Human Alveolar Basal Epithelial Cells Research Articles

Design, synthesis and evaluation of new methyl piperazine derivatives as anticancer agents

BackgroundTo overcome the problem of side effects and toxicity, development of new anticancer agents is needed. Recently, piperidine salicylanilide derivatives with nanomolar epidermal growth factor receptor (EGFR) inhibitory and cytotoxicity activity have been reported. In the present study effect of replacing piperidine in reported piperidine salicylanilide with N-methyl piperazine and changing substituent’s of phenyl ring at other end on anticancer activity have been explored. A series of sixteen methyl piperazine incorporated phenyl benzamide and phenyl methanone derivatives have been synthesized and tested in a panel of three cancer cell lines (adenocarcinomic human alveolar basal epithelial cells (A-549), human colon carcinoma (HCT-116) and human pancreatic carcinoma (MIAPaCa-2)), using gefitinib as standard. Further, to study the probable mechanism, due to their structural similarity with EGFR inhibitors, docking interactions with EGFR active site were observed using Schrodinger suite.ResultThe results indicated that most of the compounds showed promising activity; out of which, compound A-11 was most active having cytotoxicity much better than that of gefitinib. It showed IC50 value of 5.71 µM against A-549 cell line, 4.26 µM against HCT-116 colon cancer line and 31.36 µM against MIAPaCa-2 cell line.ConclusionIt was found that these compounds fit well in the active site and may be exhibiting anticancer activity via EGFR inhibition.Graphical

Targeting BamA, the essential component of the Acinetobacter baumannii β-barrel assembly machinery, hinders its ability to adhere to and invade human alveolar basal epithelial cell line

The lungs are commonly targeted by Acinetobacter baumannii. The human alveolar basal epithelial cell line, A549, serves as a valuable in vitro model for probing pathogen-cell dynamics. This study examined two Acinetobacter strains, ATCC 19606 and the clinical isolate 58ST, investigating their adherence, internalization, and cytotoxicity within the A549 cell line to illuminate pathogenic mechanisms. Anti-BamA antibodies were expressed, purified, and detected via indirect ELISA. The toxicity of BamA was assessed across BALB/c mice. Both A. baumannii strains were used to infect A549 cells to scrutinize cell invasion diversity. Serum resistance, biofilm creation and inhibition, adhesion, internalization, and intracellular proliferation of live and inactivated A. baumannii were probed with and without anti-BamA sera. A549 cell viability was evaluated in the presence of live A. baumannii and anti-BamA sera-exposed bacteria. Cytoskeleton inhibitor tests were conducted on epithelial cells. A. baumannii strains displayed differing cell invasion aptitudes, with the clinical variant manifesting the highest invasion capability. During internalization, A. baumannii cells localized within vacuoles and migrated towards the nucleus using a zipper-like invasion mechanism. Bacterial division inside host cells culminated in cell demise. Pre-treatment with anti-BamA antibodies substantially impeded A. baumannii's adherence and invasion in epithelial cells. Microscopic imaging validated the intracellular presence of A. baumannii in A549 cells, verifying their invasive potential and residency. These findings substantiate A. baumannii's capacity to proliferate in epithelial cells, with BamA pivotal role against A. baumannii-epithelial cell interplay. This study augments our insight into A. baumannii pathogenesis, facilitating the development of efficacious strategies against A. baumannii infections.

Targeting BamA, the essential component of the Acinetobacter baumannii β-barrel assembly machinery, hinders its ability to adhere to and invade human alveolar basal epithelial cell line

Targeting BamA, the essential component of the Acinetobacter baumannii β-barrel assembly machinery, hinders its ability to adhere to and invade human alveolar basal epithelial cell line

Lack of cytotoxic and genotoxic effects of mPEG-silane coated iron(III) oxide nanoparticles doped with magnesium despite cellular uptake in cancerous and noncancerous lung cells

Cytotoxic and genotoxic effects of novel mPEG-silane coated iron(III) oxide nanoparticles doped with magnesium (Mg0.1-γ-Fe2O3(mPEG-silane)0.5) have been investigated on human adenocarcinomic alveolar basal epithelial (A549) and human normal bronchial epithelial (BEAS-2B) cells. In the studies several molecular and cellular targets addressing to cell membrane, cytoplasm organelles and nucleus components were served as toxicological endpoints. The as-synthesized nanoparticles were found to be stable in the cell culture media and were examined for different concentration and exposure times. No cytotoxicity of the tested nanoparticles was found although these nanoparticles slightly increased reactive oxygen species in both cell types studied. Mg0.1-γ-Fe2O3(mPEG-silane)0.5 nanoparticles did not produce any DNA strand breaks and oxidative DNA damages in A549 and BEAS-2B cells. Different concentration of Mg0.1-γ-Fe2O3(mPEG-silane)0.5 nanoparticles and different incubation time did not affect cell migration. The lung cancer cells' uptake of the nanoparticles was more effective than in normal lung cells. Altogether, the results evidence that mPEG-silane coated iron(III) oxide nanoparticles doped with magnesium do not elucidate any deleterious effects on human normal and cancerous lung cells despite cellular uptake of these nanoparticles. Therefore, it seems reasonable to conclude that these novel biocompatible nanoparticles are promising candidates for further development towards medical applications.

Volatile Organic Compounds in Cellular Headspace after Hyperbaric Oxygen Exposure: An In Vitro Pilot Study.

Volatile organic compounds (VOCs) might be associated with pulmonary oxygen toxicity (POT). This pilot study aims to identify VOCs linked to oxidative stress employing an in vitro model of alveolar basal epithelial cells exposed to hyperbaric and hyperoxic conditions. In addition, the feasibility of this in vitro model for POT biomarker research was evaluated. The hyperbaric exposure protocol, similar to the U.S. Navy Treatment Table 6, was conducted on human alveolar basal epithelial cells, and the headspace VOCs were analyzed using gas chromatography-mass spectrometry. Three compounds (nonane [p = 0.005], octanal [p = 0.009], and decane [p = 0.018]), of which nonane and decane were also identified in a previous in vivo study with similar hyperbaric exposure, varied significantly between the intervention group which was exposed to 100% oxygen and the control group which was exposed to compressed air. VOC signal intensities were lower in the intervention group, but cellular stress markers (IL8 and LDH) confirmed increased stress and injury in the intervention group. Despite the observed reductions in compound expression, the model holds promise for POT biomarker exploration, emphasizing the need for further investigation into the complex relationship between VOCs and oxidative stress.

New silver, rhodium and iridium complexes with anthracene-functionalized N-heterocyclic carbene ligands: Crystal structures, cytotoxicity and fluorescence studies

In the present study, we have synthesized anthracene-functionalized metal complexes to investigate their cytotoxicity and photophysical properties. In this context, firstly, an Ag–NHC (NHC = N-heterocyclic carbene) complex (2a) has been synthesized by the interaction of Ag2O and N-(2-methylbenzyl)-N-((anthracen-9-yl)methyl)benzimidazolium chloride (1a). Corresponding Rh– (3a) and Ir–NHC (4a) complexes have also been synthesized by the transmetalation reaction between 2a and corresponding metal compounds. Additionally, for comparison purposes, an ether-functionalized Ag–NHC complex (2b) with N-(methoxyethyl)-N-((anthracene-9-yl)methyl)benzimidazole-2-ylidene ligand, and [AgL2]NO3 type complex (2c) with a N-coordinated N-((anthracen-9-yl)methyl)benzimidazole ligand have been synthesized. All complexes have been characterized by the combination of NMR and mass spectroscopic techniques, and elemental analyses. Moreover, solid state structures of 2a, 2b and 4a have been determined by the single crystal X-ray diffraction analysis. Cytotoxic potentials of all compounds have been tested against human lung adenocarcinoma alveolar basal epithelial cell line (A549) using the MTT assay, and all complexes performed strong anti-proliferative activity. Stability studies have disclosed that only 1a and 2c are able to retain their structure in the culture medium (DMEM) that biological assays were carried out. Photophysical measurements revealed that all compounds have similar emission bands because of the conjugation of anthracene group. Finally, 1a and 2c have been visualized by fluorescence confocal microscopy to investigate cellular uptake and subcellular distribution of the complexes, and the findings indicated that both compounds dispersed along the cell membranes nuclear regions.

Co-delivery of paclitaxel and curcumin loaded solid lipid nanoparticles for improved targeting of lung cancer: In vitro and in vivo investigation

The objective of this study was to develop nanotechnology-mediated paclitaxel (PAC) and curcumin (CUR) co-loaded solid lipid nanoparticles (PAC-CUR-SLNs) for the treatment of lung cancer, which is a leading cause of death worldwide. Around 85 % cases of lungs cancer constitute non-small cell lung cancer (NSCLC). PAC-CUR-SLNs were prepared via high pressure homogenization. The in vitro drug release of PAC-CUR-SLNs was checked followed by their in vitro cytotoxic investigation using adenocarcinomic human alveolar basal epithelial cells (A549) cell lines. Anticancer effects along with side effects of the synergistic delivery of PAC-CUR-SLNs were studied in vivo, using BALB/c mice. PAC-CUR-SLNs were nano sized (190 nm), homogeneously disseminated particles with %IE of both PAC and CUR above 94 %. PAC-CUR-SLNs released PAC and CUR in a controlled fashion when compared with free drug suspensions. The cytotoxicity of PAC-CUR-SLNs was higher than individual drug-loaded SLNs and pure drugs. Moreover, the co-delivery displayed synergistic effect, indicating potential of PAC-CUR-SLNs in lung cancer treatment. In vivo tumor investigation of PAC-CUR-SLNs exhibited 12-fold reduced tumor volume and almost no change in body weight of BALB/c mice, when compared with the experimental groups including control group. The inhibition of tumor rate on day 28 was 82.7 % in the PAC-CUR-SLNs group, which was significantly higher than the pure drugs and monotherapies. It can be concluded that, encapsulating the co-loaded antitumor drugs like PAC-CUR in SLNs may help in improved targeting of the tumor with enhanced anticancer effect.

In vitro and in vivo evaluation of the anti-infective potential of the essential oil extracted from the leaves of Plectranthus amboinicus (lour.) spreng against Klebsiella pneumoniae and elucidation of its mechanism of action through proteomics approach

Ethnopharmacological relevanceMembers of Plectranthus genus such as Plectranthus amboinicus (Lour.) Spreng is a well-known folkloric medicine around the globe in treating several human ailments such as cardiovascular, respiratory, digestive, urinary tract, skin and infective diseases. Its therapeutic value is primarily attributed to its essential oil. Although several properties of Plectranthus amboinicus essential oil have been documented, its mechanism of action and safety has not been completely elucidated. Aim of the studyTo investigate the anti-infective potential of Plectranthus amboinicus essential oil against Klebsiella pneumoniae using in vitro and in vivo bioassays and identify its mode of action. The study was conducted to scientifically validate the traditional usage of Plectranthus amboinicus oil and propose it as a complementary and alternative medication to combat Klebsiella pneumoniae infections due to emerging antibiotic resistance problem. Materials and methodsPlectranthus amboinicus essential oil was extracted through steam distillation and was chemically characterized using Gas Chromatography Mass Spectrometry (GC-MS). The antibacterial activity was assessed using microbroth dilution assay, metabolic viability assay and growth curve analysis. The mode of action was elucidated by the proteomics approach using Nano-LC-MS/MS followed by in silico analysis. The results of proteomic analysis were further validated through several in vitro assays. The cytotoxic nature of the essential oil was also confirmed using adenocarcinomic human alveolar basal epithelial (A549) cells. Furthermore, the safety and in vivo anti-infective efficacy of Plectranthus amboinicus essential oil was evaluated through survival assay, CFU assay and histopathological analysis of vital organs using zebrafish as a model organism. ResultsThe chemical characterization of Plectranthus amboinicus essential oil revealed that it is predominantly composed of thymol. Thymol rich P. amboinicus essential oil demonstrated potent inhibitory effects on Klebsiella pneumoniae growth, achieving a significant reduction at a concentration of 400 μg/mL within 4 h of treatment The nano-LC-MS/MS approach unveiled that the essential oil exerted its impact by disrupting the antioxidant defense system and efflux pump system of the bacterium, resulting in elevated cellular oxidative stress and affect the biosynthesis of biofilm. The same was validated through several in vitro assays. Furthermore, the toxicity of Plectranthus amboinicus essential oil determined using A549 cells and zebrafish survival assay established a non-toxic concentration of 400 μg/mL and 12.5 μg/mL respectively. The results of anti-infective potential of the essential oil using Zebrafish as a model organism demonstrated significantly improved survival rates, reduced bacterial load, alleviated visible signs of inflammation and mitigated the adverse effects of infection on various organs, as evidenced by histopathological analysis ensuring its safety for potential therapeutic application. ConclusionThe executed in vitro and in vivo assays established the effectiveness of essential oil in inhibiting bacterial growth by targeting key proteins associated with the bacterial antioxidant defense system and disrupted the integrity of the cell membrane, highlighting its critical role in addressing the challenge posed by antibiotic-resistant Klebsiella pneumoniae.

Activation of ERK/NF-kB Pathways Contributes to the Inflammatory Response in Epithelial Cells and Macrophages Following Manganese Exposure.

Different types of metals, including manganese (Mn), are constantly encountered in various environmental matrices due to natural and anthropogenic activities. They induce a sustained inflammatory response in various organs, which is considered to be an important priming event in the pathogenesis of several diseases. Mn-induced neuroinflammation and subsequent neurodegeneration are well recognized. However, emerging data suggest that occupationally and environmentally relevant levels may affect various organs, including the lungs. Therefore, the present study was carried out to investigate the effects of Mn (as Mn2+) exposure on the inflammatory response in human normal bronchial (BEAS-2B) and adenocarcinoma alveolar basal (A549) epithelial cells, as well as in murine macrophages (J774). Mn2+ exposure significantly induced mRNA and protein expression of various pro-inflammatory mediators (cytokines and chemokines) in all cells compared to corresponding vehicle controls. Furthermore, Mn2+ treatment also led to increased phosphorylation of extracellular-signal-regulated kinase (ERK)1/2 and nuclear factor-kappa B (NF-kB) p65 in both epithelial cells and macrophages. As expected, cells treated with inhibitors of ERK1/2 (PD98059) and NF-kB p65 (IMD0354) effectively mitigated the expression of various pro-inflammatory mediators induced by Mn2+, suggesting that ERK/NF-kB pathways have a critical role in the Mn2+-induced inflammatory response. Further, in vivo studies are required to confirm these in vitro findings to support clinical translation.

Exploring the synthesis, structure and bioactivity of pyrimidine carboxylic acid-derived organic antimony (V) complexes: Cytostatic and antimicrobial evaluations

Eight new organoantimony complexes, R3SbL2 (R = Ph, p-MePh; L = L1, L2) and (R3Sb)2OL2 (R = pHPh, m-MePh; L = L1, L2), [Ph3Sb(C5H3N2O2)2] (1), [(Ph3Sb)2O(C5H3N2O2)2] (2), [(p-tol)3Sb(C5H3N2O2)2] (3), [(m-tol)6Sb2O(C5H3N2O2)2] (4), [Ph3Sb(C5H3N2O2)2] (5), [(Ph3Sb)2O(C5H3N2O2)2] (6), [(p-tol)3Sb(C5H3N2O2)2] (7) and [(m-tol)6Sb2O(C5H3N2O2)2] (8), were designed and synthesized by the reaction of 4-pyrimidine carboxylic acid (HL1) or 5-pyrimidine carboxylic acid (HL2) with organoantimony precursors. All the complexes were characterized by elemental analysis, FT-IR, NMR (1H and 13C), and single crystal X-ray diffraction analysis. Crystal structure results reveal that the central antimony atom of all the complexes displays a triangular biconical geometry. Among them, complexes 1, 3, 5 and 7 show a monomeric structure, while complexes 2, 4, 6 and 8 have a dimeric structure with oxygen bridges. The in vitro cytostatic activities of the eight complexes against a human alveolar basal epithelial lung cancer cell lines (A549) and hepatocellular carcinoma cell lines (HepG-2) were investigated, and the results showed that the organoantimony derivatives with the tolyl groups (3, 4, 7, 8) exhibited higher in vitro cytostatic activities compared with those with the phenyl groups (1, 2, 5, 6). At the same time, bacteriostatic tests were conducted to assess the inhibitory effects of complexes 1–8 against three prevalent plant pathogenic fungi and one bacterium. The results revealed that complex 4 exhibited significant fungicidal activities, on the other hand, complex 3 exhibited higher antibacterial activity against MRSA. These results will provide significant guidance for the further exploration of potential efficient biological activity complexes.

Forced expression of microRNA-221-3p exerts protective effects against manganese-induced cytotoxicity in human lung epithelial cells

Manganese (Mn)-induced pulmonary toxicity and the underlying molecular mechanisms remain largely enigmatic. Further, in recent years, microRNAs (miRNAs) have emerged as regulators of several pollutants-mediated toxicity. In this context, our study aimed at elucidating whether miRNAs are involved in manganese (II) chloride (MnCl2) (Mn2+)-induced cytotoxicity in lung epithelial cells. Growth inhibition of Mn2+ towards normal human bronchial epithelial (BEAS-2B) and adenocarcinomic human alveolar basal epithelial (A549) cells was analyzed by MTT assay following 24 or 48 h treatment. Reactive oxygen species (ROS) generation, mitochondrial membrane potential (ΔΨm), cell cycle arrest, and apoptosis were evaluated by flow cytometry. RT-qPCR and Western blot were performed to analyze the expression of cyclins, anti-oxidant genes, and miRNAs. We used small RNA sequencing to investigate Mn2+-induced changes in miRNA expression patterns. In both cell lines, Mn2+ treatment inhibited growth in a dose-dependent manner. Further, compared with vehicle-treated cells, Mn2+ (250 μM) treatment induced ROS generation, cell cycle arrest, apoptosis, and decreased ΔΨm as well as altered the expression of cyclins and anti-oxidant genes. Sequencing data revealed that totally 296 miRNAs were differentially expressed in Mn2+-treated cells. Among them, miR-221-3p was one of the topmost down-regulated miRNAs in Mn2+-treated cells. We further confirmed this association in A549 cells. In addition, transient transfection was performed to study gain-of-function experiments. Forced expression of miR-221-3p significantly improved cell viability and reduced Mn2+-induced cell cycle arrest and apoptosis in BEAS-2B cells. In conclusion, miR-221-3p may be the most likely target that accounts for the cytotoxicity of Mn2+−exposed lung epithelial cells.

Effects of chitosan and TiO2 nanoparticles on the antibacterial property and ability to self-healing of cracks and retrieve mechanical characteristics of dental composites

The aim of this study was to improve the self-healing properties of dental nanocomposite using nanoparticles of TiO2 and chitosan. We evaluated flexural and compressive strength, crack-healing, and self-healing lifespan after 3 months of water aging. The effect of the developed composite on cell viability and toxicity was assessed by an MTT assay on human alveolar basal epithelial cells (A549 cell line). The nanocomposite included 7.5 wt% polyurea-formaldehyde (PUF) and 0, 0.5, and 1 wt% n-TiO2 and chitosan. After the fracture, the samples were put in a mold for 1–90 days to enable healing. Then, the fracture toughness of the healed nanocomposites and the healing yield were measured. The flexural strength of the nanocomposite improved by adding 0.5 wt% n-TiO2, while the compressive strength increased after adding 0.5 wt% chitosan (p > 0.1). When these two materials were used simultaneously, the flexural strength was improved by around 2%; however, the compressive strength was unaffected. Compared to the other sample, the nanocomposite with 0.5 wt% n-TiO2 and chitosan had higher KIC-healing and self-healing efficiency. Self-healing efficacy had no significant effect of water aging over 90 days compared to one day (p > 0.1), demonstrating that the PUF nanocapsules were not damaged.

Hsp Inhibitor is Affective Against Adenocarcinomic Human Alveolar Basal Epithelial Cells Through Modulating ERK/MAPK Signaling Pathway.

The extracellular signal-regulated kinase (ERK) - mitogen-activated protein kinase (MAPK) pathway regulates cell proliferation, differentiation, and apoptosis. Heat Shock Protein 90 (HSP90) is required to activate proto-oncogenic protein kinases and promotes tumor growth through anti-apoptotic effects on A549-non-small cell lung cancer (NSCLC). Therefore, deregulation of the ERK-MAPK pathway and abnormal expression of HSP90 are reasonably frequent events in NSCLC. In this study, novel perimidine-pyrazole compounds employed to block ERK-MAPK deregulation through inhibiting HSP dependent cancer cell survival mechanisms. A set of perimidine-pyrazole derivatives effects was monitored on NSCLC cell line. Array experiments performed to understand the effect of the compounds on signaling pathways and results were analyzed by gene enrichment analysis. Further, senescence and apoptosis experiments were performed to support the enrichment results along with in silico methods to determine perimidine-pyrazole/HSP interactions. Treatment of NSCLC cells with perimidine-pyrazole derivatives displayed cancer-inhibitory, pro-senescent and pro-apoptotic effects on NSCLC cells through ERK/MAPK pathway and these compounds are promising templates for designing anticancer drugs.

Evaluation of Pm2.5 Influence on Human Lung Cancer Cells Using a Microfluidic Platform.

In this study, we developed a microfluidic device that is able to monitor cell biology under continuous PM2.5 treatment. The effects of PM2.5 on human alveolar basal epithelial cells, A549 cells, and uncovered several significant findings were investigated. The results showed that PM2.5 exposure did not lead to a notable decrease in cell viability, indicating that PM2.5 did not cause cellular injury or death. However, the study found that PM2.5 exposure increased the invasion and migration abilities of A549 cells, suggesting that PM2.5 might promote cell invasiveness. Results of RNA sequencing revealed 423 genes that displayed significant differential expression in response to PM2.5 exposure, with a particular focus on pathways associated with the generation of reactive oxygen species (ROS) and mitochondrial dysfunction. Real-time detection demonstrated an increase in ROS production in A549 cells after exposure to PM2.5. JC1 assay, which indicated a loss of mitochondrial membrane potential (ΔΨm) in A549 cells exposed to PM2.5. The disruption of mitochondrial membrane potential further supports the detrimental effects of PM2.5 on A549 cells. These findings highlight several adverse effects of PM2.5 on A549 cells, including enhanced invasion and migration capabilities, altered gene expression related to ROS pathways, increased ROS production and disruption of mitochondrial membrane potential. These findings contribute to our understanding of the potential mechanisms through which PM2.5 can impact cellular function and health.

Silver(I) complexes containing antifungal azoles: significant improvement of the anti-Candida potential of the azole drug after its coordination to the silver(I) ion.

Inspired by the emergence of resistance to currently available antifungal therapy and by the great potential of metal complexes for the treatment of various diseases, we synthesized three new silver(I) complexes containing clinically used antifungal azoles as ligands, [Ag(ecz)2]SbF6 (1, ecz is econazole), {[Ag(vcz)2]SbF6}n (2, vcz is voriconazole), and [Ag(ctz)2]SbF6 (3, ctz is clotrimazole), and investigated their antimicrobial properties. The synthesized complexes were characterized by mass spectrometry, IR, UV-vis and 1H NMR spectroscopy, cyclic voltammetry, and single-crystal X-ray diffraction analysis. In the mononuclear complexes 1 and 3 with ecz and ctz, respectively, the silver(I) ion has the expected linear geometry, in which the azoles are monodentately coordinated to this metal center through the N3 imidazole nitrogen atom. In contrast, the vcz-containing complex 2 has a polymeric structure in the solid state in which the silver(I) ions are coordinated by four nitrogen atoms in a distorted tetrahedral geometry. DFT calculations were done to predict the most favorable structures of the studied complexes in DMSO solution. All the studied silver(I) complexes have shown excellent antifungal and good to moderate antibacterial activities with minimal inhibitory concentration (MIC) values in the ranges of 0.01-27.1 and 2.61-47.9 μM on the selected panel of fungi and bacteria, respectively. Importantly, the complexes 1-3 have exhibited a significantly improved antifungal activity compared to the free azoles, with the most pronounced effect observed in the case of complex 2 compared to the parent vcz against Candida glabrata with an increase of activity by five orders of magnitude. Moreover, the silver(I)-azole complexes 2 and 3 significantly inhibited the formation of C. albicans hyphae and biofilms at the subinhibitory concentration of 50% MIC. To investigate the impact of the complex 3 more thoroughly on Candida pathogenesis, its effect on the adherence of C. albicans to A549 cells (human adenocarcinoma alveolar basal epithelial cells), as an initial step of the invasion of host cells, was studied.

Synthesis and Antiviral Activity of 2′‐Modified L‐Nucleoside Analogues

AbstractNucleoside analogues have been the foundation of antiviral therapy over the past few decades. D‐nucleosides with natural stereochemistry occupies the lion share of the marketed antiviral agents. However, much less effort have been put towards the development of L‐nucleosides as antiviral agents. Herein, our effort towards the synthesis of 2′ ‐substituted L‐nucleoside analogues is reported as an emerging class of antiviral agents. Biological activity of the synthesized L‐nucleosided was evaluated against two viruses of importance, tick‐borne encephalitis virus (TBEV) and Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) in adenocarcinomic human alveolar basal epithelial cells (A459) and Vero cells. Ring opening of L‐2, 2′‐Anhydrouridine (2) with various nucleophiles to make several 2‘‐substituted L‐nucleosides is the key synthetic outcome. This development has paved the way in the synthesis of many new analogues of 2‘‐substituted L‐nucleosides for numerous applications.

Biological Synthesis, Characterization, and Therapeutic Potential of S. commune-Mediated Gold Nanoparticles.

Green-synthesized gold nanoparticles demonstrate several therapeutic benefits due to their safety, non-toxicity, accessibility, and ecological acceptance. In our study, gold nanoparticles (AuNPs) were created using an extracellular extract from the fungus Schizophyllum commune (S. commune). The reaction color was observed to be a reddish pink after a 24 h reaction, demonstrating the synthesis of the nanoparticles. The myco-produced nanoparticles were investigated using transmission electron microscopy (TEM), dynamic light scattering (DLS), and UV-visible spectroscopy. The TEM pictures depicted sphere-like shapes with sizes ranging from 60 and 120 nm, with an average diameter of 90 nm, which is in agreement with the DLS results. Furthermore, the efficiency of the AuNPs' antifungal and cytotoxic properties, as well as their production of intracellular ROS, was evaluated. Our findings showed that the AuNPs have strong antifungal effects against Trichoderma sp. and Aspergillus flavus at increasing doses. Additionally, the AuNPs established a dose-dependent activity against human alveolar basal epithelial cells with adenocarcinoma (A549), demonstrating the potency of synthesized AuNPs as a cytotoxic agent. After 4 h of incubation with AuNPs, a significant increase in intracellular ROS was observed in cancer cells. Therefore, these metallic AuNPs produced by fungus (S. commune) can be used as an effective antifungal, anticancer, and non-toxic immunomodulatory delivery agent.

Comparative studies on the cytotoxic effects induced by iron oxide nanoparticles in cancerous and noncancerous human lung cells subjected to an alternating magnetic field

The cytotoxic effects of water-based ferrofluids composed of iron oxide nanoparticles, including magnetite (Fe3O4) and maghemite (γ-Fe2O3), ranging from 15 to 100 nm, were examined on various lung cancer cells including adenocarcinomic human alveolar basal epithelial cells (A549), nonsmall lung squamous cell carcinoma (H1703), small cell lung cancer cells (DMS 114), and normal bronchial epithelial cells (BEAS-2B). The cytotoxic effect was evaluated both with and without exposure to an alternating magnetic field (AMF). The studies revealed that neither AMF nor iron oxide nanoparticles when tested individually, produced cytotoxic effects on either cancerous or noncancerous cells. However, when applied together, they led to a significant decrease in cell viability and proliferative capacity due to the enhanced effects of magnetic fluid hyperthermia (MFH). The most pronounced effects were found for maghemite (<50 nm) when subjected to an AMF. Notably, A549 cells exhibited the highest resistance to the proposed hyperthermia treatment. BEAS-2B cells demonstrated susceptibility to magnetized iron oxide nanoparticles, similar to the response observed in lung cancer cells. The studies provide evidence that MFH is a promising strategy as a standalone treatment for different types of lung cancer cells. Nevertheless, to prevent any MFH-triggered adverse effects on normal lung cells, targeted magnetic ferrofluids should be designed.

MicroRNA-195-5p mediates arsenic-induced cytotoxicity in human lung epithelial cells: Beneficial role of plant-derived tannic acid

Arsenic (As), a highly toxic metalloid, which causes environmental lung diseases and affects millions of people worldwide. Respiratory epithelial cells are essential for maintaining lung homeostasis, aberrant epithelial damage and death due to exposure to a wide range of environmental pollutants, which are considered to be the initial trigger for many pulmonary diseases. Accumulating evidence has shown that microRNAs (miRNAs) appear to be important players in various normal physiological and pathological processes. Therefore, the present study was carried out to examine the cytotoxic effects of a trivalent form of As (As3+) in normal human bronchial (BEAS-2B) and adenocarcinoma alveolar basal (A549) epithelial cells and the role of miR-195-5p. Further, we also explored the protective effects of a natural dietary polyphenol tannic acid (TA). As3+ (1 μM) treatment in BEAS-2B cells for 24 h induced cytotoxicity by decreasing the cell viability, mitochondrial membrane potential (ΔΨm) and inducing reactive oxygen species (ROS) generation, lipid peroxidation (LPO), cell cycle arrest, and apoptosis, which was associated with a significantly higher level of miR-195-5p expression compared with vehicle control. Forced expression of miR-195-5p alone suppressed cell survival, ΔΨm, regulated cell cycle distribution and induced ROS generation in BEAS-2B cells. As expected, miR-195-5p inhibition effectively rescued BEAS-2B cells from As3+-mediated toxicity, confirming the involvement of miR-195-5p in the cytotoxic effects of As3+. Further, TA pre-treatment expressively alleviated As3+-induced toxicity by suppressing ROS production, miR-195-5p expression, and increasing ΔΨm. These in vitro results indicate that miR-195-5p may be useful as a therapeutic target for treating As3+ toxicity.

Triphenylphosphine Derivatives of Allylbenzenes Express Antitumor and Adjuvant Activity When Solubilized with Cyclodextrin-Based Formulations.

Allylbenzenes (apiol, dillapiol, myristicin and allyltetramethoxybenzene) are individual components of plant essential oils that demonstrate antitumor activity and can enhance the antitumor activity of cytotoxic drugs, such as paclitaxel, doxorubicin, cisplatin, etc. Triphenylphosphine (PPh3) derivatives of allylbenzenes are two to three orders of magnitude more potent than original allylbenzenes in terms of IC50. The inhibition of efflux pumps has been reported for allylbenzenes, and the PPh3 moiety is deemed to be responsible for preferential mitochondrial accumulation and the depolarization of mitochondrial membranes. However, due to poor solubility, the practical use of these substances has never been an option. Here, we show that this problem can be solved by using a complex formation with cyclodextrin (CD-based molecular containers) and polyanionic heparin, stabilizing the positive charge of the PPh3 cation. Such containers can solubilize both allylbenzenes and their PPh3 derivatives up to 0.4 mM concentration. Furthermore, we have observed that solubilized PPh3 derivatives indeed work as adjuvants, increasing the antitumor activity of paclitaxel against adenocarcinomic human alveolar basal epithelial cells (A549) by an order of magnitude (in terms of IC50) in addition to being quite powerful cytostatics themselves (IC50 in the range 1-10 µM). Even more importantly, CD-solubilized PPh3 derivatives show pronounced selectivity, being highly toxic for the A549 tumor cell line and minimally toxic for HEK293T non-tumor cells, red blood cells and sea urchin embryos. Indeed, in many cancers, the mitochondrial membrane is more prone to depolarization compared to normal cells, which probably explains the observed selectivity of our compounds, since PPh3 derivatives are known to act as mitochondria-targeting agents. According to the MTT test, 100 µM solution of PPh3 derivatives of allylbenzenes causes the death of up to 85% of A549 cancer cells, while for HEK293T non-cancer cells, only 15-20% of the cells died. The hemolytic index of the studied substances did not exceed 1%, and the thrombogenicity index was < 1.5%. Thus, this study outlines the experimental foundation for developing combined cytostatic medications, where effectiveness and selectivity are achieved through decreased concentration of the primary ingredient and the inclusion of adjuvants, which are safe or practically harmless substances.