Cascade Cyclization of N-Cyanamide Alkenes for the Divergent Synthesis of Azido-, Nitro-, and Alkenyl-Containing Pyrroloquinazolinones.

Radical cascade cyclizations of N-cyanamide alkenes have been developed for the divergent synthesis of pyrroloquinazolinones bearing azido, alkenyl, and nitro groups by controlling the reaction conditions. The reaction temperature and the loading of the base play important roles in the different reaction pathways. These reactions are characterized by wide functional group compatibility and mild conditions.

Oxidative cascade cyclization of N-arylacrylamides with TMSN3.

An azido-radical-triggered cyclization of N-(o-cyanobiaryl)acrylamides with TMSN3via a C(sp3)-N/C(sp2)-C(sp3)/C(sp2)-N bond formation cascade is described. This reaction features mild conditions and high bond-forming efficiency, making it an efficient method for the construction of azide-substituted pyridophenanthridines.

Visible-Light-Promoted Cascade Cyclization of 3-Ethynyl-[1,1'-biphenyl]-2-Carbonitriles with Unsaturated α-Bromocarbonyls.

A visible-light-promoted cascade cyclization of 3-ethynyl-[1,1'-biphenyl]-2-carbonitriles with unsaturated α-bromocarbonyls for the synthesis of tetrahydrobenzo[mn]cyclopenta[b]acridines is described. Three C(sp3)-C(sp2) bonds, one C(sp2)-N bond, and three cycles can be formed in a single reaction through the addition of a C-centered radical to the carbon-carbon triple bond and three radical cyclizations. This reaction features mild conditions, wide substrate scope, and high bond-forming efficiency.

Copper-Catalyzed Cascade Multicomponent Reaction of Azides, Alkynes, and Selenium: Synthesis of Ditriazolyl Diselenides.

A copper-catalyzed cascade multicomponent reaction for synthesizing ditriazolyl diselenides from azides, terminal alkynes, and elemental selenium has been developed. The present reaction features utilizing readily available and stable reagents, high atom-economy, and mild reaction conditions. A possible mechanism is proposed.

[Effect of Cyr61 on Imatinib Resistance in Chronic Myeloid Leukemia and Its Mechanism].

OBJECTIVE: To investigate the effect of Cyr61 on imatinib (IM) resistance in chronic myeloid leukemia (CML) and its mechanism. METHODS: Cyr61 level in cell culture supernatant was determined by enzyme-linked immunosorbent assay. The expression of Cyr61 and Bcl-xL were measured by real-time PCR and Western blot. Cell apoptosis was analyzed using an Annexin V-APC Kit. Expression of signal pathways related proteins was determined by Western blot. RESULTS: The level of Cyr61 obviously increased in K562G cells (IM resistance to CML cell line K562). Down-regulating the expression of Cyr61 decreased the resistance of K562G cells to IM and promoted IM induced apoptosis. In CML mouse model, down-regulating the expression of Cyr61 could increase the sensitivity of K562G cells to IM. The mechanism studies showed that Cyr61 mediated IM resistance in CML cells was related to the regulation of ERK1/2 pathways and apoptosis related molecule Bcl-xL by Cyr61. CONCLUSION: Cyr61 plays an important role in promoting IM resistance of CML cells. Targeting Cyr61 or its related effectors pathways may be one of the ways to overcome IM resistance of CML cells.

Oxidative Dehydrogenative Coupling of Thiols with Alkanes for the Synthesis of Sulfoxides.

An oxidative dehydrogenative coupling of thiols with alkanes via direct C(sp3)-H bond functionalization to form a new C-S bond and S═O double bond was developed. The present reaction features the use of readily available reagents and high step- and atom-efficiency, thus providing an efficient access to sulfoxides. A possible mechanism is proposed.

Metal-carbide eutectics with multiprincipal elements make superrefractory alloys.

Materials with excellent high-temperature strength are now sought for applications in hypersonics, fusion reactors, and aerospace technologies. Conventional alloys and eutectic multiprincipal-element alloys (MPEAs) exhibit insufficient strengths at high temperatures due to low melting points and microstructural instabilities. Here, we report a strategy to achieve exceptional high-temperature microstructural stability and strength by introducing eutectic carbide in a refractory MPEA. The synergistic strengthening effects from the multiprincipal-element mixing and strong dislocation blocking at the interwoven metal-carbide interface make the eutectic MPEA not only have outstanding high-temperature strength (>2 GPa at 1473 K) but also alleviate the room-temperature brittleness through microcrack tip blunting by layered metallic phase. This strategy offers a paradigm for the design of the next-generation high-temperature materials to bypass the low-melting point limitation of eutectic alloys and diffusion-dominated softening in conventional superalloys.

Radical Annulation of 2-Cyanoaryl Acrylamides via C═C Double Bond Cleavage: Access to Amino-Substituted 2-Quinolones.

A novel annulation of 2-cyanoaryl acrylamides via C═C double bond cleavage has been developed for facile and efficient access to a broad spectrum of functionalized 4-amino-2-quinolones, which are important N-heterocycles. In this transformation, the solvent THF is demonstrated to play a crucial role, and the addition of alkyl radicals to nitrile, 1,5-hydride shift, and cleavage of the C-C bond are involved in the mechanism.

[Analysis of Predictive Value of Laboratory Indexes for Malignant Lymphoma Patients with Bone Marrow Involvement].

OBJECTIVE: To analyze the influence of bone marrow involvement (BMI) in patients with malignant lymphoma (ML) on laboratory indexes, and evaluate the laboratory markers that can be used to predict/diagnose BMI. METHODS: The clinical characteristics and laboratory indexes of 137 ML patients were analyzed retrospectively, from which the indexes of BMI in ML patients was studied. The logistic regression analysis and receiver operating curve (ROC) were used to evaluate independent risk factors and predictors of BMI diagnosis in ML patients. RESULTS: Compared with non-BMI group, the red blood cell distribution width, C-reactive protein, erythrocyte sedimentation rate, D-dimer, lactate dehydrogenase, alkaline phosphatase, ß2-microglobulin, transferrin, CA153, CA125, and soluble interleukin-2 receptor (sIL-2R) levels were increased while platelet (PLT) count was decreased in BMI group, and the difference was statistically significant (P<0.05). The blood indexes related to BMI and the statistically significant indexes in the univariate regression analysis were corrected by multivariate logistic regression analysis. The corrected results showed that T cell-related non-Hodgkin lymphoma (adjusted OR=2.18, 95%CI: 1.48-4.90, P＜0.001), clinical stage Ⅲ-Ⅳ (adjusted OR=3.32, 95%CI: 2.16-5.83, P＜0.001), sIL-2R (adjusted OR=4.26, 95%CI: 2.95-12.85, P＜0.001) were the risk factors for ML patients with BMI, while PLT (adjusted OR=0.89, 95%CI: 0.55-0.96, P= 0.003) was a protective factor. ROC analysis showed that the areas under the ROC curve of PLT and sIL-2R predicting BMI in ML patients was 0.712 (95%CI: 0.646-0.776, P<0.001) and 0.796 (95%CI: 0.739-0.853, P<0.001), respectively. The best cut-off point of PLT and sIL-2R was 160×109/L and 2 568 U/ml, respectively. The diagnostic specificities of the two indexes here were both greater than 80%. CONCLUSION: PLT and sIL2R show good diagnostic value for ML patients with BMI.

Cordyceps sinensis-derived fungus Isaria felina ameliorates experimental autoimmune thyroiditis in mice.

AIMS: This study aimed to investigate the therapeutic effect of Cordyceps sinensis-derived fungus Isaria felina on experimental autoimmune thyroiditis (EAT). METHODS: A NaI-induced EAT mouse model was established. The mice received oral administration of vehicle, low-dose Isaria felina (300 mg/kg), or high-dose Isaria felina (600 mg/kg) once a day for four weeks before euthanasia. Enzyme-linked immunosorbent assays (ELISA) was performed to measure serum thyroid-stimulating hormone (TSH) levels, thyroid antibodies, and cytokines. Hematoxylin and eosin (H&E) staining was conducted to assess histopathological changes in the thyroid tissue samples of mice. TUNEL and Bcl-2 immunohistochemistry (IHC) were performed to evaluate cell apoptosis, and cleaved caspase-3 IHC was performed to detect the relative expression in the thyroid tissue samples. RESULTS: Compared with KIO3 and KI water, NaI water consumption successfully induced EAT in mice, as evidenced by significantly increased circulating TSH and thyroid antibody levels, along with typical histopathological abnormalities of autoimmune thyroiditis (AIT) in the thyroid tissue samples. Compared with vehicle or low-dose Isaria felina, high-dose Isaria felina treatment resulted in significant reductions in white cell counts and circulating TSH, thyroid antibody, and cytokine levels of EAT mice. High-dose Isaria felina also alleviated histopathological abnormalities and attenuated TUNEL staining, Bcl-2 protein expression, and cleaved caspase-3 expression in the thyroid tissue samples. CONCLUSION: High-dose Isaria felina treatment alleviates thyroid inflammation and cell apoptosis in EAT, serving as a novel, promising therapeutic agent for AIT.

4-Sulfonyloxy/alkoxy benzoxazolone derivatives with high anti-inflammatory activities: Synthesis, biological evaluation, and mechanims of action via p38/ERK-NF-κB/iNOS pathway.

In an effort to discover new agents with high anti-inflammatory activity, 22 new 4-sulfonyloxy/alkoxy benzoxazolone derivatives were synthesized, characterized, and evaluated for their anti-inflammatory activities against lipopolysaccharide (LPS)-induced nitric oxide (NO) production and TNF-α expression in RAW 264.7 cells in vitro. Most of these compounds displayed greater inhibitory ability against NO production than the lead compound 4-o-methyl-benzenesulfonyl benzoxazolone, and the most active compound 2h exhibited the strongest inhibitory activity against NO, IL-1ß, and IL-6 production with IC50 values 17.67, 20.07, and 8.61 µΜ, respectively. The effects of 2h were comparable or stronger than those of the positive control celecoxib. Compound 2h also displayed higher activity in vivo than celecoxib in a mouse model of xylene-induced ear edema, based on their inhibitory rates of 42.69% and 30.87%, respectively. Further molecular analysis revealed that compound 2h significantly reduced the iNOS levels in cell supernatant and suppressed the protein expression of iNOS, p-p38, p-ERK, and nuclear NF-κB. The results indicated that the anti-inflammatory effect of 2h might be realized through the regulation of ERK- and p38-mediated mitogen-activated protein kinase (MAPK)-NF-κB/iNOS signaling, thereby reducing the excessive release of NO, IL-1ß, and IL-6. Our findings demonstrated that compound 2h, a new benzoxazolone derivative, could inhibit activation of the MAPK-NF-κB/iNOS pathway, supporting its potential as a novel anti-inflammatory agent.

1H NMR-based metabolomics revealed the protective effects of Guilingji on the testicular dysfunction of aging rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Guilingji (GLJ), a famous and classical traditional Chinese medicine (TCM) prescription, has been used to extend the lifespan and improve the life qualities of the elderly for hundreds of years in China. AIM OF THE STUDY: We aimed to explore the protective effects of GLJ on the testicular dysfunction of aging rats, as well as the regulating effects of GLJ on the metabolic disturbance and metabolite changes in natural aging rats. MATERIALS AND METHODS: Forty 23-month-old rats were divided randomly into four groups, including the old control group and three groups of GLJ treatment at 37.5, 75, and 150 mg/kg doses, respectively. Additionally, 10 four-month rats were included as the youth control group. Testicular dysfunction was first evaluated by measuring the changes in the wet weights of the testicles, concentration of serum testosterone (T), and morphologic changes of the testis. Subsequently, an 1H NMR-based metabolomics approach coupled with multivariate analysis, including partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) was applied to monitor the metabolite changes. RESULTS: Compared with the old control group, the wet weights of the testicles and T concentration were significantly increased, while the morphologic abnormality of testicular tissues was improved by a 4-week treatment course with GLJ. Furthermore, compared with the old control group, the urinary levels of alanine, pantothenate, phenylalanine, ß-hydroxybutyrate and pyruvate were significantly decreased after a 4-week treatment course with GLJ. Additionally, we found that amino acid metabolism and pyruvate metabolism were significantly involved in the regulatory effect of GLJ. CONCLUSIONS: The current findings provided, for the first time, sound evidence of the protective effects of GLJ on testicular dysfunction from both biochemical and metabolomics perspectives. The mechanisms of GLJ could be related to regulating amino acid metabolism and pyruvate metabolism. The current study lays an important foundation for further research and for the broad clinical application of GLJ.

Publisher Correction: Enhanced strength and ductility in a high-entropy alloy via ordered oxygen complexes.

Change history: In this Letter, owing to a production error, all the data points (except the two points for O-2 and N-2, respectively) were missing in Fig. 1b. The figure has been corrected online.

Enhanced strength and ductility in a high-entropy alloy via ordered oxygen complexes.

Oxygen, one of the most abundant elements on Earth, often forms an undesired interstitial impurity or ceramic phase (such as an oxide particle) in metallic materials. Even when it adds strength, oxygen doping renders metals brittle1-3. Here we show that oxygen can take the form of ordered oxygen complexes, a state in between oxide particles and frequently occurring random interstitials. Unlike traditional interstitial strengthening4,5, such ordered interstitial complexes lead to unprecedented enhancement in both strength and ductility in compositionally complex solid solutions, the so-called high-entropy alloys (HEAs)6-10. The tensile strength is enhanced (by 48.5 ± 1.8 per cent) and ductility is substantially improved (by 95.2 ± 8.1 per cent) when doping a model TiZrHfNb HEA with 2.0 atomic per cent oxygen, thus breaking the long-standing strength-ductility trade-off11. The oxygen complexes are ordered nanoscale regions within the HEA characterized by (O, Zr, Ti)-rich atomic complexes whose formation is promoted by the existence of chemical short-range ordering among some of the substitutional matrix elements in the HEAs. Carbon has been reported to improve strength and ductility simultaneously in face-centred cubic HEAs12, by lowering the stacking fault energy and increasing the lattice friction stress. By contrast, the ordered interstitial complexes described here change the dislocation shear mode from planar slip to wavy slip, and promote double cross-slip and thus dislocation multiplication through the formation of Frank-Read sources (a mechanism explaining the generation of multiple dislocations) during deformation. This ordered interstitial complex-mediated strain-hardening mechanism should be particularly useful in Ti-, Zr- and Hf-containing alloys, in which interstitial elements are highly undesirable owing to their embrittlement effects, and in alloys where tuning the stacking fault energy and exploiting athermal transformations13 do not lead to property enhancement. These results provide insight into the role of interstitial solid solutions and associated ordering strengthening mechanisms in metallic materials.

Anti-inflammatory effects of 4-o-methyl-benzenesulfonyl benzoxazolone (MBB) in vivo and in vitro as a novel NSAIDs lead compound.

BACKGROUND: Great attention has been paid to the development of novel anti-inflammatory drugs to overcome the adverse reactions of traditional drugs. Recently, a new compound 4-o-methyl-benzenesulfonyl benzoxazolone (MBB) we have prepared attracted our attention for its promising anti-inflammatory activity and low toxicity. The present study aimed to further investigate the anti-inflammatory effects of MBB both in vivo and in vitro in order to determine its potential as a novel NSAIDs lead compound. METHODS: The anti-inflammatory effects in vivo were evaluated using acetic acid-induced mice writhing, xylene-induced mice ear edema and collagen-induced rat arthritis. NO, TNF-α, IL-6, IL-1ß and iNOS productions by LPS-stimulated RAW264.7 cells were determined to investigate the basis of anti-inflammatory effects. Finally, the COX inhibition effect was tested in vitro using COX inhibitor screening assay kit. RESULTS: MBB could significantly decrease the writhing and ear swelling in a dose-dependent manner, and it also had a moderate anti-arthritic potential associated with an attenuation of arthritis index score, arthritis swelling, and inhibition of TNF-α and IL-1ß. MBB could inhibit the activity of NO, TNF-α, IL-6, IL-1ß and iNOS to perform its activity in vitro, but it had no effect against COX-1 and COX-2. The anti-inflammation effect may be mediated via the inhibition of iNOS to reduce the production of inflammatory mediators which should be further confirmed. CONCLUSIONS: The compound MBB displayed anti-inflammatory and anti-arthritic effect, and it could be considered as a new NSAIDs lead compound for the further structure modification to develop novel anti-inflammatory drugs.

Dynamic deformation behavior of a face-centered cubic FeCoNiCrMn high-entropy alloy.

In this study, mechanical tests were conducted on a face-centered cubic FeCoNiCrMn high-entropy alloy, both in tension and compression, in a wide range of strain rates (10-4-104 s-1) to systematically investigate its dynamic response and underlying deformation mechanism. Materials with different grain sizes were tested to understand the effect of grain size, thus grain boundary volume, on the mechanical properties. Microstructures of various samples both before and after deformation were examined using electron backscatter diffraction and transmission electron microscopy. The dislocation structure as well as deformation-induced twins were analyzed and correlated with the measured mechanical properties. Plastic stability during tension of the current high-entropy alloy (HEA), in particular, at dynamic strain rates, was discussed in lights of strain-rate sensitivity and work hardening rate. It was found that, under dynamic conditions, the strength and uniform ductility increased simultaneously as a result of the massive formation of deformation twins. Specifically, an ultimate tensile strength of 734 MPa and uniform elongation of ∼63% are obtained at 2.3 × 103 s-1, indicating that the alloy has great potential for energy absorption upon impact loading.

Heme Oxygenase-1, a Key Enzyme for the Cytoprotective Actions of Halophenols by Upregulating Nrf2 Expression via Activating Erk1/2 and PI3K/Akt in EA.hy926 Cells.

Increasing evidence has demonstrated that heme oxygenase-1 (HO-1) is a key enzyme triggered by cellular stress, exhibiting cytoprotective, antioxidant, and anti-inflammatory abilities. Previously, we prepared a series of novel active halophenols possessing strong antioxidant activities in vitro and in vivo. In the present study, we demonstrated that these halophenols exhibited significant protective effects against H2O2-induced injury in EA.hy926 cells by inhibition of apoptosis and ROS and TNF-α production, as well as induction of the upregulation of HO-1, the magnitude of which correlated with their cytoprotective actions. Further experiments which aimed to determine the mechanistic basis of these actions indicated that the halophenols induced the activation of Nrf2, Erk1/2, and PI3K/Akt without obvious effects on the phosphorylation of p38, JNK, or the expression of PKC-δ. This was validated with the use of PD98059 and Wortmannin, specific inhibitors of Erk1/2 and PI3K, respectively. Overall, our study is the first to demonstrate that the cytoprotective actions of halophenols involve their antiapoptotic, antioxidant, and anti-inflammatory abilities, which are mediated by the upregulation of Nrf2-dependent HO-1 expression and reductions in ROS and TNF-α generation via the activation of Erk1/2 and PI3K/Akt in EA.hy926 cells. HO-1 may thus be an important potential target for further research into the cytoprotective actions of halophenols.

Enantioselective Borylation of Aromatic C-H Bonds with Chiral Dinitrogen Ligands.

The borylation of C-H bonds catalyzed by transition metals has been investigated extensively in the past two decades, but no iridium-catalyzed enantioselective borylation of C-H bonds has been reported. We report a set of iridium-catalyzed enantioselective borylations of aromatic C-H bonds. This reaction relies on a set of newly developed chiral quinolyl oxazoline ligands. This process proceeds under mild conditions with good to excellent enantioselectivity, and the borylated products can be converted to enantioenriched derivatives containing new C-O, C-C, C-Cl, or C-Br bonds.

A Chiral Nitrogen Ligand for Enantioselective, Iridium-Catalyzed Silylation of Aromatic C-H Bonds.

Iridium catalysts containing dative nitrogen ligands are highly active for the borylation and silylation of C-H bonds, but chiral analogs of these catalysts for enantioselective silylation reactions have not been developed. We report a new chiral pyridinyloxazoline ligand for enantioselective, intramolecular silylation of symmetrical diarylmethoxy diethylsilanes. Regioselective and enantioselective silylation of unsymmetrical substrates was also achieved in the presence of this newly developed system. Preliminary mechanistic studies imply that C-H bond cleavage is irreversible, but not the rate-determining step.

Predicting protein structural class by incorporating patterns of over-represented k-mers into the general form of Chou's PseAAC.

Computational prediction of protein structural class based on sequence data remains a challenging problem in current protein science. In this paper, a new feature extraction approach based on relative polypeptide composition is introduced. This approach could take into account the background distribution of a given k-mer under a Markov model of order k-2, and avoid the curse of dimensionality with the increase of k by using a T-statistic feature selection strategy. The selected features are then fed to a support vector machine to perform the prediction. To verify the performance of our method, jackknife cross-validation tests are performed on four widely used benchmark datasets. Comparison of our results with existing methods shows that our method provides satisfactory performance for structural class prediction.