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Calendula officinalis is known as a popular plant with various uses as pharmaceutical agent or food additive around the world. In this study, cooper nanoparticles were green synthesized using the aqueous extract of Calendula officinalis as the stabilizing, reducing, and capping agents. The formation of CuNPs@C. officinalis was screened using different chemical technique such as FT-IR spectroscopy, XRD, SEM, and Energy EDS. The antioxidant and anti-cancer activity of CuNPs@C. officinalis was studied using common assay including free radical scavenging and MTT assays. The results confirm the green synthesized of CuNPs@C. officinalis with aspherical morphology in the range size of 19.64 to 39.15 nm. In the antioxidant test, the IC50 of CuNPs@C. officinalis and BHT against DPPH free radicals were 193 and 154 µg/mL, respectively. In the cellular and molecular part of the recent study, the treated cells with CuNPs@C. officinalis were assessed by MTT assay for 24, 48, and 72 h about the cytotoxicity and anti-human lung adenocarcinoma properties on normal (HUVEC) and lung adenocarcinoma cell lines, i.e. lung moderately differentiated adenocarcinoma (LC-2/ad), lung poorly differentiated adenocarcinoma (PC-14), and lung well-differentiated bronchogenic adenocarcinoma (HLC-1). The IC50s of CuNPs@C. officinalis were 297, 328, and 514 µg/mL against PC-14, LC-2/ad, and HLC-1 cell lines, respectively. The viability of malignant lung cell line reduced dose-dependently in the presence of CuNPs@C. officinalis. It seems that the anti-human lung adenocarcinoma effect of recent nanoparticles is due to their antioxidant effects.

Abstract Background The introduction of functional in-silico models, in addition to in-vivo tumor models, opens up new and unlimited possibilities in cancer research and drug development. The world's first digital twin of the A549 cell's electrophysiology in the human lung adenocarcinoma, unveiled in 2021, enables the investigation and evaluation of new research hypotheses about modulating the function of ion channels in the cell membrane, which are important for better understanding cancer development and progression, as well as for developing new drugs and predicting treatments. Main body The developed A549 in-silico model allows virtual simulations of the cell’s rhythmic oscillation of the membrane potential, which can trigger the transition between cell cycle phases. It is able to predict the promotion or interruption of cell cycle progression provoked by targeted activation and inactivation of ion channels, resulting in abnormal hyper- or depolarization of the membrane potential, a potential key signal for the known cancer hallmarks. For example, model simulations of blockade of transient receptor potential cation channels (TRPC6), which are highly expressed during S-G2/M transition, result in a strong hyperpolarization of the cell’s membrane potential that can suppress or bypass the depolarization required for the S-G2/M transition, allowing for possible cell cycle arrest and inhibition of mitosis. All simulated research hypotheses could be verified by experimental studies. Short conclusion Functional, non-phenomenological digital twins, ranging from single cells to cell–cell interactions to 3D tissue models, open new avenues for modern cancer research through "dry lab" approaches that optimally complement established in-vivo and in-vitro methods.

Calendula officinalis is known as a popular plant with various uses as pharmaceutical agent or food additive around the world. In this study, cooper nanoparticles were green synthesized using the aqueous extract of Calendula officinalis as the stabilizing, reducing, and capping agents. The formation of CuNPs@C. officinalis was screened using different chemical technique such as FT-IR spectroscopy, XRD, SEM, and Energy EDS. The antioxidant and anti-cancer activity of CuNPs@C. officinalis was studied using common assay including free radical scavenging and MTT assays. The results confirm the green synthesized of CuNPs@C. officinalis with aspherical morphology in the range size of 19.64 to 39.15 nm. In the antioxidant test, the IC50 of CuNPs@C. officinalis and BHT against DPPH free radicals were 193 and 154 µg/mL, respectively. In the cellular and molecular part of the recent study, the treated cells with CuNPs@C. officinalis were assessed by MTT assay for 24, 48, and 72 h about the cytotoxicity and anti-human lung adenocarcinoma properties on normal (HUVEC) and lung adenocarcinoma cell lines, i.e. lung moderately differentiated adenocarcinoma (LC-2/ad), lung poorly differentiated adenocarcinoma (PC-14), and lung well-differentiated bronchogenic adenocarcinoma (HLC-1). The IC50s of CuNPs@C. officinalis were 297, 328, and 514 µg/mL against PC-14, LC-2/ad, and HLC-1 cell lines, respectively. The viability of malignant lung cell line reduced dose-dependently in the presence of CuNPs@C. officinalis. It seems that the anti-human lung adenocarcinoma effect of recent nanoparticles is due to their antioxidant effects. [ABSTRACT FROM AUTHOR]

Background: The introduction of functional in-silico models, in addition to in-vivo tumor models, opens up new and unlimited possibilities in cancer research and drug development. The world's first digital twin of the A549 cell's electrophysiology in the human lung adenocarcinoma, unveiled in 2021, enables the investigation and evaluation of new research hypotheses about modulating the function of ion channels in the cell membrane, which are important for better understanding cancer development and progression, as well as for developing new drugs and predicting treatments. Main body: The developed A549 in-silico model allows virtual simulations of the cell’s rhythmic oscillation of the membrane potential, which can trigger the transition between cell cycle phases. It is able to predict the promotion or interruption of cell cycle progression provoked by targeted activation and inactivation of ion channels, resulting in abnormal hyper- or depolarization of the membrane potential, a potential key signal for the known cancer hallmarks. For example, model simulations of blockade of transient receptor potential cation channels (TRPC6), which are highly expressed during S-G2/M transition, result in a strong hyperpolarization of the cell’s membrane potential that can suppress or bypass the depolarization required for the S-G2/M transition, allowing for possible cell cycle arrest and inhibition of mitosis. All simulated research hypotheses could be verified by experimental studies. Short conclusion: Functional, non-phenomenological digital twins, ranging from single cells to cell–cell interactions to 3D tissue models, open new avenues for modern cancer research through "dry lab" approaches that optimally complement established in-vivo and in-vitro methods. [ABSTRACT FROM AUTHOR]

A unique starch encapsulated Cu2O nanoparticles were synthesized through a simple and ‘green’ route using ultrasonic irradiation. The polar functional groups on the starch (OH) facilitate the NP capping and stabilization. Structural features of the material were assessed over several advanced techniques like fourier transformed infra-red (FT-IR), UV–vis spectroscopy, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), energy dispersive X-ray analysis (EDX) elemental mapping, transmission electron microscopy (TEM), X-ray diffraction analysis (XRD), and inductively coupled plasma-atomic emission spectrometry (ICP-AES) analysis. It was catalytically explored in reducing an organic dye (Methylene blue - MB) in the presence of NaBH4 at ambient conditions, being monitored in a UV–vis spectrophotometer. The nanocatalyst was recycled 11 times keeping consistency in its reactivity. Biologically, the nanocomposite exhibited excellent cytotoxicity against lung adenocarcinoma (PC-14, LC-2/ad and HLC-1) cell lines without affecting the normal (HUVEC) cell line. IC50values of the nanocomposite were found at 618, 56 and 379 against HLC-1, LC-2/ad, and PC-14 cell lines respectively and accordingly, PC-14 afforded the best adenocarcinoma activity.

The characteristics that grant the most malignancy to cancer cells are the ability to evade apoptotic mechanisms and the capacity to migrate beyond the boundaries of the original tissue. Studies by our own group and others show that changes in glycosylation are now considered hallmarks of cancer cells and are also able to impact tumor malignancy. This study aims to evaluate changes in the glycosylation profile of the A549 lung cancer cells brought about by the induction of a MDR phenotype as well as investigate the relationship between drug resistance, the cell glycophenotype and EMT. We induced resistance by employing a continuous treatment with cisplatin. Our results demonstrate overexpression of ABC transporters as well as anti-apoptotic members of the Bcl-2 family, leading to a MDR phenotype. The cells also undergo a classic EMT process, displaying the iconic cadherin switch and increased of both total and oncofetal fibronectin, coupled with increased cell motility. We also managed to show changes in the expression of both glycosyltransferases and the glycan epitopes they are responsible for building. We also suggest that perhaps not only changes in cell sialylation are common during resistance induction but are essential to it. [ABSTRACT FROM AUTHOR]

Objectives: The present study was aimed to synthesize Silver nanoparticles (Ag NPs) from ethanol extract of Allium sativum to evaluate the in-vitro cytotoxicity effect on human lung adenocarcinoma cells (A549). Methods: Spetroscopic analysis were performed to determine the formation, stability, nature and the functional groups of the Ag NPs. Microscopic analysis were performed to ascertain the morphology and size of the particles. In-vitro MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay was performed to determine the cytotoxic potential of the Ag NPs on A549 lung cancer cell lines. Results: The UV–Visble spectrum confirmed the formation of the particles. Fourier Transform Infrared (FTIR) spectrum revealed the presence of carbonyl, carboxyl, primary and secondary amine groups. Powder X-ray diffraction (PXRD) established the crystalline nature and FCC structure of Ag NPs. Morphological analysis performed using Field Emission-Scanning Electron Microscopy (FESEM), High-Resolution Transmission Electron Microscopy (HRTEM), Selected Area Electron Diffraction (SAED) pattern showed spherical and rod shaped bio synthesized Ag NPs with variable size ranging from 20 nm to 40 nm. The synthesized Ag NPs showed a significant cytotoxic potential against A549 human lung cancer cells at an IC50 of 22 μg/ml. Conclusion: The present study revealed a cost-effective, simple and effective method to synthesize Ag NPs using garlic extract and the cytotoxic activity on human adenocarcinoma cells (A549) demonstrated their future application as potential anti-cancer agent.

The present study deals with Plectranthus amboinicus (Lour.), multiple potential herbs perceived as a medicinal and culinary adjunct has been used to fabricate gold (Au) nanoparticles (NPs) in an eco-benign fashion. We have primly reported the antioxidant and anticarcinogenic effects of phytofabricated Au NPs towards lung adenocarcinoma (LAC) cells (A549 cell line) in vitro. The herbal concentrate, size and dosage of Au NPs were the key variables that determined the anticarcinogenic efficacy. Results indicated that the herbal concentrate encompassing flavonoids, alkaloids and polyphenolics aided reduction and stabilisation of Au NPs supported by spectral (λmax @ 550 nm) and quantitative analyses. The Fourier transform-infrared spectra anticipated distinct phenolics and protein frequencies involved in Au NPs capping in the course of fabrication. The manipulated Au NPs of 15 nm size has significantly influenced the radical scavenging (48.1 μg) and proliferation pattern of LAC cells (A549) associated with cytotoxic characteristics and IC50 (Au NPs concentration linked with 50% mortality) defined at 16.3 μg/mL in 48 h. This nanotoxicological prospect on the use of nanomaterials as an anticancer agent would be an alternative for the emerging intrinsic resistance of cells to the drug; a great challenge pertaining to safer environmental and biological outcomes.

In current nanoscience bioengineered magnetic nanoparticles (NPs) have come into prominence with considerable impact. These advanced functional materials find outstanding applications in chemical science in catalysis, environmental issues, sensing etc, as well as in biology as drug delivery agent, chemical therapeutics and others. We have been prompted to architect and synthesize a novel Au NP adorned over chitosan-biguanidine polyplex modified core–shell type magnetic nanocomposite (Fe3O4/CS-biguanidine/Au NPs). The bioshells facilitate to protect the core ferrite NPs as well as provides stability to the synthesized Au NPs by capping. The material was characterized using different analytical techniques like Fourier Transformed Infra-Red spectroscopy (FT-IR), Inductively Coupled Plasma-Optical Emission Microscopy (ICP-OES), Field Emission Scanning Electron Microscopy (FE-SEM), Energy Dispersive X-ray spectroscopy (EDX), Transmission Electron Microscopy (TEM), Vibrating Sample Magnetometer (VSM) and X-ray Diffraction (XRD) studies. We explored the biological application of the nanocomposite in determining cytotoxicity of three adenocarcinoma cell lines (PC-14, LC-2/ad, HLC-1) through the MTT assay. The material showed very good activity by exhibiting very low % cell viability over the cell lines dose-dependently. The IC50 of Fe3O4/CS-biguanidine/Au NPs were observed 503, 398 and 475 µg/mL respectively against the three cell lines. The best output was observed at a concentration of 1000 µg/mL of catalyst in terms of cytotoxicity and inhibition of lung cancer growth. The anti-cancer potential was found in close relation to their antioxidant potential.

Pengbo Deng, Chengping Hu, Zeng Xiong, Yuanyuan Li, Juan Jiang, Huaping Yang, Yongjun Tang, Liming Cao, Rongli Lu Department of Respiratory Medicine, Key Site of National Clinical Research Center for Respiratory Diseases, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China Purpose: Large-scale studies have revealed that appropriate antiangiogenic treatment enables the recovery of the normal structure and function of solid tumor vessels. Epigallocatechin-3-gallate (EGCG), a natural extract of green tea, has multiple effects on angiogenesis. However, normalization of blood vessels due to natural ingredients has not yet been reported. Therefore, we examined the microvasculature, microenvironment, and efficacy of EGCG combined with chemotherapy in a xenograft model. Methods: We treated A549 cell (human lung adenocarcinoma cell line) xenograft-bearing nude mice with EGCG in vivo. CD31, αSMA, and collagen IV were labeled and detected using quantum-dot double-labeled immunofluorescence to measure microvessel density, microvessel pericyte-coverage index, and collagen IV expression. Vessel-perfusion function was determined by lectin injection, permeability by Evans blue extravasation, interstitial fluid pressure using the wick-in-needle technique, and hypoxia levels using a polarographic electrode and immunohistochemical pimonidazole labeling. Cisplatin concentration in tumor tissue was detected using graphite-furnace atomic absorption spectrophotometry. Xenograft mice were randomized into five groups: treated with saline, cisplatin, EGCG, EGCG + cisplatin on day 1, or EGCG + cisplatin during the vascular normalization window. Tumor-growth delay and tumor-suppression rate were measured to evaluate tumor growth. Results: EGCG treatment in vivo caused temporary changes, including transient depression of microvessel density, microvessel pericyte-coverage index, and collagen IV expression, transient elevation of vessel perfusion and permeability, and decreased interstitial fluid pressure and hypoxia. During vascular normalization, pretreatment with EGCG increased cisplatin concentration in tumor tissue compared with treatment with cisplatin only. Tumor-growth delay after treatment in the five groups during the vascular normalization window was 6.3±1.51, 7.5±1.57, 8.3±1.79, 12.1±1.35, and 15.4±1.99 days, indicating synergistic EGCG–cisplatin effects, especially during the vascular normalization window (P

Chronic inflammation is a deleterious process occurring in several pulmonary diseases; it is a driving force promoting tumorigenesis. By regulating local cyclic nucleotide concentration, cyclic nucleotide phosphodiesterases (PDE) govern important biological processes, including inflammation and proliferation. The aim of this study was to investigate the anti-inflammatory and anti-proliferative effects of NCS 613, a specific PDE4 inhibitor, on TNFα-treated human lung adenocarcinoma cell line (A549) and on human lung adenocarcinoma explants. PDE4 isoforms and inflammatory pathways mediated by p38 MAPK, ERK1/2, and IκBα were analyzed by Western blot and immunostainings. Proliferation were performed using [3H]-thymidine incorporation under different experimental conditions. TNFα-stimulation increased p38 MAPK phosphorylation and NF-κB translocation into the nucleus, which was abolished by NCS 613 treatment. Concomitantly, NCS 613 restores IκBα detection level in human adenocarcinoma. An IC50 value of 8.5 μM was determined for NCS 613 on anti-proliferative properties while ERK1/2 signaling was down-regulated in A549 cells and lung adenocarcinoma explants. These findings shed light on PDE4 signaling as a key regulator of chronic inflammation and cancer epithelial cell proliferation. It suggests that PDE4 inhibition by NCS 613 represent potential and interesting strategy for therapeutic intervention in tackling chronic inflammation and cell proliferation.

Background and objective Tumor recurrence and drug resistance are the main causes of death in tumor patients. The family of acetaldehyde dehydrogenase (ALDH) is closely related to the proliferation, migration, invasion and resistance of tumor cells, and different ALDH subtypes are expressed in different tumor cells. The aim of this study is to elucidate the ALDH subtype in human lung adenocarcinoma HCC-827/GR cells, which resistant to the gefitinib. Methods The human lung adenocarcinoma HCC-827 cells were used to generate the gefitinib-resistant HCC-827/GR cells; the expression of ALDH subtype in either HCC-827 or HCC-827/GR was detected by flow cytometry; The proliferative capacity and sensitivity to gefitinib of hcc-827/GR cells were analyzed by MTT assay before and after treatment with 100 μmol/L diethyllaminaldehyde (DEAB); Real-time quantitative PCR was used to detect the expression of ALDH subtypes at mRNA levels in hcc-827 cells and hcc-827/GR cells. Results Compared with HCC-827 cells, the positive rate of ALDH in HCC-827/GR cells increased. The proliferation ability of HCC-827/GR cells decreased after treatment with 100 μmol/L DEAB. Compared with HCC-827 cells, the expression of ALDH1A1 and ALDH1L1 mRNA was increased in hcc-827/GR cells, but the ALDH3B2 expression was decreased. Conclusion ALDH might be used as a molecular biomarker to test the gefitinib-resistant to lung adenocarcinoma cancer cells, and the ALDH1A1 may play a role in gefitinib resistance in lung cancer.

The present study deals with Plectranthus amboinicus (Lour.), multiple potential herbs perceived as a medicinal and culinary adjunct has been used to fabricate gold (Au) nanoparticles (NPs) in an eco-benign fashion. We have primly reported the antioxidant and anticarcinogenic effects of phytofabricated Au NPs towards lung adenocarcinoma (LAC) cells (A549 cell line) in vitro. The herbal concentrate, size and dosage of Au NPs were the key variables that determined the anticarcinogenic efficacy. Results indicated that the herbal concentrate encompassing flavonoids, alkaloids and polyphenolics aided reduction and stabilisation of Au NPs supported by spectral (λmax @ 550 nm) and quantitative analyses. The Fourier transform-infrared spectra anticipated distinct phenolics and protein frequencies involved in Au NPs capping in the course of fabrication. The manipulated Au NPs of 15 nm size has significantly influenced the radical scavenging (48.1 μg) and proliferation pattern of LAC cells (A549) associated with cytotoxic characteristics and IC50 (Au NPs concentration linked with 50% mortality) defined at 16.3 μg/mL in 48 h. This nanotoxicological prospect on the use of nanomaterials as an anticancer agent would be an alternative for the emerging intrinsic resistance of cells to the drug; a great challenge pertaining to safer environmental and biological outcomes. [ABSTRACT FROM AUTHOR]

Tn antigen is a tumor-associated antigen that appears on cancer cells as a result of aberrant O-glycosylation. The most studied form of Tn antigen is found in mucins, in particular, in mucin 1 (MUC1). Antibodies against this form of Tn antigen are used to diagnose tumors, as well as to generate T-killers with a chimeric receptor. Some carcinomas do not carry MUC1 and antibodies of a different specificity are required to detect Tn antigen on these cells. In our work, we searched for anti-Tn antibodies without preliminary assumptions about the proteins that may be carriers of the Tn antigen. For this purpose, we obtained several pairs of isogenic cell lines with the wild type and knockout of the Cosmc gene, which is essential for correct protein O-glycosylation. Using the created lines as immunogens, we generated a monoclonal antibody AKC3, which reacted with the Cosmc-deficient A549 lung adenocarcinoma cells and did not bind to the wild-type cells. Using mass spectrometry, as well as co-immunoprecipitation, it was shown that the AKC3 antibody recognized the Tn antigen in the context of CD44 protein – a protein important for tumor growth. The AKC3 antibody can be used for tumor diagnosis, and to generate T cells with a chimeric receptor for treatment of tumors that do not express mucins. [ABSTRACT FROM AUTHOR]

Background: Clerodendrum inerme is a folk medicinal plant used in the treatment of various illnesses such as a cough, scrofulous infection, venereal infection, skin diseases and tumors. It exhibited many pharmacological effects including hepatoprotective, anti-inflammatory, anti- bacterial, anti-oxidant and anticancer properties. Objective: The purpose of this study was to investigate the influence of methanolic extract of C. inerme leaves on migration, invasion and adhesion activities on human lung adenocarcinoma. Materials and methods: Cytotoxicity, cell motility, migration, invasion and adhesion abilities were detected by MTT, wound healing, trans-well mobilization, modified Boyden chamber and cell adhesion assay, respectively. Results: The results demonstrated that up to 400 µg/mL methanolic leaves extract has low toxicity on A549 cells showing more than 50% cell viability. At non-cytotoxic and sub-toxic doses (200 and 400 µg/mL) of methanolic leave extract significantly suppressed cell motility, migration, invasion and cell adhesion compared with the untreated control. Conclusion: These results suggested that methanolic leaves extract of C. inerme inhibited migration, invasion and adhesion of A549 cells. These findings showed new therapeutic potential for C. inerme in anti-metastatic therapy. [ABSTRACT FROM AUTHOR]

Chronic inflammation is a deleterious process occurring in several pulmonary diseases; it is a driving force promoting tumorigenesis. By regulating local cyclic nucleotide concentration, cyclic nucleotide phosphodiesterases (PDE) govern important biological processes, including inflammation and proliferation. The aim of this study was to investigate the anti-inflammatory and anti-proliferative effects of NCS 613, a specific PDE4 inhibitor, on TNFα-treated human lung adenocarcinoma cell line (A549) and on human lung adenocarcinoma explants. PDE4 isoforms and inflammatory pathways mediated by p38 MAPK, ERK1/2, and IκBα were analyzed by Western blot and immunostainings. Proliferation were performed using [3H]-thymidine incorporation under different experimental conditions. TNFα-stimulation increased p38 MAPK phosphorylation and NF-κB translocation into the nucleus, which was abolished by NCS 613 treatment. Concomitantly, NCS 613 restores IκBα detection level in human adenocarcinoma. An IC50 value of 8.5 μM was determined for NCS 613 on anti-proliferative properties while ERK1/2 signaling was down-regulated in A549 cells and lung adenocarcinoma explants. These findings shed light on PDE4 signaling as a key regulator of chronic inflammation and cancer epithelial cell proliferation. It suggests that PDE4 inhibition by NCS 613 represent potential and interesting strategy for therapeutic intervention in tackling chronic inflammation and cell proliferation. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma is the most common respiratory system tumor seen globally. Most tumors face challenges like multidrug resistance and low selectivity, thus alternative therapeutic strategies and approaches are needed. Increasing evidence from preclinical and clinical studies suggests that phytochemicals can inhibit cancer development and progression. We used Citrullus Colocynthis oil extraction, as phytochemical therapy, to inhibit cell proliferation, invasion, and enhanced cell death. The study included analyzing the extracted oil by GC-mass and assessing cell viability utilizing MTT, apoptotic, and wound healing assay. The human lung adenocarcinoma A549 cancer cell line and human breast epithelial HBL-100 normal cell line were treated with oil. The results demonstrated a significant cytotoxic effect of oil against cancer cells, the effect is accompanied by apoptotic migration arrest, with adverse no effect on normal cells. Our findings suggest that phytotherapy suppresses cancer cells and provides new insight into developing therapeutic strategies for cancer in the near future. [ABSTRACT FROM AUTHOR]

Copy number alterations (CNAs) of lincRNAs act as one of important mechanisms in disrupting lincRNA expression which may play critical roles during tumorigenesis in lung adenocarcinoma (LUAD). The copy number alterations of lincRNAs can mark the spectrum of cancer progression and may serve as biomarkers for prognosis in LUAD, however it is rarely studied. We analyzed RNASeq data for 488 LUAD patients from TCGA portal and 58 healthy subjects to identify prognostic lincRNAs predictive of patient survival. Computational analysis entailing integration of expression and copy number alteration data revealed five prognostic lincRNAs: RBPMS‐AS1, TDRKH‐AS1, LINC00578, RP11‐470 M17.2 and LINC00941. The copy number alterations in the LINC00578 and RP11‐470 M17.2 genes were positively associated with the longer overall survival of LUAD patients. The CNA in LINC00941 was negatively associated with the longer overall survival. Copy number amplification significantly correlated with increased expression of TDRKH‐AS1, which regulates telomere organization and EZH2‐mediated epigenetic silencing of CDKN1A, CDKN1B and IL24. Decreased survival of LUAD patients was associated with high LINC00941 expression. The LINC00941 regulates the PI3K‐AKT signaling pathway, focal adhesion by influencing potential targets, such as KRAS proto‐oncogene GTPase and VEGFC. These lincRNA‐based prognostic biomarkers may destroy important cancer‐related biological processes contributing to LUAD prognosis. In summary, we demonstrate the prognostic potential of four differentially expressed lincRNAs with copy number alterations (RBPMS‐AS1, TDRKH‐AS1, LINC00578 and RP11‐470 M17.2) that are positively associated with longer overall survival of LUAD patients. One differentially expressed lincRNA LINC00941 with copy number alterations was negatively associated with longer overall survival of LUAD patients. What's new? Changes in gene copy number are among the most frequent genetic anomalies occurring in human cancers. The relevance of copy number alterations (CNAs) that occur in noncoding regions, however, remains unclear. Here, investigation of CNAs in long intergenic noncoding RNAs (lincRNAs) in lung adenocarcinoma patients led to the identification of five prognostic lincRNAs. Elevated expression of one of the genes, LINC00941, which regulates PI3K‐AKT signaling and focal adhesion, was negatively associated with lung adenocarcinoma survival. The other four lincRNAs were positively associated with lengthened overall survival. The lincRNA TDRKH‐AS1 contributed to prognosis via regulation of mitochondrial activity and telomere organization. [ABSTRACT FROM AUTHOR]

Mahonia aquifolium and its secondary metabolites have been shown to have anticancer potential. We performed MTT, scratch, and colony formation assays; analyzed cell cycle phase distribution and doxorubicin uptake and retention with flow cytometry; and detected alterations in the expression of genes involved in the formation of cell–cell interactions and migration using quantitative real-time PCR following treatment of lung adenocarcinoma cells with doxorubicin, M. aquifolium extracts, or their combination. MTT assay results suggested strong synergistic effects of the combined treatments, and their application led to an increase in cell numbers in the subG1 phase of the cell cycle. Both extracts were shown to prolong doxorubicin retention time in cancer cells, while the application of doxorubicin/extract combination led to a decrease in MMP9 expression. Furthermore, cells treated with doxorubicin/extract combinations were shown to have lower migratory and colony formation potentials than untreated cells or cells treated with doxorubicin alone. The obtained results suggest that nontoxic M. aquifolium extracts can enhance the activity of doxorubicin, thus potentially allowing the application of lower doxorubicin doses in vivo, which may decrease its toxic effects in normal tissues.

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Long noncoding RNAs (lncRNAs) have been identified as oncogenes or tumor suppressors that are involved in tumorigenesis and chemoresistance. LncRNA XIST expression is upregulated in several cancers, however, its biologic role in the development of the chemotherapy of human lung adenocarcinoma (LAD) has not been elucidated. This study aimed to observe the expression of LncRNA XIST in LAD and to evaluate its biologic role and clinical significance in the resistance of LAD cells to cisplatin. LncRNA XIST expression was markedly increased in cisplatin-resistant A549/DDP cells compared with parental A549 cells as shown by qRT-PCR. LncRNA XIST overexpression in A549 cells increased their chemosensitivity to cisplatin bothin vitroandin vivoby protecting cells from apoptosis and promoting cell proliferation. By contrast, LncRNA XIST knockdown in A549/DDP cells decreased the chemoresistance. We revealed that XIST functioned as competing endogenous RNA to repress let-7i, which controlled its down-stream target BAG-1. We proposed that XIST was responsible for cisplatin resistance of LAD cells and XIST exerted its function through the let-7i/BAG-1 axis. Our findings suggested that lncRNA XIST may be a new marker of poor response to cisplatin and could be a potential therapeutic target for LAD chemotherapy. [ABSTRACT FROM PUBLISHER]

Increasing evidence indicates that inflammatory microenvironment facilitates tumor metastasis. Here, we found that LFG-500, a novel synthetic flavonoid, significantly inhibited epithelial–mesenchymal transition (EMT) in human lung adenocarcinoma A549 and H1299 cells co-cultured with LPS-challenged THP-1 cells or cultured in THP-1 cell-derived conditioned medium. Moreover, we found that TNF-α is a direct and decisive factor for promoting EMT and LFG-500 suppressed TNF-α-induced EMT and cell motility. NLRP3 knockdown inactivated NLRP3 inflammasome, which subsequently inhibited EMT and blocked cell migration, indicating that TNF-α-induced EMT requires the NLRP3 inflammasome. LFG-500 inhibited the activation of the NLRP3 inflammasome, thus inhibiting EMT. Moreover, LFG-500 treatment significantly inhibited metastasis in vivo by downregulating NLRP3 expression. Importantly, we found that NLRP3 was highly expressed in high-grade lung adenocarcinoma and that its expression was correlated with lymph node metastasis. NLRP3 and vimentin levels were significantly increased in matched metastatic lymph nodes. Moreover, a significant positive correlation was observed between their levels. Together, these results suggest that LFG-500 markedly suppresses EMT by inhibiting the NLRP3 inflammasome in the inflammatory microenvironment and that NLRP3 is a potential biomarker of lung adenocarcinoma metastasis. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of dihydroartemisinin(DHA)on apoptosis and proliferation of human lung adenocarcinoma cell line A549. Methods Human lung adenocarcinoma A549 cell line in logarithmic growth phase were randomly divided into experimental group and control group. DHA with concentration of 500 nmol/L was added into cell culture in experimental group, and dimethyl sulfoxide was added in control group. Both groups were cultured for 72 h. The cell proliferation was detected by using tetramethylazozolium salt method, the activity of Caspase3 was detected by using kits, and the levels of Bcl-2, Bax and Akt protein were detected by using western blot method. Results The cell proliferation inhibition rate and Caspase3 activity in experimental group were significantly higher than control group(P<0.05). The levels of Bcl-2 and Akt protein in experimental group were significantly lower than control group(P<0.05), but level of Bax protein was significantly higher than control group(P<0.05). Conclusion DHA could inhibit the proliferation of human lung adenocarcinoma cell line A549 and promote apoptosis of A549 cells through P13 K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Sesamol is a phenolic lignan found in sesame seeds ( Sesamum indicum L.) and sesame oil. The anticancer effects and molecular mechanisms underlying its apoptosis-inducing effect were investigated in human lung adenocarcinoma (SK-LU-1) cells. Sesamol inhibited SK-LU-1 cell growth with an IC 50 value of 2.7 mM and exhibited less toxicity toward normal Vero cells after 48 h of treatment (Selective index = 3). Apoptotic bodies—the hallmark of apoptosis—were observed in sesamol-treated SK-LU-1 cells, stained with DAPI. Sesamol increased the activity of caspase 8, 9, and 3/7, indicating that apoptotic cell death occurred through both extrinsic and intrinsic pathways. Sesamol caused the loss of mitochondrial transmembrane potential signifying intrinsic apoptosis induction. Decreasing Bid expression revealed crosstalk between the intrinsic and extrinsic apoptotic pathways; demonstrating clearly that sesamol induces apoptosis through both pathways in human lung adenocarcinoma (SK-LU-1) cells. [ABSTRACT FROM AUTHOR]

Despite the increasing lung cancer-associated death rate, its therapy has been constrained by impasse of early diagnosis. To apply non-invasive imaging for potential cancer diagnosis system, we screened human lung adenocarcinoma-specific peptides using the phage display technique. For in vivo phage-displayed peptide screening, M13 phage library displaying 2.9 × 10 random peptides was injected through tail vein to lung adenocarcinoma cell-derived xenograft mouse model. Through four rounds of biopanning, a specific peptide sequence (CAKATCPAC) was screened out with the highest frequency and was named as Pep-1, and it was analyzed for its targeting ability as an imaging probe by in vitro competitive assay to test its cell-binding ability, immunohistochemical detection in the tumor tissue, and in vivo NIR fluorescent optical imaging. The specificity of Pep-1 toward lung cancer was ensured by in vivo imaging using xenograft animals of various cancer types. The results suggest that Pep-1 is a promising diagnostic lead molecule for rapid and accurate detection of human lung adenocarcinoma. In addition, it was found that the targeting ability was much enhanced by ionizing radiation in both cell-derived and patient-derived lung adenocarcinoma xenografts, suggesting the possibility of applying Pep-1 for prognostic diagnosis after radiotherapy. Taken together, this study suggests that Pep-1 possesses a specific-targeting ability for human lung adenocarcinoma and that this peptide could be directly used as a clinically applicable imaging probe. [ABSTRACT FROM AUTHOR]

A unique starch encapsulated Cu 2 O nanoparticles were synthesized through a simple and 'green' route using ultrasonic irradiation. The polar functional groups on the starch (OH) facilitate the NP capping and stabilization. Structural features of the material were assessed over several advanced techniques like fourier transformed infra-red (FT-IR), UV–vis spectroscopy, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), energy dispersive X-ray analysis (EDX) elemental mapping, transmission electron microscopy (TEM), X-ray diffraction analysis (XRD), and inductively coupled plasma-atomic emission spectrometry (ICP-AES) analysis. It was catalytically explored in reducing an organic dye (Methylene blue - MB) in the presence of NaBH 4 at ambient conditions, being monitored in a UV–vis spectrophotometer. The nanocatalyst was recycled 11 times keeping consistency in its reactivity. Biologically, the nanocomposite exhibited excellent cytotoxicity against lung adenocarcinoma (PC-14, LC-2/ad and HLC-1) cell lines without affecting the normal (HUVEC) cell line. IC 50 values of the nanocomposite were found at 618, 56 and 379 against HLC-1, LC-2/ad, and PC-14 cell lines respectively and accordingly, PC-14 afforded the best adenocarcinoma activity. [ABSTRACT FROM AUTHOR]

T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) has been shown to play an important role in mediating NK-cell function in human diseases. However, the relationship between Tim-3 expression in natural killer (NK) cells and human lung adenocarcinoma remains unclear. We therefore investigated the expression of Tim-3 in NK cells and explored the effect of Tim-3 blockade on NK cell-mediated activity in human lung adenocarcinoma. Upregulated expression of Tim-3 on CD3-CD56 + cells ( P < 0.05) and CD3-CD56 dim cells ( P < 0.05) of patients with lung adenocarcinoma was detected by flow cytometry. Moreover, Tim-3 expression in CD3-CD56 + NK cells was higher in patients with lung adenocarcinoma with lymph node metastasis (LNM) ( P < 0.05) or with tumor stage T3–T4 ( P < 0.05). Tim-3 expression in CD56 dim NK-cell subset was higher in patients with tumor size ≥ 3 cm ( P < 0.05), or LNM ( P < 0.05) or with tumor stage T3–T4 ( P < 0.05). Further analysis showed that higher expressions of Tim-3 on both CD3-CD56 + NK cells and CD56 dim NK-cell subset were independently correlated with shorter overall survival of patients with lung adenocarcinoma (log-rank test, P = 0.0418, 0.0406, respectively). Importantly, blockade of Tim-3 signaling with anti-Tim-3 antibodies resulted in the increased cytotoxicity and IFN-γ production of peripheral NK cells from patients with lung adenocarcinoma. Our data indicate that Tim-3 expression in NK cells can function as a prognostic biomarker in human lung adenocarcinoma and support that Tim-3 could be a new target for an immunotherapeutic strategy. [ABSTRACT FROM AUTHOR]

Melatonin is an indoleamine synthesized in the pineal gland that shows a wide range of physiological and pharmacological functions, including anticancer effects. In this study, we investigated the effect of melatonin on drug-induced cellular apoptosis against the cultured human lung adenocarcinoma cells and explored the role of histone deacetylase ( HDAC) signaling in this process. The results showed that melatonin treatment led to a dose- and time-dependent decrease in the viability of human A549 and PC9 lung adenocarcinoma cells. Additionally, melatonin exhibited potent anticancer activity in vitro, as evidenced by reductions of the cell adhesion, migration, and the intracellular glutathione ( GSH) level and increases in the apoptotic index, caspase 3 activity, and reactive oxygen species ( ROS) in A549 and PC9 cells. Melatonin treatment also influenced the expression of HDAC-related molecules ( HDAC1 and Ac-histone H3), upregulated the apoptosis-related molecules ( PUMA and Bax), and downregulated the proliferation-related molecule ( PCNA) and the anti-apoptosis-related molecule (Bcl2). Furthermore, the inhibition of HDAC signaling using HDAC1 si RNA or SAHA (a potent pan-inhibitor of HDACs) sensitized A549 and PC9 cells to the melatonin treatment. In summary, these data indicate that in vitro-administered melatonin is a potential suppressor of lung adenocarcinoma cells by the targeting of HDAC signaling and suggest that melatonin in combination with HDAC inhibitors may be a novel therapeutic intervention for human lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Crotoxin (CrTX) is a neurotoxin isolated from the venom of the South American rattlesnake. Previous studies demonstrated that CrTX was able to inhibit the activity of the growth factor receptor tyrosine kinase and that CrTX possesses potent antitumor activity when combined with Iressa, an epidermal growth factor receptor inhibitor. The aim of the present study was to determine the antitumor effect of CrTX and the combination of CrTX with Iressa in lung adenocarcinoma SPCA-1 cells. The results demonstrated that CrTX inhibited the cellular growth of SPCA-1 cells via G1 arrest and induction of apoptosis. In addition, the c-Jun N-terminal kinase pathway was important in CrTX-induced apoptosis in SPCA-1 cells. Notably, CrTX was able to significantly enhance the cytotoxic effects of Iressa in SPCA-1 cells. The in vivo antitumor assay demonstrated that treatment with either CrTX or Iressa significantly inhibited tumor growth, while the combination of CrTX and Iressa demonstrated the most significant antitumor activity, which was reflected by tumor weight and angiogenesis, presented as microvascular density. Therefore, the present study suggested that CrTX is a potential anti-lung cancer agent and sensitizer of Iressa. [ABSTRACT FROM AUTHOR]

The present study was aimed to synthesize Silver nanoparticles (Ag NPs) from ethanol extract of Allium sativum to evaluate the in-vitro cytotoxicity effect on human lung adenocarcinoma cells (A549). Spetroscopic analysis were performed to determine the formation, stability, nature and the functional groups of the Ag NPs. Microscopic analysis were performed to ascertain the morphology and size of the particles. In-vitro MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay was performed to determine the cytotoxic potential of the Ag NPs on A549 lung cancer cell lines. The UV–Visble spectrum confirmed the formation of the particles. Fourier Transform Infrared (FTIR) spectrum revealed the presence of carbonyl, carboxyl, primary and secondary amine groups. Powder X-ray diffraction (PXRD) established the crystalline nature and FCC structure of Ag NPs. Morphological analysis performed using Field Emission-Scanning Electron Microscopy (FESEM), High-Resolution Transmission Electron Microscopy (HRTEM), Selected Area Electron Diffraction (SAED) pattern showed spherical and rod shaped bio synthesized Ag NPs with variable size ranging from 20 nm to 40 nm. The synthesized Ag NPs showed a significant cytotoxic potential against A549 human lung cancer cells at an IC 50 of 22 μg/ml. The present study revealed a cost-effective, simple and effective method to synthesize Ag NPs using garlic extract and the cytotoxic activity on human adenocarcinoma cells (A549) demonstrated their future application as potential anti-cancer agent. [ABSTRACT FROM AUTHOR]

Abstract: Dietary polyphenols have been reported as an effective phytochemical for health protection and cinnamic acid (CA) is one of the polyphenols that has been demonstrated having chemopreventive potential. It was known that the early and distal metastasis might lead to the high mortality of patients with lung adenocarcinoma. We previously compared and verified the inhibitory effect of cis-CA and trans-CA on phorbol-12-myristate-13-acetate (PMA)-induced invasion of human lung adenocarcinoma A549 cells. The aim of this study was to explore the underlying molecular mechanism. By gelatin zymography and semi-quantitative RT-PCR, the activities and mRNA of MMP-9/MMP-2 exerted a significantly (p <.05) dose-dependent reduction by treating with cis-CA and trans-CA. Western blots further showed that the cis-CA- and trans-CA-inhibited MMPs might partly through modulating TIMP-1 and the PAI-2-regulated uPA activity. In molecular level, the AP-1 and NF-κB as well as the downstream of the MAPK pathway might be involved in cis-CA- and trans-CA-inhibited MMPs expression. This study disclosed the molecular mechanism underlying the anti-invasive activity of cis-CA and trans-CA and concluded the cis- and trans-form of CA should be a safe and potential agent to prevent lung tumor cells from metastasizing. [Copyright &y& Elsevier]

The aim of this study is to set up single molecular secreted phosphoprotein 1 (SPP1) upstream invasive network of lung adenocarcinoma. This paper proposed an integrated method based on linear programming and a decomposition procedure with integrated analysis of the significant function cluster using Kappa statistics and fuzzy heuristic clustering. Our study proved that only modules appearing in lung adenocarcinoma include cytokine module (CXCL13, GREM1&lowbar;2 inhibition), cell adhesion module (COL11A1&lowbar;2 activation; CDH3 inhibition), and receptor binding module (NMU activation; CXCL13, GREM1&lowbar;2 inhibition), which increase the invasion of cancer cell. We compared skeletal development, signal, biological regulation, sequence variant modules between human normal adjacent tissues and lung adenocarcinoma. SPP1 skeletal development module appears in human normal adjacent tissues (COL11A1&lowbar;1 activation; COL10A1 inhibition), whereas in lung adenocarcinoma (COL11A1&lowbar;2, COL1A2 activation); signal module appears in human normal adjacent tissues (COL11A1&lowbar;1, CXCL13, MMP11, SPINK1 activation; COL10A1, COL3A1 inhibition), whereas in lung adenocarcinoma (COL11A1&lowbar;2, COL1A2, MMP12 activation; CDH3, CXCL13, GREM1&lowbar;2, MMP11, SPINK1 inhibition); biological regulation module appears in human normal adjacent tissues (CXCL13, MKI67, PYCR1 activation; NEK2, SPDEF, TOP2A&lowbar;2, TOX3&lowbar;1 inhibition), whereas in lung adenocarcinoma (HMGB3, MKI67, NMU, PYCR1, TOX3&lowbar;2 activation; CXCL13, SPDEF, TOP2A&lowbar;2 inhibition); sequence variant module appears in human normal adjacent tissues (COL11A1&lowbar;1, MKI67, MMP11 activation; ASPM, COL10A1, COL3A1, NEK2, TMPRSS4, TOP2A&lowbar;2 inhibition), whereas in lung adenocarcinoma (COL11A1&lowbar;2, COL1A2, HMMR, MKI67, MMP12 activation; ABCC3, ASPM, CDH3, MMP11, TOP2A&lowbar;2 inhibition). It can be deduced that modules above in human normal adjacent tissues reflect the invasive inhibition of normal cells, whereas in lung adenocarcinoma increase the invasion of cancer cell. Our study of SPP1 upstreaminvasive network may be useful to identify novel and potentially targets for prognosis and therapy of lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Abstract: Background: Bone metastasis is one of the most common clinical phenomena of late stage lung cancer. A major impediment to understanding the pathogenesis of bone metastasis has been the lack of an appropriate animal and cell model. This study aims to establish human lung adenocarcinoma cell line with highly bone metastases potency with 99mTc-MDP bone scintigraphy. Methods: The human lung adenocarcinoma cancer cells SPC-A-1 were injected into the left cardiac ventricle of NIH-Beige-Nude-XID (NIH-BNX) immunodeficient mice. The metastatic lesions of tumor-bearing mice were imaged with 99mTc-MDP bone scintigraphy on a Siemens multi-single photon emission computed tomography. Pinhole images were acquired on a GZ-B conventional gamma camera with a self-designed pinhole collimator. The mice with bone metastasis were sacrificed under deep anesthesia, and the lesions were resected. Bone metastatic cancer cells in the resected lesions were subjected for culture and then reinoculated into the NIH-BNX mice through left cardiac ventricle. The process was repeated for eight cycles to obtain a novel cell subline SPC-A-1BM. Real-time polymerase chain reaction (PCR) was used to compare the gene expression differences in the parental and SPC-A-1BM cells. Results: The bone metastasis sites were successfully revealed by bone scintigraphy. The established bone metastasis cell line SPC-A-1BM had a high potential to metastasize in bone, including mandible, humerus, thoracic vertebra, lumbar, femur, patella, ilium and cartilage rib. The expression level of vascular endothelial growth factor gene family, Bcl-2 and cell adhesion-related genes ECM1, ESM1, AF1Q, SERPINE2 and FN1 were examined. Gene expression difference was found between parental and bone-seeking metastasis cell SPC-A-1BM, which indicates SPC-A-1BM has metastatic capacity vs. its parental cells. Conclusion: SPC-A-1BM is a bone-seeking metastasis human lung adenocarcinoma cell line. Bone scintigraphy may be used as an accurate, sensitive, noninvasive tool to detect experimental bone metastases in intact live NIH-BNX mice. [Copyright &y& Elsevier]