Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines.

Herein, we report a visible-light-mediated palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines, affording unsaturated γ- and ε-amino acid derivatives with diverse structures. In this methodology, the diazo compound readily transforms into a hybrid α-ester alkylpalladium radical with the release of dinitrogen. The radical intermediate selectively adds to the double bond of a 1,3-diene or allene, followed by the allylpalladium radical-polar crossover path and selective allylic substitution with the amine substrate, thereby leading to a single unsaturated γ- or ε-amino acid derivative. This approach proceeds under mild and simple reaction conditions and shows high functional group tolerance, especially in the incorporation of various bioactive molecules. The studies on scale-up reactions and diverse derivatizations highlight the practical utility of this multicomponent reaction protocol.

Injectable extracellular matrix-mimetic hydrogel based on electrospun Janus fibers.

To date, the reported injectable hydrogels have failed to mimic the fibrous architecture of the extracellular matrix (ECM), limiting their biological effects on cell growth and phenotype. Additionally, they lack the micro-sized pores present within the ECM, which is unfavorable for the facile transport of nutrients and waste. Herein, an injectable ECM-mimetic hydrogel (IEMH) was fabricated by shortening and dispersing Janus fibers capable of self-curling at body temperature into pH 7.4 phosphate buffer solution. The IEMH could be massively prepared through a side-by-side electrospinning process combined with ultraviolet irradiation. The IEMHs with only 5 wt% fibers could undergo sol-gel transition at body temperature to become solid gels with desirable stability, sturdiness, and elasticity and self-healing ability. In addition, they possessed notable pseudoplasticity, which is beneficial to injection at room temperature. The results obtained from characterization analysis via scanning electron microscopy, total internal reflection fluorescence microscopy, nuclear magnetic resonance spectroscopy, and Fourier-transform infrared spectroscopy indicate that their sol-gel transition under physiological conditions stems from the synergistic action of the tight entanglements between thermally-induced self-curling fibers and the hydrophobic interaction between the fibers. An MTT assay using C2C12 myoblast cells was performed to examine the in vitro cytotoxicity of IEMHs for biomedical applications, and the cell viability was found to be more than 95%.

Stimuli-responsive rotaxane-branched dendronized polymers with tunable thermal and rheological properties.

Aiming at the creation of polymers with attractive dynamic properties, herein, rotaxane-branched dendronized polymers (DPs) with rotaxane-branched dendrons attached onto the polymer chains are proposed. Starting from macromonomers with both rotaxane-branched dendrons and polymerization site, targeted rotaxane-branched DPs are successfully synthesized through ring-opening metathesis polymerization (ROMP). Interestingly, due to the existence of multiple switchable [2]rotaxane branches within the attached dendrons, anion-induced reversible thickness modulation of the resultant rotaxane-branched DPs is achieved, which further lead to tunable thermal and rheological properties, making them attractive platform for the construction of smart polymeric materials.

Potential therapeutic target of EGF on bile duct ligation model and biliary atresia children.

BACKGROUND: The pathogenesis of liver fibrosis in biliary atresia (BA) is unclear. Epidermal growth factor (EGF) plays a vital role in liver fibrosis. This study aims to investigate the expression of EGF and the mechanisms of its pro-fibrotic effects in BA. METHODS: EGF levels in serum and liver samples of BA and non-BA children were detected. Marker proteins of EGF signaling and epithelial-mesenchymal transition (EMT) in liver sections were evaluated. Effects of EGF on intrahepatic cells and the underlying mechanisms were explored in vitro. Bile duct ligation (BDL) mice with/without EGF antibody injection were used to verify the effects of EGF on liver fibrosis. RESULTS: Serum levels and liver expression of EGF elevated in BA. Phosphorylated EGF receptor (p-EGFR) and extracellular regulated kinase 1/2 (p-ERK1/2) increased. In addition, EMT and proliferation of biliary epithelial cells were present in BA liver. In vitro, EGF induced EMT and proliferation of HIBEpic cells and promoted IL-8 expression in L-02 cells by phosphorylating ERK1/2. And EGF activated LX-2 cells. Furthermore, EGF antibody injection reduced p-ERK1/2 levels and alleviated liver fibrosis in BDL mice. CONCLUSION: EGF is overexpressed in BA. It aggravates liver fibrosis through EGF/EGFR-ERK1/2 pathway, which may be a therapeutic target for BA. IMPACT: The exact pathogenesis of liver fibrosis in BA is unknown, severely limiting the advancement of BA treatment strategies. This study revealed that serum and liver tissue levels of EGF were increased in BA, and its expression in liver tissues was correlated with the degree of liver fibrosis. EGF may promote EMT and proliferation of biliary epithelial cells and induce IL-8 overexpression in hepatocytes through EGF/EGFR-ERK1/2 signaling pathway. EGF can also activate HSCs in vitro. The EGF/EGFR-ERK1/2 pathway may be a potential therapeutic target for BA.

Photoredox-Catalyzed Carbonyl Alkylative Amination with Diazo Compounds: A Three-Component Reaction for the Construction of γ-Amino Acid Derivatives.

A photoredox-catalyzed reaction of secondary amines, aldehydes, diazo compounds, and Hantzsch ester is reported, affording biologically active γ-amino acid derivatives in high yields. This one-pot process tolerates a broad range of functional groups and various drug molecules and biologically active compounds. Remarkably, a gram-scale reaction and diverse transformations of γ-amino acid derivatives were successfully performed, and the utility of the products is demonstrated in the synthesis of therapeutic agent pregabalin.

Sweat-Resistant Silk Fibroin-Based Double Network Hydrogel Adhesives.

The adhesion between flexible epidermal sensors and human skin is essential for maintaining the stable functionality of the sensors. However, it is still challenging for epidermal electronic devices to achieve durable adhesion to the surface of the skin, especially under sweaty or humid conditions. Here, we report a silk fibroin-polyacrylamide (SF-PAAm) double network (DN) hydrogel adhesive with excellent biocompatibility, strong and durable adhesion on wet surfaces, and tunable adhesive properties. The hydrophilic PAAm network greatly improves the water retention capability of the DN hydrogel and reduces the ß-sheet crystalline content of SF, leading to excellent adhesive properties of the hydrogel across a wide range of humidity. The SF-PAAm DN hydrogel adhesive can be readily integrated with different epidermal sensor arrays and performs very well in real-time on-body sweat sensing. The SF-PAAm DN hydrogels have great potential for application in various epidermal healthcare sensors as well as medical adhesives for other medical applications.

MiRNA-4537 functions as a tumor suppressor in gastric cancer and increases the radiosensitivity of gastric cancer cells.

Radiotherapy is a common method to treat gastric cancer (GC). However, the clinical outcomes of GC radiotherapy face challenges, and the mechanisms of GC radioresistance remain unclear. Our study aimed to investigate the role and mechanism of miR-4537 in the radiation sensitivity of GC cells. Cell viability was determined by Cell Counting Kit-8. The proliferation of HGC27 and KATO III cells was measured using a colony formation assay. Flow cytometry was performed to examine the changes in cell apoptosis. Western blotting was conducted to detect the expression of zinc finger protein 587 (ZNF587) protein in HGC27 and KATO III cells. To confirm the relationship between miR-4537 and ZNF587, a luciferase reporter assay was performed. MiR-4537 was downregulated in GC tumors and cells and suppressed cell proliferation, while promoting cell apoptosis in GC. Importantly, we found that miR-4537 reduced the radioresistance of GC cells. In addition, we also confirmed that miR-4537 expression is negatively correlated with ZNF587 expression in GC tissues. MiR-4537 bound to ZNF587 and suppressed the expression level of ZNF587. Overexpression of ZNF587 partially counteracted the effects of miR-4537 on cell proliferation and apoptosis. In conclusion, in GC cells, miR-4537 inhibited the ability of cell proliferation, but on the contrary, it promoted the ability of cell apoptosis and improved radiosensitivity of the cells.

Prognosis of Biliary Atresia Associated With Cytomegalovirus: A Meta-Analysis.

Objective: The etiology of biliary atresia is unclear, but viral infection has been implicated. The aim of the current meta-analysis was to investigate relationships between cytomegalovirus (CMV) and the prognosis of biliary atresia. Methods: PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure database, and Wanfang Data electronic databases were searched for eligible studies. Each relevant text was thoroughly reviewed and examined, including related papers in their reference lists. Results: A total of nine studies including 784 patients were included in the analysis. Biliary atresia patients with CMV exhibited significantly lower jaundice clearance (odds ratio: 0.46, p < 0.0001; I 2 = 15%, p = 0.31). There were no significant differences in the rates of cholangitis or native liver survival. CMV-pp65-positive biliary atresia patients had a significantly lower rate of jaundice clearance (odds ratio: 5.87, p = 0.003; I 2 = 0%, p = 0.71) and a significantly higher rate of cholangitis (odds ratio: 0.21, p = 0.01; I 2 = 0%, p = 0.43) than CMV antibody-positive biliary atresia patients. Conclusion: Biliary atresia patients who were also infected with CMV had a poorer prognosis, particularly with respect to jaundice clearance. CMV status may influence the prognosis of biliary atresia. Clinicians should be able to routinely identify the subset of biliary atresia patients who are also CMV-positive, in order to improve native liver survival.

Radical-Mediated Strategies for the Functionalization of Alkenes with Diazo Compounds.

One of the most common reactions of diazo compounds with alkenes is cyclopropanation, which occurs through metal carbene or free carbene intermediates. Alternative functionalization of alkenes with diazo compounds is limited, and a methodology for the addition of the elements of Z-CHR2 (with Z = H or heteroatom, and CHR2 originates from N2═CR2) across a carbon-carbon double bond has not been reported. Here we report a novel reaction of diazo compounds utilizing a radical-mediated addition strategy to achieve difunctionalization of diverse alkenes. Diazo compounds are transformed to carbon radicals with a photocatalyst or an iron catalyst through PCET processes. The carbon radical selectively adds to diverse alkenes, delivering new carbon radical species, and then forms products through hydroalkylation by thiol-assisted hydrogen atom transfer (HAT), or forms azidoalkylation products through an iron catalytic cycle. These two processes are highly complementary, proceed under mild reaction conditions, and show high functional group tolerance. Furthermore, both transformations are successfully performed on a gram-scale, and diverse γ-amino esters, γ-amino alcohols, and complex spirolactams are easily prepared with commercially available reagents. Mechanistic studies reveal the plausible pathways that link the two processes and explain the unique advantages of each.

Lasso Proteins: Modular Design, Cellular Synthesis, and Topological Transformation.

Entangled proteins have attracted significant research interest. Herein, we report the first rationally designed lasso proteins, or protein [1]rotaxanes, by using a p53dim-entwined dimer for intramolecular entanglement and a SpyTag-SpyCatcher reaction for side-chain ring closure. The lasso structures were confirmed by proteolytic digestion, mutation, NMR spectrometry, and controlled ligation. Their dynamic properties were probed by experiments such as end-capping, proteolytic digestion, and heating/cooling. As a versatile topological intermediate, a lasso protein could be converted to a rotaxane, a heterocatenane, and a "slide-ring" network. Being entirely genetically encoded, this robust and modular lasso-protein motif is a valuable addition to the topological protein repertoire and a promising candidate for protein-based biomaterials.

A gold(i)-catalysed chemoselective three-component reaction between phenols, α-diazocarbonyl compounds and allenamides.

Gold(i) catalysts are considered to be efficient in promoting sp2 C-H bond insertion at the para position of unprotected phenols because of the exceptionally chemical reactivity of gold-stabilized carbophilic carbocations. Herein, we present a gold(i)-catalysed three-component reaction between phenols, diazocarbonyl compounds and allenamides, affording the corresponding three-component reaction products with excellent geometric selectivity (E : Z > 20 : 1) in moderate to high yields (up to 90%) under mild conditions. Additionally, a gram-scale transformation and diverse transformations of the resulting product show the high synthetic utility of the present three-component protocol.

A gold(i)-catalysed three-component reaction via trapping oxonium ylides with allenamides.

A gold(i)-catalysed three-component reaction between alcohols (and water), α-aryl-α-diazoesters and allenamides has been developed, affording three-component products, tert-allylic ethers (and alcohols), in moderate to excellent yields with excellent geometric selectivity (E : Z > 20 : 1). In addition, this transformation proceeds smoothly with high functional group tolerance and a broad substrate scope under exceptionally mild reaction conditions. Remarkably, a gram-scale reaction is also successfully performed, and the corresponding three-component product can readily react with easily obtained reagents, furnishing diverse products in satisfactory yields.

Asymmetric Multicomponent Reactions for Efficient Construction of Homopropargyl Amine Carboxylic Esters.

Developing an efficient and highly enantioselective protocol to access homopropargyl amines is of high interest to the synthetic community and also remains a formidable challenge for organic chemists. Here, we present integrated Rh2(OAc)4- and BINOL-derived chiral phosphoric acid cooperatively catalyzed three-component reactions of alkynyldiazoacetates, imines with various nucleophiles including alcohols, indoles, and N,N-disubstituted anilines, affording the corresponding homopropargyl amines containing two vicinal chiral centers in satisfactory yields with high to excellent diastereo- and enantioselectivities.

Transition Kinetics of Self-Assembled Supramolecular Dodecagonal Quasicrystal and Frank-Kasper σ Phases in ABn Dendron-Like Giant Molecules.

A series of noncrystalline ABn dendron-like giant molecules DPOSS-MPOSSn (n = 2-6, DPOSS: hydrophilic polyhedral oligomeric silsesquioxane (POSS) cage; MPOSS: hydrophobic POSS cage) were synthesized. These samples present a thermodynamically stable phase formation sequence from the hexagonal cylinder phase (plane group of P6mm), to the Frank-Kasper (F-K) A15 phase (space group of Pm3̅n), and further to the F-K σ phase (space group of P42/mnm), with increasing the number of MPOSS in a single molecule (n, from 2 to 6). Moreover, for DPOSS-MPOSS5 and DPOSS-MPOSS6, an intriguing dodecagonal quasicrystal (DQC) structure has been identified and revealed as a kinetic favorable metastable phase at lower temperatures, while the thermodynamically stable phase is the σ phase. The detailed investigation of the transition kinetics between the DQC and σ phase in these samples makes it possible to identify how the self-assembly directs the phase transition in terms of molecular and supramolecular aspects.

Relationship between Tissue Distributions of Modified Wuzi Yanzong Prescription () in Rats and Meridian Tropism Theory.

OBJECTIVE: To investigate the relationship between tissue distributions of modified Wuzi Yanzong prescription (, MWP) in rats and meridian tropism theory. METHODS: A high-performance liquid chromatography with Fourier transform-mass spectrometry (HPLC-FT) method was used to identify the metabolites of MWP in different tissues of rats after continued oral administration of MWP for 7 days. The relationship between MWP and meridian tropism theory was studied according to the tissue distributions of the metabolites of MWP in rats and the relevant literature. RESULTS: Nineteen metabolites, mainly flavanoid compounds, were detected in the different rat tissues and classified to each herb in MWP. Further, it was able to establish that the tissue distributions of the metabolites of MWP were consistent with the descriptions of meridian tropism of MWP available in literature, this result might be useful in clarifying the mechanism of MWP on meridian tropism. In the long run, these data might provide scientific evidence of the meridian tropism theory to further promote the reasonable, effective utilization, and modernization of Chinese medicine. CONCLUSION: The tissue distributions of MWP in vivo were consistent with the descriptions of meridian tropism of MWP.

Correction: Finite cohesion due to chain entanglement in polymer melts.

Correction for 'Finite cohesion due to chain entanglement in polymer melts' by Shiwang Cheng et al., Soft Matter, 2016, 12, 3340-3351.

Finite cohesion due to chain entanglement in polymer melts.

Three different types of experiments, quiescent stress relaxation, delayed rate-switching during stress relaxation, and elastic recovery after step strain, are carried out in this work to elucidate the existence of a finite cohesion barrier against free chain retraction in entangled polymers. Our experiments show that there is little hastened stress relaxation from step-wise shear up to γ = 0.7 and step-wise extension up to the stretching ratio λ = 1.5 at any time before or after the Rouse time. In contrast, a noticeable stress drop stemming from the built-in barrier-free chain retraction is predicted using the GLaMM model. In other words, the experiment reveals a threshold magnitude of step-wise deformation below which the stress relaxation follows identical dynamics whereas the GLaMM or Doi-Edwards model indicates a monotonic acceleration of the stress relaxation dynamics as a function of the magnitude of the step-wise deformation. Furthermore, a sudden application of startup extension during different stages of stress relaxation after a step-wise extension, i.e. the delayed rate-switching experiment, shows that the geometric condensation of entanglement strands in the cross-sectional area survives beyond the reptation time τd that is over 100 times the Rouse time τR. Our results point to the existence of a cohesion barrier that can prevent free chain retraction upon moderate deformation in well-entangled polymer melts.

[Study of effect of Humifuse Euphorbia Herb on alleviating insulin resistance in type 2 diabetic model KK-Ay mice].

[To explore the effect of Humifuse Euphorbia Herb ( HEH) on alleviating insulin resistance in type 2 diabetic KK-Ay mice. Totally 40 KK-Ay mice fed with high-fat diet were divided into four groups: the metformin group, the model group, the HEH low-dose group and the HEH high-dose group, and orally administrated with metformin hydrochloride (250 mg x kg(-1)), distilled water, humifuse euphorbia herb 1 g x kg(-1) and 2 g x kg(-1). Besides, C57BL/6J mice with ordinary feed were taken as the normal control group and orally administrated with equal distilled water. The oral administration for the five groups lasted for eight weeks. Before and after the experiment, weight, fasting glucose and insulin tolerance were determined. The morphological changes in pancreas were observed through hematoxylin-eosin (HE) staining on pancreatic tissue sections. The serum insulin, TNF-α, IL-6, adiponectin (ADPN) and leptin (LEP) were detected by ELISA. The results showed that HEH could reduce weight and fasting glucose in KK-Ay mice, alleviate hyperinsulinemia, reduce blood glucose-time AUC, increase 30-min blood glucose decline rate, relieve insulin resistance, significantly ameliorate the pathomorphological changes in pancreas in each group, decrease serum TNF-α, IL-6 and leptin levels in KK-Ay mice and rise serum ADPN level. This study proved that humifuse euphorbia herb can ameliorate the insulin resistance in KK-Ay mice, and its mechanism may be related to the effect on inflammatory factors and adipocytokines.

Design, synthesis and biological activity of aromatic diketone derivatives as HIV-1 integrase inhibitors.

A series of aromatic diketone derivatives were designed and synthesized as potential HIV-1 integrase (IN) inhibitors and evaluated to determine their ability to inhibit the strand transfer process of HIV-1 integrase. The results indicate that (Z)-1-(3-acetyl-2-hydroxy-4,6-dimethoxyphenyl)-3-hydroxy-3-(substituted)phenylprop-2-en-1-one (5a-5d) can moderately inhibit HIV-1 integrase. The cyclization and condensation products (6a-6c and 7e-7f) of compounds 5a-5d show poor inhibitory activity against HIV-1 integrase. The molecular docking results indicate that the different types of compounds act on HIV-1 integrase in different ways, and these results can explain the differences in the inhibitory activities.