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Nitrogen (N) is an essential element that plays an important role in crop biomass accumulation and quality formation. Increased crop yield is relied on excessive application of fertilizers, which usually leads to environmental pollution and unsustainable development. Thus, identification and characterization of genes involved in promoting nitrogen use efficiency is of high priority in crop breeding. The activity of nitrate reductase (NR) plays a critical role in nitrogen metabolism. In model plant Arabidopsis , NITRATE REDUCTASE 2 (NIA2), one of the two NRs, is responsible for about 90% of the NR activity. In this study, MdNIA2 gene in apple (Malus domestica) genome was screened out and identified by using AtNIA2 as bait. Phylogenetic analysis revealed that MdNIA2 had the closest evolutionary relationship with MbNIA from Malus baccata. Ectopic expression of MdNIA2 in Arabidopsis elevated the nitrogen use efficiency and increased root hair elongation and formation, resulting in promoted plant growth. Furthermore, the overexpression of MdNIA2 improved salt and drought tolerance in transgenic Arabidopsis and improved the salt tolerance of transgenic apple callus, and MdNIA2 -reagualted NO metabolism might contribute to the abiotic stress tolerance. Overall, our data indicate the critical role of MdNIA2 in regulating nitrogen utilization efficiency and abiotic stress responses. • MdNIA2 family was identified in apple for the first time. • MdNIA2 elevated the nitrogen use efficiency and increased root hair elongation and formation. • MdNIA2 may play a critical role in the regulation of plant growth and abiotic stress response. [ABSTRACT FROM AUTHOR]

A natural ursolic compound, 2α,3β-dihydroxy-urs-12-en-28-oic acid (corosolic acid, CRA) was isolated from the root of Actinidia valvata Dunn. ( A. valvata Radix). Since a large number of triterpenoid compound has marked anticancer effects toward various types of cancer cell lines in vitro , this study was carried out to investigate the anticancer effect of CRA in human gastric cancer cell line BGC823 cells and the underlying apoptotic mechanism of CRA was examined in BGC823 cell lines. The results showed that CRA significantly suppressed the viability of BGC823 cells in a concentration- and time-dependent manner. CRA also significantly increased the sub G1 population by cell cycle analysis in a concentration dependent manner. Exposure to CRA decreased p65, bcl-2, Fas, smac mRNA and protein expression, and increased IκBα, bax, survivin mRNA and protein expression. Results of immunofluorescence staining and EMSA further indicated CRA induced apoptosis by inhibiting nuclear translocation of nuclear factor NF-κB subunit p65. Consistently overall, our findings suggest that CRA induces apoptosis via inhibition of NF-κB (p65) expression level and activation of IκBα in BGC cells as a potent anticancer candidate for gastric cancer treatment. [ABSTRACT FROM AUTHOR]

Chemosensory proteins (CSPs), a class of small soluble proteins, are thought to be involved in insect chemoreceptive behavior. Here, six CSP genes, AcerCSP1–6 from Apis cerana , were cloned and characterized from worker bees' antennae. Results revealed that the AcerCSPs' amino acid sequences shared high similarity with the homologous genes of Apis mellifera , but low similarity with other insect species. Compared with corresponding CSPs of A. mellifera , AcerCSPs (1, 3, 4, and 6) exhibit quite similar gene expression profiling. On the contrary, AcerCSP2 showed a higher expression level in the forager antennae and legs than CSP2 of A. mellifera . Furthermore, AcerCSP5 was not specifically expressed in larvae, unlike CSP5 of A. mellifera . In a ligand-binding assay, AcerCSP1 and AcerCSP2, which exhibited the highest expression in antennae of A. cerana , had a stronger affinity with candidate floral chemicals and pheromones than AcerCSP4, the results of which was supported by docking analysis, suggesting that the relevance of them with A. cerana olfactory functions. Taken together, these results suggest that despite the quasi-similarity of protein sequences between A. cerana and A. mellifera , differences in tissue expression and functional characteristics between the two species still exist, indicating that homologous proteins potentially perform different tasks even in related species. [ABSTRACT FROM AUTHOR]

A natural ursolic compound, 2β, 3β, 23-trihydroxy-urs-12-ene-28-olic acid (TUA) was isolated from the root of Actinidia chinensis Planch ( A. chinensis Radix). Since a large number of triterpenoid compound has marked anticancer effects toward various types of cancer cell lines in vitro , this study was carried out to investigate the anticancer effect of TUA in non-small cell lung cancer cells (NSCLCCs) and the underlying apoptotic mechanism of TUA was examined in NCI-H460 cell lines. Cell proliferation, apoptosis and cell cycle were measured using a cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. The activity of transcription factor NF-κB was determined by EMSA method. The expression of apoptosis- and proliferation-related proteins was determined by western blotting. The effect of TUA on NF-κB mRNA expression in NCI-H460 cells was detected by RT-PCR. TUA significantly suppressed the viability of NCI-H460 cells. Also, TUA significantly increased the sub G1 population by cell cycle analysis and in a concentration dependent manner in NCI-H460 cells. Such an effect was accompanied by p65 (NF-κB subunit) inactivation by an inhibition of IκBα phosphorylation, and by inhibition of p65 mRNA expressions. Consistently Overall, our findings suggest that TUA induces apoptosis via inhibition of NF-κB (p65) expression level and activation of IκBα in NCI-H460 cells as a potent anticancer candidate for lung cancer treatment. [ABSTRACT FROM AUTHOR]

An efficient and facile α-hydroxylation of ketones catalyzed by CuBr 2 or HBr in DMSO is developed, providing secondary/tertiary α-hydroxy carbonyl compounds in moderate to good yields (up to 87%). A series of control experiments suggested that water and DMSO may work cooperatively in the hydrolysis step. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Qing Ye Dan is a well-known herbal drug that is widely used to treat viral hepatitis in the Yi and Hani minority regions in the Yunnan province of China. Materials and methods: An LC–MS/MS method was developed to determine the levels of swertiamarin in rat plasma. Swertiamarin and naringin (internal standard, IS) were extracted from rat plasma using solid-phase extraction (SPE) to purify the samples. The pharmacokinetics of the following different administration methods of swertiamarin in rats were studied: oral administration of swertiamarin alone, a Qing Ye Dan tablet (QYDT) and co-administration of swertiamarin and oleanolic acid, with each method delivering approximately 20mg/kg of swertiamarin. Non-compartmental pharmacokinetic profiles were constructed by using the software DAS (version 2.1.1), and the pharmacokinetic parameters were compared using an unpaired Student's t-test. Results: The results showed that the pharmacokinetic parameters C max , AUC0–∞, V z/F and CL z/F were significantly different (P<0.05) among the three types of swertiamarin administration. Conclusions: The data indicate that oleanolic acid and the other ingredients present in QYDT could affect the pharmacokinetic behaviour of swertiamarin in rats. [Copyright &y& Elsevier]

Abstract: In order to investigate the toxic effect of intermittent high glucose (IHG) and sustained high glucose (SHG) on rat pancreatic beta cell functions and the potential involved mechanisms, isolated rat islets and INS-1 beta cells were exposed to SHG (25mmol/l) or IHG (11.1 and 25mmol/l glucose alternating every 12h) for 72h. The results showed that IHG induced a more significant impairment of insulin release response in rat islets and INS-1 cell than SHG. Simultaneously, the intracellular levels of endoplasmic reticulum and oxidative stress were more markedly increased in islets and INS-1 cells exposed to IHG. However, there was no significant difference between reducing cell viability, insulin content and gene expression induced by SHG and IHG. Taken together, this study suggested the more serious toxic effect on rat pancreatic beta cell function induced by IHG treatment may be due to excessive activation of cellular stress. [Copyright &y& Elsevier]

Abstract: Cardiac hypertrophy is a major cause of morbidity and mortality worldwide. The hypertrophic process is mediated, in part, by oxidative stress-mediated signaling pathways. We hypothesized that isorhapontigenin (ISO), a new resveratrol analog, inhibits cardiac hypertrophy by blocking oxidative stress and oxidative stress-mediated signaling pathways. We treated cardiomyocytes with angiotensin II (Ang II) with or without ISO and found that ISO inhibited Ang II-induced cardiac hypertrophy. These effects were associated with a decrease in the levels of reactive oxygen species and H2O2 and the content of intracellular malonaldehyde and an increase in the activities of superoxide dismutase and glutathione peroxidase. Ang II induced the phosphorylation of PKC, Erk1/2, JNK, and p38 in cardiomyocytes and such phosphorylation was inhibited by ISO. ISO also blocked the PKC-dependent PI3K–Akt–GSK3β/p70S6K pathway. These effects lead to direct or indirect inhibition of NF-κB and AP-1 activation. Our results revealed that pretreatment with ISO significantly inhibited Ang II-mediated NF-κB through affecting the degradation and phosphorylation of IκBα and the activity of IKKβ and AP-1 activation by influencing the expression of c-Fos and c-Jun proteins. In addition, we also established the molecular link between activation of PKC and MAPKs and activation of NF-κB and AP-1 in cardiomyocytes. We also found that ISO treatment significantly attenuated heart weight/body weight ratio by approximately 25%, decreased posterior wall thickness and left ventricle diastolic and systolic diameters, and increased 10% fractional shortening in an aortic-banded rat model. Furthermore, treatment with ISO significantly decreased cardiac myocyte size and systolic blood pressure. These findings suggest that ISO prevents the development of cardiac hypertrophy through an antioxidant mechanism involving inhibition of different intracellular signaling transduction pathways. [Copyright &y& Elsevier]

• An extension Boekelheide-like rearrangement of 2-benzylpyridine N -oxides. • The reaction could give moderate to excellent yield with wide substrate scope. • Synthesis of phenyl-2-pyridylmethanol with high enantioselectivity. • Application for synthesis of related amide derivatives was reported. An effective method for the acylation of 2-benzylpyridine N -oxides and their fast in situ [3,3]-sigmatropic rearrangement was reported. This transformation has a wide substrate scope under mild conditions, giving moderate to excellent yields. The application for the synthesis of chiral phenyl-2-pyridylmethanol products was briefly explored. Furthermore, an interesting example of tandem substitution and in situ [3,3]-sigamatropic rearrangement of 2-benzylpyridine N -oxide with benzenecarboximidoyl chloride was reported. [ABSTRACT FROM AUTHOR]

2-Methoxyestradiol has been synthesized from 17β-estradiol with 51% overall yield. • Four steps to the synthesis of 2-methoxyestradiol with 51% overall yield. • The key step is the ruthenium-catalyzed ortho-C(sp2)-H hydroxylation of phenol carbamate. • Our approach to access 2-methoxyestradiol is amenable to scale preparation. A four-step route for the synthesis of 2-methoxyestradiol (5) starting from 17β-estradiol (1) has been achieved with a 51% overall yield. The key step was the ruthenium-catalyzed ortho-C(sp2)-H bond hydroxylation of aryl carbamates. Using dimethyl carbamate as the directing group, [RuCl 2 (p-cymene)] 2 as the catalyst, PhI(OAc) 2 as the oxidant and trifluoroacetate/trifluoroacetic anhydride (1:1) as the co-solvent, the hydroxyl group could be singly installed at the 2-position of 3-dimethylcarbamoyloxyestradiol (2) with 65% yield. Subsequent methylation of hydroxy and removal of dimethyl carbamate afforded 2-methoxyestradiol (5). [ABSTRACT FROM AUTHOR]

Retroperitoneal pseudocysts are rare entities. Egg shell–like calcified retroperitoneal pseudocyst is rarer. We report a 75-year-old woman with an egg shell–like calcified retroperitoneal pseudocyst. Subsequently, the calcified pseudocyst was dissected and excised completely through laparoscopy via a retroperitoneal approach. [Copyright &y& Elsevier]

Trichodesmium abundance was measured in the northern East China Sea (ECS) from 2006 to 2007 including four seasons. Our results showed an obvious seasonal variation of Trichodesmium that the abundance was very low in spring (0.96×10 3 trichomes/m 3 ) and increased quickly to the highest value in summer (35.7×10 3 trichomes/m 3 ), then declined successively in autumn (16.26×10 3 trichomes/m 3 ) and winter (3.17×10 3 trichomes/m 3 ). The horizontal distribution patterns of Trichodesmium were quite different among the four seasons. The seasonal variation may be mainly affected by seawater temperature. The horizontal distribution of Trichodesmium may be affected by multiple environmental factors jointly, while salinity seemed to play a more important role in shaping a horizontal distribution pattern of Trichodesmium than water temperature. Furthermore, neither the N-nutrient nor the P-nutrient was considered as a limiting factor for Trichodesmium . Comparison with adjacent areas showed that seasonal variation in this study area was similar to that in the southern ECS and the South China Sea (SCS) but different from that in Kuroshio. An estimation of N 2 fixation rate by Trichodesmium abundance indicated that Trichodesmium might be an important source of biological N 2 fixation in the shelf area of ECS. [ABSTRACT FROM AUTHOR]

In the present study, six new compounds namely, picralactones C H (1–6) along with nine known compounds (7–15) were isolated from the branches and leaves of Picrasma chinese P.Y. Chen. Their structures were determined with the help of spectroscopic techniques such as NMR, HR-ESI-MS, UV, IR and CD. Cytotoxicity of all compounds was evaluated against MDA-MB-231, SW-620 and HepG2 human cancer cell lines. Compound 4 showed cytotoxic activities. [Display omitted] • Six new quassinoids were isolated from the branches and leaves of Picrasma chinese P.Y. Chen. • Cytotoxicity of all compounds was evaluated against MDA-MB-231, SW-620 and HepG2 human cancer cell lines. • Compound 4 showed cytotoxic activities. [ABSTRACT FROM AUTHOR]

• A full-scale experimental method was proposed for gasket waterproof performance. • Four gasket profiles were tested for mechanical and waterproof performance. • The gasket mechanical and waterproof performance were discussed in detail. • The water leakage phenomenon was investigated compared with that in practice. • The detailed leakage process of gaskets was initially interpreted. This work was performed to investigate the waterproofing and mechanical behavior of sealing gaskets for circumferential joints in Tianjin metro line Z2 tunnel by a full-scale experiment. A newly developed device was introduced in detail, with test procedures, essential treatment methods, and the adopted specimens for gaskets and reinforced concrete segments. Four types of EPDM and composite cross-section gasket profiles were tested under different combinations of joint openings and offsets. The gasket mechanical performance was examined through the load versus deformation relationship, while the water pressure versus joint opening relationship was applied for identifying the gasket sealant performance. The effect of gasket opening area was then discussed, based on a comparison of the test results from two similar gasket profiles. The ratio of waterproof capacity to average contact pressure was proposed to analyze the correlation between the gasket mechanical and sealant behavior. The results showed that both of the joint opening and offset had a great influence on the gasket waterproof behavior, which generally exhibited a reduction with larger joint opening and offset. A relatively small change in gasket opening area may lead to a greater degree of variation in the gasket mechanical and waterproof performance. The leakage failure analysis indicated that bolt holes, circumferential joints and concrete cracks were the common leakage points during the tunneling construction and operation. The full-scale experimental methodology in this paper had the potential in detecting detailed leakage process of gaskets. [ABSTRACT FROM AUTHOR]

The dysregulation of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin signaling pathway has been implicated in various human cancers, and isoform-selective inhibitors targeting PI3Kα have received significant interest in recent years. In this study, we have designed and synthesized three series of substituted benzoxazole derivatives based on the clinical candidate TAK-117 (8a). A detailed structure-activity relationship (SAR) study has identified the optimal compound 18a bearing a quinoxaline scaffold. Compared to the control 8a , 18a exhibited 4.4-fold more potent inhibitory activity against PI3Kα (IC 50 : 2.5 vs 11 nM) and better isoform-selective profiles over other PI3Ks. In addition, 18a showed a 1.5-fold more potent antiproliferative effect against HCT-116 cell lines (IC 50 : 3.79 vs 5.80 μM) and a better selectivity over the normal tissue cells. The potential antitumor mechanism and in vitro metabolic stability of 18a were also investigated. Notably, pharmacokinetic assays indicated that 18a had a higher plasma exposure, a higher maximum concentration and shorter elimination time compared to 8a. [Display omitted] • 18a shows 4.4-fold more potent PI3Kα inhibition compared with TAK-117 (8a). • 18a displays higher isoform selective profiles for PI3Kα than 8a. • 18a exhibits more potent antiproliferative effect on HCT-116 cell lines. • 18a shows more favorable cellular functional characteristics when compared with 8a. • Desirable metabolic stability and pharmacokinetic profiles of 18a are presented. [ABSTRACT FROM AUTHOR]

Ten new prenylated flavonoids, named denticulains A-J (1−10), together with seven known prenylated flavonoids (11–17) were isolated from Macaranga denticulata. Their structures were elucidated on the basis of detailed spectroscopic analysis and by comparison with literature data. In addition, compounds 1 and 14 inhibited the proliferation of SW620 and HCT-116 cell lines with an IC 50 value of 46.08 μM and 56.83 μM, respectively. [Display omitted] • Ten new prenylated flavonoids were isolated from Macaranga denticulata. • Some compounds have week anticancer activities. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the present study was to determine the effect of baicalein on metabolic syndrome induced by a high-fat diet in mice. The mice developed obesity, dyslipidemia, fatty liver, diabetes and insulin resistance. These disorders were effectively normalized in baicalein-treated mice. Further investigation revealed that the inhibitory effect on inflammation and insulin resistance was mediated by inhibition of the MAPKs pathway and activation of the IRS1/PI3K/Akt pathway. The lipid-lowering effect was attributed to the blocking of synthesis way mediated by SERBP-1c, PPARγ and the increased fatty acid oxidation. All of these effects depended on AMPKα activation. These results were confirmed in the primary hepatocytes from wild type and AMPKα2 −/− mice. However, the IRS-1/PI3K/AKT pathway showed no change, which may be due to the time of stimulation and concentration. Thus, these data suggested that baicalein protects mice from metabolic syndrome through an AMPKα2-dependent mechanism involving multiple intracellular signaling pathways. [Copyright &y& Elsevier]

The development of inhibitors targeting the PI3K-Akt-mTOR signaling pathway has been greatly hindered by the on-target AEs, such as hyperglycemia and hepatotoxicities. In this study, a series of diaryl urea derivatives has been designed and synthesized based on clinical candidate gedatolisib (6aa), and most of the newly synthesized derivatives showed kinase inhibitory and antiproliferative activities within nanomolar and submicromolar level, respectively. The terminal l -prolineamide substituted derivative 6 ab showed 8.6-fold more potent PI3Kα inhibitory activity (0.7 nM) and 4.6-fold more potent antiproliferative effect against HCT116 cell lines (0.11 μM) compared with control 6aa. The potential antitumor mechanism and efficacy of 6 ab in HCT116 xenograft models have also been evaluated, and found 6 ab showed comparable in vivo antitumor activity with 6aa. The safety investigations revealed that compound 6 ab exhibited more safer profiles in the selectivity of liver cells (selectivity index: >6.6 vs 1.85) and blood glucose regulation than 6aa. In addition, the in vitro stability assays also indicated our developed compound 6 ab possessed good metabolic stabilities. [Display omitted] • A series of diaryl urea derivatives has been designed and synthesized. • 6 ab shows 8.6-fold more potent PI3Kα inhibitory activity than gedatolisib (6aa). • 6 ab exhibits 4.6-fold more potent antiproliferative effect than 6aa against HCT116. • 6 ab reveals comparable in vivo antitumor activity with the control 6aa. • 6 ab shows better metabolic stability and safer profiles compared with gedatolisib. [ABSTRACT FROM AUTHOR]

PH-sensitive PDEAEMA were grafted from SBA-15 surface via surface initiated metal free ATRP. SBA-15- g -PDEAEMA has good biocompatibility and can be endocytosed by L929 cells. The drug release rate of SBA-15- g -PDEAEMA-Qu at pH = 5.5 is significantly higher than that at pH = 7.4, so SBA-15- g -PDEAEMA can be used as a carrier for controlled release of drugs and has potential application prospects in clinical practice. [Display omitted] • SBA-15- g -PDEAEMA were synthesized by metal free SI-ATRP. • The 10-phenylphenothiazine (PTH) was used as photocatalyst of metal free SI-ATRP. • The structure and biocompatibility of the hybrid materials were also investigated. • SBA-15- g -PDEAEMA can be used as a carrier for controlled drug release. PH-sensitive amphiphilic poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) were grafted from mesoporous silica molecular sieve SBA-15 surface via metal-free atom transfer radical polymerization (metal-free ATRP). The amino group was introduced onto SBA-15 surface by silane coupling agent KH-550, followed by the ATRP initiator SBA-15-Br was obtained after bromoisobutyryl bromide (BIBB) immobilized onto SBA-15 surface. The PDEAEMA grafted SBA-15 (SBA-15- g -PDEAEMA) inorganic–organic hybrid materials were prepared by surface initiated metal-free ATRP using SBA-15-Br as initiator, 10-phenylphenothiazine (PTH) as photocatalyst, 2-(diethylamino)ethyl methacrylate (DEAEMA) as the monomer. Then, the anticancer drug quercetin was loaded onto SBA-15- g -PDEAEMA hybrid material (SBA-15- g -PDEAEMA-Qu) and the controlled release of quercetin was investigated. The analytical results indicated that the ATRP initiator has been successfully anchored onto the SBA-15 surface and the ordered structure of the mesoporous material has been maintained. The kinetic plots and the curve of the relationship between Mn and monomer conversion illustrates that the polymerization process has the characteristics of "living"/controllable radical polymerization. The TGA results showed that the graft rate of organics in SBA-15 channel is 24.7%. In vitro cytotoxicity evaluation and cell uptake assay results indicated that the cytotoxicity of SBA-15- g -PDEAEMA to the L929 cells had completely disappeared on the 3rd day, SBA-15- g -PDEAEMA has good biocompatibility and can be endocytosed by L929 cells. The drug release rate of SBA-15- g -PDEAEMA hybrid material loaded with quercetin (SBA-15- g -PDEAEMA-Qu) at pH = 5.5 is significantly higher than that at pH = 7.4, the SBA-15- g -PDEAEMA hybrid material can be used as carrier for controlled drug release and has potential application prospects in clinical practice. [ABSTRACT FROM AUTHOR]