Human Alveolar Adenocarcinoma Cells Research Articles

Wogonin suppresses human alveolar adenocarcinoma cell A549 migration in inflammatory microenvironment by modulating the IL-6/STAT3 signaling pathway.

Increasing evidence from various clinical and experimental studies has demonstrated that the inflammatory microenvironment facilitates tumor metastasis. Clinically, it will be a promising choice to suppress tumor metastasis by targeting inflammatory microenvironment. Our previous studies have demonstrated that wogonin (a bioflavonoid isolated from the traditional Chinese medicine of Huang-Qin) possesses the anti-metastatic and anti-inflammatory activity, but we have little idea about its efficacy on inflammatory-induced tumor metastasis and the mechanism underlying it. In this study, we focused on epithelial mesenchymal transition (EMT), the first step of tumor metastasis, to evaluate the effects of wogonin on tumor metastasis in inflammatory microenvironment. We found that wogonin inhibited THP-1 conditioned-medium- (CM-) and IL-6-induced EMT by inactivating STAT3 signal. And in wogonin-treated A549 cells which pretreated with THP-1 CM or IL-6, the expression level of E-cadherin, an EMT negative biomarker, increased while that of N-cadherin, Vimentin, and EMT-related transcription factors including Snail and Twist decreased. Moreover, wogonin inhibited IL-6-induced phosphorylation of STAT3, prevented p-STAT3 dimer translocation into the nucleus, and suppressed the DNA-binding activity of p-STAT3. Interestingly, similar results were obtained in the tumor xenografts mice, including downregulation of p-STAT3, N-cadherin, and Vimentin while up-regulation of E-cadherin. Wogonin also inhibit the metastasis of A549 cells in vivo. Taken all data together, we concluded that wogonin suppresses tumor cells migration in inflammatory microenvironment by inactivating STAT3 signal.

Co-delivery of plasmid DNA and doxorubicin by solid lipid nanoparticles for lung cancer therapy.

The co-delivery of DNA and antitumor drugs has the potential to treat cancer. In this study, we aimed to develop surface-modified, co-encapsulated solid lipid nanoparticles (SLN) containing enhanced green fluorescence protein plasmid (pEGFP) and doxorubicin (DOX) in order to create a multifunctional delivery system that targets lung cancer cells, in an effort to improve the efficacy of cancer therapy. DOX- and pEGFP-loaded SLN were prepared separately and then mixed to form co-encapsulated SLN (SLN/DE). Transferrin (Tf)-containing ligands were used for the surface coating of the vectors. The in vitro transfection efficiency of the modified vectors was evaluated using a human alveolar adenocarcinoma cell line (A549 cells) and the in vivo transfection efficiency of the modified vectors was evaluated using mice bearing A549 tumors. The Tf-modified DOX and pEGFP co-encapsulated SLN (T-SLN/DE) had a particle size of 267 nm with a 42 mV surface charge. The in vitro cytotoxicity of T-SLN/DE was low (cell viability was between 80 and 100% compared with the controls). T-SLN/DE displayed a remarkable therapeutic effect both in drug delivery and gene therapy. In conclusion, our results demonstrate that the multifunctional delivery system can improve the efficacy of cancer therapy through the combination of gene therapy and chemotherapy. In addition, the coating of active targeting ligands can improve the efficacy of the carriers at targeting lung cancer cells. Thus, the novel gene and drug delivery system offers an effective strategy for lung cancer gene therapy.

Synthesis of novel building blocks of benzosuberone bearing coumarin moieties and their evaluation as potential anticancer agents

A series of novel benzosuberone bearing coumarin moieties 5a–c have been synthesized and their structures were determined by analytical and spectral (FT-IR, 1H NMR, 13C NMR, HRMS) studies. The newly synthesized compounds were evaluated for their cytotoxicity against four human cancer cell lines, A549 (Human alveolar adenocarcinoma cell line), HeLa (Human cervical cancer cell line), MDA-MB-231 (Human breast adenocarcinoma cell line), MCF-7 (Human breast adenocarcinoma cell line) and normal cell line HEK293 (Human embryonic kidney cell line). Compound 5a exhibited promising cytotoxicity with IC50 values ranging from 3.35 to 16.79 μM against all the cancer cell lines like A549, HeLa, MCF-7 and MDA-MB-231, while compound 5c showed significant cytotoxicity against HeLa and MDA-MB-231 with IC50 values of 6.72 and 4.87, respectively.

Autotaxin mRNA and protein expression and regulation by salmeterol xinafoate and fluticasone propionate in lung cells (660.13)

Autotaxin (ATX) is the lyso‐phospholipase D enzyme that catalyzes the final step in the synthesis of the lipid mediator lysophosphatidic acid (LPA). ATX, LPA, and LPA receptors in the lung are all strongly associated with the pathology of pulmonary fibrosis, and increasing evidence implicates these same mediators as contributors to asthma. Accordingly, we hypothesized that the asthma drugs salmeterol xinafoate (SX), a long‐acting beta‐2 agonist bronchodilator, and fluticasone propionate (FP), an anti‐inflammatory steroid, would reduce the expression of ATX in lung cells. Cells were treated for 72 hr in the absence or presence of the drugs, alone or in combination. ATX protein assessed by Western blotting of culture medium and ATX mRNA assessed by qPCR were not detected in primary human bronchial epithelial cells or the Beas‐2B bronchial epithelial cell line. ATX protein but not mRNA was detected for human A549 alveolar adenocarcinoma cells and mouse LA4 cells, both of which represent alveolar rather than airway epithelium. Both SX and FP decreased ATX protein expression in these alveolar cells. Stronger ATX protein and mRNA signals were observed in mesenchymal cells, both primary human airway smooth muscle (HASM) cells and the HFL‐1 human fetal lung fibroblast cell line. In these cells, the level of mRNA was decreased moderately by SX, to a greater extent by FP, and decreased yet further by SX + FP. However, ATX protein was minimally decreased or not at all, despite the clear decrease in mRNA. These data reveal interesting cell type‐specific differences in ATX mRNA and protein expression, and they show that asthma therapeutic agents can reduce the expression of ATX in at least some of these cells, which may contribute to their overall therapeutic benefit in patients with asthma.Grant Funding Source: Supported by investigator‐initiated grant 115165 from GlaxoSmithKline

Long-chain Acyl-CoA Dehydrogenase Deficiency as a Cause of Pulmonary Surfactant Dysfunction

Long-chain acyl-CoA dehydrogenase (LCAD) is a mitochondrial fatty acid oxidation enzyme whose expression in humans is low or absent in organs known to utilize fatty acids for energy such as heart, muscle, and liver. This study demonstrates localization of LCAD to human alveolar type II pneumocytes, which synthesize and secrete pulmonary surfactant. The physiological role of LCAD and the fatty acid oxidation pathway in lung was subsequently studied using LCAD knock-out mice. Lung fatty acid oxidation was reduced in LCAD(-/-) mice. LCAD(-/-) mice demonstrated reduced pulmonary compliance, but histological examination of lung tissue revealed no obvious signs of inflammation or pathology. The changes in lung mechanics were found to be due to pulmonary surfactant dysfunction. Large aggregate surfactant isolated from LCAD(-/-) mouse lavage fluid had significantly reduced phospholipid content as well as alterations in the acyl chain composition of phosphatidylcholine and phosphatidylglycerol. LCAD(-/-) surfactant demonstrated functional abnormalities when subjected to dynamic compression-expansion cycling on a constrained drop surfactometer. Serum albumin, which has been shown to degrade and inactivate pulmonary surfactant, was significantly increased in LCAD(-/-) lavage fluid, suggesting increased epithelial permeability. Finally, we identified two cases of sudden unexplained infant death where no lung LCAD antigen was detectable. Both infants were homozygous for an amino acid changing polymorphism (K333Q). These findings for the first time identify the fatty acid oxidation pathway and LCAD in particular as factors contributing to the pathophysiology of pulmonary disease.

Synthesis, characterization and in vitro antitumor activity of new palladium(II) complexes with (S,S)-R2edda-type esters

Six palladium(II) complexes with (S,S)-R2edda-type esters ((S,S)-R2edda-type: (S,S)-eddch=(S,S)-ethylenediamine-N,N′-di-2-(3-cyclohexyl)propanoate, R=Me, Et, n-Pr, 1–3; (S,S)-pddch=(S,S)-propylenediamine-N,N′-di-2-(3-cyclohexyl)propanoate, R=Et, n-Pr, 4, 5; and (S,S)-eddip=(S,S)-ethylenediamne-N,N′-di-2-propanoate, R=i-Am, 6) were synthesized, characterized by IR, NMR spectroscopy, ESI-MS and elemental analysis. DFT calculations indicate that in case of 1–4, the most stable isomers are with (S,S)- and (R,S)-configuration of nitrogen atoms, but for complex 6 (R,R)- and (R,S)-N,N′-configured isomers. Furthermore, complex 5 was obtained as (S,S)-N,N′ configured isomer. Cytotoxicity study was performed against human cervical adenocarcinoma (HeLa), human alveolar basal adenocarcinoma (A549) and non-cancerous human fetal lung fibroblast (MRC-5) cell lines using colorimetric MTT assay. From the investigated palladium(II) complexes 2, 3 and 5 exhibited highest cytotoxic potential against HeLa (IC50: 28.5±3.9, 29.5±1.3 and 34.3±3.2, respectively).

Synthesis and biological evaluation of fatty imidazolines

A series of eight fatty imidazolines were synthesized under microwave-assisted conditions using different fatty acids namely octyl, decyl, dodecyl, tetradecyl and octadecyl, mixed fatty acids prepared from Sterculia foetida (containing cyclopropene-rich fatty acids), coconut (containing medium-chain-rich fatty acids), palm (containing saturated-rich fatty acids) and sunflower (containing unsaturated-rich fatty acids). Coconut, sunflower and non-edible oil S. foetida-based imidazolines were synthesized for the first time. The fatty imidazolines were evaluated for anti-fungal activity and found to be good to excellent (MIC, 4.68–18.75 μg ml−1) against the tested Candida strains as compared with fluconazole (MIC, 16–64 μg ml−1) as standard. The fatty imidazolines also exhibited excellent to moderate anti-bacterial activity (MIC, 4.68–75 μg ml−1) against Staphylococcus aureus MTCC 96, S. aureus MLS 16 MTCC 2940 and Pseudomonas aeruginosa MTCC 2453 as compared with neomycin (MIC, 18.75 μg ml−1) as standard. The cytotoxic evaluation of the imidazolines against different cancer cell lines such as HeLa (Human Cervical Cancer Cell line), A549 (Human Alveolar Adenocarcinoma Cell line), MDA-MB-231& MCF7 (Human Breast Adenocarcinoma Cell line) and Neuro2a (Mouse neuroblastoma cell line) showed excellent cytotoxicity for dodecyl (3b), tetradecyl (3c), octadecyl (3d) and coconut (3f)-based imidazolines. Sunflower-based imidazoline (3g) exhibited good anti-cancer activity towards A549, Neuro2a and palm-based imidazoline (3h) towards HeLa, A549 and MCF-7 cell lines.

Anticancer effect of salidroside on A549 lung cancer cells through inhibition of oxidative stress and phospho-p38 expression.

Oxidative stress is important in carcinogenesis and metastasis. Salidroside, a phenylpropanoid glycoside isolated from Rhodiola rosea L., shows potent antioxidant properties. The aim of the present study was to investigate the roles of salidroside in cell proliferation, the cell cycle, apoptosis, invasion and epithelial-mesenchymal transition (EMT) in A549 cells. The human alveolar adenocarcinoma cell line, A549, was incubated with various concentrations of salidroside (0, 1, 5, 10 and 20 μg/ml) and cell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Propidium iodide (PI) staining was used to determine the cell cycle by flow cytometry. Cell apoptosis was detected by Annexin V-fluorescein isothiocyanate and PI double-staining, and tumor invasion was detected by Boyden chamber invasion assay. Western blot analysis was performed to detect the expression of EMT markers, Snail and phospho-p38. The results showed that salidroside significantly reduced the proliferation of A549 cells, inhibited cell cycle arrest in the G0/G1 phase and induced apoptosis. Salidroside inhibited transforming growth factor-β-induced tumor invasion and suppressed the protein expression of Snail. As an antioxidant, salidroside inhibited the intracellular reactive oxygen species (ROS) formation in a dose-dependent manner in A549 cells, and depletion of intracellular ROS by vitamin C suppressed apoptosis by salidroside treatment. Salidroside was also found to inhibit the expression of phospho-p38 in A549 cells. In conclusion, salidroside inhibits cell proliferation, the cell cycle and metastasis and induces apoptosis, which may be due to its interference in the intracellular ROS generation, thereby, downregulating the ROS-phospho-p38 signaling pathway.

Synthesis, Characterization, DNA Binding Studies, Photocleavage, Cytotoxicity and Docking Studies of Ruthenium(II) Light Switch Complexes

A new ligand 3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2yl)phenylboronic acid and its (IPPBA) three ruthenium(II) complexes [Ru(phen)2(IPPBA)](ClO4)2 (1), [Ru(bpy)2(IPPBA)](ClO4)2 (2) and [Ru(dmb)2(IPPBA)](ClO4)2 (3) have been synthesized and characterized by elemental analysis, UV/VIS, IR, (1)H-NMR,(13)C-NMR and mass spectra. The binding behaviors of the three complexes to calf thymus DNA were investigated by absorption spectra, emission spectroscopy, viscosity measurements, thermal denaturation and photoactivated cleavage. The DNA-binding constants for complexes 1, 2 and 3 have been determined to be 7.9 × 10(5) M(-1), 6.7 × 10(5) M(-1) and 2.9 × 10(5) M(-1). The results suggest that these complexes bound to double-stranded DNA in an intercalation mode. Upon irradiation at 365 nm, three ruthenium complexes were found to promote the cleavage of plasmid pBR322 DNA from super coiled form І to nicked form ІІ. Further in the presence of Co(2+), the emission of DNA-Ru(ΙΙ) complexes can be quenched. And when EDTA was added, the emission was recovered. The experimental results show that all three complexes exhibited the "on-off-on" properties of molecular "light switch". The highest Cytotoxicity potential of the complex1 was observed on the Human alveolar adenocarcinoma (A549) cell line. Good agreement was generally found between the spectroscopic techniques and molecular docked model which provides further evidence of groove binding.

Overexpression of PRMT6 does not suppress HIV-1 Tat transactivation in cells naturally lacking PRMT6

BackgroundProtein arginine methyltransferase 6 (PRMT6) can methylate the HIV-1 Tat, Rev and nucleocapsid proteins in a manner that diminishes each of their functions in in vitro assays, and increases the stability of Tat in human cells. In this study, we explored the relationship between PRMT6 and HIV-1 Tat by determining the domains in each protein required for interaction.MethodsThrough domain mapping and immunoprecipitation experiments, we determined that both the amino and carboxyl termini of PRMT6, and the activation domain within Tat are essential for interaction. Mutation of the basic domain of Tat did not affect the ability of PRMT6 to interact with Tat.ResultsWe next used the A549 human alveolar adenocarcinoma cell line, which naturally expresses undetectable levels of PRMT6, as a model for testing the effects of PRMT6 on Tat stability, transactivation, and HIV-1 replication. As previously observed, steady state levels and the protein half-life of Tat were increased by the ectopic expression of PRMT6. However, no down regulation of Tat transactivation function was observed, even with over 300-fold molar excess of PRMT6 plasmid. We also observed no negative effect on HIV-1 infectivity when A549 producer cells overexpressed PRMT6.ConclusionsWe show that PRMT6 requires the activation domain, but surprisingly not the basic domain, of Tat for protein interaction. This interaction between Tat and PRMT6 may impact upon pathogenic effects attributed to Tat during HIV-1 infection other than its function during transactivation.

Abstract 2604: Involvement of circulating fibrocytes in the progression of adenocarcinomas by modulating EMT and tumor microenvironment.

Abstract Background: Circulating fibrocytes (CFs) are bone marrow derived, mesenchymal progenitor cells that have emerging role in many diseases. CFs was shown to participate in tissue remodeling in pulmonary hypertension and fibrosis, via secretion of different cytokines and growth factors. Nevertheless, their role in the lung cancer still has to be delineated. Thus, our aim is to identify the role of CFs in lung cancer progression and metastatic potential. Results/methods: We generated CFs by isolating human peripheral blood mononuclear cells (PBMCs) and culturing them for 10 days until they differentiated into CFs. Purity (≥95%) of the CFs population was analyzed by flow cytometry and immunofluorescence. Co-culturing of A549 (human alveolar adenocarcinoma cells) and CFs for 12 and 24 hrs, followed by collection of conditioned medium (CM) and RNA from both cells yielded interesting results. Co-cultured CM promoted proliferation (1.31±0.07 versus 1.5±0.13) and migrating capacity (64.6±26.5 versus 472.8±103.4) of A549 tumor cells. In addition, co-cultured CM caused epithelial-to-mesenchymal transition (EMT) of A549 cells; epithelial markers (E-cadherin, cytokeratin) were downregulated, and mesenchymal markers (α-smooth muscle actin, fibronectin) were upregulated. In vivo to study the CFs involvement in lung cancer, we co-injected CFs with A549 cells or A549 cells alone and measured the tumor growth after 28 days. The tumor size was significantly increased (1354.8±333.6 versus 3042.4±373.4) in co-injected group (CF+A549) compared to A549 alone. Screening for genes regulated in co-injected group tumors showed regulation of tumor microenvironment, an increase in macrophage markers (CSF1R, CD68, CD200, MMD), angiogenesis markers (EDNRB, THBS1) and ECM remodeling markers (MMP14, CTSB, CTSH) compared to A549 tumor alone. Conclusions: We believe that circulating fibrocytes may play positive role in the tumor growth and progression. The increase in EMT and migration, may suggest their involvement in invasion and metastasis. Targeting CFs and their secretory molecules can be of therapeutic importance in lung cancer. Citation Format: Alina Asafova, Vandana Nikam, Anja Schmall, Werner Seeger, Robert Voswinckel, Rajkumar Savai. Involvement of circulating fibrocytes in the progression of adenocarcinomas by modulating EMT and tumor microenvironment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2604. doi:10.1158/1538-7445.AM2013-2604

Internalization of Bacillus intermedius ribonuclease (BINASE) induces human alveolar adenocarcinoma cell death

Ribonuclease (RNase) treatment represents a novel mechanism based approach to anticancer therapy as an alternative to the DNA damaging drugs commonly used in clinical practice. Apart from their ribonucleolytic activity, cytotoxic effects have attracted a considerable attention to RNases because of their potential as selective agents for treatment of certain malignancies. Among these enzymes, Binase, an RNase from Bacillus intermedius, has shown promising results. Here, we have found that binase selectively attacked human A549 alveolar adenocarcinoma cells to trigger an apoptotic response, whereas normal lung epithelial cells LEK were not affected by the ribonuclease. The tumor transformation led to the modification of certain cellular characteristics causing cell sensitivity to binase. Although a general mode for RNases cytotoxicity includes their penetration into the cell, translocation to the cytosol and degradation of ribonucleic acid, many aspects of this process have not been fully elucidated. Our data revealed the following time-dependent changes induced by binase in A549 cells: (a) fast permanent internalization of the enzyme during the first hours of treatment; (b) temporary increase in cellular permeability for macromolecules during the 4–6 h of treatment; (c) apoptotic alterations in population after 24 h and (d) DNA fragmentation and cell death after 72 h of treatment with binase. Elucidation of these molecular strategies used by this promising toxin provides us essential information for the development of new anticancer drugs.

Comprehensive Study on the Toxicology of Surface-Coated ZnO Nanoparticles in Human Alveolar Adenocarcinoma (A549) Cells

The impact of surface coating of zinc oxide nanoparticles (ZnO NPs) with chitosan, cell culture medium and oleic acid (OA) on their cytotoxicity in human alveolar adenocarcinoma (A549) cells has been studied in terms of particle induced-toxicity, membrane damage, generation of intracellular reactive oxygen species (ROS) and cell apoptosis. The chitosan-coated NPs with negatively charged hydroxyl group are less toxic than OA-coated NPs with positively charged alkyl groups, thereby highlights its potential for reducing metal oxide NPs toxicity. The potential of surface coatings to reduce the cytotoxicity was ordered as chitosan-, mediumand OA-coated. The reduction in the cytotoxicity of surface-coated ZnO NPs was attributed to lesser interaction of NPs with the cells and decrease in Zn2+ ions into the cell medium, resulting in decrease of reactive oxygen species production and apoptotic cell death. The mechanism involved in the cytotoxicity of ZnO NPs was also studied in detail.

TNF-α Lectin-Like Domain Derived Peptide Modulates Epithelial Sodium Channel Current

Sodium absorption by epithial sodium channel (ENaC) is main driving force of lung liquid clearance at birth and lung edema clearance in adulthood. We investigated the molecular mechanism underlying the modulation of ENaC current by TNF-α and TNF-α lectin-like domain derived (TIP) peptides. With the help of the patch-clamp technique we show that TIP peptides caused a substantial increase in amiloride sensitive sodium current through ENaC in human alveolar adenocarcinoma cells (A549), in both whole cells as well as single channel configurations. ENaCs in A549 cells are proteolytically cleaved. This model cell line mimics the ENaC as in edema conditions. We next analyze the effect of TIP peptide in heterologous expression systems. To do so, we transiently transfect hENaC in CHO cells and studied the effect of TIP peptide. Our results show that TIP peptide has direct interaction with ENaC and can modulate the amiloride sensitive sodium current through these channels. In contrast, we barely observe an effect of TIP peptide when applied to the extracellular side of the HNEC cell line RPMI2650. It is widely accepted that two different populations of ENaC are expressed in cells. First, proteolytically cleaved with high open probability called active ENaCs and the second naive with low open probability silent/near silent ENaCs. In RPMI2650 cells ENaC are near silent. To activate these near silent ENaC in RPMI cells we applied Trypsin to the extracellular side and subsequently demonstrate that TIP peptide modulates the sodium current considerably. Our results strongly support a model where modulation of ENaC with TIP peptide AP301 happens in proteolytically active channels and that assaying proteolytic cleavage of ENaC could report on the benefit of therapeutic interventions.1. Hribar M, et al. (1999) Eur J Immunol 29: 3105-3111

Synthesis, characterization and cytotoxic activity of palladium (II) carbohydrate complexes

Carbohydrate containing pyridyl triazole ligands, 5-deoxy-1,2-O-isopropylidene-5-(4-(2-pyridyl)-1H-1,2,3-triazole-1-yl)-α-D-xylofuranose (2a), 3-O-Benzyl-5-deoxy-1,2-O-isopropylidene-5-(4-(2-pyridyl)-1H-1,2,3-triazol-1-yl)-α-D-xylofuranose (2b), methyl-5-deoxy-2,3-O-isopropylidene-5-(4-(2-pyridyl)-1H-1,2,3-triazol-1-yl)-β-D-ribofuranoside, (2c) and 6-deoxy-1,2:3,4-di-O-isopropylidene-6-(4-(2-pyridyl)-1H-1,2,3-triazol-1-yl)-α-D-galactopyranose (2d) were prepared by the ‘click’ reaction of 2-ethynyl pyridine with the corresponding azides. The palladium complexes were synthesised by the reaction of pyridyl triazole ligands with [Pd(COD)Cl2] in dichloromethane. All the compounds were characterised by NMR, IR, mass and elemental analysis. Structural characterization of the ligand 2a was done by X-ray crystallography. The ligands and complexes were tested for their cytotoxic activity on different cell lines like A549 (human alveolar adenocarcinoma cells), Neuro2a (mouse neuroblastoma cells), HeLa (cervical carcinoma cancer cells), MDA-MB-231 (human breast adenocarcinoma cells) and MCF7 (human breast adenocarcinoma cells). The complexes showed considerable cytotoxicity while the ligands were non-toxic on the tested cell lines. Pyridyl-carbohydrate triazole ligands were prepared by means of Cu(II) catalysed 1,3-dipolar cycloaddition reaction. Palladium (II) complexes were prepared by treating these ligands with [Pd(COD)Cl2]. The ligands and their palladium complexes were studied for their cytotoxic activity.

Synthesis and cytotoxicity evaluation of highly functionalized pyranochromenes and pyranopyrans

A series of fluorinated tetrahydropyrano[3,2-c]chromenes and dihydropyrano[3,2-b]pyran derivatives have been synthesized and their in vitro cytotoxic activities have been determined in cervical cancer cell line (HeLa), human breast adenocarcinoma cell line (MDA-MB-231 and MCF-7) and human alveolar adenocarcinoma cell line (A549). Compounds 4g, 4k, 4p showed a very potent activity against MDA-MB-231, and 4c, 4p showed promising activity against MCF-7, while compounds 4c, 4g, 4p showed moderate activity against HeLa.

Heterogeneous virulence of pandemic 2009 influenza H1N1 virus in mice

BackgroundUnderstanding the pathogenesis of influenza infection is a key factor leading to the prevention and control of future outbreaks. Pandemic 2009 Influenza H1N1 infection, although frequently mild, led to a severe and fatal form of disease in certain cases that make its virulence nature debatable. Much effort has been made toward explaining the determinants of disease severity; however, no absolute reason has been established.ResultsThis study presents the heterogeneous virulence of clinically similar strains of pandemic 2009 influenza virus in human alveolar adenocarcinoma cells and mice. The viruses were obtained from patients who were admitted in a local hospital in China with a similar course of infection and recovered. The A/Nanchang/8002/2009 and A/Nanchang/8011/2009 viruses showed efficient replication and high lethality in mice while infection with A/Nanchang/8008/2009 was not lethal with impaired viral replication, minimal pathology and modest proinflammatory activity in lungs. Sequence analysis displayed prominent differences between polymerase subunits (PB2 and PA) of viral genomes that might correlate with their different phenotypic behavior.ConclusionsThe study confirms that biological heterogeneity, linked with the extent of viral replication, exists among pandemic H1N1 strains that may serve as a benchmark for future investigations on influenza pathogenesis.

Synthesis, Crystal Structure, Electronic Spectroscopy, Electrochemistry and Biological Studies of Ferrocene–Carbohydrate Conjugates

AbstractA series of six new ferrocene–carbohydrate conjugates was prepared from pentose and hexose sugar derivatives. These include the ferrocenecarbaldehyde acetal 2, four ferrocenyltriazoles 4a–d derived from furanose sugar and the ferrocenyltriazole 4e derived from a pyranose sugar. The compounds were characterised by spectroscopic means and the structures of the new conjugates 2 and 4a were determined by means of X‐ray crystallography. A UV/Vis study of these compounds performed in aqueous solutions under physiological conditions confirmed their stability. The CD spectral analysis shows the effect of the nature of substituents of the carbohydrate moieties. The electrochemical studies conducted in a buffer solution display one‐electron reversible oxidation processes for these compounds. These results indicate that the compounds are suitable for conducting biological studies. The cytotoxicity and antimicrobial activity of these conjugates were investigated on different cancer cell lines and microbes, respectively. These compounds exhibit moderate to good cytotoxicity towards cell lines like A549 (human alveolar adenocarcinoma cells), Neuro2a (mouse neuroblastoma cells), HeLa (cervical carcinoma cancer cells), MDA‐MB‐231 (human breast adenocarcinoma cells) and MCF‐7 (human breast adenocarcinoma cells). The compounds show antibacterial activity against both Gram‐positive and Gram‐negative pathogens. Compound 2 exhibits excellent inhibitory activity against E. coli with a MIC value of 4.8 μg mL–1. In addition, compounds 2 and 4a also exhibit antioxidant activity comparable to the standard antioxidant ascorbic acid.

Synthesis and antitumor activities of a new series of 4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives

A new series of 4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives have been designed and synthesized. The antitumor activities of the target compounds have been evaluated in vitro against two human cancer cell lines including A549 (human alveolar adenocarcinoma cell) and H460 (human lung cancer) by MTT assay. Most of the target compounds exhibited significant antitumor activities against A549 and H460 cancer cell lines. The most potent compound 4-(benzo[d][1,3]dioxol-5-yl)-8,9-difluoro-2-(4-methylpiperazin-1-yl)-4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine (CH05) (IC50 = 0.44 μM, 3.07 μM) was 2.0 and 8.4 times more active than gefitinib (IC50 = 0.89 μM, 16.81 μM) against A549 and H460 cell lines, respectively.

ZnO nanorod-induced apoptosis in human alveolar adenocarcinoma cells via p53, survivin and bax/bcl-2 pathways: role of oxidative stress

Zinc oxide (ZnO) nanoparticles (NPs) are increasingly recognized for their utility in biological applications, including biosensor and medicine. However, little is known about the toxicity mechanisms of ZnO nanorods in human cells. This study was designed to investigate the possible mechanisms of apoptosis induced by ZnO nanorods in human alveolar adenocarcinoma (A549) cells. ZnO nanorod was found to induce cytotoxicity, reactive oxygen species (ROS) generation, oxidative stress and activities of caspase-3 & caspase-9 in a dose- and time-dependent manner. Western blot results showed that ZnO nanorods induced the expression of heat shock protein 70, a first-tier marker of cell damage and a cell-cycle checkpoint protein p53. Moreover, pro-apoptotic protein bax was upregulated and the antiapoptotic proteins, survivin and bcl-2, were downregulated in ZnO nanorod exposed cells. In conclusion, our data demonstrateas that ZnO nanorod induced apoptosis in A549 cells through ROS and oxidative stress via p53, survivin, bax/bcl-2 and caspase pathways. From the Clinical EditorThis study describes the mechanisms of apoptosis induced by ZnO nanorods in human alveolar adenocarcinoma cells.