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Craft beer because of its fresh flavor, unique taste, and rich nutrition is becoming more popular to consumers. Compared with industry beer, craft beer is often nonfiltered and nonpasteurized, for this reason, it has a short shelf life and is more susceptible to microbial spoilage, which may cause the quality deterioration of craft beer and the formation of biogenic amine as a harmful factor for consumer's health. In this study, the 23 beer-spoilage bacteria were isolated from craft beer, which were identified as 15 Lactobacillus (L.) brevis, 3 L. plantarum, 1 L. parabuchneri, 2 L. paracasei, and 2 Pediococcus damnosus. Among 23 beer-spoilage isolates, 20 representatives were able to form tyramine, histamine, putrescine, cadaverine, and/or tryptamine in MRS broth. The nine Lactobacillus strains were incubated in beer and produced tyramine, histamine, putrescine, cadaverine, and/or tryptamine during beer storage process. Logistic and Gompertz model could be adopted to respectively describe the kinetics of microorganism growth and biogenic amine formation. The relationship between the biogenic amines and biomass was simulated by Luedeking-Piret model very well, and showed that the formation of biogenic amine was mainly bacteria growth-associated in beer. These findings may be helpful for finding the preventive measures to control biogenic amine formation and for enhancing the safety of craft beer. PRACTICAL APPLICATION: The selection of the biogenic amine-producing spoilage bacteria from craft beer and the investigation their kinetics of the growth and biogenic amines production under beer environmental conditions was very helpful for finding preventive measures to eliminate or reduce biogenic amine formation and for appropriate increase in food safety.

A unified method for direct C4-H halogenation of indoles has been accomplished with the assistance of anthranilic acids as suitable transient directing groups. Exclusive site selectivity (one out of five potential reactive sites) as well as good functional group tolerance was obtained to install three kinds of halogen atoms (Cl, Br and I, respectively) by using inexpensive N-halosuccinimides (NXS) as halogen sources under mild conditions. Taking advantage of the rich functional groups in the product, a diversity of nitrogen-containing heterocycles were facily constructed via one-step late-stage derivations.

Great progress has been made in the tandem annulation of enynes in the past few years. This review only presents the corresponding reactions of 1,3-enyne structural motifs to provide the functionalized pyridine and pyrrole derivatives. The functionalization reactions cover iodination, bromination, trifluoromethylation, azidation, carbonylation, arylation, alkylation, selenylation, sulfenylation, amidation, esterification, and hydroxylation. We also briefly introduce the applications of the products and the reaction mechanisms for the synthesis of corresponding N-heterocycles.

Background Increasing studies focused on the regulatory roles of circular RNAs (circRNAs) in diverse cancers. This study was to evaluate the function and mechanism of circRNA Scm-like with four malignant brain tumor domains 2 (circ-SFMBT2) in esophageal cancer (EC). Methods The circ-SFMBT2, microRNA-107 (miR-107) and solute-linked carrier family A1 member 5 (SLC1A5) levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was evaluated by 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) assay, colony formation assay and EdU assay. Cell apoptosis and invasion were detected by flow cytometry and transwell assay. Glutamine metabolism was assessed by the corresponding kits for glutamine consumption, α-ketoglutarate production and glutamate production. Western blot was used for protein quantification. The binding analysis was performed using dual-luciferase reporter assay, RNA immunoprecipitation (RIP) and pull-down assays. The functional research of circ-SFMBT2 in vivo was performed by xenograft tumor assay. Exosomes were identified by morphological observation and protein detection. Results Circ-SFMBT2 was overexpressed in EC samples and cells. Circ-SFMBT2 downregulation inhibited EC cell proliferation, invasion and glutamine metabolism. Circ-SFMBT2 targeted miR-107 and the regulation of circ-SFMBT2 was achieved by sponging miR-107. SLC1A5 was a target of miR-107, and it worked as an oncogene in EC cells. MiR-107 retarded the EC progression by downregulating SLC1A5. Circ-SFMBT2 could affect the SLC1A5 expression by targeting miR-107. Circ-SFMBT2 regulated EC progression in vivo by miR-107/SLC1A5 axis. Circ-SFMBT2 was transferred by exosomes in EC cells. Conclusion These results suggested that circ-SFMBT2 upregulated the SLC1A5 expression to promote the malignant development of EC by serving as a miR-107 sponge.

Folate may be involved in the detoxification of heavy metals. This has been demonstrated in animal studies, in in vivo and in vitro studies, and clinical evaluations. However, knowledge regarding the associations between serum folate and blood concentrations of cadmium and lead is limited. We aimed to investigate the relationship between serum folate levels and blood concentrations of cadmium and lead in US adults. Data on 15,501 adults were obtained from the 1999–2006 National Health and Nutrition Examination Survey (NHANES) and used for the analysis. Information on serum folate concentrations and blood levels of lead and cadmium was derived from laboratory measurements in the NHANES. Multivariable linear regression was used to examine the relationship between serum folate levels and blood concentrations of cadmium and lead in US adults, controlling for confounders. The serum folate concentration was negatively correlated with blood levels of cadmium and lead (P-trends 60 mL/min/1.73 m2), the association between serum folate concentrations and blood levels of cadmium and lead was found to be more stable in adults with eGFR > 60 mL/min/1.73 m2, both in males and females. These findings warrant future studies to explore the mechanisms responsible for the beneficial role of folate in regulating cadmium and lead concentrations in the blood.

The major cause of pulmonary vascular remodeling in broilers is abnormal proliferation of vascular smooth muscle cells (VSMCs), and one of the main causes of pulmonary hypertension syndrome (PHS) in broilers is pulmonary artery vascular remodeling. Forty Arbor Acres (AA) broilers were randomly divided into four groups (n = 10): a control group (deionized water, 0 g/L NaCl), a freshwater group (FW, deionized water + 1 g/L NaCl), highly salinized freshwater group 1 (H-SFW-1, deionized water + 2.5 g/L NaCl) and highly salinized freshwater group 2 (H-SFW-2, deionized water + 5 g/L NaCl). The results of in vivo experiments showed that vascular smooth muscle of the broilers could be significantly proliferated by intake of high-salinity fresh water (H-SFW-1 & H-SFW-2), which significantly increased the content of angiotensin II (Ang II) and the expression of angiotensin II type 1 (AT1) receptor protein. Meanwhile, it significantly decreased the expression of dopamine receptor D4 (DRD4) protein. The results of in vitro experiments showed that exogenous Ang II induced the proliferation of primary VSMCs in broilers, which could be significantly inhibited by DRD4 agonists (D4A, HY-101384A) and enhanced by DRD4 inhibitors (D4I, HY-B0965). In addition, the results of immunoblotting and fluorescence quantitative PCR showed that AT1 receptors could be negatively regulated by DRD4 in VSMCs of broilers, either at the transcriptional or translational level. At the same time, the expression of AT1 receptor could be increased by DRD4 inhibition by D4I and decreased by DRD4 activation by D4A. The negative regulatory effect of DRD4 on AT1 receptor occurred in a dose-dependent manner. These results indicate that long-term intake of highly salinized fresh water can cause PHS in broilers, accompanied by varying degrees of proliferation of pulmonary artery smooth muscle. This mechanism may involve response of its receptor being induced by increased Ang II, while DRD4 can negatively regulate it.

OBJECTIVE To investigate the potential therapeutic role of porous SiO2 -coated ultrasmall selenium particles nanospheres (Se@SiO2 nanospheres) pretreatment in acute pancreatitis (AP) and to investigate the related mechanism. METHODS C57BL/6 mice were randomized to the normal control (CON) group, the AP (induced by cerulein injection) (CAE) group, and AP pretreated with Se@SiO2 nanocomposites at 1 and 2 mg/kg (CAE + 1 or 2 mg/kg Se@SiO2 ) groups, respectively. Serum levels of amylase and lipase, inflammatory cytokines (interleukin [IL]-6, IL-1β and tumor necrosis factor [TNF]-α), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine (Cr) were measured, and histopathology was performed to examine the tissue samples of the pancreas, lungs, kidneys and liver. Immunofluorescence assay of reactive oxygen species (ROS), myeloperoxidase (MPO) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling were conducted, and levels of MPO, malondialdehyde, superoxide dismutase and glutathione were evaluated. Finally, Western blot analysis was used to evaluate protein expressions of Nrf2, HO-1, NQO1, TLR4, MyD88 and p-p65 in pancreatic tissue. RESULTS Se@SiO2 nanospheres alleviated pathological damage to the pancreas, and reduced pancreatic enzymes and inflammatory cytokines. Injury to other organs such as the liver, lungs and kidneys was also alleviated, as indicated by decreased ALT, AST, BUN, and Cr levels as well as improved histopathology. Moreover, Se@SiO2 nanospheres reduced oxidative stress, and ultimately inhibited TLR4/ MyD88/p-p65 pathway and increased the protein expressions of NQO1, Nrf2, and HO-1. CONCLUSION Se@SiO2 nanospheres may alleviate AP by relieving oxidative stress and targeting the TLR4/Myd88/p-p65 and NQO1/Nrf2/HO-1 pathways.

Without employing any transition metal and other additives, efficient methods for selective difluoromethylations of β-keto amides with TMSCF2Br reagent have been developed under mild conditions. This protocol allows a convenient access to various α-difluoromethyl β-keto amides with excellent yields (up to 93%) and high carbon/oxygen (C/O) regioselectivities (up to 99:1). The C/O selectivity of β-keto amides could be easily reversed and controlled by simply changing the base. This protocol can be easily scaled-up and the C-difluoromethylation product could be reduced into CF2H-containing amino alcohol derivatives. Moreover, the first enantioselective electrophilic difluoromethylation of β-keto amides has been achieved by phase-transfer catalysis.

The W18O49 nanoparticles were synthesized by solvothermal method with tungsten chloride as raw material and n-propanol as solvent. Polyethylene glycol 400 (PEG-400) was modified for W18O49 nanoparticles (W18O49@PEG). The structure and morphology of W18O49 and W18O49@PEG were characterized by XRD and SEM. Methylene blue aqueous solution was used as wastewater adsorption model. And the comparative experiments with other absorbent materials, such as artificial zeolite and activated carbon were also conducted. The results revealed that after modifying by PEG-400, W18O49 has a better adsorption performance than other materials due to its large specific surface area and high surface energy. Finally adsorption circulation experiment was performed，the results indicate that the W18O49@PEG nanoparticles show great potential in the treatment of colored wastewater.

The electrochemical production of green and low-cost ammonia requests the development of high-performance electrocatalysts. In this work, the ampoule method was applied to modulate the surface of the zinc electrode by implanting defects and low-valent active sites. The N-doped ZnS electrocatalyst was thus generated by sulfurization with thiourea and applied for electrocatalytic nitrogen reduction reaction (ENRR). Given the rich sulfur vacancies and abundant Zn-N active sites on the surface, excellent catalytic activity and selectivity were obtained, with an NH3 yield rate of 2.42 × 10–10 mol s−1 cm−2 and a Faradaic efficiency of 7.92% at − 0.6 V vs. RHE in 0.1 M KOH solution. Moreover, the as-synthesized zinc electrode exhibits high stability after five recycling tests and a 24 h potentiostatic test. The comparison with Zn foil, non-doping ZnS/Zn and recent metal sulfide electrocatalysts further demonstrated advanced catalytic performance of N@ZnS/Zn for ENRR. By simple synthesis, S vacancies, and N-doping defects, this promising electrocatalyst would represent a good addition to the arena of transition-metal-based catalysts with superior performance in ENRR. Graphic abstract

A one-pot procedure for deprotecting carboxylic esters under nonhydrolytic conditions is described. Typical alkyl carboxylates are readily deblocked to the carboxylic acids by the action of aluminum powder and iodine in anhydrous acetonitrile. Cleavage of lactones affords the corresponding ω-iodoalkylcarboxylic acids. Aryl acetylates undergo deacetylation with the participation of the neighboring group. This method enables the selective cleavage of alkyl carboxylic esters in the presence of aryl esters.

Alleviating cardiac dysfunction improves the prognosis of heart failure patients. Lycorine is an alkaloid with several beneficial biological properties. Here, we used mice to evaluate the effect of lycorine on cardiac dysfunction elicited by isoproterenol. Mice were divided into four groups: control, lycorine, isoproterenol, and isoproterenol + lycorine. Mice in the combined group were treated daily with 10 mg/kg isoproterenol intraperitoneally for 2 weeks and 5 mg/kg lycorine was given simultaneously intraperitoneally for 4 weeks. Cardiac structure and function were assessed by echocardiography, hematoxylin and eosin staining, and Masson’s trichrome staining. Isoproterenol-induced cardiac dysfunction and histopathological injury that was significantly improved by treatment with lycorine. Western blotting and the quantitative real-time polymerase chain reaction were used to explore the molecular mechanisms of these effects. Levels of the inflammatory cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, were increased by treatment with isoproterenol; these increases were significantly reduced by lycorine, with involvement of the NF-κB signaling pathway. The fibrotic factors, collagen I and collagen III, were increased by isoproterenol and decreased by treatment with lycorine through inhibiting activation of the Smad signaling pathway. In addition, lycorine alleviated oxidative stress as evidenced by a reduction in total reactive oxygen species in the isoproterenol + lycorine group compared to the isoproterenol group. Lycorine exerted an anti-apoptotic effect as evidenced by upregulating Bcl-2 and downregulating Bax. Overall, our findings demonstrate that lycorine protects against cardiac dysfunction induced by isoproterenol by inhibiting inflammation, fibrosis, oxidative stress, and apoptosis.

A polymer based bag filter with high temperature resistance plays a key role in dust and acid gas treatment in the power industry. Currently, the polymers used for preparing filters with improved heat resistance include those with a high content of aromatic units. But the aromatic structure inevitably leads to a high melting point, which is disadvantageous for melt spinning. Here, we report a polyamide 66 and polyamide 6T copolymer (PA66-co-PA6T) fiber with both high thermal stability and good spinnability. The retention rates of heat resistance of fibers after heat treatment at 185 °C and 200 °C were higher than 97.8% and 88.4%, respectively. This high thermal stability is ascribed to the high thermal degradation activation energy (E), which was confirmed by DSC, TG, and XRD characterization studies and fitting of kinetic data. PA66-co-PA6T with good melt spinnability, high heat resistance strength and low cost is expected to be applied in high-temperature resistance filtration equipment such as bag filters, expanding the application range of PA66 materials.

The quinazolinone skeleton is a common structure found in natural alkaloids and synthetic drugs. In recent years, some quinazolinone derivatives have been found to exhibit good luminescence properties. Benefitting from excellent biocompatibility, low toxicity, and high efficiency, quinazolinones have become promising candidates for use as fluorescent probes, biological imaging reagents and luminescent materials. This review focuses on recent advances relating to the luminescence properties of quinazolinones and their applications in fluorescent probes, biological imaging. Fluorescent probes based on the 2-(2′-hydroxyphenyl)-4(3H)-quinazolinone (HPQ) structure are summarized. Newly developed quinazolinone molecules for environmentally sensitive probes and two photon fluorescence bioimaging are discussed. A brief outlook relating to the future of quinazolinone-based probes and luminescent materials is also included.

Effective transfer and utilization of the photogenerated electrons are a key factor for achieving highly efficient H2 generation by photocatalytic water splitting. Apart from the activity of the co-catalyst, the interface between the co-catalyst and semiconductor is of particular importance. Guided by DFT calculations, single-atom (SA) Pt doped carbon nitride (CN) is successfully synthesized for use as the co-catalyst to the semiconducting CuS. The catalyst system (Pt1-CN@CuS) exhibits an enhanced photocatalytic performance for water splitting with a H2 production rate of 25.4 μmol h-1 and an apparent quantum yield (AQY) of 50.3 % under the illumination of LED-530. Solar-to-hydrogen (STH) conversion efficiency is calculated to be 0.5 % under AM 1.5 illumination. This is the very first investigation of SA as the co-catalyst, which decreases the overpotential of CN during the water splitting and lowers interfacial resistance of the catalyst/co-catalyst and co-catalyst/electrolyte.

Here, we report that SHP2 knockdown enhances glucose consumption, ameliorates insulin resistance, activates IRS‐2 and AKT, and inhibits ERK1/2 phosphorylation in liver., Diabetes is a chronic metabolic disease characterized by insulin resistance (IR). SHP2 has previously been identified as a potential target to reduce IR in diabetes. Here, we examined the effects of SHP2 on glucose consumption (GC), IR level and the expression of insulin receptor substrate (IRS), AKT and extracellular signal‐regulated kinase (ERK)1/2 proteins in a cellular and animal model of diabetes. IR was induced in hepatocellular carcinoma (HCC) cells, and SHP2 was up‐regulated or down‐regulated in cells. Diabetic rats were treated with SHP2 inhibitor. GC of cells, and the weight, total cholesterol, triglycerides, fasting blood glucose, fasting insulin, homeostasis model assessment‐IR index and insulin sensitivity (ISI) of the rats were analyzed. The levels of SHP2 and the activation of IRS‐2, AKT and ERK1/2 in cells and rats were measured by quantitative real‐time PCR (qRT‐PCR) or western blot. GC was reduced, but expression of SHP2 was enhanced in IR HCC cells. Phosphorylation of IRS‐2 and AKT in IR HCC cells and diabetic rats was decreased, whereas phosphorylation of ERK1/2 was enhanced. In both the cell and animal models, SHP2 knockdown enhanced GC, ameliorated IR, activated IRS‐2 and AKT, and inhibited ERK1/2 phosphorylation, in contrast with the effects of SHP2 overexpression. SHP2 knockdown may enhance GC and ameliorate IR through phosphorylation of IRS‐2 via regulating AKT and ERK1/2 in liver.

In this study, two homogeneous polysaccharides (PFC-1 and PFC-2) having anti-atherosclerotic activity were isolated from Fructus Corni. PFC-1 and PFC-2 were 1,6-α-glucans with the molecular weight of 4.4 kDa and 82.0 kDa, respectively. In the in vitro experiments, PFC-1 and PFC-2 showed significant inhibitory effects on the cholesterol accumulation in RAW264.7 macrophages induced by oxidized low-density lipoproteins (ox-LDL), and the inhibitory rate of PFC-2 was 81.62%. Apolipoprotein E-deficient (ApoE−/−) mice fed high-fat diet (HFD) were used to evaluate the anti-atherosclerotic effects of PFC-2 in vivo. The aortic root lipid area decreased by 55.01% in the PFC-2-administered group as compared to the model group. PFC-2 decreased the levels of serum low-density lipoprotein cholesterol, total cholesterol, triglycerides, and malondialdehyde, increased the superoxide dismutase activity, and reduced the contents of lipid and macrophages in the aortic sinus plaque in ApoE−/− mice fed with HFD. Furthermore, PFC-2 markedly inhibited the expression of type A1 scavenger receptor (SR-A1) and cluster of differentiation 36 (CD36) in ox-LDL-treated macrophages. Taken together, 1,6-α-glucans from Fructus Corni showed significant anti-atherogenic effect, and the mechanism is related to enhanced antioxidant activity of the ApoE−/− mice and down-regulated the expression of SR-A1 and CD36 proteins in macrophages.

A feasible arylaminomethyl radical-triggered tandem annulation reaction has been developed toward a large variety of poly fused heterocycles, tetrahydroimidazo[1,5-a]quinoxalin-4(5H)-ones, by reacting diverse quinoxalin-2(1H)-ones with various N-arylglycines in green solvent (DMC) in the presence of CsPbBr3 under white-light irradiation conditions.

Developing hydrogen evolution reaction (HER) electrocatalysts with high activity, durability and moderate price is essential for sustainable hydrogen energy utilization. Here, the facile coupling of carbon dots (CDs, 0D carbon materials) and carbon fibres (CFs, 1D carbon materials) for enhanced electrochemical hydrogen production was demonstrated. Electrochemical tests revealed that the CD/CF catalysts showed outstanding catalytic activity with a small overpotential of 280 mV at the current density of 10 mA cm-2 , a small Tafel slope of 87 mV dec-1 and prominent durability. Percolation theory was for the first time introduced to interpret the catalytic mechanism of the CD/CF catalysts. The special morphology assembled by the 0D carbons constituted the percolating clusters and promoted electron transport throughout the 1D carbons. The strategy and theory can be adapted to general electrocatalytic applications for achieving and interpreting precise tuning on highly efficient electron transfer in electrocatalysts.

Gout and hyperuricemia can seriously affect the quality of life; at present, however, existing medicines are unable to meet all clinical needs. In the current study, a novel peptide (i.e., rice-derived-peptide-3 (RDP3), AAAAMAGPK-NH2, 785.97 Da) in water extract obtained from shelled Oryza sativa fruits was identified. Testing revealed that RDP3 (minimum effective concentration 100 μg/kg) did not show both hemolytic and acute toxicity, and reduced uric acid levels in the serum of hyperuricemic mice by inhibiting xanthine oxidase activity and decreasing urate transporter 1 expression. RDP3 also alleviated renal injury in hyperuricemic mice by decreasing NLRP3 inflammasome expression. Furthermore, RDP3 alleviated formalin-induced paw pain and reduced monosodium urate crystal-induced paw swelling and inflammatory factors in mice. Thus, this newly identified peptide reduced uric acid levels and renal damage in hyperuricemic mice and showed anti-inflammatory and analgesic activities, indicating the potential of RDP3 as an antigout medicine candidate.

Background Gallbladder cancer (GBC) is the most common biliary tract malignant cancer worldwide. It has been reported that microRNA-575 (miR-575) was involved in the tumorigenesis of many cancers. However, the role of miR-575 during the progression of GBC remains largely unknown. Methods The expression of miR-575 in GBC cells was detected by quantitative real-time polymerase chain reaction. The proliferation of GBC cells was examined by CCK-8 assay and Ki-67 staining. Apoptosis of GBC cells was measured by flow cytometry, and cell invasion was tested by transwell assay. Moreover, protein expressions in GBC cells were evaluated using Western blot. The target gene of miR-575 was predicted using Targetscan and miRDB. Finally, xenograft tumor model was established to verify the function of miR-575 in GBC in vivo. Results Our findings indicated that miR-575 antagonist decreased the proliferation and invasion of GBC cells. In addition, miR-575 antagonist significantly induced apoptosis of GBC cells via inducing G1 arrest. Meanwhile, p27 Kip1 was found to be a direct target of miR-575 with luciferase reporter assay. Moreover, miR-575 antagonist significantly decreased the expressions of CDK1 and cyclin E1 and upregulated the levels of cleaved caspase3 and p27 Kip1 in GBC cells. Finally, miR-575 antagonist notably suppressed GBC tumor growth in vivo. Conclusion Downregulation of miR-575 significantly inhibited the tumorigenesis of GBC via targeting p27 Kip1. Thus, miR-575 might be a potential novel target for the treatment of GBC.

The gas generation features of coals at different maturities were studied by the anhydrous pyrolysis of Jurassic coal from the Minhe Basin in sealed gold tubes at 50 MPa. The gas component yields (C1, C2, C3, i-C4, n-C4, i-C5, n-C5, and CO2); the δ13C of C1, C2, C3, and CO2; and the mass of the liquid hydrocarbons (C6+) were measured. On the basis of these data, the stage changes of δ13C1, δ13C2, δ13C3, and δ13CO2 were calculated. The diagrams of δ13C1–δ13C2 vs ln (C1/C2) and δ13C2–δ13C1 vs δ13C3–δ13C2 were used to evaluate the gas generation features of the coal maturity stages. At the high maturity evolution stage (T > 527.6 °C at 2 °C/h), the stage change of δ13C1 and the CH4 yield are much higher than that of CO2, suggesting that high maturity coal could still generate methane. When T 2 is generated by breaking bonds between carbons and heteroatoms. The reaction between different sources of coke and water may be the reason for the complicated stage change in $$\delta^{{{13}}} {\text{C}}_{{{\text{CO}}_{{2}} }}$$ δ 13 C CO 2 when the temperature was higher than 455 °C. With increasing pyrolysis temperature, δ13C1–δ13C2 vs ln (C1/C2) has four evolution stages corresponding to the early stage of breaking bonds between carbon and hetero atoms, the later stage of breaking bonds between carbon and hetero atoms, the cracking of C6+ and coal demethylation, and the cracking of C2–5. The δ13C2–δ13C1 vs δ13C3–δ13C2 has three evolution stages corresponding to the breaking bonds between carbon and hetero atoms, demethylation and cracking of C6+, and cracking of C2–5.

Soluble epoxide hydrolase (sEH) is related to arachidonic acid cascade and is over-expressed in a variety of diseases, making sEH an attractive target for the treatment of pain as well as inflammatory-related diseases. A new series of memantyl urea derivatives as potent sEH inhibitors was obtained using our previous reported compound 4 as lead compound. A preferential modification of piperidinyl to 3-carbamoyl piperidinyl was identified for this series via structure-based rational drug design. Compound A20 exhibited moderate percentage plasma protein binding (88.6%) and better metabolic stability invitro. After oral administration, the bioavailability of A20 was 28.6%. Acute toxicity test showed that A20 was well tolerated and there was no adverse event encountered at dose of 6.0g/kg. Inhibitor A20 also displayed robust analgesic effect invivo and dose-dependently attenuated neuropathic pain in rat model induced by spared nerve injury, which was better than gabapentin and sEH inhibitor (±)-EC-5026. In one word, the oral administration of A20 significantly alleviated pain and improved the health status of the rats, demonstrating that A20 was a promising candidate to be further evaluated for the treatment of neuropathic pain.

The high mutation rate of COVID-19 and the prevalence of multiple variants strongly support the need for pharmacological options to complement vaccine strategies. One region that appears highly conserved among different genus of coronaviruses is the substrate binding site of the main protease (Mpro or 3CLpro), making it an attractive target for the development of broad-spectrum drugs for multiple coronaviruses. PF-07321332 developed by Pfizer is the first orally administered inhibitor targeting the main protease of SARS-CoV-2, which also has shown potency against other coronaviruses. Here we report three crystal structures of main protease of SARS-CoV-2, SARS-CoV and MERS-CoV bound to the inhibitor PF-07321332. The structures reveal a ligand-binding site that is conserved among SARS-CoV-2, SARS-CoV and MERS-CoV, providing insights into the mechanism of inhibition of viral replication. The long and narrow cavity in the cleft between domains I and II of main protease harbors multiple inhibitor binding sites, where PF-07321332 occupies subsites S1, S2 and S4 and appears more restricted compared with other inhibitors. A detailed analysis of these structures illuminated key structural determinants essential for inhibition and elucidated the binding mode of action of main proteases from different coronaviruses. Given the importance of main protease for the treatment of SARS-CoV-2 infection, insights derived from this study should accelerate the design of safer and more effective antivirals.

Background The above experimental results show that SBP-2A isolated and purified from Scutellaria barbata may be a candidate drug for further evaluation in cancer prevention, which provides a clue for further studies on the molecular mechanism of its anticancer activity against human liver cancer cells.Methods The crude polysaccharide of Scutellaria barbata (SBP) was extracted with water and precipitated with alcohol. Optimal extraction conditions were determined by response surface methodology: the solid-liquid ratio was 1:25, the extraction time was 2 h, and the extraction temperature was 90 °C. With these conditions, the average extraction efficiency was 3.85 ± 0.13%. SBP was purified with a DEAE-52 cellulose column and Sephadex G-100 dextran gel column to obtain SBP-1A and SBP-2A fractions. The polysaccharide content, molecular weight, monosaccharide composition and basic structure were preliminarily identified. Then, a MTT assay was used to identify the polysaccharide components with anti-hepatoma effects. The antitumor activity of SBP-2A was evaluated by colony formation tests, morphological observations, apoptosis and cell cycle analyses.Results Structural analysis showed that SBP-1A and SBP-2A were mainly composed of arabinose and galactose, but the molar ratios were different; these were homogeneous acidic polysaccharide components with high purity, and the average molecular weights were 1.15 × 105 Da and 1.4 × 105 Da, respectively. FT-IR spectra showed that SBP-1A and SBP-2A contained uronic acid β-glucan, and the sugar residue of the polysaccharide was mainly pyranose. MTT and colony formation assays showed that SBP-2A significantly inhibited the proliferation of HepG2 cells. The cell distribution at different apoptotic stages was determined by the Hoechst 33258 test and Annexin V-FITC/PI staining. Flow cytometric analysis showed that SBP-2A induced HepG2 cell apoptosis by blocking the G1 phase.Conclusions Two polysaccharides (SBP-1A and SBP-2A) had been isolated from Scutellaria barbata. Preliminary characterization of the SBP-1A and SBP-2A was investigated. The anticancer activities were studied in vitro. SBP-2A significantly inhibited the proliferation of HepG2 cells and induced cells apoptosis by blocking the G1 phase.

In this paper, 21 naphthalene-chalcone derivatives were synthesized and their biological effects were evaluated. The results showed that compounds 2a–2u displayed clear antidepressant activity at 30 mg/kg in the forced swimming test. Compounds 2h, 2o, 2t, and 2u exhibited a good antidepressant effect in the forced swimming test and tail suspension test at 30 mg/kg. Compounds 2h, 2o, 2t, and 2u but had no effect on locomotor activity in the open-field test in mice. In addition, the most antidepressant activity of compound 2o is likely mediated by increased serotonin and norepinephrine levels in central nervous system. Compounds 2a–2u also showed the analgesic and anti-inflammatory effects at 30 mg/kg.

Colorectal cancer is associated with changed IgG glycosylation, but the alteration in specific subclasses of IgG is unknown. Initially, we optimized five common IgG glycopeptide enrichment methods to acquire a comprehensive profile of IgG glycopeptides. However, an incomplete tryptic digestion of IgG occurred when using an ordinary protease to protein ratio, which significantly impacted the final statistical analysis. Herein, we introduced a two-step enzymatic digestion, enabling the complete digestion of IgG glycopeptides and further improving the detection intensity of the target glycopeptides. In order to rapidly process and automatically integrate the MS data, we developed a simple and effective code using MATLAB. Following statistical analysis, we observed that IgG1_H3N4F1 and IgG1_H3N4 were substantially increased in CRC, while IgG1_H5N5F1, IgG1_H5N4F1S1 and IgG2_H5N4F1 were markedly decreased. A further evaluation of the diagnostic performance showed that they all achieved a fair performance in discriminating the patients from the normal. In terms of the glycan features, it was demonstrated that the CRC progression was associated with increased agalactosylation, and the decreased digalactosylation and galactosylation per antenna on the diantenna glycans of IgG1 and IgG2. Concurrently, the decreased sialylation of IgG1 was strongly correlated with CRC. Moreover, an analysis of tumor-specific glycosylation showed that the alterations of IgG glycosylation were more significant in colon cancer, and no obvious difference was observed between colon and rectal cancer. This study comprehensively optimized the glycopeptide enrichment methods, evaluated the enzymatic digestion effect, and explored the association between CRC progression and subclass-specific glycosylation.

The key to photocatalytic efficient decomposition of VOCs is to significantly improve carrier separation-efficiency of the photocatalyst. Herein, we synthesized a novel photocatalytic composite material of I-deficient BiO1.2I0.6/WO3 by solvothermal method coupling with thermal decomposition. The PL spectrum and photoelectrochemical tests found that WO3 compounded by 40 wt% BiO1.2I0.6 greatly promoted its separation efficiency of carriers. This was mainly caused by the potential difference of band edge between the 40 wt% BiO1.2I0.6 and WO3 driving reverse shift of carriers in their space charge-layer. The 40 wt% BiO1.2I0.6/WO3 achieved 58.8% mineralization ratio in the process of degrading typical VOCs, toluene after 8 h irradiation, which was 15.9 and 2 times those of BiO1.2I0.6 and WO3, respectively. Gaussian calculation and ESR investigation demonstrated that toluene was decomposed by h+ and hydroxyl radical (·OH) under irradiation.

Ceramic TiB2, a layered metal diboride with remarkable conductivity and chemical stability, are potential electrocatalyst towards hydrogen evolution reaction (HER). However, high overpotential (>1 V) is required for pristine TiB2 to drive water splitting, which is less than satisfactory in future hydrogen economy. Herein, conductive polypyrrole (PPy) encapsulating TiB2 (TiB2@PPy) has been developed via vapor phase polymerization, as the electrocatalyst for HER. Theoretically, the PPy shell serves both as electron-transfer channels to accelerate electron migration, and as Mott-Schottky centre to modify the electronic structure of TiB2. Beneficially, more improved HER performance has been achieved with the overpotential of 432 mV at 10 mA cm−2, superior to that of pristine TiB2 (848 mV at 10 mA cm−2). Moreover, excellent stability is presented during 1000 CV cycles and 10 h constant evaluation. Our study provides a new avenue to create efficient HER electrocatalyst via conductive PPy engineering.

Herein, we report the natural ligand quebrachitol (QCT) as a promoter for a Cu(II) catalyst, which is highly effective for N-arylation of various amines and related aryl halides. A series of diarylamine derivatives were obtained in high yields by using diethylene glycol (DEG) as both ligand and solvent. The C–N coupling reactions proceed under mild conditions and exhibit good functional group tolerance.

A photocatalyst with a high separation efficiency of carriers is crucial for the photocatalytic efficient decomposition of volatile organic compounds (VOCs). In this work, a new iodine-deficient BiO1.2 I0.6 /Bi2 O3 photocatalyst was developed through a solvothermal approach coupled with thermal decomposition. The 2 wt % BiO1.2 I0.6 /Bi2 O3 sample demonstrated optimal photocatalytic activity for the degradation of toluene, achieving a 55.1 % mineralization ratio under 8 h of irradiation, which was 14.9 and 2.1 times higher than those of BiO1.2 I0.6 and Bi2 O3 , respectively. Compared with BiO1.2 I0.6 and Bi2 O3 , 2 wt % BiO1.2 I0.6 /Bi2 O3 exhibited the weakest fluorescence band, highest photocurrent density, and lowest impedance; thus suggesting that Bi2 O3 compounded by 2 wt % BiO1.2 I0.6 distinctly promoted the separation efficiency of carriers. The hydroxyl radical (. OH) was the main active species, apart from holes, for the photocatalytic degradation of toluene.

A cobalt-catalyzed direct carbonylative synthesis of phthalimide motifs from N-(pyridin-2-ylmethyl)benzamides has been developed. Various phthalimide derivatives were obtained in moderate to excellent yields (up to 98%) by using 2-picolylamine as an efficient directing group and benzene-1,3,5-triyl triformate (TFBen) as a convenient CO surrogate.

Using cheap, readily available, and economic active MnO2 as an oxidant, a series of 2,4-disubstituted quinazoline-3-oxides were synthesized in good to excellent yields by oxidation of the corresponding 1,2-dihydroquinazoline-3-oxides under mild conditions. This novel approach is simple and convenient and provides a series of 2,4-disubstituted quinazoline-3-oxides.

Myo-inositol is originally applied as a cardiovascular medicine in clinic, which can be multi-ton manufactured via extraction from the byproducts in agricultural product processing such as defatted rice bran and corn-soaking water. Herein, the application of myo-inositol (MI) as a novel versatile tridentate O-donor ligand has been first described for promoting Cu-catalyzed amination reaction in aqueous medium.

A cobalt-catalyzed C-H carbonylation of naphthylamides for the synthesis of benzo[cd]indol-2(1H)-one scaffolds has been developed. The reaction employs a traceless directing group and uses benzene-1,3,5-triyl triormate as the CO source, affording various free (NH)-benzo[cd]indol-2(1H)-ones in moderate to high yields (up to 88%). Using this protocol, the total synthesis of BET bromodomain inhibitors A and B was accomplished as well.

Poly(amidoamine) dendrimers grafted on carbon nanotubes have been appended with iron(II)-α-keto acid (benzoylformate) complex of polypyridyl ligand to design artificial non-heme oxygenase model. This nano-enzyme was applied for selective catalytic oxidation of organic molecules. Although the carbon nanotubes serve as a robust heterogeneous platform, the amine terminals of dendrimers provide catalysts binding sites and the amide bonds provide a necessary second coordination sphere similar to the enzymatic polypeptide chains. Such a hybrid design prevented the deactivation of the primary active sites leading to 8 times faster oxidative decarboxylation rates than those of its homogeneous analogue. An electrophilic iron(IV)-oxo intermediate has been intercepted, which catalyzes the selective oxidation of alcohols to aldehydes and incorporates single oxygen atoms into sulfides and olefins by using aerial oxygen with multiple turnover numbers. The catalyst was consecutively regenerated three times by mild chemical treatment and showed negligible loss of activity.

A novel quinazolinone-based fluorescent dye, 6-dimethylamino-2-(quinolin-2-yl)- quinazolin-4(3H)-one (DMAQQ), has been designed and synthesized. This quinazolinone-based dye exhibited good efficient solvatochromic fluorescence with appreciated fluorescence quantum yield in different organic solvents (0.57–0.78) and remarkable two-photon fluorescence. The theoretical calculation showed that it was derived from charge transfer (CT) character and intramolecular hydrogen bond. Further investigation on the interaction with anions also showed that the fluorescence intensity of this dye decreased and quenched through the destruction of intramolecular hydrogen bond by the addition of hydrogen bond strong acceptor. As a good bioimaging candidate, DMAQQ showed excellent biocompatibility. More importantly, DMAQQ exhibited blue and green one-photon fluorescence emission in HeLa cells with the Pearson's coefficient 0.39, which suggested possible different local polarity in HeLa cells. And the DMAQQ also showed bright green fluorescence in HeLa cells, which excited by two-photon, offering a new dye platform for high spatial resolution bio-imaging application.

Over the past 20 years, Severe acute respiratory syndrome CoV (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV) and severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), have all emerged, causing severe epidemic human respiratory diseases throughout the globe. Developing broad spectrum drugs would be invaluable in responding to new emerging coronaviruses of the future and could address unmet urgent clinical needs. Main protease (Mpro, also known as 3CLpro) has a major role in the replication of a coronavirus life cycle and is one of the most important drug targets for anticoronavirus agents. We show that a natural product, noncovalent inhibitor shikonin, can pan-main protease inhibitor of SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-HKU1, HCoV-NL63 and HCoV-229E with micromolar IC50 values. Structures of the main protease of different coronavirus genus, SARS-CoV from betacoronaviruses and HCoV-NL63 from alphacoronaviruses, were determined by X-ray crystallography and reveals that the inhibitor interacts with key active-site residues in a unique mode. The structure of the main protease inhibitor complex presents an opportunity to discover a novel series of broad-spectrum inhibitors. These data provide substantial evidence that shikonin and its derivatives may be effective against most coronaviruses, as well as emerging coronaviruses in the future. Given the importance of main protease for the coronavirus therapeutic indication, insights from these studies should accelerate the development and design of safer and more effective antiviral agents. Importance The current pandemic has created an urgent need for broad spectrum inhibitors of SARS-CoV-2. Main protease is relatively conservative compared with the spike protein and thus is one of the most promising drug targets for developing anticoronavirus agents. We have solved crystal structures of main protease of SARS-CoV and HCoV-NL63 bound to shikonin. The structures provide important insights that have broad implications for understanding the structural basis underlying enzyme activity, and can facilitate rational design of broad spectrum anticoronavirus ligands as new therapeutic agents.

Gout is a disease involving abnormal purine metabolism that is widespread in mammals and birds. Goose is especially susceptible for gout in early stage. However, a few studies investigated the ontogenetic pattern of goslings with purine metabolic abnormality. Our studies were conducted to investigate whether persistent purine metabolic abnormality would lead to aggravation of visceral inflammation and intestinal microbiota dysbiosis in goose. A total of 132 1-day-old Magang geese were randomly divided into six replicates and fed a high-calcium and protein meal-based diet from 1 to 28 days. The experiment lasted for 28 days. Liver and kidney damages were observed in 14- and 28-day-old Magang geese, and liver inflammation increased with increasing age. In 28-day-old Magang geese, serum CAT and liver GSH-Px activity were significantly reduced. Furthermore, jejunum intestinal barrier was impaired and the abundance of Bacteroides was significantly reduced at the genus level. Collectively, the high-calcium and high-protein (HCP) meal-based diet caused liver and kidney damage in 28-day-old Magang geese, leading to hyperuricemia and gout symptoms, and the intestinal barrier is impaired and the intestinal flora is disrupted.

Prussian blue (PB) is a safe photothermal agent for tumor therapy, yet poor photothermal effect and single therapeutic function severely restrict its further clinical applications. Herein, a biodegradable “Nano-donut” (CMPB-MoS2-PEG) is fabricated for magnetic resonance (MR) imaging and enhanced photothermal therapy (PTT)/ chemodynamic therapy (CDT)/chemotherapy through responsive catalysis in tumor microenvironment (TME). The “Nano-donut” is organically composed of Cu/Mn ions doped-PB and MoS2. The porous donut structure of CMPB-MoS2-PEG endows them as a carrier for delivery of doxorubicin hydrochloride (DOX) to tumor site. The framework of Nano-donut specifically decomposes in TME due to the reaction between Fe2+/Fe3+ and H2O2. The multivalent elements (Cu/Fe/Mn ions) decrease the bandgap and then enhance CDT by synergistically catalyzing H2O2 into toxic ·OH. Meanwhile, the Mn4+ also reacts with H2O2 to generate O2, improving the hypoxia of TME and enhancing the chemotherapy effect of released DOX. The MoS2 mingles in the PB, which significantly enhances photothermal conversion efficiency (η) effect of PB from 16.02% to 38.0%. In addition, Fe3+ as T2-weighted MR imaging agent can achieve MR imaging-guided therapy. The data clearly shows Nano-donut/DOX nanocomposites (NCs) have a remarkable inhibition for cancer cells and excellent biological safety in tumor treatment.

Secreted protein acidic and rich in cysteine (SPARC) may play a notable role in aqueous humor outflow through the trabecular meshwork (TM). SPARC is a potential therapeutic target in glaucoma, and the mechanism by which it regulates intraocular pressure remains unclear. The present study aimed to observe the effects of SPARC in human TM cells (HTMCs) in vitro. SPARC was downregulated by recombinant lentiviral vectors in HTMCs, and the subsequent levels of F-actin expression, zonula occludens-1 (ZO-1) expression and cellular phagocytosis were observed and calculated. It was revealed that after 48 h of culture, the expression levels of SPARC, F-actin and ZO-1 were significantly decreased in the lentivirus group compared with those in the blank control and empty vector control groups. The downregulation of SPARC promoted phagocytosis in HTMCs after 24 or 48 h of culture. This indicated that the downregulation of SPARC decreased the expression levels of the cytoskeleton-associated proteins F-actin and ZO-1, promoted phagocytosis in HTMCs and may affect the outflow of aqueous humor via the TM pathway.