[Docking-based virtual screening of MEK1 inhibitors from Chinese herbs].

The hyperphosphorylation of MEK1(mitogen-activated protein kinase kinase 1) is one of the causesfor melanoma. It is important to discover a potential medicine for melanoma through virtual screening of chemical composition of Chinese material medica on MEK1. In this study, a docking pocket model and Flex Search model were built by using a MEK1 crystal structure, the similarity between connector conformation and gametophyte conformation in the crystal structure was 0.784.There was a linear relationship between total score and pIC50on MEK1 inhibitors, with R²=0.937, which further indicated the reliability of the virtual screening model.The search library of traditional Chinese medicine database on the Lipinski's rule was docked with the pocket model, and then 50 compounds with a totalscore of more than 7.0 were obtained by the Flex model. In this paper, top 10 active ingredients in screening results showed atotal score of more than that of positive medicines. It is expected to further research the inhibition of MEK1 and melanoma.

[Three photons quantum-cutting system on the rear surface of cells to improve the efficiencies of solar cells].

The authors present a solar cell model with a three photons quantum-cutting system on the rear surface, then the method of calculation of limiting efficiencies was used to get the maximum efficiency 58.58% at the band gap Eg=0.9315 eV, and in contrast with two-photons quantum-cutting system, it is greatly improved. The result can prove that the three-photons quantum-cutting has a great sense to improve the efficiencies of solar cells. It is the exciting development for us to find out the useful luminescence materials to get the high efficiency.

Polymorphisms in BER and NER pathway genes: effects on micronucleus frequencies among vinyl chloride-exposed workers in Northern China.

In this study, a group of 317 workers occupationally exposed to vinyl chloride monomer and 166 normal, unexposed referents in Shandong province (Northern China) were examined for chromosomal damage in peripheral lymphocytes using the cytokinesis-blocked micronucleus (CB-MN) assay. The exposure group (3.47±2.65)‰ showed higher micronucleus frequency than the unexposed workers (2.51±1.96)‰ (P<0.01). We explored the relationship between genetic polymorphisms of XRCC1 (-77C/T, Arg194Trp, Arg280His, Arg399Gln), APE1 Asp148Glu, XPA Ala23Gly, XPC.PAT, XPC Ala499Val, XPC Lys939Gln, XPF 5'-UTR T2063A, XPG Exon15 G-C, ERCC13'-UTR C8092A and susceptibility of chromosomal damage in all the subjects. It was found that XRCC1 -77, XRCC1 280, APE1148, XPC.PAT, XPG Exon15 G-C, and ERCC13'-UTR C8092A polymorphisms showed no significant associations with micronucleus frequency in unexposed workers. However, among the exposed workers individuals with XRCC1 (-77C/T, Arg194Trp, Arg280His, Arg399Gln) polymorphisms had a significantly higher micronucleus frequency as seen in mean frequency ratios (FR) compared with their homozygous wild-type genotypes (FR=1.21, 95% CI: 1.05-1.39; P<0.01); (FR=1.14, 95% CI: 1.00-1.38; P<0.05) and (FR=1.26, 95% CI: 1.11-1.44; P<0.01); (FR=1.23, 95% CI: 1.08-1.46; P<0.01). Four SNP sites in the nucleotide excision repair (NER) pathway were associated with susceptibility for MN frequency in either unexposed or exposed workers. Further, we observed the gene-MN association changed with exposure for XRCC1 (-77C/T, Arg194Trp, Arg280His, Arg399Gln), XPA Ala23Gly, XPC Ala499Val, XPC Lys939Gln, XPF 5'-UTR T2063A. Moreover, Individuals carrying the XPC (PAT)-(499)-(939) diplotype, PAT-CG/PAT-TG, had a higher MN frequency, compared with individuals carrying the wild-type PAT-CA/PAT-CA.

Design, synthesis and evaluation of novel pyrimidinylaminothiophene derivatives as FGFR1 inhibitors against human glioblastoma multiforme.

Vascular endothelial growth factor receptors (VEGFRs) have emerged as the most promising anti-angiogenic therapeutic targets for the treatment of recurrent glioblastomas (GBM). However, anti-VEGF treatments led to the high proportion of non-responder patients or non lasting clinical response and the tumor progression to the greater malignant stage. To overcome these problems, there is an utmost need to develop innovative anti-angiogenic therapies. In this study, we report the development of a series of new FGFR1 inhibitors. Among them, compound 4i was able to potently inhibit FGFR1 kinase activities both in vitro and in vivo. This compound displayed strong anti-angiogenic activity in HUVECs and anti-tumor growth and anti-invasion effects in U-87MG cell line. These results emphasize the importance of FGFR1-mediated signaling pathways in GBM and reveal that pharmacological inhibition of FGFR1 can enhance the anti-tumoral, anti-angiogenic and anti-metastatic efficiency against GBM. These data support targeting of FGFR1 as a novel anti-angiogenic strategy and highlight the potential of compound 4i as a promising anti-angiogenic and anti-metastatic candidate for GBM therapy.

Gene Therapy with p14/tBID Induces Selective and Synergistic Apoptosis in Mutant Ras and Mutant p53 Cancer Cells In Vitro and In Vivo.

Any gene therapy for cancer will be predicated upon its selectivity against cancer cells and non-toxicity to normal cells. Therefore, safeguards are needed to prevent its activation in normal cells. We designed a minimal p14ARF promoter with upstream Ap1 and E2F enhancer elements and a downstream MDR1 inhibitory element, TATA box, and a transcription initiation site (hereafter p14ARFmin). The modified p14ARFmin promoter was linked to bicistronic P14 and truncated BID (tBID) genes, which led to synergistic apoptosis via the intrinsic and extrinsic pathways of apoptosis when expressed. The promoter was designed to be preferentially activated by mutant Ras and completely inhibited by wild-type p53 so that only cells with both mutant Ras and mutant p53 would activate the construct. In comparison to most p53 gene therapies, this construct has selective advantages: (1) p53-based gene therapies with a constitutive CMV promoter cannot differentiate between normal cells and cancer cells, and can be toxic to normal cells; (2) our construct does not induce p21WAF/CIPI in contrast to other p53-based gene therapies, which can induce cell cycle arrest leading to increased chemotherapy resistance; (3) the modified construct (p14ARFmin-p14-tBID) demonstrates bidirectional control of its promoter, which is completely repressed by wild-type p53 and activated only in cells with both RAS and P53 mutations; and (4) a novel combination of genes (p14 and tBID) can synergistically induce potent intrinsic and extrinsic apoptosis in cancer cells.

GDU-952, a novel AhR agonist ameliorates skin barrier abnormalities and immune dysfunction in DNFB-induced atopic dermatitis in mice.

The aryl hydrocarbon receptor (AhR) is widely expressed in the skin. It controls immune-mediated skin responses to various external environmental signals, promote terminal differentiation of epidermal keratinocytes and participates the maintenance of the skin barrier function. As a therapeutic target, AhR activation modulates many diseases progression driven by immune/inflammatory processes such as atopic dermatitis (AD) and psoriasis. In this study, we revealed that GDU-952 is a novel AhR agonist, which is able to decreases IgE serum levels, to inhibit pro-inflammatory cytokines such as IL-6 and TNF-α and to induce immunoregulatory effects through restoring Th1/Th2 immune balance and promoting CD4+FOXP3+regulatory T (Treg) populations in AD skin lesions. Furthermore, GDU-952 can strengthen the skin barrier function through upregulating epidermal differentiation-related and tight junction proteins. This may alleviate AD symptoms, such as dermatitis scores, epidermal hyperplasia and mast cell infiltration. These results offer a rationale for further preclinical/clinical studies to evaluate the possible use of GDU-952 in the management of AD.

Impact of polyphenols extracted from Tricholoma matsutake on UVB-induced photoaging in mouse skin.

BACKGROUND: Despite Tricholoma matsutake has been used as natural health products with multiple medicinal properties, detailed information about its polyphenolic composition as sources of anti-photoaging agents remains to be determined. OBJECTIVE: To investigate the impact of polyphenols extracted from Tricholoma matsutake (TME) on Ultraviolet B (UVB)-induced skin photoaging. MATERIALS AND METHODS: Various factors of oxidative stress and inflammation as well as histological and immunohistochemical analysis in the mouse dorsal skin were determined after UVB radiation. RESULTS: Topical administration with TME suppressed the UVB-induced skin thickness, wrinkles and erythema, and increased skin collagen content. Furthermore, TME decreased reactive oxygen species (ROS) level, upregulated glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), and glucose-6-phosphate dehydrogenase (G6PDH) activities and inhibited the expression of IL-1, IL-6, IL-8, and TNF-α in mice irradiated with UVB. TME could reduce UVB-induced p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation and effectively inhibited the activity of the transcriptional factor nuclear factor-kappa B (NF-κB), thereby reducing the cyclooxygenase-2 (COX-2) expression, which is an important mediator of inflammatory cascade leading to the inflammatory response. CONCLUSION: Our data demonstrated that TME had various beneficial effects on UVB-induced skin photoaging due to its antioxidant and anti-inflammatory activities, and it might be exploited as a promising natural product in skin care, anti-photoaging and the therapeutic intervention of skin disorders related to both oxidative stress and inflammation.

Improvement of Skin Barrier Dysfunction by Phenolic-containing Extracts of Lycium barbarum via Nrf2/HO-1 Regulation.

Lycium barbarum have received an increasing popularity due to its powerful biological activity and medicinal use. However, the effect of Lycium barbarum on skin remains largely uncharacterized. The general purpose of this paper was to characterize the phenolic compounds in Lycium barbarum extract (LBE) using LC-HRMS/QTOF method and to investigate whether topical administration of LBE can repair skin barrier dysfunction in mice. Our data demonstrated that LBE could not only decrease ROS level and matrix metalloproteinase expression, but also strengthen intrinsic antioxidant defense system including SOD, GSH-Px and CAT, thereby resulting in increased skin collagen content and an improvement of UV-induced skin erythema, thickness and wrinkles. Improved skin barrier functions were highly correlated with increased expression of filaggrin, involucrin and loricrin as well as antioxidant proteins such as Nrf2 and HO-1 in UV-irradiated mice, suggesting that LBE may be promising natural products at a lower cost for the topical application in the treatment of skin diseases with defective barrier function.

[Chinese medicine prevention and treatment of AIDS in terms of constitution theory].

The significant effects of constitutional factor on AIDS were addressed. Acquired immunodeficiency syndrome (AIDS), caused by HIV, is mainly characterized as decreased immune function or immune deficiency. It has strong infectiousness and higher mortality, so it is one of the diseases that attract great attention to clinical prevention and treatment. The constitution not only exerts significant effect on the immune function of patients with AIDS, but also plays important roles in the development, prognosis, and outcomes of AIDS. Therefore, it is of great referential significance in both clinical and scientific studies of AIDS by exploring Chinese medicine prevention and treatment of AIDS from the angle of constitution.

[Improvement of anti-stokes energy transfer between rare earth ions--2. Numerical calculation and analysis].

The dynamics of all levels were calculated numerically in the present article for Er(0.5)Yb(3):FOV oxyfluoride nanophase vitroceramics. The population dynamical processes were analyzed carefully. It was found for the first time that traditional phonon-assisted energy transfer theory of rare earth ion energy transfer can not well explain the observed experimental calibrated results, as it does not take into account the difference between Stokes and anti-Stokes process. A coefficient, the improved factor of the intensity ratio of Stokes to anti-Stokes process in quantum Raman theory compared to classical Raman theory, was introduced for the first time to successfully describe the anti-Stokes energy transfer. The theoretical improvement results are coincident with experiments very well. This improvement is very significant and indispensable when the photonics of nanomaterials is probed.

[Optical parameters of Er3+ in Er3+ : YVO4].

In the present paper the authors firstly measured the absorption spectra of Er3+ in the sample Er3+ : YVO4 (0.5%), then calculated the intensity parameters are calculated by using the Judd-Ofelt theory. After that the authors dealed with some predicted spectroscopic parameters, such as the oscillator strength, spontaneous radiative transition rate, branching ratio and integrated emission cross section. And Er : YVO4 crystal application value has been analyzed with the optical parameters. Especially there are large oscillator strengths and large integrated emission cross sections in the transitions of 4 I1/2 --> 4 I15/2, 2 H11/2 --> 4I15/2, 4S3/2 --> 4 I15/2, and 4F9/2 --> 4 I15/2. So, they are more worth of attention. Moreover, by comparing the Er-doped yttrium vanadate crystal and other Er-doped crystal optical properties, the authors can see the advantages of YVO4 as laser crystal. Finally, the authors discussed the splitting of the energy levels of Er3+ in the crystal YVO4 based on the group theory.

Four new species of Oreocharis (Gesneriaceae) in Yunnan province, China.

Four new species of Oreocharis (Gesneriaceae) are described and illustrated. These new species grow in pairs in montane forests in Yunnan province, China. One pair grows in Wenshan county, Southeast Yunnan, viz. Oreocharis eriocarpa W.H. Chen & Y.M. Shui and O. wenshanensis W.H. Chen & Y.M. Shui and another pair grows in Yongde county, Southwest Yunnan, viz. O. fulva W.H. Chen & Y.M. Shui and O. lacerata W.H. Chen & Y.M. Shui. Their morphological and geographical relationship with similar species is discussed and the IUCN endangered status is provided, based on the available data.

[Study on terahertz spectra of multi-walled carbon nanotubes].

In the present paper, the authors report the characterization of multiwalled carbon nanotube at terahertz (THz) frequency range using terahertz time-domain spectroscopy. The surface appearances and microanalysis of multiwalled carbon nanotubes were measured by scanning electron microscope in order to fully understand the unique features and applications of multiwalled carbon nanotube. The results show that the refractive indexes of the sample decrease with increasing frequency in the frequency range of 0.2 to 2 THz, while the absorption coefficients of the sample increase with increasing frequency. In addition, the curve of terahertz absorption coefficients can be fitted by a straight line with a slope of 1.92. From the results of scanning electron microscope, the ranges of inner diameter and outer diameters of the sample were from 5 to 15 nm and from 15 to 25 nm, respectively, and its length was in the order of micrometer. The results of microanalysis of its elemental composition showed that the content of element C was about 94% and the rest were O and Cl elements, which were impurity elements. Mathematical modes of terahertz absorption and refractive indexes in the frequency range of 0.2 to 2.0 THz were established after taking into account Taylor expansion and Maxwell's equations, and the calculation was in relatively good agreement with the observed values of the sample in general. The terahertz refractive indexes and absorption properties of multiwalled carbon nanotube were mainly attributed to the chemical compositions and molecular weight, and carbon nanotubes with different content of carbon could show different terahertz absorption spectra and disclose different unique functions.

Improved large-scale production of vitamin B12 by Pseudomonas denitrificans with betaine feeding.

The strategy of betaine control for vitamin B12 large-scale fermentation by Pseudomonas denitrificans was investigated in this paper. The results obtained in shake-flask experiments demonstrated that betaine could greatly stimulate vitamin B12 biosynthesis but had an inhibition to cell growth. Based on the influence of betaine on the fermentation of P. denitrificans, betaine feeding was a beneficial strategy to solve the inconsistency between cell growth and vitamin B12 production. As a result, an effective and economical strategy of betaine feeding was established for vitamin B12 fermentation in 120-m3 fermenter, in which betaine was continuously fed to maintain betaine concentration of the broth at the range of 5-7g/l during 50-140h of fermentation.

CYP2E1 mRNA expression, genetic polymorphisms in peripheral blood lymphocytes and liver abnormalities in Chinese VCM-exposed workers.

OBJECTIVE: To study the relationship between expression of cytochrome P4502E1 (CYP2E1) in human lymphocytes, variant CYP2E1 genotype, exposure to vinyl chloride monomer (VCM), and liver abnormalities in VCM-exposed workers. METHODS: A case-control study was performed on 90 male occupationally exposed workers and 42 matched male nonexposed controls. Data were collected based on health surveillance, workplace investigation and questionnaire Survey. Total RNA and DNA were isolated from peripheral blood lymphocytes, and CYP2E1 mRNA expression was determined using RT-PCR, and the presence of CYP2E1 polymorphisms was identified based on PCR-RFLP. RESULTS: The mRNA expression of CYP2E1 in exposed workers (0.89+/-0.46) was significantly higher than in nonexposed controls (0.61+/-0.35) (P < 0.01). Logistic regression analysis demonstrated a statistically significant association between CYP2E1 mRNA expression levels and liver abnormalities in the VCM-exposed workers (OR = 3.66, P < 0.05). The genotype frequency for CYP2E1 variants among VCM-exposed workers was not significantly different between workers with liver abnormalities and those without. CONCLUSIONS: Liver abnormalities in subjects exposed to VCM are positively associated with expression of peripheral blood lymphocyte mRNA, which is significantly increased in exposed workers compared to nonexposed controls. Therefore, CYP2E1 mRNA levels may be useful for health surveillance and protection of VCM-exposed workers.

Aromatic-turmerone ameliorates imiquimod-induced psoriasis-like inflammation of BALB/c mice.

Psoriasis is a usual immune-mediated inflammatory skin disease with undefined pathogenesis. Aromatic-turmerone (ATM) is a mainly constituent of essential oil from Curcuma longa L. It has been shown to exhibit strong anti-oxidant, anti-tumor activities and anti-inflammatory effects. In this study, we investigated the effects of ATM on imiquimod (IMQ)-induced psoriasis-like BALB/c mice and its molecular mechanisms for anti-inflammatory effect. ATM showed inhibition of the transfer of CD8+ T cells in epidermis, and reduced expression of NF-κB and COX-2 as well as phosphorylation of p38 MAPK. It also decreased the level of TNF-α and IL-6, and down-regulates IL-17 IL-22 and IL-23 mRNA synthesis. Notably, we demonstrated that topically applied ATM alleviated skin inflammation in IMQ-induced mice. These results indicate that ATM, a natural active compound exhibits anti-inflammatory activity and is a promising candidate molecule to treat inflammatory skin diseases, such as psoriasis.

Analysis of microRNA expression and micronuclei frequency in workers exposed to vinyl chloride monomer in China.

AIM: To identify differently expressed miRNAs associated with vinyl chloride monomer (VCM) and micronuclei (MN) frequency. METHOD: In discovery stage, we used microarray to detect miRNAs expression in peripheral blood lymphocytes between six low and six high VCM-exposed workers grouped by medium cumulative exposure dose. Then we validated four miRNAs using real-time quantitative reverse transcription PCR (qRT-PCR) and detected the micronuclei frequencies using cytokinesis-block micronucleus assay in 94 VCM-exposed workers and 53 healthy control subjects. RESULTS & CONCLUSION: We found eight miRNAs significantly downregulated and seven miRNAs upregulated (|Fold Change| >2; p < 0.05) in the high-exposure group through microarray. We validate that miR-222-3p, miR-146a-5p and miR-151a-5p were downregulated, while miR-22-3p was upregulated in VCM-exposed group (all p < 0.01). Furthermore, we found that expression of miR-22-3p was upregulated in the high micronuclei (MN) frequency subjects. In conclusion, our study suggested that these four miRNAs could be biomarkers of VCM exposure, and moreover miR-22-3p was correlated with MN frequency.

Baicalin protects neonatal rat brains against hypoxic-ischemic injury by upregulating glutamate transporter 1 via the phosphoinositide 3-kinase/protein kinase B signaling pathway.

Baicalin is a flavonoid compound extracted from Scutellaria baicalensis root. Recent evidence indicates that baicalin is neuroprotective in models of ischemic stroke. Here, we investigate the neuroprotective effect of baicalin in a neonatal rat model of hypoxic-ischemic encephalopathy. Seven-day-old pups underwent left common carotid artery ligation followed by hypoxia (8% oxygen at 37°C) for 2 hours, before being injected with baicalin (120 mg/kg intraperitoneally) and examined 24 hours later. Baicalin effectively reduced cerebral infarct volume and neuronal loss, inhibited apoptosis, and upregulated the expression of p-Akt and glutamate transporter 1. Intracerebroventricular injection of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) inhibitor LY294002 30 minutes before injury blocked the effect of baicalin on p-Akt and glutamate transporter 1, and weakened the associated neuroprotective effect. Our findings provide the first evidence, to our knowledge that baicalin can protect neonatal rat brains against hypoxic-ischemic injury by upregulating glutamate transporter 1 via the PI3K/Akt signaling pathway.

Association of Telomere Length With Chromosomal Damage Among Chinese Workers Exposed to Vinyl Chloride Monomer.

OBJECTIVE: To explore the relationship between relative telomere length (RTL) and chromosomal damage represented by micronucleus (MN) frequencies among vinyl chloride monomer (VCM) -exposed workers. METHODS: A group of 126 VCM-exposed workers, 60 internal controls, and 25 external controls were examined for RTL by Quantitative polymerase chain reaction and MN frequencies by cytokinesis-block micronucleus test. Cumulative exposure dose was used to estimate the exposure of VCM-exposed workers. RESULTS: The RTL were significantly shorter in exposed workers and internal controls than in external controls. The exposed workers had significantly increased MN frequencies than both control groups. Additionally, MN frequencies were negatively associated with RTL in VCM-exposed group. CONCLUSIONS: VCM exposure may alter telomere length, which could be a potential biomarker of susceptibility to chromosomal damage.

An immunosensor based on magnetic relaxation switch and polystyrene microparticle-induced immune multivalency enrichment system for the detection of Pantoea stewartii subsp. Stewartii.

A rapid, sensitive, and simple immunosensor has been developed for the detection of Pantoea stewartii subsp. Stewartii (Pss). This immunosensor combines magnetic relaxation switch (MRS) assay with polystyrene microparticle-induced immune multivalency enrichment system. Comparing to conventional enzyme-linked immunosorbent assay (ELISA), the immunosensor developed in this study provides higher sensitivity and requires less analysis time. The detection limit of Pss obtained by immunosensor was determined to be 10(3)cfu/mL, 50 times lower than that by ELISA (5×10(4)cfu/mL), while the analysis time required by immunosensor is 30min much shorter than that by ELISA. The average recoveries studied with Pss at various spiking levels ranged from 85.5% to 93.4% with a relative standard deviation (RSD) below 6.0%. No cross-reaction with the other five strains was found, demonstrating a good specificity of Pss detection. The results showed that the MRS immunosensor combined with PS-induced immune multivalency enhancement system is a promising platform for the determination of large biological molecules due to its high sensitivity, specificity, homogeneity, and speed.