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Background: Shengmai San (SMS), a Chinese classic herbal formula, has been widely used for the treatment of Qi-Yin deficiency syndrome in Asia. Modern pharmacological studies have shown that SMS improves the cognitive function. However, the quality markers (Q-markers) for SMS still need further research.Purpose: Using chinmedocmics strategy to systematically evaluate the efficacy of SMS in the treatment of APPswe/PS1dE9 (APP/PS1) transgenic model of Alzheimer's disease (AD) and to discover the efficacy-related Q-markers.Methods: The effect of SMS on APP/PS1 mice was evaluated by behavioral test, immunohistochemistry and urine metabolic profile, and the urine marker metabolites associated with SMS treatment of AD were characterized using metabolomics method. In the premise of efficacy, Serum Pharmacochemistry of Traditional Chinese Medicine was applied to investigate the in vivo constituents of SMS. A correlation analysis between marker metabolites of therapeutic effects and serum constituents was completed by chinmedomics approach.Results: SMS had a therapeutic effect on APP/PS1 mice, and 34 potential urine biomarkers were reversed by SMS treatment. A total of 17 in vivo constituents were detected, including 14 prototype components and 3 metabolites. The correlation analysis showed that eight constituents were extremely correlated with protective effects of SMS in AD, and considered as potential Q-markers of SMS, including schisandrin, isoschisandrin, angeloylgomisin Q, gomisin D, angeloylgomisin H, gomisin M2, ginsenoside F1, 20(R)-ginsenoside Rg3.Conclusion: This study has demonstrated that chinmedomics is novel strategy for discovering the potential effective constituents from herbal formula, which are recognized as Q-markers. [ABSTRACT FROM AUTHOR]

Abstract: Fructose is a nutritional composition of fruits and honey. Its excess consumption induces insulin resistance-associated metabolic diseases. Hypothalamic insulin signaling plays a pivotal role in controlling whole-body insulin sensitivity and energy homeostasis. Quercetin, a natural flavonoid, has been reported to ameliorate high fructose-induced rat insulin resistance and hyperlipidemia. In this study, we investigated its regulatory effects on the hypothalamus of high fructose-fed rats. Rats were fed 10% fructose in drinking water for 10 weeks. After 4 weeks, these animals were orally treated with quercetin (50 and 100 mg/kg), allopurinol (5 mg/kg) and water daily for the next 6 weeks, respectively. Quercetin effectively restored high fructose-induced hypothalamic insulin signaling defect by up-regulating the phosphorylation of insulin receptor and protein kinase B. Furthermore, quercetin was found to reduce metabolic nutrient sensors adenosine monophosphate-activated protein kinase (AMPK) activation and thioredoxin-interacting protein (TXNIP) overexpression, as well as the glutamine–glutamate cycle dysfunction in the hypothalamus of high fructose-fed rats. Subsequently, it ameliorated high fructose-caused hypothalamic inflammatory lesions in rats by suppressing the activation of hypothalamic nuclear factor κB (NF-κB) pathway and NOD-like receptor 3 (NLRP3) inflammasome with interleukin 1β maturation. Allopurinol had similar effects. These results provide in vivo evidence that quercetin-mediated down-regulation of AMPK/TXNIP and subsequent inhibition of NF-κB pathway/NLRP3 inflammasome activation in the hypothalamus of rats may be associated with the reduction of hypothalamic inflammatory lesions, contributing to the improvement of hypothalamic insulin signaling defect in this model. Thus, quercetin with the central activity may be a therapeutic for high fructose-induced insulin resistance and hyperlipidemia in humans. [Copyright &y& Elsevier]

Abstract: Anthracnose caused by Colletotrichum spp. is one of the most destructive diseases of cultivated strawberry (Fragaria × ananassa Duchesne) worldwide. The correlation between NBS–LRR genes, the largest class of known resistance genes, and strawberry anthracnose resistance has been elusive. BLAST search in NCBI identified 94 FvNBSs in the diploid genome of strawberry Fragaria vesca, with 67 of the TIR–NBS–LRR type. At least 36 FvNBSs were expressed, with 25% being non-coding genes. Two F. vesca ecotypes, HLJ and YW, showed great variations in both morphological and physiological responses upon C. gloeosporioides infection. qRT-PCR revealed that 5 of the 12 leaf-expressed FvNBSs displaying opposite transcription responses to C. gloeosporioides infection in two ecotypes. These results showed that the transcriptional responses of several FvNBSs were involved in the ecotype-specific responses to C. gloeosporioides in F. vesca. These FvNBSs hold potential in characterizing molecular components and developing novel markers associated with anthracnose resistance in strawberry. [Copyright &y& Elsevier]

NRF2, a transcription factor that regulates cellular redox and metabolic homeostasis, plays a dual role in human disease. While it is well known that canonical intermittent NRF2 activation protects against diabetes-induced tissue damage, little is known regarding the effects of prolonged non-canonical NRF2 activation in diabetes. The goal of this study was to determine the role and mechanisms of prolonged NRF2 activation in arsenic diabetogenicity. To test this, we utilized an integrated transcriptomic and metabolomic approach to assess diabetogenic changes in the livers of wild type, Nrf2 −/−, p62 −/−, or Nrf2 −/−; p62 −/− mice exposed to arsenic in the drinking water for 20 weeks. In contrast to canonical oxidative/electrophilic activation, prolonged non-canonical NRF2 activation via p62-mediated sequestration of KEAP1 increases carbohydrate flux through the polyol pathway, resulting in a pro-diabetic shift in glucose homeostasis. This p62- and NRF2-dependent increase in liver fructose metabolism and gluconeogenesis occurs through the upregulation of four novel NRF2 target genes, ketohexokinase (Khk), sorbitol dehydrogenase (Sord), triokinase/FMN cyclase (Tkfc), and hepatocyte nuclear factor 4 (Hnf4A). We demonstrate that NRF2 and p62 are essential for arsenic-mediated insulin resistance and glucose intolerance, revealing a pro-diabetic role for prolonged NRF2 activation in arsenic diabetogenesis. • The role of non-canonical activation of the Nrf2 signaling pathway in type II diabetes has not been determined. • Chronic activation of Nrf2 promotes a pro-diabetic shift in the liver polyol pathway that increases blood glucose levels. • Four newly identified Nrf2 target genes are responsible for the diabetogenic shift in liver carbohydrate metabolism. [ABSTRACT FROM AUTHOR]

A diamond film was deposited using a two-step process in which nitrogen is added during the second step. We compare the defects in {001} and {111} growth sectors from the two-steps: dislocation loops found in {001} growth sectors of the first step disappear in {001} growth sectors with N-doping, whereas the density of planar defects in {111} growth sectors strongly increases. It is suggested that N-doping stops vacancies from aggregating to form dislocation loops or vacancy clusters. [Copyright &y& Elsevier]

Aging increases susceptibility to lung disease, but the topic is understudied, especially in relation to environmental exposures with the bulk of rodent studies using young adults. This study aims to define the pulmonary toxicity of naphthalene (NA) and the impacts of a dietary antioxidant, ergothioneine (ET), in the liver and lungs of middle-aged mice. NA causes a well-characterized pattern of conducting airway epithelial injury in the lung in young adult mice, but NA's toxicity has not been characterized in middle-aged mice, aged 1–1.5 years. ET is a dietary antioxidant that is synthesized by bacteria and fungi. The ET transporter (ETT), SLC22A4, is upregulated in tissues that experience high levels of oxidative stress. In this study, middle-aged male and female C57BL/6 J mice, maintained on an ET-free synthetic diet from conception, were gavaged with 70 mg/kg of ET for five consecutive days. On day 8, the mice were exposed to a single intraperitoneal NA dose of 50, 100, 150, or 200 mg/kg. At 24 hours post NA injection samples were collected and analyzed for ET concentration and reduced (GSH) and oxidized glutathione (GSSG) concentrations. Histopathology, morphometry, and gene expression were examined. Histopathology of mice exposed to 100 mg/kg of NA suggests reduction in toxicity in the terminal airways of both male (p ≤ 0.001) and female (p ≤ 0.05) middle-aged mice by the ET pretreatment. Our findings in this study are the first to document the toxicity of NA in middle-aged mice and show some efficacy of ET in reducing NA toxicity. • Differential expression of Phase 2 associated genes were measured by lung location. • Microdissection allowed study of lung location naphthalene dose effects by sex. • Naphthalene pulmonary toxicity was measured in middle-aged mice for the first time. • Oral ergothioneine pretreatment led to modest reductions in naphthalene toxicity. [ABSTRACT FROM AUTHOR]

• A mathematical model of rolling force imbedding the deformation penetration coefficient is established. • The rolling force is positive correlation with the deformation penetration coefficient and the roller velocity. • The larger the reduction and the ratio of the plate thickness to diameter are, the bigger the required rolling force are. The deformation characteristic of an ultra-heavy plate in thickness direction is described by introducing a parameter, called deformation penetration coefficient, and the rolling force model taking this parameter into account in the broadside stage is established. In this paper, the deformation penetration coefficient is defined as the ratio of the actual deformation depth to the overall plate thickness, which is shown as the function of the initial thickness, the pass reduction and the critical shape factor. Since the plate width speard can be neglected during broadside rolling, a two-dimensional velocity field is constructed by simplifying a classical three-dimensional velocity field. For the purpose of solving the problem of functional integration originated from the nonlinear Mises specific plastic power, the simplified velocity field is analyzed by the geometric approximation (GA) yield criterion, and the internal deformation power is obtained. Moreover, the friction power and the shear power are obtained by the inner product method of the strain vector and the mean velocity intergral method, respectively. The analytical solution of rolling force is obtained by the variational method, and its value for each pass is compared with the measured data from a domestic factory. The comparison result shows that the rolling force model in this paper has a high predictive accuracy, since the maximum error is less than 8.6%. The rolling parameter analysis shows that the deformation penetration coefficient, the pass reduction and the ratio of plate thickness to diameter affect the rolling force of the ultra-heavy plate apparently. [ABSTRACT FROM AUTHOR]

Summary: Epidemiological evidence demonstrates the neuroendocrine link between stress, depression and diabetes. This study observed glucose intolerance of rats exposed to chronic unpredictable mild stress (CUMS) in oral glucose tolerance test (OGTT). CUMS procedure significantly up-regulated corticotropin-releasing factor (CRF)-related peptide urocortin 2 expression and elevated cAMP production, resulting in over-expression of suppressor of cytokine signaling 3 (SOCS3) in hypothalamic arcuate nucleus (ARC) of rats. Furthermore, SOCS3 activation blocked insulin signaling pathway through the suppression of insulin receptor substrate 2 (IRS2) phosphotyrosine and phosphatidylinositol-3-kinase (PI3-K) activation in hypothalamic ARC of CUMS rats after high-level of insulin stimulation. These data indicated that CUMS procedure induced the hyperactivity of CRF system, and subsequently produced conditional loss of insulin signaling in hypothalamic ARC of rats. More importantly, icariin and fluoxetine with the ability to restrain CRF system hyperactivity improved insulin signaling in hypothalamic ARC of CUMS rats, which were consistent with the enhancement of glucose tolerance in OGTT, showing anti-diabetic efficacy. Although effective in OGTT, anti-diabetic drug pioglitazone failed to restore hypothalamic ARC CRF system hyperactivity, paralleling with its inability to ameliorate the loss of insulin signaling and depression-like behavior in CUMS rats. These observations support the hypothesis that signal cross-talk between hypothalamic CRF system and insulin may be impaired in depression with glucose intolerance and suggest that icarrin and fluoxetine aiming at CRF system may have great potential in the prevention and treatment of depression with comorbid diabetes. [ABSTRACT FROM AUTHOR]

• A twin elliptical die whose junction is smoothly connected is designed. • The drawing force of the twin elliptical die is the smallest compared with those based on the conical die and the single elliptical die. • A higher reduction leads to the increase of the optimal die angle at a specific friction factor. According to the stream function requirement, a twin elliptical die for rod or wire drawing is designed, and the subsequent plastic mechanical analysis is carried out. In terms of the volume constant condition, a kinematically admissible velocity field describing the drawing process is constructed. Based on the velocity field, the analytical expression of internal plastic deformation energy rate accounting for the non-zero shear strain rate is obtained by using the mean value theorem of integral. Then, the analytical expression of friction energy rate is also derived by the mean value theorem of integral. Ultimately, the analytical expression of the drawing force is obtained based on the upper bound method. It is found that there exists the optimal die semi-angle which depends on the relative reduction and friction factor. The analytical drawing force based on the twin elliptical die is validated by the corresponding simulated results, and a very agreement is found since the relative errors between them are less than 9.2%. [ABSTRACT FROM AUTHOR]

P-glycoprotein (P-gp) is an important factor leading to multidrug resistance (MDR) in cancer treatment. The co-administration of anticancer drugs and P-gp inhibitors has been a treatment strategy to overcome MDR. In recent years, tyrosine kinase inhibitor Lapatinib has been reported to reverse MDR through directly interacting with ABC transporters. In this work, a series of P-gp inhibitors (1–26) was designed and synthesized by integrating the quinazoline core of Lapatinib into the molecule framework of the third-generation P-gp inhibitor Tariquidar. Among them, compound 14 exhibited better MDR reversal activity than Tariquidar. The docking results showed compound 14 displayed the L-shaped molecular conformation. Importantly, compound 14 increased the accumulation of Adriamycin (ADM) and rhodamine 123 (Rh123) in MCF7/ADM cells. Besides, compound 14 significantly increased ADM-induced apoptosis and inhibited the proliferation, migration and invasion of MCF7/ADM cells. It was also demonstrated that compound 14 significantly inhibited the growth of MCF7/ADM xenograft tumors by increasing the sensitivity of ADM. In summary, compound 14 has the potential to overcome MDR caused by P-gp. [Display omitted] • Novel P-gp inhibitors were designed, synthesized and bioevaluated. • Compound 14 exhibits better MDR reversal activity than third-generation P-gp inhibitor Tariquidar. • Compound 14 inhibited the efflux function of P-gp. • Compound 14 significantly inhibited the growth of MCF7/ADM xenograft tumors. [ABSTRACT FROM AUTHOR]

In this work, a serial of Fe/Fe 3 N based nanocomposites were synthesized by high-temperature pyrolytic method. Structural characterizations show that the small Fe/Fe 3 N nanoparticles uniformly dispersed on the surface of carbon films, where thin carbon may effectively enhance the stability of Fe/Fe 3 N and the carbon films can accelerate the migration of electrons. Moreover, Fe/Fe 3 N based composite can significantly increase the effective area of bare GCE because of its high conductivity, large surface area, and good catalytic property. These structural advantages enhance the electrochemical performance of the constructed electrodes toward simultaneous dopamine (DA) and acetaminophen (AP) sensing. Under optimum condition, the linear ranges for DA and AP detection were 0.05–66.4 μM and 0.05–56.9 μM, respectively. In addition, due to its high sensitivity, good selectivity and strong stability, Fe/Fe 3 N-900@GCE can also be applied for detecting DA and AP in real samples. This work provides a simple and effective strategy for constructing new electrode materials for small biomolecule sensing. Core-Shell Fe/Fe 3 N/carbon nanocomposites were synthesized by high-temperature pyrolytic method, and were developed as electrochemical sensors for dopamine and acetaminophen detection. [Display omitted] • Core-shell Fe/Fe 3 N/carbon composite was prepared by high-temperature pyrolytic method. • The carbon shells enhance the stability of Fe/Fe 3 N@C and accelerate the migration of electrons. • The construct electrode reveals high sensitivity toward simultaneous sensing of DA and AP. • The construct electrode can be used to detect DA and AP in commercial medicines. [ABSTRACT FROM AUTHOR]

Abstract: An ab initio calculation based on density functional theory is applied to study the doping stability and electronic structure of wurtzite Zn1−x Cd x O alloys. It is found that the different alloy configurations of Zn1−x Cd x O with a given Cd content are possible thermodynamically, but having different band gaps. With increasing Cd content, the formation enthalpy of Zn1−x Cd x O alloy increases sharply. The Cd-content dependence of the band-gap values can be fitted with a second-order polynomial. The reduction of band gap can be attributed to the contributions of the hybridization of Zn-4s and Cd-5s, the enhancement of p–d repulsion, and the tensile strain due to Cd-doping. [Copyright &y& Elsevier]

Reactive sputtering deposition has been widely applied to the preparation of oxide films, but a method is still needed to stably control the deposition process and the film growth. In this work, the plasma in the vicinity of sputtering target is studied by optical emission spectroscopy and the atomic oxygen density ([O]) is linked to the sputtering mode and the growth of NiO films. The NiO films can be deposited either in oxide mode or in the transition region, whereas the [O] value plays an important role in determining the growth behavior of NiO films and the crystallinity. In the transition region, the (111)-oriented growth of NiO films is preferential and the crytallinity is improved with the decrease in the [O] value. In the oxide mode, the NiO films are preferentially (001)-oriented and exhibit a relatively good crystallinity. By fixing the O 2 /Ar flow ratio at a constant, the [O] value is explored as a function of substrate temperature, showing that the oxygen desorption may have significant impacts on the [O] value as the substrate temperature is higher than 400 °C. • Determining the role of atomic oxygen in reactive sputtering deposition of NiO films. • Establishing an OES method of determining atomic oxygen density. • Linking the growth behavior of NiO films being to atomic oxygen density. [ABSTRACT FROM AUTHOR]

The aim of the present study was to further characterize the expression of the CYP2A genes in human nasal mucosa. Fetal nasal tissues at 12–26 weeks of gestational age and surgical biopsy tissues from various regions of nasal cavity of adult patients were studied to determine whether CYP2A proteins can be detected by immunoblot in adults, whether higher levels of CYP2A proteins are present in adult than in fetal nasal mucosal microsomes, and whether CYP2A13 mRNA is more abundant than CYP2A6 mRNA in fetal nasal mucosa. In adults, immunoblot analysis detected CYP2A proteins in microsomes of the olfactory region from 8 of 10 individuals, but in none of the nasal microsomes of the respiratory region from 47 patients. Quantitative immunoblot analysis confirmed that CYP2A proteins are selectively expressed in the olfactory region in both adult and fetal tissues. Interestingly, the levels of CYP2A proteins in nasal microsomes were generally higher in fetuses than in adults. In the fetus, the level of CYP2A13 mRNA was much higher than that of CYP2A6 mRNA, as has been previously found in adult nasal mucosa. Immunohistochemical studies confirmed that, in the fetus, the CYP2A proteins are expressed in the supporting cells in the olfactory epithelium and in the Bowman’s glands in the lamina propria. The prenatal expression of the CYP2A proteins in the olfactory mucosa suggests potential risks of developmental toxicity from maternally derived xenobiotics, since both CYP2A6 and CYP2A13 are known to be efficient in the metabolic activation of tobacco-specific nitrosamines and other respiratory toxicants. [Copyright &y& Elsevier]

• A closure criterion is established for central elliptical voids by the upper bound method based on a triangular velocity field. • The n σ decreases with the increase of l / h ¯ , and increases with the increase of aspect ratio η. • A larger reduction and a smaller aspect ratio are more conducive to void closure. To investigate the evolution behavior of a centrally elliptical void in thick slab during rolling, a critical criterion for closing a central elliptical void is established through the energy analysis. According to the condition of volume constancy, a triangular velocity field embedding an elliptical void is established. Based on the velocity field, the minimum value of rolling energy rate, composed of shear energy rate and cracking energy rate, is calculated. According to the balance principle of energy rate, the expression of relative stress factor is obtained. Then, a mechanical criterion for void closure is derived from the basis of extreme condition, and the effects of void size, aspect ratio, geometrical shape parameter, thickness-to-radius ratio, and the relative reduction on the void closure are analyzed. Several rolling processes with different elliptical voids under seven aspect ratios are simulated by the finite element method (FEM), and the evolution characteristic of the void is revealed. The analytical results based on the mechanical criterion and those by the FEM are compared. It is shown that the two prediction results are in good agreement, and a flat void is easier to be closed than a sharp one. Also, the simulated rolling force and torque are obtained through the FEM model, and the comparison result confirms the validity of the upper bound solution. Finally, a rolling experiment with a prefabricated void is carried out to check the reliability of the closure criterion, and a good consistence is also found. In addition, the shortage of the present investigation based on 2D simulation for assessing the mechanical criterion is discussed as a prospect of the future research. [ABSTRACT FROM AUTHOR]