Search

In this paper, we document the construction of functionalized and fused eight-membered carbocycles by the triflic anhydride-mediated cyclization of 7-enamides. Taking advantage of the high electrophilicity of the nitrilium ion intermediates, generated in situ from secondary N-(2,6-dimethyl)anilides, the nonactivated, trisubstituted alkene-nitrilium cyclization reactions proceeded smoothly to afford nonconjugated β,γ-enimines (for fused 6/6/8 ring systems), conjugated α,β-enimines (for 6/5/8), or fused 5/8 ring systems in good yields. When the cyclization reactions were followed by one-pot acidic hydrolysis, the reaction led directly to the corresponding α,β-enones. For some substrates, the reaction afford an efficient access to pendent cyclic β,γ-enimines/enones.

The cycling stability and rate performance of anode materials should be increased to meet the demands for automotive power batteries with a long-life and fast charging capability. In this study, a silica/graphite anode material was synthesized in situ via a hydrolysis-calcination route using ethyl orthosilicate as the silicon source. The morphology and structure of silica/graphite anode materials were examined by SEM, XRD, and XPS techniques. The electrochemical properties of silica/graphite materials were investigated by galvanostatic charge–discharge, cyclic voltammetry and electrochemical impedance spectroscopy techniques. The results showed that amorphous silica microspheres were embedded in the graphite matrix. This structure not only strengthened the bonding of Si–O–C but also improved the composition of the solid-electrolyte interphase. The specific capacity of the silica/graphite anode material could be stabilized at approximately 450 mAh g−1 after 300 cycles at a current density of 100 mA g−1, resulting in stable lithium storage due to the synergistic effect between the silica and graphite.

Ten types of Tf2O/TTBP-mediated amide transformation reactions were investigated. The results showed that compared with pyridine derivatives 2,6-di-tert-butyl-4-methylpyridine (DTBMP) and 2-fluoropyridine (2-F-Pyr.), TTBP can serve as an alternative amide activation system for the direct transformation of both secondary and tertiary amides. For most surveyed examples, higher or comparable yields were generally obtained. In addition, Tf2O/TTBP combination was used to promote the condensation reactions of 2-(tert-butyldimethylsilyloxy)furan (TBSOF) with both tertiary and secondary amides, the one-pot reductive Bischler-Napieralski-type reaction of tertiary lactams, and Movassaghi and Hill's modern version of the Bischler-Napieralski reaction. The value of the Tf2O/TTBP-based methodology was further demonstrated by the concise and high-yielding syntheses of several natural products.

Organic-inorganic hybrid superlattices (OIHSLs) hold attractive physical and chemical properties, while the construction of single-crystal covalent OIHSLs has not been achieved. Herein a coordination assembly strategy was proposed to create a single-crystal covalent OIHSL PbBDT (BDT=1,4-benzenedithiolate), where layered [PbS 2 ] sublattice covalently connects with benzene sublattice. The covalent bonding offers better thermo-/chemi-stability, inter-sublattice electron transport, and unique organic-group-functionalized surface, which may enable better performances in chemical applications than non-covalent OIHSL. These features endow PbBDT with the highest sensitivity, the lowest detection limit and excellent selectivity towards NO 2 at room temperature among all chemiresistive gas-sensing materials with reported response time less than 2 min without the need of light assistance.

Macrophage activation is a key contributing factor for excessive inflammatory responses of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Geranylgeranyl diphosphate synthase (GGPPS) plays a key role in the development of inflammatory diseases. Our group previously showed that GGPPS in alveolar epithelium have deleterious effects on acute lung injury induced by LPS or mechanical ventilation. Herein, we examined the role of GGPPS in modulating macrophage activation in ALI/ARDS. We found significant increased GGPPS expression in alveolar macrophages in patients with ARDS compared with healthy volunteers and in ALI mice induced by LPS. GGPPS-floxed control ( GGPPSfl/fl) and myeloid-selective knockout ( GGPPSfl/fl LysMcre) mice were then generated. Interestingly, using an LPS-induced ALI mouse model, we showed that myeloid-specific GGPPS knockout significantly increased mortality, aggravated lung injury, and increased the accumulation of inflammatory cells, total protein, and inflammatory cytokines in BALF. In vitro, GGPPS deficiency upregulated the production of LPS-induced IL-6, IL-1β, and TNF-α in alveolar macrophages, bone marrow-derived macrophages (BMDMs), and THP-1 cells. Mechanistically, GGPPS knockout increased phosphorylation and nuclear translocation of NF-κB p65 induced by LPS. In addition, GGPPS deficiency increased the level of GTP-Rac1, which was responsible for NF-κB activation. In conclusion, decreased expression of GGPPS in macrophages aggravates lung injury and inflammation in ARDS, at least partly by regulating Rac1-dependent NF-κB signaling. GGPPS in macrophages may represent a novel therapeutic target in ARDS.

The secondary explosive welding process promotes the diffusion of the carbon element and accumulation of chromium carbide, which leads to a decrease of tensile properties and toughness of the material. In this work, the average shear strength value increased from 400 to 421 MPa. The crack of the fatigue specimens started from the inclusions rich in alumina near the surface, and the harmful hard-phase inclusions were exposed because of stress concentration. The maximum load limit of 10CrNi3MoV steel undergoing secondary explosive welding was between 590 and 605 MPa.

Although the combination of chemotherapy and immunotherapy is a hot topic in lung cancer, little is understood regarding the possible mechanisms behind their synergy. Moreover, safety is a major concern for clinicians while performing chemotherapy. Therefore, it is important to determine the appropriate dose and period of chemotherapy for combining it with immunotherapy, and investigate the underlying synergistic mechanism. Here, we showed that carboplatin can induce DNA damage and activate the canonical STING/TBK1/IRF3 pathway and non-canonical STING-NF-κB signaling complex. Further, low-dose carboplatin changed the "cold" tumor into a "hot" tumor via the signaling hub STING, augmenting CD8+ T-cell infiltration, increasing PD-L1 expression, and hence potentiating the anti-tumor effect of PD-1 inhibitors; importantly, there were no adverse effects. Furthermore, knocking down STING in tumor cells effectively reversed PD-L1 upregulation and STING pathway activation, and reduced the anti-tumor effect of low-dose carboplatin and carboplatin-PD-1 inhibitor combination. Our findings collectively reported a previously unexplored role of low-dose carboplatin targeting in the STING pathway and provided an economical, useful and safe option for improving the efficacy of PD-1 inhibitors in lung cancer.

Although it is widely accepted that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are readily available, robustly reproducible, and physiologically appropriate human cells for clinical applications and research in the cardiovascular field, hiPSC-CMs cultured in vitro retain an immature metabolic phenotype that limits their application, and little is known about the underlying molecular mechanism controlling mitochondrial metabolic maturation during human induced pluripotent stem cells (hiPSCs ) differentiation into cardiomyocytes. In this study, we found that peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) played an important role in inducing mitochondrial biogenesis and establishing oxidative phosphorylation (OXPHOS) during the cardiac differentiation of hiPSCs. Knocking down PGC-1α by siRNA impaired mitochondrial respiration, while upregulating PGC-1α by ZLN005 promoted mitochondrial biosynthesis and function by regulating the expression of downstream genes involved in mitochondrial dynamics and oxidative metabolism in hiPSC-CMs. Furthermore, we found that estrogen-related receptor α (ERRα) was required for the induction of PGC-1α stimulatory effects in hiPSC-CMs. These findings provide key insights into the molecular control of mitochondrial metabolism during cardiac differentiation and may be used to generate more metabolically mature cardiomyocytes for application.

In this paper, a dual-ligand design strategy is demonstrated to modulate the performance of the electronically conductive metalorganic frameworks (EC-MOFs) thin film with a spray layer-by-layer assembly method. The thin film not only can be precisely prepared in nanometer scale (20–70 nm), but also shows the pin-hole-free smooth surface. The high quality nano-film of 2,3,6,7,10,11-hexaiminotriphenylene (HITP) doped Cu-HHTP enables the precise modulation of the chemiresistive sensitivity and selectivity. Selectivity improvement over 220% were realized for benzene vs. NH3, as well as enhanced response and recovery properties. In addition, the selectivity of the EC-MOF thin film sensors toward other gases (e.g. triethylamine, methane, ethylbenzene, hydrogen, butanone, and acetone) vs. NH3 at room temperature is also discussed.

Fungal chitinases play essential roles in chitin degradation, cell wall remodeling, chitin recycling, nutrition acquisition, autolysis, and virulence. In this study, 18 genes of the glycoside hydrolase 18 (GH18) family were identified in the Isaria cicadae genome. Seventeen of the genes belonged to chitinases and one was an endo-β-N-acetylglucosaminidase (ENGase). According to phylogenetic analysis, the 17 chitinases were designated as subgroups A (7 chitinases), B (7), and C (3). The exon–intron organizations of these genes were analyzed. The conserved regions DxxDxDxE and S/AxGG and the domains CBM1, CBM18, and CBM50 were detected in I. cicadae chitinases and ENGase. The results of analysis of expression patterns showed that genes ICchiA1, ICchiA6, ICchiB1, and ICchiB4 had high transcript levels in the different growth conditions or developmental stages. Subgroup A chitinase genes had higher transcript levels than the genes of all other chitinases. Subgroup B chitinase genes (except ICchiB7) presented higher transcript levels in chitin medium compared with other conditions. ICchiC2 and ICchiC3 were mainly transcribed in autolysis medium and in blastospores, respectively. Moreover, ICchiB1 presented higher transcript levels than genes of other chitinases. This work provides an overview of the GH18 chitinases and ENGase in I. cicadae and provides a context for the chitinolytic potential, functions, and biological controls of these enzymes of entomopathogenic fungi.

Melongenaterpenes A-L (1-12), 12 new sesquiterpenoids with rare spiro[4.5]decane skeletons, were isolated from the roots of Solanum melongena. Their 2D structures and relative configurations were determined based on NMR and HRESIMS data. The absolute configuration of melongenaterpene A (1) was defined by X-ray crystallographic analysis. The absolute configurations of the remaining compounds were determined by comparison of their NMR data with 1 and consideration of the biosynthetic pathway. This is the first report of the crystal structure of a vetispirane-type sesquiterpenoid. None of the compounds exhibited cytotoxic activity against the three human cancer cell lines HepG2, HeLa, and MCF-7.

Vesicular monoamine transporter 2 (VMAT2) is essential for synaptic transmission of all biogenic amines in the brain including serotonin, norepinephrine, histamine, and dopamine (DA). Given its crucial role in the neurophysiology and pharmacology of the central nervous system, VMAT2 is recognized as an important therapeutic target for various neurological disorders such as tardive dyskinesia (TD). Here, a novel series of dihydrotetrabenazine derivative analogs were designed and synthesized to evaluate their effects on [3H]dihydrotetrabenazine (DTBZ) binding and [3H]DA uptake at VMAT2. Of these analogs, compound 13e showed a high binding affinity for VMAT2 (IC50 = 5.13 ± 0.16 nM) with excellent inhibition of [3H]DA uptake (IC50 = 6.04 ± 0.03 nM) in striatal synaptosomes. In human liver microsomes, 13e was more stable (T1/2 = 161.2 min) than other reported VMAT2 inhibitors such as DTBZ (T1/2 = 119.5 min). In addition, 13e effectively inhibited the spontaneous locomotor activity (percent inhibition at 3 μmol/kg = 64.7%) in Sprague-Dawley rats. Taken together, our results indicate that 13e might be a promising lead compound for the development of novel treatments of TD.

Three new compounds, namely massonside C (1), massonianoside F (2), and 3, 8-dimethyl- herbacetin-7-O-β-D-glucopyranoside (3), together with five known compounds (4-8), were isolated from the fresh needles of Pinus massoniana. Their structures were established by 1D, 2D NMR, HRMS and comparison with the literature data. The absolute configuration of 1 was confirmed by a combination of X-ray single crystal analysis. All isolated compounds were evaluated for the protective effect of human umbilical vein endothelial cells against oxidative damage.

An efficient and mild protocol for the direct and flexible synthesis of 3-amino-1,4-diynes bearing an aza-quaternary carbon from tertiary amides and lactams has been established. The one-pot method consists of in situ activation of amides with trifluoromethanesulfonic anhydride, followed by double addition of alkynyllithium reagents at a concentration of 0.5 mol·L-1 in dichloromethane. This constitutes an extension of the method of direct reductive bisalkylation of amides that allows both employing alkynyllithium reagents as the first-addition nucleophiles and incorporating an alkynyl group as the first-introduced group.

Three new lignanamides, melongenamide E–G (1–3), together with fourteen known analogues (4-17) were isolated by bioassay-guided fractionation from the roots of Solanum melongena L. The chemical structures of all isolated compounds were elucidated using 1D and 2D NMR experiments and by comparing their spectroscopic and physical data with values from the published literature. These isolated compounds were tested for their inhibitory activities on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in a macrophage cell line RAW 264.7. Compounds 1–7 and 10 showed moderate inhibition of NO production with IC50 values ranging from 10.6 ± 2.3 to 33.7 ± 2.7 μM.

Carbon-rich two-dimensional (2D) materials show significant potential in energy storage and conversion applications. A conjugated 2D covalent organic polymer (COP) with embedded triphenylene (TP) units was synthesized by Glaser–Hay cross-coupling and validated by Raman, IR, XPS and NMR spectroscopy. TP-COP exhibited a uniform pore size of 5.4 A and laminar structure with an interlayer spacing of 3.8 A, which could be mechanically exfoliated to yield few-layered nanosheets. Interfacial polymerization produced the continuous TP-COP films from quasi-monolayer to multilayer. As the anode materials of lithium batteries, TP-COP delivered large reversible capacity up to 1624 mA h g−1, high charge rate, and good recycling ability. These properties are likely due to the presence of lithium ions in both the interspace of the expanded sp2 moieties and the in-plane nanopores of TP-COP.

The antibiofilm activity and molecular mechanism of a natural phenolic compound, 3-p-trans-coumaroyl-2-hydroxyquinic acid (CHQA) against Staphylococcus aureus were investigated in this study. Crystal violet staining and XTT reduction assay demonstrated that CHQA could prominently prevent the biofilm formation of S. aureus accompanied with decrease in metabolic activity of biofilm cells. Meanwhile, microscopic observations revealed that CHQA caused a huge collapse on the architecture of S. aureus biofilm. Moreover, CHQA specifically inhibited the initial attachment phase of biofilm development and reduced S. aureus adhesion to fibrinogen. Fluorescence resonance energy transfer assay and molecular simulation showed that CHQA inhibited the activity of S. aureus sortase A (SrtA) through binding to the active region via non-covalent interactions. Additionally, CHQA efficiently reduced S. aureus attachment to stainless steel. Hence, these results suggested CHQA as a potential bacterial biofilm inhibitor which achieved antibiofilm activity through affecting the attachment phase of biofilm formation by targeting SrtA.

Norepinephrine adjusts sensory processing in cortical networks and gates plasticity enabling adaptive behavior. The actions of norepinephrine are profoundly altered by recreational drugs like ethanol, but the consequences of these changes on distinct targets such as astrocytes, which exhibit norepinephrine-dependent Ca2+ elevations during vigilance, are not well understood. Using in vivo two-photon imaging, we show that locomotion-induced Ca2+ elevations in mouse astroglia are profoundly inhibited by ethanol, an effect that can be reversed by enhancing norepinephrine release. Vigilance-dependent astroglial activation is abolished by deletion of α1A-adrenergic receptor from astroglia, indicating that norepinephrine acts directly on these ubiquitous glial cells. Ethanol reduces vigilance-dependent Ca2+ transients in noradrenergic terminals, but has little effect on astroglial responsiveness to norepinephrine, suggesting that ethanol suppresses their activation by inhibiting norepinephrine release. Since abolition of astroglia Ca2+ activation does not affect motor coordination, global suppression of astroglial networks may contribute to the cognitive effects of alcohol intoxication., The effects of norepinephrine on sensory processing in cortical networks are altered by recreational drugs like ethanol. The authors show that ethanol suppresses the activation of astrocytes by inhibiting norepinephrine release which may contribute to the cognitive effects of alcohol intoxication.

Amitraz is an acaricide that is widely used in apiculture. Several studies have reported that in honeybees (Apis mellifera Linnaeus; Hymenoptera: Apidae), amitraz affects learning, memory, behavior, immunity, and various other physiological processes. Despite this, few studies have explored the molecular mechanisms underlying the action of amitraz on honeybees. Here, we investigated the transcriptome of honeybees after exposure to 9.4 mg/L amitraz for 10 d, a subchronic dose. Overall, 279 differentially expressed genes (DEGs) were identified (237 upregulated, 42 downregulated). Several, including Pla2, LOC725381, LOC413324, LOC724386, LOC100577456, LOC551785, and P4504c3, were validated by quantitative PCR. According to gene ontology, DEGs were mainly involved in metabolism, biosynthesis, and translation. Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that amitraz treatment affected the relaxin signaling pathway, platelet activation, and protein digestion and absorption.

Zinc sulfate is an important mineral nutrient for yeast stress tolerance. In this study, IPL1, PRP6, and RTC1 whose expression are responsive to zinc sulfate, were investigated on their effects on inhibitor tolerance and ethanol fermentation by Saccharomyces cerevisiae. Yeast strains were developed through replacing native promoters by the constitutive PGK1 promoter for these genes. The engineered yeast strains showed improved ethanol fermentation in the presence of acetic acid and mixed inhibitors. Meanwhile, enhanced ethanol titer from corncob hydrolysate was achieved, and up to 19.5% more ethanol was produced using the engineered yeast strain carrying the RTC1 promoter replacement. The results in this study provides basis for further engineering yeast strains to improve efficiency of lignocellulosic biorefinery.

Antimicrobial compounds from natural sources are a promising alternative to address the consumer demand of food without chemical additives. In this study, antimicrobial peptides (AMPs) from infected Musca domestica pupae (Md‐AMPs) bred under clean conditions were isolated and prepared on a large scale. In these Md‐AMPs, seven AMPs families were identified by liquid chromatography–tandem mass spectrometry. Md‐AMPs at concentrations from 0.4 to 0.8 mg/ml exhibited antibacterial activity and showed negligible hemolytic activity against human erythrocytes. Md‐AMPs increased bacterial membrane permeability of four tested strains, resulting in the leakage of phosphorus‐containing materials and Ca²⁺. Md‐AMPs bound plasmid DNA and inhibited its migration in a concentration‐dependent manner. Treatment with Md‐AMPs alone or in combination with nisin, and ethylenediaminetetraacetic acid was efficient in inhibiting bacterial growth in chilled pork and extended the shelf life up to 6 days. PRACTICAL APPLICATIONS: Insects have been widely used as foods and many biofunctional components are found in insects. In this work, we isolated and prepared AMPs from M. domestica, and its antibacterial activity, hemolytic activity, and mechanism of action were investigated. Trials in real food products showed that Md‐AMPs alone or a combination of three natural antimicrobials could remarkably inhibit bacterial growth in chilled pork. These results suggest that Md‐AMPs can be used as food preservatives.

Aim: Tryptophan (Trp) and kynurnine (Kyn) are a pair of biomarkers for indoleamine 2,3-dioxygenase which closely related to the tumor immune escape. To evaluate the effect of drugs on the indoleamine 2,3-dioxygenase activity, the specific and accurate LC–MS/MS methods were developed and validated for simultaneous determination Kyn and Trp in mouse plasma and tumor tissues using surrogate analytes Kyn-d4 and Trp-d5 calibrators. Results: Plasma and tumor homogenates samples were pretreated with the solid phase extraction which assured the method having high recovery (>90% in plasma and >80% in tumor) and no matrix effect. The methods were validated for specificity, linearity, accuracy and precision, recovery, matrix effect and stability using surrogate analytes Kyn-d4 and Trp-d5 in authentic matrices. Conclusion: The validated methods have been successfully applied to the pharmacodynamic study of INCB024360 in CT26 tumor bearing mice after single dose and multiple dosing.

The direct transformation of amides is an emerging area in organic synthesis. Starting from common secondary amides, a novel and flexible approach to α-trifluoromethylamines is described. This one-pot method consists of the in situ activation of amides with triflic anhydride (Tf2O), partial reduction with 1,1,3,3-tetramethyldisiloxane (TMDS), and nucleophilic trifluoromethylation with trifluoromethyltrimethylsilane (TMSCF3). Thanks to the mild conditions, the reaction exhibited high chemoselectivity and good functional group tolerance.

Hybrid metal halides with high chemistry versatility and electronic tunability is a promising material system for new-generation lighting and displaying. Lowing the dimensionality of inorganic moieties gives rise to the broad-band white emission of those materials. Here a new 1D hybrid lead bromide (dbod)Pb2Br6 (dbod2+=1,4-Diazoniabicyclo[2.2.2]octane, 1,4-dipropy2+) was synthesized using organic dbod2+ as the spacer and balance cation. The compound showed a very broad emission with a full width half-maximum of 244 nm. With good electron conductivity, this series of compounds hold potential for the application of white-light LEDs.

Employing triflic anhydride/2-fluoropyridine as an activation system, the coupling reactions of secondary N-aryl amides with terminal alkynes yielded substituted quinolines in moderate to excellent yields. The reaction tolerated both electron-donating and electron-withdrawing groups at the benzamide moiety. Electron-rich aryl acetylenes served as excellent coupling partners, and aliphatic terminal alkynes such as cyclopropyl and conjugate vinyl acetylenes could also be used as reaction partners. By means of 2D NMR techniques (heteronuclear multiple bond correlation (HMBC), heteronuclear single quantum correlation (HSQC)), nitrilium ions were probed as reactive intermediates which are in contrast with that suggested by Movassaghi on the basis of in situ IR monitoring experiments. On the basis of these results, a plausible mechanism for the formation of quinolines was suggested.

Indoleamine 2,3-dioxygenase (IDO) is involved in tumor immune escape and resistance to chemotherapy, and is clinically correlated with tumor progression. IDO inhibitors show marginal efficacy as single agents; therefore, combinations of these inhibitors with other therapies hold promise for cancer therapy. The aim of this study was to investigate the synergistic antitumor effects of IDO inhibitor NLG919 in combination with different regimens of paclitaxel in a murine B16-F10 melanoma model. NLG919 increased the cytotoxic activity of paclitaxel toward B16-F10 cells in the presence of pretreatment with interferon (IFN)-γ in vitro. In B16-F10 tumor-bearing mice, NLG919 was uniformly distributed throughout tumors and decreased kynurenine levels and kynurenine/tryptophan ratios in tumors and plasma for 6–12 h. NLG919 suppressed tumor growth in a dose-dependent manner and exhibited maximum efficacy at 100 mg/kg. In combination with different regimens of paclitaxel, NLG919 displayed synergistic antitumor effects, and NLG919 did not increase the side effects of paclitaxel. Within the tumors, the percentage of CD3+, CD8+, and CD4+ T cells and secretion of IFN-γ and interleukin-2 were synergistically increased, whereas the percentage of CD4+CD25+ regulatory T cells was decreased. NLG919 can potentiate the antitumor efficacy of paclitaxel without increasing its side effects, suggesting that the combination of IDO inhibitor-based immunotherapy with chemotherapy could be a potential strategy for cancer treatment.

We describe the design and execution of a novel synthetic route to the tricyclic core of haliclonin A, a tetracyclic marine natural product. The approach features Bachi’s thiol-medicated free radical cyclization of alkenyl isocyanide to build the bridged ring system, and ring-closing metathesis (RCM) reaction to form the macrocycle. Execution of the synthetic plan ultimately resulted in a diazatricyclic compound. By means of 2D NMR techniques, the structure of this compound was revealed to an unexpected product 8 . Analysis of the synthetic pathways allowed concluding that the unexpected product is a result of an “unexpected” migration of olefinic bond during dioxolanation of the 2-cyclohexenone derivative 7 . This investigation also resulted in a concise construction of the functionalized hexahydro-1 H -isoindole-1,5(4 H )-dione 12 and the macrocyclic tricyclic ring system 8 .

Bone is an especially prone metastatic site for breast cancer, and to block the vicious cycle between bone resorption and tumor growth is an important strategy for the treatment of breast cancer bone metastasis. In this paper, pH- and redox-sensitive as well as breast cancer bone metastasis-targeting nanoparticles (DOX@ALN-(HA-PASP)CL) were prepared, and also their anti-tumor activity and anti-bone resorption effect were investigated in detail. The in vitro experimental results indicated that DOX released from DOX@ALN-(HA-PASP)CL exhibited a GSH-, DTT- and pH-dependent manner. Moreover, in an in vitro 3D breast cancer bone metastasis model, DOX@ALN-(HA-PASP)CL decreased bone resorption through inhibiting the proliferation of human breast cancer cells (MDA-MB-231 cells) and reducing the activity of osteoclasts. The in vivo experimental results indicated that a large amount of DOX was delivered to a breast cancer bone metastasis site after tumor-bearing mice were treated with DOX@ALN-(HA-PASP)CL; meanwhile, DOX@ALN-(HA-PASP)CL significantly decreased the tumor volume and bone resorption in tumor-bearing mice without causing obvious systemic toxicity. In conclusion, the in vitro and in vivo experimental results indicate that DOX@ALN-(HA-PASP)CL has great potential in the treatment of breast cancer bone metastasis.

Defect engineering has been regarded as a promising strategy for tuning the chemical modification on graphene surfaces in order to achieve novel physicochemical properties. However, there have been very few studies that have quantitatively evaluated the activating effect of defects on chemical reactivity. Here we showed the controllable chemical functionalization of single-layer graphene (SLG) by defect engineering and quantitatively evaluated the activating effects of defects on their surrounding areas on graphene by a simplified geometric model. The tunable density of the grafted aryl group on SLGs by defect engineering was demonstrated to be able to direct sequential supramolecular assembly and spatial patterning was achieved.

OBJECTIVE To investigate the effect and underlying mechanisms of combined medicated thread moxibustion therapy plus needle picking therapy of Zhuang nationality medicine on antioxidant levels in a rat model of sciatica. METHODS One hundred Wistar rats, of specific pathogen free level, were randomly divided into five groups: normal control group, model group, medicated thread moxibustion group, needle picking group, and combination group. Each group contained 20 rats. In the model, medicated thread moxibustion, needle picking, and combination groups, sciatica models were established through chronic constriction injury of the sciatic nerve. After the model was established, the rats in the medicated thread moxibustion, needle picking, and combination groups were given the corresponding therapies for 21 days. The control and model groups received no treatment. Reactive oxygen species, superoxide dismutase, malondialdehyde, and total antioxidant capacity changes were determined. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NADPH oxidases 4 (NOX4) mRNA expression and the morphology of cells were observed to detect apoptosis of gamma-aminobutyric acid ergic (GABAergic) neurons. RESULTS Compared with control group, reactive oxygen species and malondialdehyde levels rose significantly in the model group (P < 0.01), while superoxide dismutase and total antioxidant capacity levels were lowered (P < 0.05). Compared with the model group, reactive oxygen species and malondialdehyde decreased in the needle picking group (P < 0.05), while superoxide dismutase levels were increased (P < 0.05); reactive oxygen species and malondialdehyde significantly decreased in the combination group (P < 0.01). In addition, the model group had higher NOX4 mRNA expression than that of the control group (P < 0.05), and the combination group had lower expression levels than that of the model group (P < 0.05). Apoptosis of GABAergic neurons was observed in the model group, and was attenuated after combined therapy. CONCLUSION The medicated thread moxibustion therapy plus needle picking therapy of Zhuang nationality medicine can prevent oxidative damage in the rat model of sciatica via down-regulating NOX4 expression, improving antioxidant capacity, and inhibiting the oxidative damage pathway of GABAergic neurons.

An integrated petrological and geochemical analysis of surface and drilled oil sands from the Middle Jurassic Yan’an Formation in the southern Ordos Basin was conducted to investigate the petrophysical properties, organic matter origin/type, and thermal maturity and their relation to environmental conditions during sediment deposition. Petrographic analysis (thin section, scanning electron microscopy (SEM), and porosity and permeability determination) of the oil sand was performed to establish the relationships between porosity and permeability and bulk density, reservoir quality index (RQI), normalized porosity index (NPI), and flow zone indicator (FZI). Geochemical analyses include oil extraction, column chromatography, and gas chromatography–mass spectrometry (GC-MS). The strong correlation between RQI and permeability (R2 = 0.98) reveals that porosity has a good correlation with RQI. The positive correlations between porosity and permeability and NPI and RQI (R2 = 0.77 and R2 = 0.65, respectively) show that the studied rocks contain many large pores with pore-to-pore throat connection structures that enhance permeability, which is further supported by the relatively high connection coefficient between NPI and RQI (R2 = 0.65). The organic matter in the Yan’an Formation is mainly composed of oil-prone type I kerogen indicated by the recovery of a large amount of crude oil rich in saturated hydrocarbon fractions from the extracted oil. The biomarker signatures of the analyzed oil (nC13-nC35, Pr/n-C17 and Ph/n-C18, and low C27/C29 regular sterane) reveal predominantly land plant materials as organic input sources based on the average concentration of αααC27:C28:C29 sterane 20R of approximately 38%, 22%, and 40%, respectively, and on high values of tricyclic terpane/αβC30 hopane and regular sterane/αβC30 hopane. Deposition within a lacustrine paleoenvironment under anoxic conditions enhanced organic matter preservation in the area based on the low Pr/Ph ratios (average 0.74), low αβC31-22R-hopane/αβC30 hopane ratios, and high C26/C25 tricyclic terpane ratios, as well as the presence of gammacerane and low water salinity. Biomarker maturity parameters (e.g., C32 homohopane 22S/(22S + 22R), moretane/hopane, and C29 sterane 20S/(20S + 20R) ratios and CPI) show that the extracted oil sand entered the early oil window stage.

Discovering sugar metabolism genes is of great interest for lignocellulosic biorefinery. Xylose isomerases (XIs) were commonly screened from metagenomes derived from bovine rumen, soil, and other sources. However, so far, XIs and other sugar-utilizing enzymes have not been discovered from fecal metagenomes. In this study, environmental DNA from the fecal samples collected from yellow cattle (Bos taurus) was sequenced and analyzed. In the whole 14.26 Gbp clean data, 92 putative XIs were annotated. After sequence analysis, seven putative XIs were heterologously expressed in Escherichia coli and characterized in vitro. The XIs 58444 and 58960 purified from E. coli exhibited 22% higher enzyme activity when compared with that of the native E. coli XI. The XI 58444, similar to the XI from Lachnospira multipara, exhibited a relatively stable activity profile across different pH conditions. Four XIs were further investigated in budding yeast Saccharomyces cerevisiae after codon optimization. Overexpression of the codon-optimized 58444 enabled S. cerevisiae to utilize 6.4 g/L xylose after 96 h without any other genetic manipulations, which is 56% higher than the control yeast strain overexpressing an optimized XI gene xylA*3 selected by three rounds of mutation. Our results provide evidence that a bovine fecal metagenome is a novel and valuable source of XIs and other industrial enzymes for biotechnology applications.

Cardiovascular disease is one of the leading causes of morbidity and mortality worldwide. Mangiferin is a natural glucosylxanthone with antioxidant and anti-inflammatory properties, which has been confirmed to protect cardiac cells from myocardial infarction and myocardial ischemia reperfusion injury (MIRI), however, the underlying mechanism is still unclear. As oxidative stress is a major pathogenesis of MIRI, an H9C2 cell injury induced by hydrogen peroxide (H2O2) was established to simulate MIRI in vitro. Herein, the protective effect of mangiferin against MIRI was evaluated and the isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics was applied to explore the underlying molecular mechanism. In this research, mangiferin markedly ameliorated the oxidative imbalance by increasing the antioxidative capacity of the H9C2 cell. Moreover, proteomics analysis revealed that mangiferin pretreatment brought twenty differently-expressed proteins back to normal, most of which were related to glucose and fatty acid metabolism. Glycolysis, citrate cycle, and fatty acid degradation pathways were highlighted by Kyoto Encyclopedia of Gene and Genomes (KEGG) analysis. Western blot validation of six cardiac metabolism-related proteins were consistent with the proteomics analysis. Taken together, mangiferin protected the cardiomyocytes from MIRI by enhancing the antioxidant capacity and increasing the activities of glycolysis, citrate cycle, and fatty acid degradation pathways.

A versatile organocatalytic asymmetric conjugate addition of nitroalkanes to β-substituted cyclic α,β-enones to yield cyclic ketones bearing all-carbon quaternary stereogenic centers at β-C has been developed. This is an extension of the method that we developed during the total synthesis of (−)-haliclonin A, which features the employment of structurally relatively simple, cheap and easily available primary amine-thiourea derived from (R,R)-1,2-diaminocyclohexane as the chiral catalyst. The method shows wide substrate scope, good functional group tolerance, which allows a quick access to multi-functionalized chiral compounds. The synthetic potential of the method was demonstrated by one-step transformations of the nitro-ketone adducts to four other classes of compounds. The absolute configurations of adducts were determined by comparison of both the retention time of chiral HPLC analysis and sense of specific optical rotation with those of a known compound. The enantioselective control mechanism was rationalized based on the DFT computational studies.

A strategy is outlined for the synthesis of loline alkaloids. This second-generation approach features direct access to the requisite vicinal diamino motif by a Cu(OTf) 2 -mediated highly trans -diastereoselective vinylogous Mannich reaction (VMR) of Ellman N - tert -butanesulfinyl imine derived from isopropylidene-protected ( S )-glyceraldehyde, with N -Boc-2- tert -(butyldimethylsilyloxy)pyrrole (TBSOP). Fleming’s method was employed for the introduction of a hydroxyl group at C4 of the adduct, which gave the undesired diastereomer in 40% yield. The intramolecular S N reaction of the pyrrolizidine derivative to build the etheral bridge proved to be difficult, and produced N -Bus-norloline in only 20% yield. In light of the valuable information gained during this investigation, an improved version of the second-generation approach is being investigated, which is expected to provide a concise and efficient access to the challenging loline alkaloids.

The first total synthesis of the alkaloid (-)-haliclonin A is reported. The asymmetric synthesis relied on a novel organocatalytic asymmetric conjugate addition of nitromethane with 3-alkenyl cyclohex-2-enone to set the stereochemistry of the all-carbon quaternary stereogenic center. The synthesis also features a Pd-promoted cyclization to form the 3-azabicyclo[3,3,1]nonane core, a SmI2 -mediated intermolecular reductive coupling of enone with aldehyde to form the requisite secondary chiral alcohol, ring-closing alkene and alkyne metathesis reactions to build the two aza-macrocyclic ring systems, and an unprecedented direct transformation of enol into enone.

We report the asymmetric vinylogous Mannich reactions (VMRs) of N-Boc-2-tert-(butyldimethylsilyloxy)pyrrole (TBSOP) with N-tert-butanesulfinylimines. The reaction is highly anti-diastereoselective and shows good generality for the direct construction of a variety of vicinal anti-diamine motifs that are found in a number of biologically active alkaloids and medicinal agents. A VMR adduct was elaborated in six steps into the 1-aminopyrrolizidine alkaloid (+)-absouline, which constitutes the second and also the most efficient total synthesis of the natural enantiomer of the title alkaloid.

The first asymmetric total synthesis of (-)-verrupyrroloindoline (20% overall yield in 6 steps) is described. The short approach was enabled by Buchwald's Cu(II)-catalyzed asymmetric conjugate reduction, DMDO-triggered one-pot four-step tandem reaction, and the first amide-selective Ir-catalyzed direct reduction of β-carboethoxy tertiary lactam. Along with the total synthesis, the absolute configuration of natural verrupyrroloindoline was determined as 7 R,10 R,11 R.

The imino-Nazarov cyclization of the polysubstituted pentan-1,4-diene-3-imines was realized. To this aim, a one-pot procedure involving reductive alkenyliminylation of α,β-unsaturated secondary amides with potassium organotrifluoroborates, followed by acid-catalyzed imino-Nazarov cyclization of the polysubstituted pentan-1,4-diene-3-imine intermediates, was studied systematically. This mild, operationally simple, flexible, and high-yielding protocol efficiently affords polysubstituted pentan-1,4-diene-3-imines, cyclopentenimines, and α-amino cyclopentenones, which are useful scaffolds in organic synthesis. The substituent effect at the C2 position of the polysubstituted pentan-1,4-diene-3-imines was studied by means of density-functional theory calculations. Results suggested that the electron-donating group facilitates the imino-Nazarov cyclization process.

In order to inhibit the growth of lung cancer bone metastasis and reduce the bone resorption at bone metastasis sites, a bone metastasis target micelle DOX@DBMs-ALN was prepared. The size and the zeta potential of DOX@DBNs-ALN were about 60 nm and −15 mV, respectively. DOX@DBMs-ALN exhibited high binding affinity with hydroxyapatite and released DOX in redox-responsive manner. DOX@DBMs-ALN was effectively up taken by A549 cells and delivered DOX to the nucleus of A549 cells, which resulted in strong cytotoxicity on A549 cells. The in vivo experimental results indicated that DOX@DBMs-ALN specifically delivered DOX to bone metastasis site and obviously prolonged the retention time of DOX in bone metastasis site. Moreover, DOX@DBMs-ALN not only significantly inhibited the growth of bone metastasis tumour but also obviously reduced the bone resorption at bone metastasis sites without causing marked systemic toxicity. Thus, DOX@DBMs-ALN has great potential in the treatment of lung cancer bone metastasis.

The synthesis of pandamarilactonines in high enantiopurity is challenging due to the configurational instability of the pyrrolidin-2-yl butenolide moiety present in these alkaloids. In an attempted asymmetric synthesis of pandamarilactonine-B (2), an unanticipated syn-diastereoselective (dr = 95 : 5) asymmetric vinylogous Mannich reaction (VMR) between 3-methyl-2-(tert-butyldimethylsilyloxy)furan 9b and the Ellman (RS)-N-tert-butanesulfinimine 10a was observed. The methyl group at C-3 of TBSOF has been shown to play the role of a switch of diastereoselection in the VMR. This work ended with a concise three-pot protecting-group-free total synthesis of (−)-pandamarilactonine-A. The puzzle about the configurational instability of the pyrrolidinyl butenolide skeletons has also been disclosed by controlled experiments and with the help of computation.

An efficient approach to N-monosubstituted β,β-difunctionalized enamines, a class of versatile building blocks for the synthesis of bioactive compounds, is reported. The method is based on the triflic anhydride-mediated direct aza-Knoevenagel-type condensation of secondary amides with active methylene compounds. The reaction showed good chemoselectivity and functional group tolerance. A number of title compounds have been synthesized in good to excellent yields in one pot from readily available starting materials.

A versatile and divergent two-step transformation of malimides to racemic tetramates and tetramic acids is described. The method consists of Grignard reagent addition with malimides to give hemiaminals and concentrated HCl-promoted chemoselective transformations of the latter. When running the reaction in CH2Cl2 and in the presence of 2.5 molar equiv. of conc. HCl, 5-alkyltetramates were formed, while in neat conc. HCl, 5-alkyltetramic acids were obtained. Using this method, a variety of title compounds were prepared in good to excellent yields (82%–99%, and 76%/85%). The work also constitutes a formal racemic total synthesis of reutericyclin. On the basis of the experimental evidences and of a deuterium labeling experiment, a plausible reaction mechanism was proposed. This work thus demonstrated two new types of step economical and chemodivergent transformations starting from malic acid.

The asymmetric total synthesis of (+)-N-acetyl norloline, the putative biogenic precursor of all known loline alkaloids, has been achieved in 12 steps from commercially available (R)-glyceraldehyde acetonide. The synthesis relies on the Rassu/Casiraghi's vinylogous aldol reaction, an intramolecular oxa-heteroconjugate addition and a reductive amination to establish the four contiguous stereogenic centers and construct the strained oxygen-bridge under mild conditions.

Isolariciresinol-9'-O-α-L-arabinofuranoside (MWS‑19) isolated from Pinus massoniana Lamb. Fresh pine needles is the major ingredient of the Songling Xuemaikang capsule therapy used for hypertension. The present study aimed to investigate the effects and underlying mechanisms of MWS‑19 on hydrogen peroxide (H2O2)‑induced apoptosis in human umbilical vein endothelial cells (HUVECs). To investigate the effect of MWS‑19 on apoptosis in HUVECs, an oxidative stress‑induced apoptosis model was established in HUVECs using H2O2, and the present study performed Hoechst 33258 staining and a Cell Counting Kit‑8 (CCK‑8) assay. Furthermore, western blot analysis was also performed to investigate the underlying mechanism of the effects of MWS‑19 on the model. The results demonstrated that MWS‑19 reversed the effects of H2O2 on cell apoptosis at a concentration range of 15.6‑250 µg/ml, with dose‑dependent increases in cell growth. Hoechst staining indicated that 500 µM H2O2 induced HUVEC apoptosis, and MWS‑19 markedly protected HUVECs against apoptosis at 31.3, 62.5 and 125 µg/ml. Furthermore, the protein expression of phosphatidylinositol 3‑kinase (PI3K), phosphorylated‑Akt and Bcl‑2‑associated agonist of cell death (Bad) were increased, and reduced caspase‑3 activation was observed, following treatment with MWS‑19 in H2O2‑treated HUVECs. Additionally, the PI3K inhibitor wortmannin attenuated PI3K/Akt/Bad signaling induced by MWS‑19 treatment and neutralized the effect of MWS‑19 on the growth of HUVECs. In conclusion, the results of the present study indicate that MWS‑19 may protect against H2O2‑induced HUVEC apoptosis via the PI3K/Akt/Bad signaling pathway. MWS‑19 may serve an important role in the prevention of oxidative damage in vascular endothelial cells in hypertension patients.

Background: Sodium formononetin-3’-sulphonate (Sul-F) is a derivative of the isoflavone formononetin. In this study, we investigated whether Sul-F can regulate angiogenesis and the potential mechanism in vitro. Methods: We examined the effects of Sul-F on cell proliferation, cell invasion, and tube formation in the human umbilical vein endothelial cell line (HUVEC). To better understand the mechanism involved, we investigated effects of the following compounds: cAMP response element-binding protein (CREB) inhibitor 2-naphthol-AS-E-phosphate (KG-501), early growth response 3 (Egr-3) siRNA, vascular endothelial growth factor (VEGF) antagonist soluble VEGF receptor 1 (sFlt-1), VEGF receptor 2 blocker SU-1498, Wnt5a antagonist WIF-1 recombinant protein (WIF-1), and inhibitor of Wnt/β-catenin recombinant Dickkopf-1 protein (DKK-1). HUVEC proliferation was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). A scratch adhesion test was used to assess cell invasion ability. Matrigel tube formation assay was performed to test capillary tube formation ability. Activation of the VEGF/CREB/Egr-3/Vascular cell adhesion molecule 1 (VCAM-1) pathway in HUVEC was tested by Western blot analysis. Results: Our results suggest that Sul-F induced angiogenesis in vitro by enhancing cell proliferation, invasion, and tube formation. The increase in proliferation and tube formation by Sul-F was counteracted by DKK-1, WIF-1, SU1498, KG-501, sFlt-1, and Egr-3 siRNA. Conclusions: These results may suggest that Sul-F induces angiogenesis in vitro via a programed Wnt/β-catenin pathway and VEGF/CREB/Egr-3/VCAM-1 signaling axis.

The aim of this study was to investigate the effect of interleukin-10 (IL-10) gene deficiency on mouse liver function. The experimental mice were divided into wild-type and IL-10 knockout groups. Serological biomarkers for liver functions were detected by the automatic biochemical analyzer AU5400. The pathological changes were assessed by the light microscope. The levels of inducible nitric oxide synthase (iNOS) and interleukin-1β (IL-1β) in liver tissues were determined by quantitative real-time PCR and enzyme-linked immunosorbent assay. Compared with the wild type, the serum levels of albumin (ALB), total protein, total bilirubin and direct bilirubin in IL-10-deficient mice were significantly decreased (P < 0.05). No obvious pathological changes including liver necrosis and inflammatory cell infiltration were found. The expression of iNOS and IL-1β genes, the serum levels of iNOS and IL-1β were significantly higher in IL-10-deficient mice than in wild-type mice (P < 0.05). The absence of IL-10 gene can significantly decrease serum ALB and bilirubin. The effect may be related to the upregulation of iNOS and IL-1β.

A strategy for the absolute quantitation of metabolic enzymes in rat liver microsomes was developed based on shotgun-based proteomics approach. Rat liver microsomes were digested with trypsin, and drug metabolizing enzymes were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) using standard curves based on custom synthesized specific peptides for each enzyme. The assays for cytochrome P450 (CYP450) and uridine diphosphoglucuronosyl transferase (UGT) showed good linearity ( r > 0.995) with lower limits of quantitation of 10 nM. A synthetic isotope labeled specific peptide was then used as internal standard to determine UGT1A1 by stable isotope dilution method. The labeled peptide behaved similarly to the unlabeled peptide in LC-MS/MS and the assay was linear in matrix solution. The UGT1A1 concentration was detected by the labeled peptide method to be 18.2 pmol mg −1 protein compared with 17.3 pmol mg −1 protein obtained by the standard curve method. Although the consistent results were achieved by the two methods, the stable isotope dilution method was more convenient and more suitable for high throughput determinations in complex systems.

Two new sesquiterpene glycosides, namely massonside A (1) and massonside B (2), were isolated from the n-Bu extract of the fresh needles of Pinus massoniana Lamb. Their structures were established by 1D, 2D nuclear magnetic resonance and high-resolution mass spectrometry. Their biological activities were profiled by the anti-HBV and anti-HCV assays.

A novel migration-addition sequence was discovered for the reaction of enantioenriched N-tert-butanesulfinyl iminoacetate 1a with functionalized benzylzinc bromide reagents, producing tert-leucine derivatives in excellent diastereoselectivity (dr 98:2). The absolute configurations of two new chiral centers were unambiguously assigned by chemical transformations and X-ray crystallography. In addition, the regio- and diastereoselectivities of this novel reaction were both explained through the key N-sulfinamine intermediate M6 generated by the tert-butyl radical attack on the imine. Computational analysis of this reaction process, which was performed at the B3LYP/6-311++G(3df,2p)//B3LYP/6-31G*-LANL2DZ level, also supported our proposed two-stage mechanism.