Adenocarcinoma Cell Research Articles

Epigenetic Regulation of CXC Chemokine Expression by Environmental Electrophiles Through DNA Methyltransferase Inhibition.

Ubiquitously distributed environmental electrophiles covalently modify DNA and proteins, potentially leading to adverse health effects. However, the impacts of specific electrophiles on target proteins and their physiological roles remain largely unknown. In the present study, we focused on DNA methylation, which regulates gene expression and physiological responses. A total of 45 environmental electrophiles were screened for inhibitory effects on the activity of DNA methyltransferase 3B (DNMT3B), a key enzyme in DNA methylation, and four compounds were identified. We focused on 1,2-naphthoquinone (1,2-NQ), an air pollutant whose toxicity has been reported previously. Interestingly, we found that 1,2-NQ modified multiple lysine and histidine residues in DNMT3B, one of which was near the active site in DNMT3B. It was found that 1,2-NQ altered gene expression and evoked inflammatory responses in lung adenocarcinoma cell lines. Furthermore, we found that 1,2-NQ upregulated CXCL8 expression through DNA demethylation of the distal enhancer and promoted cancer cell growth. Our study reveals novel mechanisms of epigenetic regulation by environmental electrophiles through the inhibition of DNMT3B activity and suggests their physiological impact.

VASN promotes the aggressive phenotype in ARID1A-deficient lung adenocarcinoma

Loss of ARID1A has been reported to drive the progression of lung adenocarcinoma, yet the underlying mechanism remains elusive. In this study, we performed secretome analysis to identify the key secreted proteins regulating lung adenocarcinoma progression. We showed that the VASN level was significantly elevated in the conditioned medium from ARID1A-depleted A549 and H1299 cells. Restoration of ARID1A in ARID1A-depleted lung adenocarcinoma cells prevented the upregulation and secretion of VASN. Clinical analysis demonstrated a negative correlation between ARID1A and VASN expression in ARID1A-mutated lung adenocarcinomas. The patients with ARID1A-mutated lung adenocarcinoma had significantly higher concentrations of serum VASN than healthy controls. Moreover, serum VASN concentrations were associated with TNM stage, lymph node metastasis, and overall survival of the patients with ARID1A-mutated lung adenocarcinoma. Functional studies indicated that VASN overexpression potentiated the proliferation, invasion, and tumorigenesis of lung adenocarcinoma cells. Antibody neutralization of VASN suppressed the aggressiveness of ARID1A-depleted lung adenocarcinoma cells both in vitro and in vivo. Addition of recombinant VASN protein promoted the proliferation and invasion of lung adenocarcinoma cells. Additionally, knockdown of Notch1 blocked the aggressive phenotype induced by recombinant VASN protein. In conclusion, our data uncover the role of VASN in mediating the progression of ARID1A-depleted lung adenocarcinoma and highlight VASN as a promising therapeutic target for this disease.

Potential probiotic Lactiplantibacillus plantarum strains alleviate TNF-α by regulating ADAM17 protein and ameliorate gut integrity through tight junction protein expression in in vitro model

BackgroundLactiplantibacillus species are extensively studied for their ability to regulate host immune responses and functional therapeutic potentials. Nevertheless, there is a lack of understanding on the mechanisms of interactions with the hosts during immunoregulatory activities.MethodsTwo Lactiplantibacillus plantarum strains MKMB01 and MKMB02 were tested for probiotic potential following Indian Council of Medical Research (ICMR) guidelines. Human colorectal adenocarcinoma cells such as HT-29, caco-2, and human monocytic cell THP-1 were also used to study the potential of MKMB01 and MKMB02 in regulating the host immune response when challenged with enteric pathogen Salmonella enterica typhimurium. Cells were pre-treated with MKMB01 and MKMB02 for 4 h and then stimulated with Salmonella. qRT-PCR and ELISA were used to analyze the genes and protein expression. Confocal microscopy and field emission scanning electron microscopy (FESEM) were used to visualize the effects. An Agilent Seahorse XF analyzer was used to determine real-time mitochondrial functioning.ResultsBoth probiotic strains could defend against Salmonella by maintaining gut integrity via expressing tight junction proteins (TJPs), MUC-2, and toll-like receptors (TLRs) negative regulators such as single Ig IL-1-related receptor (SIGIRR), toll-interacting protein (Tollip), interleukin-1 receptor-associated kinase (IRAK)-M, A20, and anti-inflammatory transforming growth factor-β and interleukin-10. Both strains also downregulated the expression of pro-inflammatory cytokines/chemokines interleukin-1β, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor-alpha (TNF-α), interleukin 6, and nitric oxide (NO). Moreover, TNF-α sheddase protein, a disintegrin and metalloproteinase domain 17 (ADAM17), and its regulator iRhom2 were downregulated by both strains. Moreover, the bacteria also ameliorated Salmonella-induced mitochondrial dysfunction by restoring bioenergetic profiles, such as non-mitochondrial respiration, spare respiratory capacity (SRC), basal respiration, adenosine triphosphate (ATP) production, and maximal respiration.ConclusionsMKMB01 and MKMB02 can reduce pathogen-induced gut-associated disorders and therefore should be further explored for their probiotic potential.

KEFIRAN in vitro biological activity on enterocytes and mesodermal origin cell lines: Focus on adenocarcinoma cells HT29

Kefiran, the exopolysaccharide found in the fermented milk named “kefir” has been receiving attention over the last years due to its interesting biological and functional properties. It is a non-digestible branched glucogalactan with a molecular weight higher than 1 106 Da. Kefiran was isolated from kefir grains and its biological activity was assessed on different cell lines. Proliferation (trypan blue exclusion assay), mitochondrial activity (MTT assay), viability (Alive-Vulnerable-Dead model, AVD) and cell death were studied. It was found that proliferation was not inhibited in mesodermal cell line MC3 (osteoblast cell line) or in not-invasive colonocytes (Caco-2/TC7 cell line); on the contrary, the high invasive HT29 cell line and the UMR106 osteosarcoma cell line were sensitive to kefiran 0.5 mg/mL, and a significant diminishment on cell proliferation was found by trypan blue dye exclusion assay. Kefiran maintained mitochondrial activity while increased cell death processes in a dose-dependent way in HT29 cell line. When viability was assessed by AVD model, it was found that kefiran increased vulnerability status of neoplasic cell line HT29. In summary, in the present work, we shown that kefiran has a different effect on tumor and non-tumor cell lines. Our results contribute to the understanding of kefiran effect on the empirical antitumoral effect attributed to kefir consumption.

Genetic profile of ferroptosis in non-small cell lung carcinoma and pharmaceutical options for ferroptosis induction.

Lung cancer (LC) is the leading cause of cancer-related deaths and the second most commonly diagnosed malignancy worldwide. Lung adenocarcinoma (LUAD) and lung squamous cell LC (LUSCC) are the most common subtypes of non-small cell LC (NSCLC). Early diagnosis of LC can be challenging due to a lack of biomarkers. The overall survival (OS) of patients with NSCLC is still poor despite the enormous efforts that have been made to develop novel treatments. Understanding fundamental molecular and genetic mechanisms is necessary to develop new therapeutic approaches for NSCLC. A recently identified type of programmed cell death known as ferroptosis is one potential approach. Ferroptosis causes oxidative damage and the death of cancerous cells by peroxidizing unsaturated phospholipids and accumulating reactive oxygen species (ROS) in an iron-dependent manner. Ferroptosis-related gene (FRG) signatures have recently been evaluated for their ability to predict patient OS and prognosis. These analyses show FRGs are involved in cancer progression, and may serve as promising biomarkers for tumor diagnosis and therapy. Moreover, we summarize the current pharmaceutical options of ferroptosis induction and their underlying molecular mechanism in LC. Therefore, this review aims to provide a comprehensive summary of FRG-based prognostic models, their associated metabolic and signaling pathways, and promising therapeutic options for ferroptosis induction in NSCLC.

Microbial synthesis of zinc oxide nanoparticles and their potential biological application as an antimicrobial and anticancer agent

Zinc oxide nanoparticles (ZnO-NPs) are a type of metal oxide nanomaterial, recognized as a valuable and adaptable inorganic compound owing to its distinctive physical and chemical properties. Nanosized ZnO particles exhibit substantial antibacterial properties attributable to their diminutive size, which can activate various bactericidal mechanisms within the bacterial cell, including interactions with the bacterial surface or core, the generation of reactive oxygen species (ROS), the release of Zn2+, and potential endocytosis by cells. ZnO NPs nanoparticles were extracellularly produced using pigment extracts from the PP6 strain. Agar well screening indicated that PP6 secondary metabolites possess antibacterial properties. UV–Vis spectroscopy was used to analyze the external growth of nanoparticles. Scanning Electron Microcopy (SEM), Fourier Transform Infrared Spectroscopy (FTIR), and X-ray diffraction (XRD) techniques were employed to analyze the shape, stability, crystalline structure, and coating of strain PP6 ZnO NPs. The PP6 ZnO NPs demonstrated an antibiofilm impact on the bacterial pathogens tested, which was dependent on the dosage. Elevated levels of lipid peroxidation (LPO) and reduced antioxidant activity are indicative of apoptosis in cancer cells. The synthesized ZnO NPs nanoparticles were assessed for their anticancer properties by performing the MTT assay on HT-29 human colorectal adenocarcinoma cells. ZnO NPs nanoparticles exposed to HT-29 cells the viability was reduced significantly in proportion to the concentration of nanoparticles. Additional comprehensive study will be needed to fully understand their mechanism.

Ultra-Performance Liquid Chromatography and Mass Spectrometry Characterization, and Antioxidant, Protective, and Anti-Inflammatory Activity, of the Polyphenolic Fraction from Ocimum basilicum.

Ocimum basilicum is a valuable plant widely consumed worldwide and considered a rich source of polyphenols. This study examined the impact of the polyphenolic fraction isolated from basil (ObF) on human normal colon epithelial cells and human colorectal adenocarcinoma cells, evaluating its anti-inflammatory and protective activity against oxidative stress. The phytochemical characterization of the fraction was performed using ultra-performance liquid chromatography (UPLC) with a photodiode detector (DAD) and mass spectrometry (MS). UPLC-DAD-MS revealed that ObF predominantly contains caffeic acid derivatives, with rosmarinic acid and chicoric acid being the most abundant. The fraction demonstrated high antioxidant potential, as shown by DPPH assays, along with significant reducing power (FRAP). Furthermore, it prevented the depletion of antioxidant enzymes, including superoxide dismutase and catalase, and decreased malonylodialdehyde (MDA) in induced oxidative stress condition. Additionally, it exhibited a significant protective effect against H2O2-induced cytotoxicity in human normal colon epithelial cells. Although it had no impact on the viability of adenocarcinoma cells, it significantly reduced IL-1β levels in the neoplastic microenvironment. Our study demonstrated that basil polyphenols provide significant health benefits due to their antioxidant and protective activities.

Differentiation of pathological subtypes and Ki-67 and TTF-1 expression by dual-energy CT (DECT) volumetric quantitative analysis in non-small cell lung cancer

BackgroundTo explore the value of dual-energy computed tomography (DECT) in differentiating pathological subtypes and the expression of immunohistochemical markers Ki-67 and thyroid transcription factor 1 (TTF-1) in patients with non-small cell lung cancer (NSCLC).MethodsBetween July 2022 and May 2024, patients suspected of lung cancer who underwent two-phase contrast-enhanced DECT were prospectively recruited. Whole-tumor volumetric and conventional spectral analysis were utilized to measure DECT parameters in the arterial and venous phase. The DECT parameters model, clinical-CT radiological features model, and combined prediction model were developed to discriminate pathological subtypes and predict Ki-67 or TTF-1 expression. Multivariate logistic regression analysis was used to identify independent predictors. The diagnostic efficacy was assessed by the area under the receiver operating characteristic curve (AUC) and compared using DeLong’s test.ResultsThis study included 119 patients (92 males and 27 females; mean age, 63.0 ± 9.4 years) who was diagnosed with NSCLC. When applying the DECT parameters model to differentiate between adenocarcinoma and squamous cell carcinoma, ROC curve analysis indicated superior diagnostic performance for conventional spectral analysis over volumetric spectral analysis (AUC, 0.801 vs. 0.709). Volumetric spectral analysis exhibited higher diagnostic efficacy in predicting immunohistochemical markers compared to conventional spectral analysis (both P < 0.05). For Ki-67 and TTF-1 expression, the combined prediction model demonstrated optimal diagnostic performance with AUC of 0.943 and 0.967, respectively.ConclusionsThe combined predictive model based on volumetric quantitative analysis in DECT offers valuable information to discriminate immunohistochemical expression status, facilitating clinical decision-making for patients with NSCLC.

Food grade titanium dioxide induced endoplasmic reticulum stress in colon cells: Comparison between normal and colorectal carcinoma cells

BackgroundFood-grade titanium dioxide (E171) has been under scrutiny in the last decade since its possible adverse effects; however, the cellular mechanisms underlying E171 toxicity have not been thoroughly described. AimWe aimed to compare the effects of E171 on endoplasmic reticulum (ER) homeostasis in normal and cancer colon cells. Experimental designWe exposed normal, carcinoma, and adenocarcinoma cells to 0.1, 1, 10, 50 and 100 μg/cm2 of E171 for 24, 48 and 72 h, and we evaluated ER stress, cell viability, titanium uptake, intracellular calcium concentration, and gene expression related to unfolded protein response (UPR) and chaperone pathways. ResultsCell viability decreased only after 72 h of exposure to 100 μg/cm2 of E171. Adenocarcinoma cells internalized higher titanium amounts than normal and carcinoma cells, but the effects in ER distribution, intracellular calcium concentration, and gene expression were similar among the three cell lines. The expression of UPR and chaperone pathways were downregulated at the lowest concentrations but upregulated at the highest concentrations in the three cell lines. ConclusionE171 induces ER stress through alterations in ER distribution, intracellular calcium, and UPR and chaperone protein pathways.

Dipicolinate‐Ruthenium‐NHC/trpy Complexes: Pincer Ligand Induced Hemilability of Dipicolinate and Enhancement of Cytotoxic Property

AbstractA ruthenium(II) aquo complex [Ru(dipic)(PPh3)2(OH2)], (1 A), bearing O,N,O‐coordinated 2,6‐dipicolinate was synthesized via reaction of [Ru(PPh3)3Cl2] with 2,6‐dipicolinic acid. Crystal structure of 1 A was determined. Utilizing 1 A as a synthon, three new complexes were synthesized. Reaction of 1 A with a bidentate NHC‐ligand, viz. 1‐methyl‐3‐(2′‐pyridyl)imidazole (IMeCN), afforded [Ru(dipic)(IMeCN)(PPh3)], (2 A). Similar reactions of 1 A with two pincer ligands, viz. 2,6‐bis(1′‐methyl imidazolyl)pyridine (IMeCNC) and 2,2′;6′,2“‐terpyridine (trpy), respectively yielded [Ru(dipic)(IMeCNC)(PPh3)], (3 A) and [Ru(dipic)(trpy)(PPh3)], (3 B). Structure of 2 A was optimized by DFT method. Structures of 3 A and 3 B were determined by X‐ray crystallography. In both 3 A and 3B the 2,6‐dipicolinate ligand was found to be N,O‐coordinated with one carboxy end remaining unbound to the metal center. Anticancer property of 2 A, 3 A and 3 B was studied and compared. Cytotoxicity of 3 A, studied against three selected cancer cell lines, viz. chronic myelogenous leukemia cell line (K562), hepatocellular carcinoma cell line (HepG2) and breast adenocarcinoma cell line (MCF7), was found to be the most promising. It displayed the best activity against K562, while it did not have any appreciable effect on its normal counterpart, viz. the human peripheral blood mononuclear cells (hPBMC). The comparative cytotoxicity studies indicated that presence of the C,N,C‐coordinated pincer NHC ligand in 3 A, together with presence of the free carboxylate end of N,O‐coordinated dipic ligand, are presumably responsible for its superior cytotoxic behavior.

Comparative cellular toxicity between silver and poly (lactic-co-glycolic acid) nanoparticles

Nanoparticles composed of poly (lactic‑co‑glycolic acid) (PLGANPs) and silver (AgNPs) are relevant in the context of their interactions with biological systems. This study aims to evaluate the potential in vitro cytotoxic effects of both PLGANPs and AgNPs on a human colorectal adenocarcinoma cell line (Caco‑2). The impact of nanoparticles on cellular toxicity, morphology, microvilli density and viscoelasticity were assessed. After 48 hours incubation with PLGANPs, cells exhibited a modest proliferation compared to the control (6 to14%), low reactive nitrogen species (RNS) production (2 μM) and higher microvilli densities. In contrast, AgNPs displayed significant toxicity (LC50 = 3.76 μg/mL) and elevated RNS production.

TGF-β-Induced PAUF Plays a Pivotal Role in the Migration and Invasion of Human Pancreatic Ductal Adenocarcinoma Cell Line Panc-1.

Pancreatic adenocarcinoma upregulated factor (PAUF) was initially identified as a secreted protein that is substantially expressed in pancreatic ductal adenocarcinoma (PDAC). PAUF also affects invasiveness, motility, and the proliferation of cells in several types of cancer. Recently, PAUF was reported to play a pivotal role in the TLR4-mediated migration and invasion of PDAC cells. However, the mechanism inducing PAUF expression and its functional role in TGF-β-stimulated PDAC cells have not yet been studied. Thus, we first assessed whether TGF-β regulates PAUF expression in several PDAC cell lines and found a significant increase in PAUF expression in Smad signaling-positive Panc-1 cells treated with TGF-β. We also found that the PAUF promoter region contains a Smad-binding element. TGF-β-treated Panc-1 cells showed an increase in PAUF promoter activity, but this effect was not observed in TGF-β-stimulated Smad4-null BxPC-3 cells. Restoring Smad4 expression increased the PAUF promoter activity and expression in Smad4-overexpressing BxPC-3 cells treated with TGF-β. We further found that PAUF aggravated the TGF-β-induced epithelial-mesenchymal transition (EMT) in Panc-1 and BxPC-3 cells via the activation of MEK-ERK signaling. These results indicate that TGF-β/Smad signaling-mediated upregulation of PAUF plays a crucial role in EMT progression by activating the TGF-β-mediated MEK-ERK signaling pathway.

Immune regulation and prognostic prediction model establishment and validation of PSMB6 in lung adenocarcinoma.

Lung cancer is one of the most common malignant tumors, and patients are often diagnosed at an advanced stage, posing a substantial risk to human health, so it is crucial to establish a model to forecast the prognosis of patients with lung cancer. Recent research has indicated that proteasome 20S subunit 6 (PSMB6) may be closely associated with anti-apoptotic pathways, and proliferation transduction signals in tumor cells of different tumors. However, the precise role of PSMB6 in the immunoregulatory processes within lung adenocarcinoma (LUAD) is yet to be elucidated. By analyzing the TCGA database, we discovered a positive correlation between the expression of PSMB6 and tumor growth trends, and lung adenocarcinoma patients with elevated PSMB6 expression levels had a worse prognosis. Our findings suggest a close correlation between PSMB6 expression levels, immune cell infiltration and immune checkpoint gene expression, which suggests that PSMB6 may become a new independent prognostic indicator. In addition, we developed a prognostic model of PSMB6-regulated immune infiltration-associated genes by analyzing the link between PSMB6 and the immune microenvironment. This model can not only predict the prognosis of lung adenocarcinoma but also forecasts the patient's reaction to immunotherapy. The validity of this research outcome has been confirmed by the GSE31210 and IMvigor210 cohorts. Analysis of the Kaplan-Meier Plotter database indicates that individuals with elevated levels of PSMB6 expression exhibit a poorer prognosis. Additionally, in vitro experiments demonstrated that knockdown of PSMB6 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells while promoting their apoptosis. Overall, our findings suggest that PSMB6 could remarkably influence the management and treatment of lung adenocarcinoma, opening new avenues for targeted immunotherapeutic strategies.

S100A16 stabilizes the ITGA3‑mediated ECM‑receptor interaction pathway to drive the malignant properties of lung adenocarcinoma cells via binding MOV10.

Lung adenocarcinoma (LUAD) is highly associated with lung cancer‑associated mortality. Notably, S100 calcium‑binding protein A16 (S100A16) has been increasingly considered to have prognostic value in LUAD; however, the underlying mechanism remains unknown. In the present study, S100A16 expression levels in LUAD tissues and cells were respectively analyzed by the UALCAN database and western blotting. Cell Counting Kit‑8 and 5‑ethynyl‑2'‑deoxyuridine assays were used to examine cell proliferation, whereas wound healing, Transwell and tube formation assays were used to assess cell migration, invasion and angiogenesis, respectively. Western blotting was also used to examine the expression levels of proteins associated with metastasis, angiogenesis, focal adhesion and the extracellular matrix (ECM)‑receptor interaction pathways. The relationship between S100A16 and Mov10 RNA helicase (MOV10) was predicted by bioinformatics tools, and was verified using a co‑immunoprecipitation assay. Furthermore, the interaction between MOV10 and integrin α3 (ITGA3) was verified by RNA immunoprecipitation assay, and the actinomycin D assay was used to detect ITGA3 mRNA stability. The results demonstrated that S100A16 expression was increased in LUAD tissues and cell lines, and was associated with unfavorable outcomes. Knocking down S100A16 expression hindered the proliferation, migration, invasion and angiogenesis of LUAD cells. Furthermore, S100A16 was shown to bind to MOV10 and positively modulate MOV10 expression in LUAD cells, while MOV10 overexpression partially reversed the suppressive role of S100A16 knockdown on the aggressive phenotypes of LUAD cells. Furthermore, it was demonstrated that S100A16 regulated the stability of ITGA3 mRNA via MOV10 to mediate ECM‑receptor interactions. In conclusion, S100A16 may bind to MOV10 to stabilize ITGA3 mRNA and regulate ECM‑receptor interactions, hence contributing to the malignant progression of LUAD.

Salivary Gland Tumours in Children and Adolescents-A Study in Shaheed Monsur Ali Medical College &amp; Hospital, Uttara, Dhaka, Bangladesh

Introduction: Salivary gland carcinomas (SGCs) are rare neoplasms in adults, but are exceedingly infrequent in children, with a reported annual incidence of 0.8–1.4 per million populations under 20 years old. Like other pediatric very rare tumors, SGCs in children and adolescents often present diagnostic and therapeutic challenges for pathologists, surgeons, and pediatric oncologists. Objective: To assess the salivary gland tumours in children and adolescents. Methods: A cross-sectional observational study was carried out at Dept. of ENT, Shaheed Monsur Ali Medical College &amp; Hospital, Uttara, Dhaka, Bangladesh from January to June 2023. Total 60 patients included in our study. Our pre-operative clinical diagnoses were based on size, shape, mobility, fixity of the tumour to the underlying structures, ulceration of overlying skin, involvement of facial nerve by its malignant transformation and fine needle aspiration cytology. All patients, or their guardians, gave their informed consent for data collection within the national rare tumour group and analysis. Results: Total sixty (60) cases of salivary gland tumours were available for our study. Out of 55% were male and 45% were female patients. Incidence of tumours is highest in the age group of 41-50 with 13 cases (21.6% of the total). The least affected age group was the 0-10 group with only one patient (3.3%). Women accounted for 16 cases of the total 33 benign neoplasias (55% of the total). Of the 33 benign tumour, 18 were in males (54.5% of all benign tumours) and 15 were in females (45.5%). Total 60 operated cases). Of these, 32 were pleomorphic adenomas (53.3%) and 1 was an adenolymphoma (1.6%). the total number of malignant tumours confirmed by HPE were 27 (45%). Of these, most numerous was adenoid cystic carcinoma in 8 cases (13.3%). squamous cell carcinoma and muco epidermoid carcinoma were found in 6 cases each (10%). There were 4 and 3 cases of adenocarcinoma (6.6%) and acinic cell carcinoma (5%) respectively. The parotid glands were also the sole location for the 3 acinic cell carcinomas. No tumours were found in the sublingual gland. The majority of the tumours found in the parotid gland were benign tumours, mainly pleomorphic adenomas with 24 cases (75% of the total parotid tumours). Conclusions: The tumours were equally distributed between males and females. The tumours were most commonly found in the third to fifth decades of life. The most common benign tumour and the most common tumour overall was pleomorphic adenoma making up 54.5% of all tumours. Surgical excision was the most commonly done treatment. The most commonly done surgical procedure was superficial parotidectomy.

Copper(II), zinc(II) and cadmium(II) complexes with the O-picolyl ether of chiral α-aminooxime of natural (+)-limonene: synthesis, structures, luminescence and cytotoxicity

Copper(II), zinc(II) and cadmium(II) complexes, [CuLCl2], [ZnLCl2] and [CdLCl2], with a new derivative of chiral α-aminooxime of natural (+)-limonene bearing a pycolyl group (L) were synthesized. The complexes are mononuclear, the L molecules act as N,N,N-tridentate chelating ligands. The computations support the fact that the N,N,N–chelation by a metal ion is thermodynamically preferred over the N,N–chelation for all complexes. The ligand L and the complexes [ZnLCl2] and [CdLCl2] exhibit fluorescence, with the emission spectra depending on the excitation wavelength. L emits in close to white region, while the Zn(II) and Cd(II) complexes demonstrate blue emission. Due to chelation-induced fluorescence enhancement effect, the fluorescence quantum yield increases when going from L to [ZnLCl2] and [CdLCl2]. The complex [CdLCl2] displays cytotoxicity against the HepG2 cell line (IC50 = 14.3 ± 1.5 μM), which is almost twice as high as that of cisplatin. The human breast adenocarcinoma cell line (MCF-7) is more sensitive to [CuLCl2] (IC50 = 43.4 ± 0.4 μM) than to [CdLCl2].

Treatment of a mutant KRAS lung cancer cell line with polyisoprenylated cysteinyl amide inhibitors activates the MAPK pathway, inhibits cell migration and induces apoptosis.

KRAS mutations are the most common oncogenic mutations in lung adenocarcinoma in Black Americans. Polyisoprenylated Cysteinyl amide Inhibitors (PCAIs) constitute a group of potential cancer therapy agents that we designed to specifically disrupt and suppress hyperactive G-protein signaling, such as that caused by mutated RAS proteins. Here we determine the effects of PCAIs on the viability, G-protein levels, downstream mediators, and apoptosis-related proteins on the KRAS-mutated, Black American-derived lung adenocarcinoma cell line, NCI-H23. Of the 17 PCAIs tested, compounds NSL-YHJ-2-27 and NSL-YHJ-2-46 showed the most potency with EC50 values of 2.7 and 3.3 μM, respectively. Western blotting was used to determine the effect of the PCAIs on the phosphorylation levels of MAPK pathway enzymes. After 48 h exposure to 5 μM of the PCAIs, NSL-YHJ-2-46, the MAPK proteins BRAF, MEK1/2, ERK1/2, and p90RSK were activated through phosphorylation by 90, 190, 150 and 120%, respectively. However, CRAF/RAF1 phosphorylation decreased by 40%, suggesting significant changes in the KRAS/MAPK signaling patterns. Furthermore, 5 μM of NSL-YHJ-2-27 depleted the singly polyisoprenylated monomeric G-proteins RAC 1/2/3 and CDC42 by 77 and 76%, respectively. The depletion of these key cytoskeletal proteins may account for the observed inhibition of cell migration and invasion, and spheroid invasion observed on exposure to NSL-YHJ-2-27 and NSL-YHJ-2-46. Treatment with 5 μM of NSL-YHJ-2-27 suppressed full-length inactive caspase 3 and 7 levels by 72 and 91%, respectively. An analysis of cells treated with the fluorescently labeled active caspase 3/7 irreversible inhibitor, CaspaTagTM Caspase-3/7 in situ reagent revealed a 124% increase in active caspase at 3 μM over controls. These findings clearly show the direct effects of the PCAIs on the RAS signaling pathway. Given the profound increases observed in RPS6KA1/p90RSK phosphorylation, future work will involve a determination whether the proapoptotic isoforms of RPS6KA1/p90RSK are phosphorylated due to the PCAIs treatments. These results support the potential use of the PCAIs as targeted therapies against cancers with KRAS mutations.

Antioxidant and Anti-Inflammatory Effects of Nettle Polyphenolic Extract: Impact on Human Colon Cells and Cytotoxicity Against Colorectal Adenocarcinoma.

Urtica dioica L. is one of the most widely utilized medicinal plants commonly applied in the form of tea, juice, and dietary supplements. This study aimed to assess the effect of the U. dioica ethanol-water extract (UdE) and polyphenolic fraction isolated from the extract (UdF) on normal human colon epithelial cells and to evaluate their protective activity against induced oxidative stress. The cytotoxic potential against human colorectal adenocarcinoma (HT29) and the anti-inflammatory effects were also investigated. UPLC-MS-DAD analysis revealed that both extracts were abundant in caffeic acid derivatives, specifically chlorogenic and caffeoylmalic acids, and therefore, they showed significant protective and ROS scavenging effects in normal human colon epithelial cells. Moreover, they had no negative impact on cell viability and morphology in normal cells and the extracts, particularly UdF, moderately suppressed adenocarcinoma cells. Furthermore, UdF significantly decreased IL-1β levels in HT29 cells. Our research indicates that U. dioica may provide significant health advantages because of its antioxidant and anti-inflammatory effects.

Exploring Nanocarriers for Boosting Entacapone Bioavailability: A Journey through System Characterization and Assessment of Toxicity and Pharmacological and 2D Permeability Paybacks.

Catechol-O-methyltransferase inhibitors (iCOMT), such as entacapone, have been successfully employed to treat tremor-related symptoms of Parkinson's disease. However, iCOMT has been associated with a short half-life and poor oral bioavailability. Nanobased drug delivery systems have often been used to overcome this type of setbacks. Therefore, entacapone was encapsulated in PEGylated poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) via a nanoprecipitation process, as well as in PEGylated nanostructured lipid carriers (NLCs) using a solvent emulsification/evaporation method. Both nanoformulations presented sub-200 nm populations, with zeta-potential (ZP) values close to -30 mV, and showed stability at different pHs, while maintaining their physicochemical properties mostly intact, presenting only a change in their superficial charge (ZP values), indicating their interaction. Both nanoformulations presented interaction with mucins, which anticipates good permeation and bioavailability for oral and topical administration. No cytotoxic effects were observed for lyophilized PLGA NPs encapsulating entacapone, in which 2-hydroxypropyl-ß-cyclodextrin (HPβCD) was used as a cryoprotectant at 3% concentration (HP-PLGA@Ent), in human hepatocellular carcinoma (HepG2), human neuroblastoma (SH-SY5Y), or human epithelial colorectal adenocarcinoma (Caco-2) cell lines. Conversely, NLCs encapsulating entacapone (W-NLCs@Ent) presented cytotoxic effects on the HepG2 cell line, likely due to intracellular lipid accumulation or storage. Both nanoformulations maintained a COMT inhibition effect in HepG2 cells, using 3-BTD as the COMT probe. An increase of entacapone permeability in both monolayer and coculture models (Caco-2 and Caco-2/HT29-MTX, respectively) was observed for the developed nanoformulations. Overall, this work shows that encapsulated entacapone in different nanocarriers could be a stimulating alternative to solve entacapone setbacks, since they improve its physicochemical properties and permeability while still maintaining the COMT inhibitory activity.

Protective Effects of Nettle Tea on SKOV-3 Ovarian Cancer Cells Through ROS Production, Apoptosis Induction, and Motility Inhibition Without Altering Autophagy.

Urtica dioica L. (UD), also known as the stinging nettle, has long been used in traditional medicine for its wide range of health benefits. The current study focuses on the effect of nettle tea on the growth and proliferation of one of the most aggressive ovarian adenocarcinoma cell line, SKOV-3 cells. To examine this, cytotoxicity, cell cycle analysis, and ROS assays were performed, along with Annexin V/PI dual staining, cell death ELISA, Western blot analysis, and motility assays. The results showed that a UD aqueous extract (UDAE) can inhibit the growth and proliferation of SKOV-3 cells in a dose- and time-dependent manner by promoting cellular fragmentation. This was accompanied by an increase in two apoptotic hallmarks, the flipping of phosphatidylserine to the outer membrane leaflet and DNA fragmentation as revealed by cell death ELISA. This aqueous extract showed a pro-oxidant activity while also activating the extrinsic caspase-dependent apoptotic pathway with no alteration in autophagy markers. Furthermore, the extract showed promising inhibitory effect on the migratory capacities of aggressive ovarian cancer cells, in vitro.