Recent advances in c-Met-based dual inhibitors in the treatment of cancers.

The cellular-mesenchymal epithelial transition factor (c-Met) is a receptor tyrosine kinase (RTK) located on the 7q31 locus encoding the Met proto-oncogene and plays a critical role in regulating cell proliferation, metastasis, differentiation, and apoptosis through various signaling pathways. However, its aberrant activation and overexpression have been implicated in many human cancers. Therefore, c-Met is a promising target for cancer treatment. However, the anticancer effect of selective single-targeted drugs is limited due to the complexity of the signaling system and the involvement of different proteins and enzymes. After inhibiting one pathway, signal molecules can be transmitted through other pathways, resulting in poor efficacy of single-targeted drug therapy. Dual inhibitors that simultaneously block c-Met and another factor can significantly improve efficacy and overcome some of the shortcomings of single-target inhibitors, including drug resistance. In this review, We introduced c-Met kinase and the synergism between c-Met and other anti-tumor targets, then dual-target inhibitors based on c-Met for the treatment of cancers were summarized and their design concepts and structure-activity relationships (SARs) were discussed elaborately, providing a valuable insight for the further development of novel c-Met-based dual inhibitors.

In-field and non-destructive determination of comprehensive maturity index and maturity stages of Camellia oleifera fruits using a portable hyperspectral imager.

To efficiently detect the maturity stages of Camellia oleifera fruits, this study proposed a non-invasive method based on hyperspectral imaging technology. First, a portable hyperspectral imager was used for the in-field image acquisition of Camellia oleifera fruits at three maturity stages, and ten quality indexes were measured as reference standards. Then, factor analysis was performed to obtain the comprehensive maturity index (CMI) by analyzing the change trends and correlations of different indexes. To reduce the high dimensionality of spectral data, the successive projection algorithm (SPA) was employed to select effective feature wavelengths. The prediction models for CMI, including partial least squares regression (PLSR), support vector regression (SVR), extreme learning machine (ELM), and convolutional neural network regression (CNNR), were constructed based on full spectra and feature wavelengths; for CNNR, only the raw spectra were used as input. The SPA-CNNR model exhibited more promising performance (RP = 0.839, RMSEP = 0.261, and RPD = 1.849). Furthermore, PLS-DA models for maturity discrimination of Camellia oleifera fruits were developed using full wavelength, characteristic wavelengths and their fusion CMI, respectively. The PLS-DA model using the fused dataset achieved the highest maturity classification accuracy, with the best simplified model achieving 88.6 % accuracy in prediction set. This study indicated that a portable hyperspectral imager can be used for in-field determination of the internal quality and maturity stages of Camellia oleifera fruits. It provides strong support for non-destructive quality inspection and timely harvesting of Camellia oleifera fruits in the field.

Identification of a pathogen causing fruiting body rot of Sanghuangporus vaninii.

Sanghuangporus vaninii is a medicinal macrofungus that is increasingly cultivated in China. During cultivation, it was found that the fruiting body of S. vaninii was susceptible to pathogenic fungi, resulting in significant economic losses to the industry. The symptoms of the disease occur in the initial stage of fruiting body development. The isolate YZB-1 was obtained from the junction of the diseased and healthy areas of the fruiting body. In order to verify the pathogenicity of YZB-1, its purified spore suspension was inoculated into the exposed area nearby the developing fruiting body of S. vaninii. After 10 days, the same disease symptoms appeared in the inoculated area. Morphological identification and molecular analysis of rDNA ITS region confirmed that the isolate YZB-1 was identified as Trichoderma virens. The temperature stability assay revealed that the mycelia of YZB-1 grew the fastest at 25 °C, with growth slowing down gradually as the temperature increased or decreased. Dual-culture tests of T. virens and S. vaninii showed that the inhibition rate of T. virens on S. vaninii mycelium was the highest (79.01 ± 2.79%) at 25 °C, and more green spores were produced at the intersection of T. virens and S. vaninii.

Evaluation of Dual-Band Near-Infrared Spectroscopy and Chemometric Analysis for Rapid Quantification of Multi-Quality Parameters of Soy Sauce Stewed Meat.

The objective of this study was to evaluate the performance of near-infrared spectroscopy (NIRS) systems operated in dual band for the non-destructive measurement of the fat, protein, collagen, ash, and Na contents of soy sauce stewed meat (SSSM). Spectra in the waveband ranges of 650-950 nm and 960-1660 nm were acquired from vacuum-packed ready-to-eat samples that were purchased from 97 different brands. Partial least squares regression (PLSR) was employed to develop models predicting the five critical quality parameters. The results showed the best predictions were for the fat (Rp = 0.808; RMSEP = 2.013 g/kg; RPD = 1.666) and protein (Rp = 0.863; RMSEP = 3.372 g/kg; RPD = 1.863) contents, while barely sufficient performances were found for the collagen (Rp = 0.524; RMSEP = 1.970 g/kg; RPD = 0.936), ash (Rp = 0.384; RMSEP = 0.524 g/kg; RPD = 0.953), and Na (Rp = 0.242; RMSEP = 2.097 g/kg; RPD = 1.042) contents of the SSSM. The quality of the content predicted by the spectrum of 960-1660 nm was generally better than that for the 650-950 nm range, which was retained in the further prediction of fat and protein. To simplify the models and make them practical, regression models were established using a few wavelengths selected by the random frog (RF) or regression coefficients (RCs) method. Consequently, ten wavelengths (1048 nm, 1051 nm, 1184 nm, 1191 nm, 1222 nm, 1225 nm, 1228 nm, 1450 nm, 1456 nm, 1510 nm) selected by RF and eight wavelengths (1019 nm, 1097 nm, 1160 nm, 1194 nm, 1245 nm, 1413 nm, 1441 nm, 1489 nm) selected by RCs were individually chosen for the fat and protein contents to build multi-spectral PLSR models. New models led to the best predictive ability of Rp, RMSEP, and RPD of 0.812 and 0.855, 1.930 g/kg and 3.367 g/kg, and 1.737 and 1.866, respectively. These two simplified models both yielded comparable performances to their corresponding full-spectra models, demonstrating the effectiveness of these selected variables. The overall results indicate that NIRS, especially in the spectral range of 960-1660 nm, is a potential tool in the rapid estimation of the fat and protein contents of SSSM, while not providing particularly good prediction statistics for collagen, ash, and Na contents.

Ultra-high-efficiency capture of lead ions over acetylenic bond-rich graphdiyne adsorbent in aqueous solution.

A satisfactory material with high adsorption capacity is urgently needed to solve the serious problem of environment and human health caused by lead pollution. Herein, hydrogen-substituted graphdiyne (HsGDY) was successfully fabricated and employed to remove lead ions from sewage and lead-containing blood. The as-prepared HsGDY exhibits the highest adsorption capacity of lead among the reported materials with a maximum adsorption capacity of 2,390 mg/g, i.e., ~five times larger than that of graphdiyne (GDY). The distinguished hexagonal hole and stack mode of HsGDY allows the adsorption of more lead via its inner side adsorption mode in one single unit space. In addition, the Pb 6s and H 1s hybridization promotes the strong bonding of lead atom adsorbed at the acetylenic bond of HsGDY, contributing to the high adsorption capacity. HsGDY can be easily regenerated by acid treatment and showed excellent regeneration ability and reliability after six adsorption-regeneration cycles. Langmuir isotherm model, pseudo second order, and density functional theory (DFT) demonstrated that the lead adsorption process in HsGDY is monolayer chemisorption. Furthermore, the HsGDY-based portable filter can handle 1,000 µg/L lead-containing aqueous solution up to 1,000 mL, which is nearly 6.67 times that of commercial activated carbon particles. And, the HsGDY shows good biocompatibility and excellent removal efficiency to 100 µg/L blood lead, which is 1.7 times higher than that of GDY. These findings suggest that HsGDY could be a promising adsorbent for practical lead and other heavy metal removal.

Parameter optimization of the spiral fertiliser discharger for mango orchards based on the discrete element method and genetic algorithm.

Introduction: In order to solve the problems of inaccurate fertilization, unstable fertilization and low fertiliserutilization rate in mango orchard. Methods: A small spiral fertiliser discharger was designed based on the agronomic characteristics of fertilization in mango orchard. The fertilizing performance test and parameter optimization of thespiral fertiliser discharger were carried out by combining bench and simulation test. Firstly, the main influencing factors of the fertilizing performance of the spiral fertiliser discharger were analyzed by theoretical calculation formula, and the range of its value was preliminarily determined. At the same time, the digital and discrete element models of the spiral fertiliser discharger were established. Then,the discrete element model of granular fertiliser was established on the basis of the physical and related mechanical simulation parameters of granular fertiliser obtained by experimental statistics.Taking the variable coefficient of fertilizing stability as the response value, the method of singlefactor simulation fertilizing test was used to explore the parameters that have a significant influence on the variable coefficient of fertilizing stability. The response surface method (RSM) was used tosimulate the fertilizing performance of three significant parameters. Based on the quadraticregression orthogonal rotation combination design test, a second-order regression mathematicalmodel between the variable coefficient of fertilizing stability and the significant parameters wasestablished. The variable coefficient of fertilizing stability was as small as possible. The geneticalgorithm (GA) was used to optimize the regression model. Finally, the verification test of thefluidity and applicability of different fertilisers was carried out. Results: The results of single factor test showed that the diameter of spiral blade, pitch and rotationalspeed of fertilizing shaft have significant influence on the variable coefficient of fertilizing stability.The optimal parameter combination of the spiral fertiliser discharger was obtained: 98.44 mm for thediameter of spiral blade, 54.8 mm for the pitch, and 24.43 r/min for the rotational speed of fertilizingshaft. The verification results showed that the average relative error of the test was small, and themass flow rate of different fertilisers and the variable coefficient of fertilizing stability could meetthe agronomic requirements of fertilization in mango orchards. The reliability of the discrete elementsimulation test results and research methods of the spiral fertiliser discharger was verified. Conclusion: The results and methods of this study can provide reference for the development of mangoorchard fertilization machinery and related fertilizing performance test.

Interference of EFNA4 suppresses cell proliferation, invasion and angiogenesis in hepatocellular carcinoma by downregulating PYGO2.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Ephrin A4 (EFNA4) acts as an oncogene in multiple cancers but is little known in HCC. It is revealed that EFNA4 is highly expressed in patients with HCC and influences the proliferation of HCC cells; however, detailed regulatory mechanism of EFNA4 in HCC needs to be unveiled. Here, we discovered that EFNA4 was highly expressed in HCC cell lines. EFNA4 knockdown greatly suppressed cell proliferation, migration and invasion, as well as inhibiting angiogenesis in Huh7 cells. EFNA4 was demonstrated to interact with pygopus-2 (PYGO2) and positively regulate PYGO2 expression. Gene gain- and loss-of-function experiments revealed that the anti-tumor effect of EFNA4 knockdown was partly abolished by PYGO2 overexpression. Furthermore, EFNA4 knockdown blocked wnt/ß-catenin signaling in Huh7 cells, which was then abolished by PYGO2. In conclusion, this study further ensured the oncogenic role of EFNA4 in HCC, and disclosed that EFNA4 knockdown suppressed cell proliferation, invasion, angiogenesis, and wnt/ß-catenin signaling in HCC by downregulating PYGO2.

Merging photoredox with copper catalysis: enantioselective remote cyanation via 1,4-heteroaryl migration.

We have developed a photoredox/Cu dual catalyzed enantioselective remote cyanation via 1,4-heteroaryl migration. Experimental and computational studies have been carried out to reveal the reaction mechanism and explain the origins of the regio- and enantioselectivities of the remote cyanation process. This methodology exhibits mild conditions, a broad substrate scope and good regio- and enantioselectivities, which provides a unique approach for catalyst-controlled asymmetric backbone recombination of molecules via functional group migration.

Feasibility of identifying the authenticity of fresh and cooked mutton kebabs using visible and near-infrared hyperspectral imaging.

Mutton kebab is an attractive type of meat product with high nutritional value, and is favored by consumers worldwide. However, mutton kebab is often subjected to adulteration due to its high price. Chicken, duck, and pork are frequently used as adulterated substitutes. The purpose of current study aims at developing a methodology based on hyperspectral imaging (HSI, 400-1000 nm) for identifying the authenticity of fresh and cooked mutton kebabs. Kebab samples were individually scanned using HSI system in their fresh and cooked states. Spectra of chicken, duck, pork, and mutton kebabs were first extracted from representative regions of interest (ROIs) identified in their calibrated hyperspectral images. After that, principal component analysis (PCA) was carried out, and results showed that the first three or two PCs were effective for identifying fresh or cooked samples of different meat species. Different effective modeling algorithms including k-nearest neighbor (KNN), partial least squares discriminant analysis (PLS-DA), and support vector machine (SVM) algorithms combined with different preprocessing methods were employed to develop classification models. Performances exhibited that PLS-DA models using raw spectra outperformed the KNN and SVM models, and the accuracies reached both 100 % in prediction sets for fresh and cooked meat kebabs, respectively. Moreover, compared to iteratively variable subset optimization (IVSO), random frog (RF), and successive projections algorithm (SPA) algorithms, the PC loadings successfully screened 14 and 8 effective wavelengths for fresh and cooked meat kebabs, respectively, from the complex original full-band wavelengths. The PC-PLS-DA models showed the optimal predicted performances with overall classification accuracies of 97.5 % and 100 %, sensitivity values of 1.00 and 1.00, specificity values of 0.97 and 1.00, precisions of 0.91 and 1.00, for fresh and cooked mutton kebabs, respectively. Furthermore, the visualization of classification maps confirmed the experimental results intuitively. Overall, it was evident that HSI showed immense potential to identify the authenticity of fresh and cooked mutton kebabs when substituted by different meats including chicken, duck, and pork.

Photoredox/copper cocatalyzed domino cyclization of oxime esters with TMSCN: access to antifungal active tetrasubstituted pyrazines.

A photoredox/copper cocatalyzed domino cyclization of oxime esters with TMSCN has been developed. A range of structurally novel tetrasubstituted pyrazines have been obtained. This method features high bond-forming efficiency, high step economy, broad substrate scope, and gram-scale synthesis. Moreover, preliminary bioactivity evaluation of pyrazine products shows their promising antifungal activities.

Resveratrol ameliorates muscle atrophy in chronic kidney disease via the axis of SIRT1/FoxO1.

Chronic kidney disease (CKD) is often associated with muscle atrophy. However, the underlying molecular mechanisms are still not well understood. Here, we treated 5/6-nephrectomized (5/6Nx) rats with resveratrol and found that this treatment greatly improves renal function as evidenced by reduced proteinuria and cystatin C. Moreover, resveratrol ameliorates renal fibrosis by reducing transforming growth factor ß (TGF-ß) and connective tissue growth factor (CTGF). Meanwhile, muscle atrophy in these 5/6Nx rats was largely attenuated by resveratrol. Immunoprecipitation revealed that SIRT1 physically interacts with FoxO1 in muscle, and this interaction was weakened in 5/6Nx rats. As a consequence, acetylated FoxO1 was increased in muscle of 5/6Nx rats. The application of resveratrol markedly reverses this trend. These data point out that SIRT1 is a key factor for linking renal disease and muscle atrophy. Indeed, both renal dysfunction and muscle atrophy were further aggravated by 5/6Nx in Sirt1+/- mice. Taken together, our data indicate that SIRT1 plays a pivotal role in muscle atrophy in CKD, and FoxO1 might be a substrate of SIRT1 in this process. Furthermore, resveratrol, together with other agonists of SIRT1, may hold great therapeutic potentials for treating CKD and its related muscle atrophy.

Roles of microRNA-186 and vascular endothelial growth factor in hepatocellular carcinoma complicated with portal vein tumor thrombus.

The present study aims to investigate the role and underlying mechanism of microRNA (miR)-186 in patients with hepatocellular carcinoma (HCC) complicated with portal vein tumor thrombus. Blood samples from 29 HCC patients with portal vein tumor thrombus were collected between January 2014 and September 2015 in Huai'an First People's Hospital, while blood from 36 HCC patients without vein tumor thrombus was also collected in the same period. In addition, tumor thrombus specimens were collected from the HCC patients with portal vein tumor thrombus, and peritumoral tissues of the tumor thrombus were used as the control. Reverse transcription-quantitative polymerase chain reaction, ELISA and western blot analyses were applied to detect vascular endothelial growth factor (VEGF) expression at the mRNA and protein levels. Bioinformatics prediction was used to predict the target of miR-186, and then miR-186 expression was detected. Furthermore, dual-luciferase reporter assay was used to validate whether miR-186 directly targeted VEGF. Following transfection with agomiR-186, the expression levels of miR-186 and VEGF were detected, while MTT assay was used to detect EA.hy926 cell proliferation subsequent to small interfering RNA (siRNA) silencing. The results identified that VEGF was significantly increased in the tumor thrombus and blood samples of HCC patients with vein tumor thrombus at the mRNA and protein levels, while miR-186 expression was significantly decreased (P<0.05). Following silencing VEGF by siRNA transfection, the proliferation of EA.hy926 cells was inhibited. In addition, VEGF expression was significantly decreased and cell proliferation was reduced when upregulating miR-186. Dual-luciferase reporter assay demonstrated that miR-186 regulated VEGF expression through complementary binding to 3'-untranslated region. In conclusion, VEGF was significantly increased in tumor thrombus and blood samples from HCC patients with vein tumor thrombus, which may be associated with the downregulation of miR-186. Thus, miR-186 may promote the development and progression of vein tumor thrombus in HCC.

miR-486 as an unfavorable prognostic biomarker for patients with non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common malignant tumor in China. miR-486 was found to be associated with many tumors. In previous study, we aimed to investigate the expression and prognostic value of miR-486 in patients with NSCLC. METHODS: In order to measure the expression of miR-486 in 140 NSCLC patients, in situ hybridization (ISH) was made. The staining of miR-486 was scored by two independent investigators. Then, the prognostic value of miR-486 was evaluated by plotting Kaplan-Meier survival curves and making multivariate analysis. RESULTS: miR-486 was mainly expressed in the cytoplasm of tumor cells. miR-486 expression was corrected with tumor differentiation (P=0.011) but not with any other clinicopathological characteristics. However, high expression of miR-486 was significantly correlated with shortened overall survival (OS) in NSCLC patients (P=0.001), especially in stage I patients (P=0.005). Multivariate analysis revealed that miR-486 was an independent prognostic factor in NSCLC patients (P=0.002). CONCLUSIONS: miR-486 high expression predicts poor survival in patients with NSCLC. miR-486 could be used as an unfavorable prognostic biomarker for NSCLC patients.

miR-486-5p functions as an oncogene by targeting PTEN in non-small cell lung cancer.

PURPOSE: Lung cancer, the leading cause of cancer-related death worldwide, shows a poor 5-year overall survival rate. In our previous study, we demonstrated that miR-486-5p can be a potential blood-based biomarker for early diagnosis and recurrence prediction of non-small cell lung cancer (NSCLC). The aim of the present study was to investigate the possible roles and related target genes of miR-486-5p in NSCLC progression. METHODS: pcDNA3.1(+)/Pri-miR486 recombinant plasmid and miR-486-5p inhibitor were transfected into NSCLC cells and theirs effects were evaluated by qRT-PCR. Then, MTT assay and Colony formation assay were performed to determine the potential roles of miR-486-5p played on NSCLC cellular proliferation and cloning in vitro. We also initially investigated the target genes of miR-486-5p by using bioinformatic methods, qRT-PCR and western blot. RESULTS: pcDNA3.1(+)/Pri-miR486 recombinant plasmid significantly upregulated the expression of miR-486-5p, while miR-486-5p inhibitor significantly downregulated its expression. Upregulation of miR-486-5p promoted the cellular proliferation and cloning, while miR-486-5p silencing restrained the cellular proliferation and cloning. Furthermore, four potential target genes (PIK3R1, PTEN, MAP3K7 and FOXO1) of miR-486-5p were screened out. Finally, we found that upregulation of miR-486-5p in NSCLC cells significantly reduced PTEN and increased AKT expression levels, whereas miR-486-5p silencing increased PTEN and reduced AKT expression. Therefore, we believe that miR-486-5p can regulate PTEN-PI3 K/AKT signaling. CONCLUSIONS: miR-486-5p acts as an oncogene in the progression of NSCLC by influencing PTEN-PI3 K/AKT signaling. miR-486-5p may provide potential therapeutic targets for NSCLC.

Downregulation of HIF-2α Reverse the Chemotherapy Resistance of Lung Adenocarcinoma A549 Cells to Cisplatin.

BACKGROUND Cisplatin (DDP)-based systemic chemotherapy has been widely used in the treatment of postoperative or advanced NSCLC patients, however, its effective rate is only 14~40%. HIF-2α can upregulate drug-resistant-related genes expression and lead to chemotherapy resistance in many tumors. However, little is known about the relationship between HIF-2α and chemotherapy resistance of lung cancer cells. MATERIAL AND METHODS In our study, the siRNA expression vectors targeting the HIF-2α gene were designed, constructed, and transfected into A549 cells. MTT assay and western blot analysis of P-glycoprotein 1 (P-gp) were used to explore the transfer influence of HIF-2α gene silencing on the A549 cells in the cisplatin-based chemotherapy resistance. RESULTS After transfection with the siRNAHIF-2α into A549 cells, mRNA and protein expression of HIF-2α were downregulated. At the same time, expression of P-gp decreased significantly. Furthermore, the sensitivity to cisplatin significantly increased. CONCLUSIONS The constructed siRNA expression vectors can effectively suppress the expression of HIF-2α and P-gp, which then can reverse the chemotherapy resistance of A549 cells.

High expression of SLC6A10P contributes to poor prognosis in lung adenocarcinoma.

PURPOSE: To investigate the expression profile and prognostic value of SLC6A10P in patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: TCGA datasets were used to investigate the differential expression of SLC6A10P in NSCLC, lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC). Expression of SLC6A10P was measured by in situ hybridization in tissue microarrays containing 136 NSCLC (51 LUAD and 85 LUSC) patients. The prognostic value of SLC6A10P was then evaluated. RESULTS: SLC6A10P was highly expressed in tumor tissues compared with normal lung tissues. High SLC6A10P expression was associated with lymph node metastasis (NSCLC, P = 0.0054; LUAD, P = 0.0149), more advanced tumor stage (NSCLC, P = 0.0126; LUAD, P = 0.0416) and poor overall survival (NSCLC, P = 0.0248; LUAD, P = 0.0316) in NSCLC and LUAD. Multivariate analysis revealed that SLC6A10P was an independent prognostic factor in LUAD patients (P = 0.017). SLC6A10P showed no association with clinicopathological parameters and no prognostic value in LUSC. CONCLUSION: SLC6A10P is highly expressed in tumor tissues and its high expression predictspoor survival in patients with LUAD. SLC6A10P might serve as a novel therapeutic target and prognostic biomarker in LUAD patients in the future.

Circulating LncRNAs Serve as Diagnostic Markers for Hepatocellular Carcinoma.

BACKGROUND/AIMS: Circulating (serous or plasmic) long non-coding RNA (lncRNA) as biomarkers for predicting the diagnosis or prognosis of human disease have been well documented. Due to the sensibility or specificity limitation of Alpha Fetoprotein (AFP), a cluster lncRNAs were revealed as fingerprints for hepatocellular carcinoma (HCC). In this study, we enrolled all the reported circulating lncRNAs in HCC as candidate targets and examined in an independent cohort. METHODS: The candidate lncRNAs were determined by qRT-PCR divided into training and validation sets. The risk score analysis was employed to evaluate the potential diagnosis ability of the lncRNAs independently or combining with AFP value. The receiver operating characteristic curve (ROC) was applied for presentation of sensibility or specificity. RESULTS: Among the ten candidate circulating lncRNA, LINC00152, RP11-160H22.5, XLOC014172 and LOC149086 were screened with significant difference in training set. Further investigation in validation set indicated LINC00152, RP11-160H22.5 and XLOC014172 might be the fingerprints for HCC comparing with chronic hepatitis (CH) patients or healthy controls. The risk score analysis revealed the combination of three lncRNAs with AFP could distinguish the HCC from either CH or healthy control with the area under curve value (AUC) of 0.986 and 0.985, respectively. CONCLUSION: The three lncRNAs may act as novel biomarkers for acting as fingerprint in HCC combining with AFP.

HIF-2α not HIF-1α overexpression confers poor prognosis in non-small cell lung cancer.

HIF-α may play an important role in the process of tumorigenesis as well as tumor progression. Although a number of investigations have established the significance of HIF-1α in several human tumors, there is still little information available on the clinical significance of HIF-2α expression in non-small cell lung cancer (NSCLC). In present study, immunohistologic expression of HIF-1α/ HIF-2α was studied in a tissue microarray of 140 Stage I-III NSCLCs and correlated with clinicopathologic parameters and clinical outcome. We found that HIF-1α/ HIF-2α showed a cytoplasmic pattern of expression in tumor cells while normal lung components showed negative or weak cytoplasmic staining. High HIF-1α and HIF-2α expression was noted in 49/140 (35.0%) and in 64/140 (45.7%) of the cases respectively. There was no direct correlation between HIF-1α and HIF-2α expression ( p = 0.200). The high HIF-2α expression was associated with histology (squamous cell carcinoma vs. adenocarcinomas) in these patients ( p = 0.001). Patients in advanced tumor stage had frequent high expression of HIF-2α ( p = 0.007), and the similar high expression was also observed in advanced T or N stage ( p = 0.030 and 0.043, respectively). HIF-1α showed a marginal association with T stage ( p = 0.084), which showed a higher expression in early tumor stage. Univariate analysis of the overall survival demonstrates that HIF-2α expression but not HIF-1α was related to poor outcome ( p = 0.005) and it retained significance in multivariate analysis ( p = 0.046). In conclusion, HIF-2α expression was related to tumor size, lymph node metastasis, tumor stage and histology. We also found a positive prognostic value of HIF-2α protein expression. HIF-2α might serve as a potential prognosis biomarker in evaluating progression and prognosis of NSCLC. We believe that our study will be of great benefit to the clinical treatment and prognostic evaluation of NSCLC.

Design, synthesis and evaluation of novel potent angiotensin II receptor 1 antagonists.

A series of new angiotensin II (Ang II) receptor 1 antagonists were designed, synthesized and evaluated. All compounds showed nanomolar affinities for the angiotensin II type 1 receptor in radioligand binding assays and could reduce blood pressure significantly in spontaneously hypertensive rats(SHRs). From which, compound 2b displayed higher affinity binding to angiotensin II type 1 receptor at the same order of magnitude to irbesartan with an IC50 value of 1.26 ± 0.08 nM in radioligand binding assays. 2b showed an efficient and long-lasting effect in reducing blood pressure, the maximal reducing responses were 40.62 ± 4.08 mmHg of MBP at 15 mg/kg and 28.39 ± 2.09 mmHg at 10 mg/kg in SHRs, 39.56 ± 4.83 mmHg at 15 mg/kg and 29.05 ± 2.20 mmHg at 10 mg/kg in RHRs, the significant antihypertensive effect lasted beyond 12 h both in SHRs and in RHRs. In the single-dose pharmacokinetic experiments, compound 2b could be absorbed efficiently and metabolized smoothly in Wistar rats after oral administration. The values of Cmax, Tmax, AUC0-72 and MRT0-72 were 885.61 ± 432.7 ng/mL, 5.67 ± 1.51 h, 6110.28 ± 7398.33 ng/mL h and 7.87 ± 2.30 h at 10 mg/kg, 2945.55 ± 1543.67 ng/mL, 4.33 ± 0.82 h, 26473.62 ± 12217.16 ng/mL h and 10.24 ± 6.94 h at 15 mg/kg, 5759.03 ± 1331.75 ng/mL, 5 ± 1.10 h, 89488.44 ± 18413.15 ng/mL·h and 12.89 ± 2.0 h at 30 mg/kg respectively. The T1/2 values of the three groups were similar, about 9-10 h. Compound 2b was distributed into tissues rapidly and extensively after oral administration. The level of it was the highest in the liver, followed by in spleen, kidney, and the lowest in brain. The acute toxicity assays of 2b proved its low acute toxicity with an LD50 value of 1551.71 mg/kg, and no toxicity reaction appeared at dose of 1200.00 mg/kg. These encouraging results make compound 2b an effective, long-lasting and safe anti-hypertensive drug candidate and worthy of further investigation.

Synthesis and biological evaluation of new fluorine substituted derivatives as angiotensin II receptor antagonists with anti-hypertension and anti-tumor effects.

The synthesis and pharmaceutical activity of new potent non-tetrazole angiotensin II (Ang II) receptor antagonists were described. These compounds were fluorine substituted derivatives of Losartan, Valsartan and Irbesartan with carboxylic acid group as replacements to the known potent tetrazole moiety at the 2'-biphenyl position. Their activities were evaluated by Ang II receptor binding assay as well as by in vivo assay. All of the synthesized compounds showed nanomolar affinity for the AT(1) receptor subtype. The vivo biological evaluation showed that compounds 1a, 2 and 4 produced a dose-dependent antihypertensive effect both in spontaneously hypertensive rats (SHR) and renal hypertensive rats (RHR). Compound 4 especially showed an efficient and long-lasting effect in reducing blood pressure which can last more than 24 h at dose of 10 mg/kg in SHR, which was much better than control Losartan and Valsartan. Compound 4 can also inhibit the prostate cancer in vitro and in vivo. So compound 4 was selected for in-depth investigation as potent, novel and long-lasting non-tetrazole anti-hypertension and anti-tumor drug candidate.