study, our purpose was to determine the autophagy-related mRNA signature to predict the overall survival of patients with pRCC. MATERIALS AND METHODS: A total of 284 patients with pathologic confirmed pRCC in The Cancer Genome Atlas (TCGA) dataset were recruited and included. We choose patients who have smoked less than 15 years but staging 3 or 4 (including nontobacco exposure) vs. more than 15 years but staging 1 or 2. Fourteen differentially expressed mRNAs were found with fold change > 2 and P value < 0.001 through limma package after making a pair between nontobacco exposure or less than 15 years and tobacco exposure more than 15 years by matchIt package. RESULTS: Six mRNAs were identified to be significantly associated with overall survival. Then, using a risk score based on the signature of these six mRNAs, we divided the patients into low-risk and high-risk groups with significantly different OS. Further multivariate Cox regression analyses revealed that the 6-mRNA signature was independent of age, TNM stage, and tumor type. In the present study, a novel 6-mRNA signature that is useful in survival prediction in pRCC patients was developed. If validated, this mRNA signature might assist in selecting high-risk subpopulation that needs more aggressive therapeutic intervention. The risk score involved in several cancer-related pathways was identified using gene set enrichment analysis. CONCLUSION: We initially generated a six autophagy-related genes' signature, which correlates with AJCC N stage, tumor type, and pathological stage and independently predicts OS.

Eremophilane-Type Sesquiterpenoids From the Endophytic Fungus Rhizopycnis vagum and Their Antibacterial, Cytotoxic, and Phytotoxic Activities.

Fourteen new eremophilane-type sesquiterpenoids, named rhizoperemophilanes A~N (1~14), together with eight known congeners, were isolated from the culture of the endophytic fungus Rhizopycnis vagum. The structures of the new compounds were elucidated by extensive spectroscopic analyses, as well as ECD calculations and the modified Mosher's method for the assignment of the absolute configurations. Rhizoperemophilane J (10) contains an uncommon C-4/C-11 epoxy ring, while rhizoperemophilane N (14) features an unprecedented 3-nor-eremophilane lactone-lactam skeleton. These metabolites were evaluated for their antibacterial, cytotoxic, and phytotoxic activities. Among them, compounds 11, 16, and 20 displayed antibacterial activities, while 14 showed selective cytotoxicity against NCI-H1650 and BGC823 tumor cells. Moreover, compounds 5, 6, 12, 13, 16, and 19 exhibited strong phytotoxic activities against the radicle elongation of rice seedlings.

Gold/Lewis acid catalyzed oxidative cyclization involving activation of nitriles.

A gold-catalyzed oxidative cyclization of alkyne-nitriles using water or alcohol as the external nucleophiles has been developed. The catalytic system, featured with gold and Lewis acid dual catalysis, allows a facile synthesis of functionalized isoquinolin-1(2H)-ones and 1-alkoxy-isoquinolines with a wide structural diversity.

GC-Derived EVs Enriched with MicroRNA-675-3p Contribute to the MAPK/PD-L1-Mediated Tumor Immune Escape by Targeting CXXC4.

MicroRNAs (miRNAs) delivered by gastric cancer (GC)-secreted extracellular vesicles (GC-EVs) are associated with the immune escape in GC. Microarray analysis based on the GEO: GSE112369 dataset identified the presence of poorly expressed CXXC finger protein 4 (CXXC4) in GC, which was validated in clinical samples of GC patients. Moreover, prediction based on TargetScan analysis demonstrated the putative miR-675-3p binding site in the 3' UTR region of CXXC4. Thereby, our study aims to determine the role of GC-EV-encapsulated miR-675-3p in GC. First, CXXC4 was found to be negatively correlated with programmed cell death 1 ligand 1 (PD-L1). The effects of mitogen-activated protein kinase (MAPK) signaling on GC were evaluated using activator of the MAPK pathway. The overexpression of CXXC4 led to a downregulated MAPK signaling pathway, thus decreasing PD-L1 expression to augment the proliferation and activation of T cells co-cultured with GC HGC-27 cells. GC-EV-encapsulated miR-675-3p negatively regulated the expression of its target gene CXXC4. GC-EV-encapsulated miR-675-3p increased PD-L1 expression to stimulate the immune escape in vitro and EV-encapsulated miR-675-3p accelerated cisplatin resistance in vivo. Collectively, the aforementioned findings present a mechanism in which EV-mediated miR-675-3p upregulates PD-L1 expression, promoting immune escape in GC.

CXXC finger protein 4 inhibits the CDK18-ERK1/2 axis to suppress the immune escape of gastric cancer cells with involvement of ELK1/MIR100HG pathway.

Gastric cancer, is the fourth most common tumour type yet, ranks second in terms of the prevalence of cancer-related deaths worldwide. CXXC finger protein 4 (CXXC4) has been considered as a novel cancer suppressive factor, including gastric cancer. This study attempted to investigate the possible function of CXXC4 in gastric cancer and the underlying mechanism. The binding of the ETS domain-containing protein-1 (ELK1) to the long non-coding RNA MIR100HG promoter region was identified. Then, their expression patterns in gastric cancer tissues and cells (SGC7901) were detected. A CCK-8 assay was used to detect SGC7901 cell proliferation. Subsequently, SGC7901 cells were co-cultured with CD3+ T cells, followed by measurement of CD3+ T cell proliferation, magnitude of IFN-γ+ T cell population and IFN-γ secretion. A nude mouse model was subsequently developed for in vivo validation of the in vitro results. Low CXXC4 expression was found in SGC7901 cells. Nuclear entry of ELK1 can be inhibited by suppression of the extent of ELK1 phosphorylation. Furthermore, ELK1 is able to bind the MIR100HG promoter. Overexpression of CXXC4 resulted in weakened binding of ELK1 to the MIR100HG promoter, leading to a reduced proliferative potential of SGC7901 cells, and an increase in IFN-γ secretion from CD3+ T cells. Moreover, in vivo experiments revealed that CXXC4 inhibited immune escape of gastric cancer cells through the ERK1/2 axis. Inhibition of the CXXC4/ELK1/MIR100HG pathway suppressed the immune escape of gastric cancer cells, highlighting a possible therapeutic target for the treatment of gastric cancer.

Reducing higher alcohols by nitrogen compensation during fermentation of Chinese rice wine.

Excessive amount of higher alcohols in alcoholic beverages causes unwell and side-effect for consumers although adequate consumption offers joy and pleasure. Therefore, reducing higher alcohols in alcoholic beverages is necessary. We used nitrogen compensation to reduce higher alcohols with Chinese rice wine as an experimental model. Higher alcohols including isobutyl alcohols, isoamyl alcohols, and ß-phenethyl alcohols were significantly decreased by 19.27, 23.03 and 19.43%, respectively, when 200 mg/L (NH4)2HPO4, 5% (w/v) yeast, and 11% wheat Koji were added to fermentation broth. Meanwhile, important quality parameters remained unchanged including free amino acids, organic acids, biogenic amines, and esters. The expression of glutamate dehydrogenase 1 gene (GDH1) and glutamine synthetase gene (GLN1) was significantly enhanced, 26.9- and 1.9-folds respectively. These results suggest that ammonium compensation could effectively decrease higher alcohols in Chinese rice wine by activating glutamate dehydrogenase (GDH) pathway in ammonium assimilation.

Deficiency of SCAMP5 leads to pediatric epilepsy and dysregulation of neurotransmitter release in the brain.

Secretory carrier membrane proteins (SCAMPs) play an important role in exocytosis in animals, but the precise function of SCAMPs in human disease is unknown. In this study, we identified a homozygous mutation, SCAMP5 R91W, in a Chinese consanguineous family with pediatric epilepsy and juvenile Parkinson's disease. Scamp5 R91W mutant knock-in mice showed typical early-onset epilepsy similar to that in humans. Single-neuron electrophysiological recordings showed that the R91W mutation significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) at a resting state and also increased the amplitude of evoked EPSCs. The R91W mutation affected the interaction between SCAMP5 and synaptotagmin 1 and may affect the function of the SNARE complex, the machinery required for vesicular trafficking and neurotransmitter release. Our work shows that dysfunction of SCAMP5 shifted the excitation/inhibition balance of the neuronal network in the brain, and the deficiency of SCAMP5 leads to pediatric epilepsy.

Rhizovagine A, an unusual dibenzo-α-pyrone alkaloid from the endophytic fungus Rhizopycnis vagum Nitaf22.

Rhizovagine A (1), a novel dibenzo-α-pyrone alkaloid with an unprecedented 5/5/6/6/6 fused pentacyclic skeleton, was isolated from the endophytic fungus Rhizopycnis vagum Nitaf22. The structure was elucidated by comprehensive spectroscopic analysis, in combination with quantum chemical 13C NMR and electronic circular dichroism (ECD) calculations for configurational assignment. A plausible biosynthetic pathway for 1 was proposed. Compound 1 displayed acetylcholinesterase inhibitory activity.

IL-8 is involved in radiation therapy resistance of esophageal squamous cell carcinoma via regulation of PCNA.

Esophageal squamous cell carcinoma (ESCC) is one of the prevalent and deadly cancers worldwide, especially in Eastern Asia. Our present study revealed that the expression of IL-8 was increased in radiation therapy resistance of ESCC cells. Targeted inhibition of IL-8 by its neutralization antibody (anti-IL-8) can re-sensitize ESCC cells to radiation therapy and suppress the expression of proliferating cell nuclear antigen (PCNA). IL-8 can regulate the expression of PCNA via modulating its mRNA stability and promoter activity. Mechanistically, IL-8 can regulate the expression of miR-27b-5p, which can directly bind with 3'UTR of PCNA to decrease its mRNA stability. Further, anti-IL-8 can decrease the expression of transcription factor YY1, which can bind with the promoter of PCNA to increase its transcription. Taken together, our data revealed that IL8 can regulate the radiation resistance of ESCC cells and expression of PCNA. It suggested that targeted inhibition of IL-8 may improve the clinical treatment efficiency of radio therapy.

Benzofurazan N-Oxides as Mild Reagents for the Generation of α-Imino Gold Carbenes: Synthesis of Functionalized 7-Nitroindoles.

An efficient gold-catalyzed [3 + 2] annulation of benzofurazan N-oxides with ynamides has been developed, which provides a concise and regioselective access to highly functionalized 7-nitroindoles. Although N-oxides are often considered as oxygen transfer reagents in gold catalysis, benzofurazan N-oxide was found to act as a facile precursor for an α-imino gold carbene intermediate. Benzofurazan can also react with ynamides to afford quinoxaline N-oxides via a [4 + 2] annulation process.