Photoinduced Copper-Catalyzed Enantioselective Allylic C(sp3)-H Oxidation of Acyclic 1-Aryl-2-alkyl Alkenes as Limiting Substrates.

Herein, we disclose a simple copper-catalyzed method for enantioselective allylic C(sp3)-H oxidation of unsymmetrical acyclic alkenes, specifically 1-aryl-2-alkyl alkenes. The C-H substrates are used in limiting amounts, and the products are obtained with high enantioselectivity, E/Z-selectivity, and regioselectivity. The method exhibits broad functional group tolerance, and E/Z-alkene mixtures are suitable C-H substrates. The transformation is enabled by light irradiation, which sustains the enantioselective copper catalysis by photoinduced oxidant homolysis.

New Function of Cholesterol Oxidation Products Involved in Osteoporosis Pathogenesis.

Osteoporosis (OP) is a systemic bone disease characterized by decreased bone strength, microarchitectural changes in bone tissues, and increased risk of fracture. Its occurrence is closely related to various factors such as aging, genetic factors, living habits, and nutritional deficiencies as well as the disturbance of bone homeostasis. The dysregulation of bone metabolism is regarded as one of the key influencing factors causing OP. Cholesterol oxidation products (COPs) are important compounds in the maintenance of bone metabolic homeostasis by participating in several important biological processes such as the differentiation of mesenchymal stem cells, bone formation in osteoblasts, and bone resorption in osteoclasts. The effects of specific COPs on mesenchymal stem cells are mainly manifested by promoting osteoblast genesis and inhibiting adipocyte genesis. This review aims to elucidate the biological roles of COPs in OP development, starting from the molecular mechanisms of OP, pointing out opportunities and challenges in current research, and providing new ideas and perspectives for further studies of OP pathogenesis.

Soil Moisture Retrieval in Farmland Areas with Sentinel Multi-Source Data Based on Regression Convolutional Neural Networks.

As an important component of the earth ecosystem, soil moisture monitoring is of great significance in the fields of crop growth monitoring, crop yield estimation, variable irrigation, and other related applications. In order to mitigate or eliminate the impacts of sparse vegetation covers in farmland areas, this study combines multi-source remote sensing data from Sentinel-1 radar and Sentinel-2 optical satellites to quantitatively retrieve soil moisture content. Firstly, a traditional Oh model was applied to estimate soil moisture content after removing vegetation influence by a water cloud model. Secondly, support vector regression (SVR) and generalized regression neural network (GRNN) models were used to establish the relationships between various remote sensing features and real soil moisture. Finally, a regression convolutional neural network (CNNR) model is constructed to extract deep-level features of remote sensing data to increase soil moisture retrieval accuracy. In addition, polarimetric decomposition features for real Sentinel-1 PolSAR data are also included in the construction of inversion models. Based on the established soil moisture retrieval models, this study analyzes the influence of each input feature on the inversion accuracy in detail. The experimental results show that the optimal combination of R2 and root mean square error (RMSE) for SVR is 0.7619 and 0.0257 cm3/cm3, respectively. The optimal combination of R2 and RMSE for GRNN is 0.7098 and 0.0264 cm3/cm3, respectively. Especially, the CNNR model with optimal feature combination can generate inversion results with the highest accuracy, whose R2 and RMSE reach up to 0.8947 and 0.0208 cm3/cm3, respectively. Compared to other methods, the proposed algorithm improves the accuracy of soil moisture retrieval from synthetic aperture radar (SAR) and optical data. Furthermore, after adding polarization decomposition features, the R2 of CNNR is raised by 0.1524 and the RMSE of CNNR decreased by 0.0019 cm3/cm3 on average, which means that the addition of polarimetric decomposition features effectively improves the accuracy of soil moisture retrieval results.

Chemoenzymatic Method for Glycoproteomic N-Glycan Type Quantitation.

Glycosylation is one of the most important post-translational modifications in biological systems. Current glycoproteome methods mainly focus on qualitative identification of glycosylation sites or intact glycopeptides. However, the systematic quantitation of glycoproteins has remained largely unexplored. Here, we developed a chemoenzymatic method to quantitatively investigate N-glycoproteome based on the N-glycan types. Taking advantage of the specificity of different endoglycosidases and isotope dimethyl labeling, six N-glycan types of structures linked on each glycopeptide, including high-mannose/hybrid, biantennary, and triantennary with/without core fucose, were quantified. As a proof of principle, the glycoproteomic N-glycan type quantitative (glyco-TQ) method was first used to determine the N-glycan type composition of the immunoglobulin G1 (IgG1) Fc fragment. Then we applied the method to analyze the glycan type profile of proteins from the breast cancer cell line MCF7, and we quantitatively revealed the N-glycan type microheterogeneity at the glycopeptide and glycoprotein level. The novel quantitative strategy to evaluate the relative intensity of the six states of N-glycan type glycosylation on each site provides a new avenue to investigate the function of glycoproteins in broad areas, such as cancer biomarker research, pharmaceuticals characterization, and antiglycan vaccine development.

Organocatalytic Enantioselective Synthesis of Atropisomeric Aryl-p-Quinones: Platform Molecules for Diversity-Oriented Synthesis of Biaryldiols.

Presented here is a class of novel axially chiral aryl-p-quinones as platform molecules for the preparation of non-C2 symmetric biaryldiols. Two sets of aryl-p-quinone frameworks were synthesized with remarkable enantiocontrol by means of chiral phosphoric acid catalyzed enantioselective arylation of p-quinones by central-to-axial chirality conversion. These aryl-p-quinones were then used to access a wide spectrum of highly functionalized non-C2 symmetric biaryldiols with excellent retention of the enantiopurity.

Titanocene(III)-Catalyzed Three-Component Reaction of Secondary Amides, Aldehydes, and Electrophilic Alkenes.

An umpolung Mannich-type reaction of secondary amides, aliphatic aldehydes, and electrophilic alkenes has been disclosed. This reaction features the one-pot formation of C-N and C-C bonds by a titanocene-catalyzed radical coupling of the condensation products, from secondary amides and aldehydes, with electrophilic alkenes. N-substituted γ-amido-acid derivatives and γ-amido ketones can be efficiently prepared by the current method. Extension to the reaction between ketoamides and electrophilic alkenes allows rapid assembly of piperidine skeletons with α-amino quaternary carbon centers. Its synthetic utility has been demonstrated by a facile construction of the tricyclic core of marine alkaloids such as cylindricine C and polycitorol A.

Methylamidation for isomeric profiling of sialylated glycans by nanoLC-MS.

The analysis of isomeric glycans is a challenging task. In this work, a new strategy was developed for isomer-specific glycan profiling using nanoLC-MS with PGC as the stationary phase. Native glycans were derivatized in the presence of methylamine and trispyrrolidinophosphonium hexafluorophosphate and reduced by the ammonia-borane complex. Methylamidation stabilized the retention time and peak width and improved the detection sensitivity of sialylated glycans to 2-80-fold in comparison to previous ESI-MS methods using the positive-ion mode. Up to 19 tetrasialylated glycan species were identified in the derivatized human serum sample, which were difficult to detect in the sample without derivatization. Furthermore, due to high detection sensitivity and chromatographic resolution, more isomeric glycans could be identified from the model glycoprotein Fetuin and the human serum sample. As a result, up to seven isomers were observed for the disialylated biantennary glycan released from Fetuin, and three of them were identified for the first time in this study. Using the developed analytical strategy, a total of 293 glycan species were obtained from the human serum sample, representing an increase of over 100 peaks in comparison to the underivatized sample. The strategy greatly facilitates the profiling of isomeric glycans and the analysis of trace-level samples.

Solid-phase methylamidation for sialoglycomics by MALDI-MS.

Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has been a major approach for glycan analysis. However, the preferential cleavage of the sialic acid moiety by in- and post-source decay influences the determination of sialylated glycans by MALDI-MS. Many chemical derivatization methods were introduced to stabilize the sialylated glycan during MALDI-MS. Among current derivatization methods, methylamidation is a promising means for simultaneous analysis of natural sialylated glycans regardless of their sialic acid linkage types. Here, a novel derivatization method was developed, in which proteins were conjugated on the solid-phase support in order to stabilize the sialic acids by methylamidation and to reduce sample loss and contamination during the derivatization process. This derivatization strategy was used to investigate N-glycans from fetuin, a glycoprotein containing different types of complex N-glycans. The developed method was also applied to the N-glycan profiling of human serum from patients and healthy volunteers. Results were consistent with N-glycan profiling by HPLC-fluorescence detection. This new method provided a sensitive, simple, and robust approach for profiling glycan structures of complex samples.

ZnO nanoparticles encapsulated cellulose-lignin film for antibacterial and biodegradable food packaging.

Foodborne illness caused by consuming foods contaminated by pathogens remains threating to the public health. Despite considerable efforts of using renewable source materials, it is highly demanding to fabricate food packaging with multiple properties including eco-friendliness, bactericidal effect and biocompatibility. Here, sodium lignosulfonate (SL) and ZnO nanoparticles (ZnO NPs) were used as functional filler and structure components, respectively, on the cellulose nanofibers (CNFs)-based films, which endows the produced membrane (CNF/SL-ZnO) the UV-light blocking, antioxidant, and antimicrobial characteristics. Due to the interconnected polymeric structure, the prepared CNF/SL-ZnO films possessed considerable mechanical properties, thermal stability, and good moisture barrier capability. Moreover, the tested samples exhibited an improved shelf life in food packaging. Furthermore, metagenome analysis revealed superior biodegradability of obtained films with negligible side effect on the soil microenvironment. Therefore, the biocompatible, degradable, and antibacterial CNF/SL-ZnO film holds enormous potential for sustainable uses including food packaging.

Recent developments for intermolecular enantioselective amination of non-acidic C(sp3)-H bonds.

Enantioenriched chiral amines are of exceptional importance in the pharmaceutical industry. Recently, several new methods for the installation of these functional groups directly from non-acidic C(sp3)-H bonds by catalytic intermolecular enantioselective amination have been reported. These methods represent significant advances of the field and most of them display high levels of enantioselectivity, utilize the C(sp3)-H substrate as the limiting reagent, feature good functional group tolerance, and show compatibility with late-stage C(sp3)-H amination of advanced substrates. This perspective provides an overview of the recent developments in this rapidly advancing field and outlines possibilities and limitations, which will help identify unsolved challenges and guide future research efforts.

Evaluation of the gut microbiome alterations in healthy rats after dietary exposure to different synthetic ZnO nanoparticles.

AIMS: Although synthetic ZnO nanoparticles (Nano-ZnO) as an alternative of ZnO compounds have been extensively used such as in livestock production, the increased consuming of Nano-ZnO has raised considerable concerns in environmental pollution and public health. Because of the low digestion of Nano-ZnO, the systematic studies on their interactions with gut microbiota remain to be clarified. MATERIALS AND METHODS: Nano-ZnOs were prepared by co-precipitation (ZnO-cp) and high temperature thermal decomposition (ZnO-td) as well as the commercial type (ZnO-s). Transmission electron microscopy (TEM) was used to monitor the morphology of Nano-ZnO. CCK-8 assay was used for cytotoxicity evaluation. Total antioxidant capacity assay, total superoxide dismutase assay, and lipid peroxidation assay were used to evaluate oxidative states of rats. 16S rRNA was used to study the impact of Nano-ZnO on the rat gut microbiome. KEY FINDINGS: Both ZnO-cp and ZnO-td exhibited low cytotoxicity while ZnO-s and ZnO-td exhibited prominent antibacterial activities. After a 28-day oral feeding with 1000 mg/kg Zn at dietary dosage, ZnO-s showed slight effect on causing oxidative stress in comparison with that of ZnO-cp and ZnO-td. Results of 16S rRNA sequencing analysis indicated that ZnO-td as a promising short-term nano-supplement can increase probiotics abundances like strains belonged to the genus Lactobacillus and provide the antipathogenic effect. SIGNIFICANCE: The results of the gut microbiome alteration by synthetic Nano-ZnO not only provide solution to exposure monitoring of environmental hazard, but rationalize their large-scale manufacture as alternative additive in the food chain.

An Integrated Proteomics and Metabolomics Strategy for the Mechanism of Calcium Oxalate Crystal-Induced Kidney Injury.

Renal fibrosis is the pathological repair reaction of the kidney to chronic injury, which is an important process of chronic kidney disease (CKD) progressing to end-stage renal failure. Nephrolithiasis is one of the most common renal diseases, with waist and abdomen pain, hematuria, urinary tract infection, and other clinical symptoms, which can increase the risk of renal fibrosis. Oxalate crystal-induced kidney injury is an early stage of nephrolithiasis; it is of great significance to explore the mechanism for the prevention and treatment of nephrolithiasis. A rodent model of calcium oxalate (CaOx) crystal-induced kidney injury was used in the present study, and a network analysis method combining proteomics and metabolomics was conducted to reveal the mechanism of crystal kidney injury and to provide potential targets for the intervention of nephrolithiasis. Using the metabolomics method based on the UHPLC-Q/TOF-MS platform and the iTRAQ quantitative proteomics method, we screened a total of 244 metabolites and 886 proteins from the kidney tissues that had significant changes in the Crystal group compared with that in the Control group. Then, the ingenuity pathway analysis (IPA) was applied to construct a protein-to-metabolic regulatory network by correlating and integrating differential metabolites and proteins. The results showed that CaOx crystals could induce inflammatory reactions and oxidative stress through Akt, ERK1/2, and P38 MAPK pathways and affect amino acid metabolism and fatty acid ß-oxidation to result in kidney injury, thus providing an important direction for the early prevention and treatment of nephrolithiasis.

Direct arylation of N-heterocycles enabled by photoredox catalysis.

N-Heterobiaryls are common skeletons found in biological molecules, pharmaceuticals and ligands. Herein, we document an efficient and redox-neutral photocatalytic system to obtain functionalized N-heterobiaryls under mild conditions. Substrates bearing variegated functional groups are compatible with the developed photocatalytic conditions. This method is translatable to gram-scale synthesis, with a photocatalyst loading as low as 0.1 mol% and minimal variation of the yield. The starting materials are commercially available, demonstrating the practicality and accessibility of this methodology. Interestingly, phenols can serve both as coupling partners and proton donors. Arenes without a phenolic hydroxyl group also underwent efficient coupling with HFIP as a solvent.

Photoredox-Catalyzed Decarboxylative Cross-Coupling of α-Amino Acids with Nitrones.

A decarboxylative cross-coupling reaction of α-amino acids with nitrones via visible-light-induced photoredox catalysis has been established for easy access to ß-amino hydroxylamines and vicinal diamines with structural diversity, which is featured with simple operation, mild conditions, readily available α-amino acids, and a broad scope of nitrone substrates. The application of this protocol can furnish efficient synthetic strategies for some valuable vicinal diamine-containing molecules.

Elevated colonic microbiota-associated paucimannosidic and truncated N-glycans in pediatric ulcerative colitis.

Pediatric ulcerative colitis (UC) is a distinct type of inflammatory bowel disease with severe disease activity and rapid progression, which can lead to detrimental life-long consequences. The pathogenesis of pediatric UC remains unclear, although dysbiosis of the gut microbiota has been considered an important factor. In this study, we collected intestinal mucosal-luminal interface microbiota samples from a cohort of treatment-naïve pediatric UC or control patients and used two different mass spectrometry-based glycomic approaches to examine the N-glycans that were associated with the microbiota. We observed abundant small N-glycans that were associated with the microbiota and found that the pediatric UC microbiota samples contained significantly higher levels of these atypical N-glycans compared to those of controls. Four paucimannosidic or other truncated N-glycans were identified to successfully segregate UC from control patients with an area under the ROC curve of ≥0.9. This study indicates that the aberrant metabolism of glycans in the intestinal by gut microbiota may be involved in the pathogenesis of UC and intestinal N-glycans, including small glycans, can act as novel biomarker candidates for pediatric UC. SIGNIFICANCE: There is no cure for pediatric ulcerative colitis (UC) due to its unclear pathogenesis and the diagnosis of UC in children still largely depends on invasive colonoscopic examination. Recent evidence suggests that the dysbiosis of intestinal microbiota is associated with the onset and development of UC, however how the microbiota interact with the host remains unclear. This study used two different mass spectrometry-based glycomic approaches to quantitatively examine N-glycans that are associated with colonic mucosal-luminal interface microbiota of pediatric UC or control patients. To the best of our knowledge, this is the first comprehensive glycomic study of intestinal microbiota samples in UC, which demonstrated that intestinal microbiota was associated with abundant atypical small N-glycans with elevated levels in UC than controls. This study also identified four intestinal paucimannosidic or other truncated N-glycans as promising biomarker candidates for pediatric UC. These findings shed light on the mechanism study of host-microbiome interactions in UC and indicate that atypical glycans present in the gut can be a source for UC biomarker discovery.

6'-O-Galloylpaeoniflorin Attenuates Osteoclasto-genesis and Relieves Ovariectomy-Induced Osteoporosis by Inhibiting Reactive Oxygen Species and MAPKs/c-Fos/NFATc1 Signaling Pathway.

Emerging evidence suggests bright prospects of some natural antioxidants in the treatment of osteoporosis. 6'-O-Galloylpaeoniflorin (GPF), an antioxidant isolated from peony roots (one of very widely used Oriental medicines, with various anti-inflammatory, antitumor, and antioxidant activities), shows a series of potential clinical applications. However, its effects on osteoporosis remain poorly investigated. The current study aimed to explore whether GPF can attenuate osteoclastogenesis and relieve ovariectomy-induced osteoporosis via attenuating reactive oxygen species (ROS), and investigate the possible mechanism. After the culture of primary murine bone marrow-derived macrophages/monocytes were induced by the use of macrophage colony-stimulating factor (M-CSF) and the receptor activator of NF-κB ligand (RANKL) and then treated with GPF. Cell proliferation and viability were assessed by Cell Counting Kit-8 (CCK-8) assay. Thereafter, the role of GPF in the production of osteoclasts and the osteogenic resorption of mature osteoclasts were evaluated by tartrate-resistant acid phosphatase (TRAP) staining, podosome belt formation, and resorption pit assay. Western blotting and qRT-PCR examination were performed to evaluate proteins' generation and osteoclast-specific gene levels, respectively. The ROS generation in cells was measured in vitro by 2',7'-Dichlorodi-hydrofluorescein diacetate (DCFH-DA). Ovariectomy-induced osteoporosis mouse administered with GPF or vehicle was performed to explore the in vivo potential of GPF, then a micro-CT scan was performed in combination with histological examination for further analysis. GPF suppressed the formation of osteoclasts and podosome belts, as well as bone resorption when induced by RANKL through affecting intracellular ROS activity, MAPKs signaling pathway, and subsequent NFATc1 translocation and expression, as well as osteoclast-specific gene expression in vitro. In vivo study suggested that exposure to GPF prevented osteoporosis-related bone loss in the ovariectomized mice. These findings indicate that GPF attenuates osteoclastogenesis and relieves ovariectomy-induced osteoporosis by inhibiting ROS and MAPKs/c-Fos/NFATc1 signaling pathway. This suggested that GPF may be potentially used to treat bone diseases like periodontitis, rheumatoid arthritis, and osteoporosis associated with osteoclasts.

Comparison of the methods for profiling N-glycans-hepatocellular carcinoma serum glycomics study.

Monitoring serum glycomics is one of the most important emerging approaches for diagnosis of various cancers, and the majority of previous studies were based on MALDI-MS or HPLC analysis. Considering the difference of these analytical methods employed for serum glycomics, it is necessary to compare the effectiveness of different analytical methods for monitoring the aberrant changes in serum glycomics. In this study, a strategy based on machine learning was firstly applied for comparing the analysis results of MALDI-MS and HPLC on the same serum glycomics of hepatocellular carcinoma (HCC) samples. The capability of these two analytical methods for identifying HCC is demonstrated by the classification results obtained from MALDI-MS and HPLC data. In addition, by comparing glycomics which were significantly correlated with HCC based on MALDI-MS and HPLC, some N-glycans which may be the potential biomarkers for HCC were identified, validating the capability of these two analytical methods for the differentiated identification in the analysis of glycomics. Meanwhile, it is noteworthy that various physiological and environmental factors may cause the aberrant changes in glycosylation, and all these interference factors may be minimized by analyzing the same sample sets of HCC. Overall, these results showed that MALDI-MS and HPLC are complementary in qualitative and quantitative analysis of serum glycomics.

Dual catalysis for enantioselective convergent synthesis of enantiopure vicinal amino alcohols.

Enantiopure vicinal amino alcohols and derivatives are essential structural motifs in natural products and pharmaceutically active molecules, and serve as main chiral sources in asymmetric synthesis. Currently known asymmetric catalytic protocols for this class of compounds are still rare and often suffer from limited scope of substrates, relatively low regio- or stereoselectivities, thus prompting the development of more effective methodologies. Herein we report a dual catalytic strategy for the convergent enantioselective synthesis of vicinal amino alcohols. The method features a radical-type Zimmerman-Traxler transition state formed from a rare earth metal with a nitrone and an aromatic ketyl radical in the presence of chiral N,N'-dioxide ligands. In addition to high level of enantio- and diastereoselectivities, our synthetic protocol affords advantages of simple operation, mild conditions, high-yielding, and a broad scope of substrates. Furthermore, this protocol has been successfully applied to the concise synthesis of pharmaceutically valuable compounds (e.g., ephedrine and selegiline).

Characterization of O-acetylation in sialoglycans by MALDI-MS using a combination of methylamidation and permethylation.

O-Acetylation of sialic acid in protein N-glycans is an important modification and can occur at either 4-, 7-, 8- or 9-position in various combinations. This modification is usually labile under alkaline reaction conditions. Consequently, a permethylation-based analytical method, which has been widely used in glycomics studies, is not suitable for profiling O-acetylation of sialic acids due to the harsh reaction conditions. Alternatively, methylamidation can be used for N-glycan analysis without affecting the base-labile modification of sialic acid. In this report, we applied both permethylation and methylamidation approaches to the analysis of O-acetylation in sialic acids. It has been demonstrated that methylamidation not only stabilizes sialic acids during MALDI processing but also allow for characterization of their O-acetylation pattern. In addition, LC-MS/MS experiments were carried out to distinguish between the O-acetylated glycans with potential isomeric structures. The repeatability of methylamidation was examined to evaluate the applicability of the approach to profiling of O-acetylation in sialic acids. In conclusion, the combination of methylamidation and permethylation methodology is a powerful MALDI-TOF MS-based tool for profiling O-acetylation in sialic acids applicable to screening of N-glycans.

MALDI-MS analysis of sialylated N-glycan linkage isomers using solid-phase two step derivatization method.

Sialic acids usually locate at the terminal of many glycan structures in either α(2,3) or α(2,6) linkage, playing different roles in various biological and pathological processes. Several linkage specific carboxyl derivatization methods have been reported to discriminate between α(2,3) and α(2,6)-linked sialic acids by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). Among them, ethyl esterification was recently reported to achieve linkage specific derivatization between α(2,3) and α(2,6)-linked sialic acids with good selectivity. However, the method suffered from the instability of the generated lactones and byproducts of the derivatives. To overcome these shortcomings, a solid-phase two step derivatization method was introduced to convert the α(2,6)-linked sialic acid into ethyl esters and the α(2,3)-inked counterparts into N-methyl amides, respectively. Under the optimized derivatization conditions, our method was able to achieve accurate relative quantification of N-glycan as well as their corresponding sialylated linkage types, superior to the ethyl esterification method. The solid phase derivatization strategy was further applied to investigate N-glycans from biosimilar antibody drug and human serum from patients and healthy volunteers. This method has the potential to be used in the biomarker discovery and pharmaceutical industry.