Normal Lung Cells Research Articles

Membrane Partitioning of TEMPO Discriminates Human Lung Cancer from Neighboring Normal Cells.

The plasma membranes of normal and cancer cells of the lung, breast, and colon tissues show considerably different lipid compositions that greatly influence their physicochemical properties. Partitioning of the spin probe 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) into the membranes of human lung normal and carcinoma cells was assessed by EPR spectroscopy to estimate the impact of the lipid compositions. The goal was to reveal potential strategies for cancer therapy attributable to the membrane properties. The study was conducted at pH values of 7.3 and 6.2, relevant to the microenvironments of normal and cancer cells, respectively. The TEMPO partitioning was examined in the temperature interval of 283-317K to reveal the efficacy of local hyperthermia used in chemotherapy. Results indicate that the TEMPO partitioning coefficient for the membranes of human lung carcinoma cells is significantly higher compared with that of neighboring normal cells. Increased partition coefficients were observed at relatively higher temperatures in both normal and cancer cells. However, compared to the normal cells, the cancer cells demonstrated higher partition coefficients in the studied temperature range. The data obtained with C12SL (spin-labeled analog of lauric acid) indicate that increased membrane dynamics of the cancer cells is a possible mechanism for enhanced partitioning of TEMPO. Free energy values for partitioning estimated for pH values of 6.2 and 7.3 show that TEMPO partitioning requires 30% less energy in the cancer cells at pH 7.3. TEMPO and its derivatives have previously been considered as theranostic agents in cancer research. Data suggest that TEMPO derivatives could be used to test if complementary alkalization therapy is effective for cancer patients receiving standard chemotherapy with local hyperthermia.

Doxorubicin-sanguinarine nanoparticles: formulation and evaluation of breast cancer cell apoptosis and cell cycle

Background Therapeutic resistance fails cancer treatment. Drug-nanoparticle combinations overcome resistance. Sanguinarine-conjugated nanoparticles may boost sanguinarine’s anticancer effects. Methods Sanguinarine, HPMC-NPs, and doxorubicin were tested on Adriamycin-resistant MCF-7/ADR breast cancer cells, parent-sensitive MCF-7, and MCR-5 normal cells (DX). Results Regular distribution, 156 nm diameter, <1 μm average size, 100% intensity—SN is therapeutic. Furthermore, the obtained NPs showed PDI = 0.145, zeta-potential=-37.6, and EE%=90.5%. DX sensitized MCF-7 cells (IC50 = 1.4 μM) more than MCF-7/ADR cells (IC50 = 27 μM) with RR = 19.3. SA and SN were more toxic to MCF-7/ADR cells (overexpressed with P-gp) than their sensitive parent MCF-7 cells (IC50 = 4 μM, RR = 0.6 and 0.6 μM, RR = 0.7). MCR-5 normal lung cells were more resistant to SA (IC50 = 7.2 μM) and SN (IC50 = 1.6 μM) with a selection index > 2. Synergistic cytotoxic interactions reduced the IC50 from 27 μM to 1.6 (CI = 0.1) and 0.9 (CI = 0.4) after DX and nontoxic dosages (IC20) of SA and SN. DS and SN killed 27.1% and 39.4% more cells than DX (7.7%), SA (4.9%), SN (5.5%), or untreated control (0.3%). DS and DSN lowered CCND1 and survival in MCF-7/ADR cells while raising p21 and Casp3 gene and protein expression. Conclusions Cellular and molecular studies suggested adjuvant chemosensitizers SA and SN to reverse MDR in breast cancer cells.

Mangifera indica L. kernel ethanol extract inhibits cell viability and proliferation with induction of cell cycle arrest and apoptosis in lung cancer cells

ABSTRACT In this study, we investigated the effects of an ethanolic extract of Mangifera indica L. kernel on the viability and proliferation of human lung cancer cells. We utilized MTT and BrdU cell proliferation assays, morphological assessments, cell cycle analyses, and apoptosis assays to investigate the extract’s effects on lung cancer (A549 and NCI-H292) and normal lung (MRC-5) cells. The extract demonstrated a toxicity toward cancer cells compared to normal cells with dose-dependent anti-proliferative effect on lung cancer cells. The extract also caused differential effects on the cell cycle, inducing G0/G1 arrest and increasing the Sub-G1 population in both lung cancer and normal lung cells. Notably, the extract induced loss of membrane integrity, shrinkage, membrane blebbing, and apoptosis in lung cancer cells, while normal cells exhibited only early apoptosis. Furthermore, the extract exhibited higher toxicity towards NCI-H292 cells, followed by A549 and normal MRC-5 cells in decreasing order of potency. Our results suggest that the ethanolic extract of M. indica L. kernel has significant potential as a novel therapeutic agent for treating lung cancer cells, given its ability to induce apoptosis in cancer cell lines while causing minimal harm to normal cells.

Biochemical changes in lipid and protein metabolism caused by mannose-Raman spectroscopy studies.

Biochemical analysis of human normal bronchial cells (BEpiC) and human cancer lung cells (A549) has been performed by using Raman spectroscopy and Raman imaging. Our approach provides a biochemical compositional mapping of the main cell components: nucleus, mitochondria, lipid droplets, endoplasmic reticulum, cytoplasm and cell membrane. We proved that Raman spectroscopy and Raman imaging can distinguish successfully BEpiC and A549 cells. In this study, we have focused on the role of mannose in cancer development. It has been shown that changes in the concentration of mannose can regulate some metabolic processes in cells. Presented results suggest lipids and proteins can be considered as Raman biomarkers during lung cancer progression. Analysis obtained for bands 1444 cm-1, and 2854 cm-1 characteristic for lipids and derivatives proved that the addition of mannose reduced levels of these compounds. Results obtained for protein compounds based on bands 858 cm-1, 1004 cm-1 and 1584 cm-1 proved that the addition of mannose increases the values of protein in BEpiC cells and blocks protein glycolisation in A549 cells. Noticing Raman spectral changes in BEpiC and A549 cells supplemented with mannose can help to understand the mechanism of sugar metabolism during cancer development and could play in the future an important role in clinical treatment.

Downregulation of TRIB3 enhances the sensitivity of lung cancer cells to amino acid deprivation by suppressing AKT activation.

Tribbles pseudokinase 3 (TRIB3), a member of the mammalian Tribbles family, is implicated in multiple biological processes. This study aimed to investigate the biological functions of TRIB3 in lung cancer and its effect on amino acid-deprived lung cancer cells. TRIB3 mRNA expression was elevated in lung cancer tissues and cell lines compared to normal lung tissues and cells. TRIB3 knockdown markedly reduced the viability and proliferation of H1299 lung cancer cells. Deprivation of amino acids, particularly arginine, glutamine, lysine, or methionine, strongly increased TRIB3 expression via ATF4 activation in H1299 lung cancer cells. Knockdown of TRIB3 led to transcriptional downregulation of ATF4 and reduced AKT activation induced by amino acid deprivation, ultimately increasing the sensitivity of H1299 lung cancer cells to amino acid deprivation. Additionally, TRIB3 knockdown enhanced the sensitivity of H1299 cells to V-9302, a competitive antagonist of transmembrane glutamine flux. These results suggest that TRIB3 is a pro-survival regulator of cell viability in amino acid-deficient tumor microenvironments and a promising therapeutic target for lung cancer treatment.

The effect of light irradiation on a nitro-ruthenium porphyrin complex in the induced death of lung cancer cells in two- and three-dimensional cultures: Insights into the effect of nitric oxide.

Efforts to find compounds selectively affecting cancer cells while sparing normal ones have continued to grow. Nitric oxide (NO) is critical in physiology and pathology, including cancer. It influences cellular processes like proliferation, apoptosis, and angiogenesis. The intricate interaction of NO with cancer cells offers innovative treatment possibilities, but its effects can vary by concentration and site. Ruthenium complexes capable of releasing NO upon stimulation show for this purpose. These versatile compounds can also enhance photodynamic therapy (PDT), a light-activated approach, which induces cellular damage. Ruthenium-based photosensitizers (PSs), delivering NO and producing reactive oxygen species (ROS), offer a novel strategy for improved cancer treatments. In this study, a nitro-ruthenium porphyrin conjugate: {TPyP[Ru(NO2)(bpy)2]4}(PF6)4, designated RuNO2TPyP, which releases NO upon irradiation, was investigated for its effects on lung cells (non-tumor MRC-5 and tumor A549) in 2D and 3D cell cultures. The findings suggest that this complex has potential for PDT treatment in lung cancer, as it exhibits photocytotoxicity at low concentrations without causing cytotoxicity to normal lung cells. Moreover, treatment of cells with RuNO2TPyP followed by light irradiation (4 J cm-2) can induce apoptosis, generate ROS, promote intracellular NO formation, and has anti-migratory effects. Additionally, the complex can modify tumor cell structures and induce photocytotoxicity and apoptosis in a 3D culture. These outcomes are attributed to the internalization of the complex and its subsequent activation upon light irradiation, resulting in NO release and singlet oxygen production.

Four newly synthesized enones induce mitochondrial-mediated apoptosis and G2/M cell cycle arrest in colorectal and cervical cancer cells.

Over the last few decades, we have gained insight into how researchers attempted to modify some natural molecules to be utilized as prospective agents for cancer treatment. Many scientists synthesized new natural compounds by incorporating specific functional groups and metals that improved their antitumor activity while reducing undesirable side effects. In this investigation, we synthesized four novel structurally modified enones that differ in the functional groups attached to the carbonyl group of the enone system (methyl - E1; isopropyl - E2; isobutyl - E3; and cyclopropyl - E4) and explored their anticancer potential against human carcinoma of the colon HCT-116, the cervical HeLa, and normal lung cells MRC-5. From the findings, all the newly synthesized enones exhibited potent cytotoxic activity against the cancer cells while normal cells remained unharmed, with varying potencies among the various enones. We employed the MTT assay to assess enones's (E1-E4) cytotoxic effects, IC50 values and selectivity index in tumor cells. Furthermore, the newly synthesized enones induced cell death in cancer cells through apoptosis by promoting changes in cellular morphology, activating apoptotic regulators Bax and caspase 3, and inhibiting Bcl-2. The enones induced changes in the mitochondrial membrane potential, a release of cytochrome c, and a cell cycle arrest at the G2/M phase, thus inhibiting the growth of cancer cells. In conclusion, we demonstrated the anticancer potential of newly synthesized enones as promising candidates for future cancer treatments, especially for colon cancer, due to their selective cytotoxicity against these cancer cells. Further, in vivo studies are warranted to explore their full therapeutic potential.

Synthesis and Characterization of Novel Diethylenetriamine Based Sulfonamide Ligands and Their Bidentate Platinum(II) Complexes Toward Anticancer Drug Leads

Diethylenetriamine (dienH) is one of the most biologically compatible chelate frameworks. Its hydrophilic amine moiety was functionalized via N-sulfonylation with sulfonyl chloride to produce two novel ligands; N(SO2)(bzd)dienH (L1) and N(SO2)(4-Mebip)dienH (L2) and two reported ligands; N(SO2)(1-nap)dienH (L3) and N(SO2)(2-nap)dienH (L4). Treatment of cis-Pt(DMSO)2Cl2with L1, L2, L3 and L4 afforded four novel neutral complexes [Pt(N(SO2)(bzd)dienH)Cl2] (C1), [Pt(N(SO2)(4-Mebip)dienH)Cl2] (C2), [Pt(N(SO2)(1-nap)dienH)Cl2] (C3) and [Pt(N(SO2)(2-nap)dienH)Cl2] (C4) respectively. All synthesized compounds were characterized by 1H NMR, UV-Vis, FTIR and fluorescence spectroscopy. Aliphatic diethylenetriamine protons of the ligands appeared in the 3.00 -2.30 ppm region in 1H NMR spectra recorded in DMSO-d6. Upon complexation, the appearance of two broad NH peaks between 5.00 -7.00 ppm region and another broad peak between 7.00-8.00 ppm confirmed the bidentatedenticity of the ligands vs tridentate. The formation of metal complexes was further supported by FTIR spectra in which the S-N stretching band for the metal complexes appears at lower wavenumbers compared to that of the corresponding free ligands. Emission spectra were recorded in methanol and intense fluorescence properties were observed in the 331-364 nm range for the ligands, whereas the corresponding Pt complexes showed quenched fluorescence. In vitro cytotoxic effects were investigatedusing sulforhodamine B assay, where L2 (&lt; 10 μg/mL) demonstrated increased levels of cytotoxicity followed by C2 (&lt; 25 μg/mL) and C4 (&lt; 50 μg/mL) to non-small cell lung cancer cells in dose and time-dependent manner, with less or no cytotoxic effects to normal lung cells tested. Among the compounds tested, C1 and C3 displayed comparatively lower but more potent cytotoxic effects on lung cancer cells. Notably, these compounds did not exhibit any toxicity towards normal cells. Thus, they hold promise as lead compounds for the development of chemotherapeutic agents targeting lung cancer.&#x0D; Keywords: Platinum, Sulfonamide, Biphenyl, Benzodioxan, aphthalene

The role of glucose and fructose on lipid droplet metabolism in human normal bronchial and cancer lung cells by Raman spectroscopy

Fructose is one of the most important monosaccharides in the human diet that the human body needs for proper metabolism. This paper presents an approach to study biochemical changes caused by sugars in human normal bronchial cells (BEpiC) and human cancer lung cells (A549) by Raman spectroscopy and Raman imaging. Results after supplementation of human bronchial and lung cells with fructose are also discussed and compared with results obtained for pure human bronchial and lung cells. Based on Raman techniques we have proved that peaks at 750 cm−1, 1126 cm−1, 1444 cm−1, 1584 cm−1 and 2845 cm−1 can be treated as biomarkers to monitor fructose changes in cells. Results for fructose have been compared with results for glucose. Raman analysis of the bands at 750 cm−1, 1126 cm−1, 1584 cm−1 and 2845 cm−1 for pure BEpiC and A549 cells and BEpiC and A549 after supplementation with fructose and glucose are higher after supplementation with fructose in comparison to glucose. The obtained results shed light on the uninvestigated influence of glucose and fructose on lipid droplet metabolism by Raman spectroscopy methods.

Psephellus huber-morathii (Wagenitz) Wagenitz'in potansiyelini keşfetme: Fitokimyasal bileşiminin kapsamlı bir UHPLC-MS/MS analizi ve antioksidan, antimikrobiyal ve antiproliferatif aktivitelerinin değerlendirmesi

Aims: Psephellus huber-morathii (PH) is an endemic species in the Eastern Anatolia Region. In this study, besides the biological activities of the 70% methanol extract of PH, its comprehensive phytochemical composition was investigated.&#x0D; Material and methods: The phenolic composition of the PH extract was analyzed using the UHPLC-MS/MS method. To evaluate its antimicrobial characteristics, the microdilution technique was employed. The antioxidant capabilities, total phenolic and flavonoid contents of the extract were determined using the spectrophotometer. Additionally, the effects of the extracts on cell proliferation and NCI-60 survival parameter values were assessed using the MTT assay.&#x0D; Results: Quinic acid and chlorogenic acid were major compounds. The extract showed high antioxidant activity in DPPH (IC50:13.9±0.4 μg mL-1) and FRAP (61.3±2.3 mg TE g extract-1) methods. The total phenolic and flavonoid contents of the extract were found as 52.2±1.9 mg GAE g extract-1 and 28.6±0.9 mg QE g extract-1, respectively. &#x0D; Discussion: The extract showed low antiproliferative activity against normal lung and retinal cell lines, promising anticancer effect on gynecological and colon cancer cells, and moderate antimicrobial activity against Bacillus cereus and Enterococcus faecium.&#x0D; Conclusions: The study demonstrated the medicinal potential and value of PH extract against infectious diseases and cancer.

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.

Development and characterization of inhaled nintedanib-loaded PLGA nanoparticles using scalable high-pressure homogenization technique

Presently, non-invasive targeted drug delivery to the lungs represents a routinely investigated approach to treat challenging disorders such as pulmonary fibrosis. Nintedanib (Nint) is an FDA-approved drug for treating idiopathic pulmonary fibrosis and certain interstitial lung diseases. Nint acts as a multiple tyrosine kinase inhibitor, demonstrating anti-neoplastic effects in non-small cell lung cancer. However, limitations of oral administration of Nint include low bioavailability and high dose requirement for adequate therapeutic efficacy, resulting in adverse effects like abdominal pain, sickness, diarrhea, and vomiting. In this project, Nint was reformulated into PLGA nanoparticles (Nint-NPs) for direct-lung administration to address these deficiencies and enhance its potential. In this project, Nint-NPs were designed utilizing a high-pressure homogenization (HPH) approach with excellent reproducibility and scale-up feasibility. Selected Nint-NP formulation revealed 43.3 ± 4.0 % of entrapment efficiency and 179.8 ± 3.1 nm of size. In-vitro release study showed an initial burst release of 36.0 ± 7.5 % within 30 min, followed by sustained release up to 71.0 ± 4.3 % by 96 h. Further, Nint-NPs were found to be stable after 1-month of storage in refrigerated and accelerated conditions. Interestingly, the results of lung deposition demonstrated ideal MMAD values less than 5 μm in all three nebulizer types tested (jet, breath-actuated jet, and vibrating mesh nebulizers), indicating Nint-NPs are appropriate for deep-lung delivery. In-vitro cellular uptake analysis exhibited higher internalization of NPs in alveolar epithelial cells and lung fibroblasts while avoiding macrophage uptake. Toxicity studies on normal lung cells indicated Nint-NPs were safe for use. Taken together, inhalation therapy of Nint-NPs offers a favorable alternative to oral capsules for treating respiratory diseases.

Repurposing Study of 4-Acyl-1-phenylaminocarbonyl-2-substituted-piperazine Derivatives as Potential Anticancer Agents—In Vitro Evaluation against Breast Cancer Cells

Breast cancer is the most common type of cancer in women. Although current treatments can increase patient survival, they are rarely curative when the disease is advanced (metastasis). Therefore, there is an urgent need to develop new cytotoxic drugs with a high selectivity toward cancer cells. Since repurposing approved drugs for cancer therapy has been a successful strategy in recent years, in this study, we screened a library of antiviral piperazine-derived compounds as anticancer agents. The compounds included a piperazine ring and aryl urea functions, which are privileged structures present in several anti-breast cancer drugs. The selective cytotoxic activity of a set of thirty-four 4-acyl-2-substituted piperazine urea derivatives against MCF7 breast cancer cells and MCF 10A normal breast cells was determined. Compounds 31, 32, 35, and 37 showed high selective anticancer activity against breast cancer cells and were also tested against another common type of cancer, non-small cell lung cancer (A549 lung cancer cells versus MRC-5 lung normal cells). Compounds 35 and 37 also showed selectivity against lung cancer cells. These results suggest that compounds 35 and 37 may be promising hit compounds for the development of new anticancer agents.

Pulmonary Aspergillosis in Naïve Non-neutropenic Lung Cancer Patients

Abstract: Pulmonary aspergillosis is the most common mould infection of the lungs. Patients with chronic lung disease or mild immunodeficiency are at risk. Lung cancer represents an oncological challenge. Limited data are available about aspergillosis in newly diagnosed non-neutropenic lung cancer patients. Objectives:: The aim of this work was to evaluate naïve lung cancer patients for the presence of as-pergillosis, identify fungal isolates, and determine antifungal susceptibility. The inhibitory effect of secondary metabolites of fungal isolates on the human fibroblast cell line was also assessed. Results:: Aspergillus isolates were detected in 33 BAL samples out of the 69 patients (47.8%). The commonest isolate was A. niger. There was no significant correlation between total fungal count and age of patients. The antifungal Micafungin had a broad-spectrum and potent fungistatic activity against all fungal species, with A. niger being the most sensitive. MTT assay was performed to evaluate the cytotoxic effect of both A. niger and A. fumigatus on normal lung cells (WI-38) and re-vealed that toxicity was concentration-dependent and A. niger had significantly lower IC 50, indi-cating more toxicity. Conclusion:: In the context of the diagnosis of lung cancer, maintaining vigilance is crucial to diag-nose fungal infection as aspergillosis. Initiation of proper management can help improve patient outcomes.

MiR-218-5p Targeting TPX2 Regulates p53 Pathway and Inhibits Malignant Progression of Lung Adenocarcinoma

Lung adenocarcinoma (LUAD) is a major subtype of lung cancer, and its treatment and diagnosis remain a hot research topic. Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is highly expressed in a variety of cancer cells and may be associated with the progression of LUAD. This study aimed to investigate the effect of TPX2 on the malignant progression of LUAD cells and the regulatory mechanisms. The expression of gene TPX2 in LUAD tissues from The Cancer Genome Atlas (TCGA) database was analyzed by bioinformatics analysis techniques. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of TPX2 and miR-218-5p in human lung normal cell lines and human LUAD cell lines. Western blot was used to detect TPX2 protein expression in cell lines and its effect on the expression of key proteins in the p53 signaling pathway. The relationship between TPX2 and miR-218-5p was predicted using bioinformatics and verified by dual luciferase reporter gene assay. Cell counting kit-8 (CCK-8) assay, cell clone formation, cell scratching, Transwell assay, and flow cytometry were used to detect the effects of miR-218-5p and TPX2 on LUAD cell function. TPX2 was significantly overexpressed in LUAD cells, and knockdown of TPX2 inhibited LUAD cell proliferation, migration, and invasion, promoted apoptosis and induced G2/M phase block, and promoted the expression of key proteins in the p53 signaling pathway. miR-218-5p, an upstream regulator of TPX2, could inhibit its expression. Overexpression of miR-218-5p eliminated the malignant development caused by high expression of TPX2, inhibited the malignant processes of LUAD cells such as proliferation and migration as well as promoted the p53 signaling pathway. miR-218-5p targets and inhibits TPX2 expression and exerts an inhibitory effect on the malignant progression of LUAD cells via p53.

Exploring the anti-cancer potential of methanolic extract from Simarouba glauca: Induction of apoptosis and growth inhibition in lung cancer cells

The causes behind lung cancer etiology remain unknown, and treatment failure is often caused by medication resistance, recurrence, and metastasis. Clinical development of novel therapeutic molecules to overcome drug resistance remains a problem. The purpose of this study was to evaluate the potential of Simarouba glauca triterpenoids among two different plant extracts (leaf extract and bark extract) in two human cell lines: lung adenocarcinoma (A549) and normal lung (L132) cell lines using four different solvents. The concentration yield of methanolic bark extract and leaf extracts was found to be higher compared to the other solvents using the Soxhlet method of extraction. Phytochemical analysis using Liberman-Burchard's test conducted confirmed the presence of triterpenoids in Methanolic extract from barks of Simarouba glauca. Comparative cytotoxicity potential among the extracts from bark and leaves, bark extracts showed an IC50 and LD50 as 350 μg/mL and 300 μg/mL respectively on the A549 cell lines of lung carcinoma. Cell cycle analysis using Methanolic bark extracts in comparison to the leaf extracts showed the arrest of the proliferation of A549 cells at the G0/G1 stage with a significant increase in cells at a level of 42.33%, 23.93%–23.47%, 17.96% respectively. Increased Reactive Oxygen Species (ROS) levels in the A549 cells in 1 h treated with bark extract and leaf extract than in the untreated cells. The methanolic extract from both the bark and leaves was found to be the most potent presenting potential arrest of cell cycle, reactive oxygen species generation and apoptosis. In summary, our study has found that the S. glauca-based plant extract has the anticancer potential by triggering apoptosis.

Hydromethanolic leaves extract of Dalbergia sissoo Roxb. ex DC. induces apoptosis in lung adenocarcinoma cells

Plants have a wide range of active secondary metabolites that are frequently utilized to treat cancer. For the research, Dalbergia sissoo Roxb. ex DC. leaves (DS) were hydromethanolically extracted, and their phytochemical content was determined. Total phenolics and flavonoids were quantified along with the measurement of in vitro antioxidant and cytotoxic activities. The bioactive components in the extract were identified with the use of Gas Chromatography with High-Resolution Mass Spectrometry (GC-HRMS). The crude extract contained 177.500 ± 0.019 mg/ml of flavonoids and 296.122 ± 0.002 mg/ml of Gallic Acid Equivalent (GAE) phenolics. Moreover, plant crude extract showed significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) activity (IC50, 14.06 ± 0.18 μg/ml), 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) [ABTS] activity (IC50, 25.97 ± 1.04 μg/ml), superoxide scavenging activity (IC50, 149.91 ± 0.39 μg/ml), and hydrogen peroxide scavenging activity (IC50, 133.37 ± 2.30 μg/ml). The thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) methods were used to confirm the presence of phenolic compounds. DS effectively scavenges nitric oxide. The crude extract of DS exhibited good cytotoxic effects on lung cancer cells (A549) with an IC50 value of 90.56 ± 2.32 (μg/ml), and less toxicity on normal lung cells (WI-38) with an IC50 value of 381.10 ± 1.58 (μg/ml). IC50 value of methotrexate (the standard drug) was 10.20 ± 1.82 μg/ml on A549 cells and 26.21 ± 1.14 μg/ml on WI-38 cells. Various staining techniques [4, 6-diamidino-2-phenylindole (DAPI), Acridine orange/Ethidium Bromide (AO/EB) staining, Giemsa staining] were used to determine the plausible mechanism of DS to induce apoptosis. The inhibiting mechanism of the crude extract was further demonstrated by the clonogenic assay and qualitative and quantitative measurements of Reactive Oxygen Species (ROS). Real-time polymerase chain reaction (RT-PCR) analysis revealed the induction of apoptosis in A549 cells through the activation of caspases 9 and 3 together with TRAIL receptors. In a nutshell, hydromethanolic extract of DS resulted in distinct apoptotic morphological alterations, ROS production, the initiation of apoptosis via activating the TRAIL receptors, caspase 9 and 3, and the suppression of colony formation in A549 cells.

Comprehensive analysis of cuproptosis and copper homeostasis genotyping and related immune land scape in lung adenocarcinoma

Cuproptosis is a manner of cell death which is related to the homeostasis of copper ions in the cellular environment and is expected to open a new direction of anti-tumor therapy. However, the studies on cuproptosis and copper homeostasis in lung adenocarcinoma (LUAD) are still limited. In this study, we identified new cuproptosis and copper homeostasis related genes (CHRGs) which were effective in stratifying genotyping clusters with survival differences based on transcriptomic data obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Weighted Gene Co-expression Network Analysis (WGCNA) further expands the screening boundary of CHRGs, and finally we established a 10-CHRGs-based prognostic signature using lasso-penalized cox regression method, which were validated in GSE30219. Comprehensive bioinformatics analysis revealed these genes are potential regulators of modulating immunotherapy efficacy, drug resistance, tumor microenvironment infiltration, and tumor mutation patterns. Lastly, the scRNA-seq datasets GSE183219 and GSE203360 offers the evidences that CHRGs signature are mainly distributed in cancer epithelial cells, real time quantitative polymerase chain reaction (RT-qPCR) also confirmed the differential expression of these genes between normal lung cell line and lung adenocarcinoma cell lines. Collectively, our findings revealed new cuproptosis and copper homeostasis related genotyping clusters and genes which may play important roles in predicting prognosis, influencing tumor microenvironment and drug efficacy in LUAD patients.

Cover: Journal of the Chinese Chemical Society 10/2023

In this figure, a 1,2,3‐triazole linker bridged flavanol and benzenesulfonamide as hybrid molecules via click chemistry. The twelve target molecules were evaluated against human non‐small‐cell lung cancer cells (A549 and H1975), and two of them performed promising anti‐cancer activity while being selective and sparing MRC5 normal lung cells. More details about this figure will be discussed by Dr. Tzenge‐Lien Shih and his coworkers on page 1924–1936 in this issue. image

Design, synthesis of (±)-millpuline A and biological evaluation for the lung cell protective effects through SRC.

In this paper, a visible-light-induced intermolecular [2+2] photocycloaddition reaction based on flavonoids was constructed to address the problems of low yield, poor physicochemical properties, and lack of target definition in total synthesis of(±)-millpuline A whose bioactivity remains unknown. As a result, 20 derivatives (B1-B20) were synthesized for bioactivity evaluation. Consequently, lung cell protective effects of (±)-millpuline A andB13awere revealed for the first time and the crucial role of stereoconfiguration of the cyclobutane moiety in their protective effects against NNK in normal lung cells was demonstrated. Moreover, through target prediction and experimental verification in MLE-12 cells, SRC was determined to be the target of (±)-millpuline A regarding its protective effect in NNK-induced lung cell injury. Results from RT-Q-PCR and HTRF experiments verified that (±)-millpuline A could repress SRC activity through a transcriptional mechanism but not acting as an inhibitor to directly bind to and thereby inhibit SRC protein. The results in this paper are informative for the further development of visible light-catalyzed cycloaddition of flavon-oids and lay a scientific foundation for understanding the bioactivity and underlying mechanism of (±)-millpuline A and other structurally similar natural skeletons.