Dose-dependent Cytotoxicity Research Articles

Ellagic Acid Potentiates the Inhibitory Effects of Fluconazole Against Candida albicans

Background/Objectives: Antifungal resistance to azoles, coupled with the increasing prevalence of Candida albicans infections, represents a significant public health challenge and has driven the search for new natural compounds that can act as alternatives or adjuvants to the current antifungals. Ellagic acid (EA) has demonstrated antifungal activity; however, its effects are not fully understood. In this study, we investigated the in vitro anti-Candida activity of EA and its ability to potentiate the effects of fluconazole (FLZ) on C. albicans. Methods: The Minimum Inhibitory Concentration (MIC) of EA was determined by broth microdilution and its interaction with FLZ was assessed using a checkerboard assay. Additionally, we examined the effects of EA on yeast-to-hypha transition, inhibition of biofilm formation, time–kill kinetics, hemolytic activity, and cytotoxicity in HeLa ATCC® CCL-2™ cells. Results: EA exhibited MIC values ranging from 250 to 2000 µg/mL and showed synergistic and additive interactions with FLZ, resulting in a marked reduction in the MIC values of FLZ (up to 32-fold) and EA (up to 16-fold). In the time–kill assay, the most effective combinations were 4× EA MIC, 2× EA MIC, and FIC EA + FLZ, which showed fungicidal activity. Furthermore, EA did not show hemolytic activity and demonstrated low and dose-dependent cytotoxicity in HeLa cells, with no cytotoxic effects observed in combination with FLZ. EA and the synergistic combination of EA and FLZ interfered with both the yeast-to-hypha transition process in C. albicans cells and biofilm formation. In addition to its antifungal efficacy, EA demonstrated a favorable safety profile at the concentrations used. Conclusions: This study presents promising results regarding the potential use of EA in combination with FLZ for the treatment of C. albicans infections.

Discovery of novel CDK4/6 inhibitors from fungal secondary metabolites

The development of targeted therapies for breast cancer, particularly those focusing on cyclin-dependent kinases 4/6 (CDK4/6), has significantly improved patient outcomes. However, the currently approved CDK4/6 inhibitors are associated with various side effects, underscoring the need for novel compounds with enhanced efficacy and safety profiles. This study aimed to identify potential CDK4/6 inhibitors from MeFSAT, a database of fungal secondary metabolites using an in-silico screening approach. The virtual screening process incorporated drug-likeness filters, ADME and toxicity predictions, consensus molecular docking, and 200 ns molecular dynamics simulations. Out of 411 initial compounds, two molecules demonstrated favorable binding interactions and stability with the CDK4/6 protein complex. The MTT assay showed that MSID000025 had dose-dependent cytotoxicity against MCF7 breast cancer cells. This suggests that MSID000025 could be a good candidate CDK4/6 inhibitor for treating breast cancer. Our study highlights the potential of fungal secondary metabolites as a source of novel compounds for drug discovery. It provides a framework for identifying CDK4/6 inhibitors with improved therapeutic properties.

1,5- diaryl pyrazole-loaded chitosan nanoparticles as COX-2 inhibitors, mitigate neoplastic growth by regulating NF-κB pathway in-vivo zebrafish model

Non-steroidal anti-inflammatory drugs (NSAIDs) have been researched for their capacity to reduce cancer incidence, primarily due to their COX-2 inhibition properties. However, concerns have arisen regarding the precision of their targeting abilities. Nanoparticle approaches are revolutionizing cancer treatment by enabling targeted drug delivery, which enhances the efficacy and reduces the toxicity of chemotherapy. Particularly, chitosan-based nanoparticles are noteworthy for their biocompatibility, biodegradability, and ability to improve drug delivery. In this study, we synthesized folic acid-conjugated, 1,5-diaryl pyrazole-loaded chitosan (FA-CS-DP) nanoparticles using the ionic gelation method. The bioavailability and anti-neoplastic effects in a 7,12-dimethylbenzanthracene (DMBA)-exposed zebrafish model was investigated. MTT assay showed dose-dependent cytotoxicity of FA-CS-DP nanoparticles against MCF-7 breast cancer. The nanoparticles showed no toxicity to zebrafish embryos up to 100 μg/mL. The nanoparticle reduced oxidative stress and enhanced apoptosis in zebrafish exposed to DMBA. The morphological examination suggests that tumor growth was prevented in the zebrafish's surface and internal regions. The gene expression analysis confirmed the decrease in the expression of anti-inflammatory genes, such as cox-2 and nf-κb, and apoptosis inhibitor genes, such as bcl-2 and mdm2. By regulating the anti-inflammatory and apoptosis inhibitor genes, FA-CS-DP nanoparticle prevents neoplastic growth in the zebrafish model.

Anticancerous activity of Annona muricata-mediated cerium doped nickel ferrite spinel nanoparticles

Nickel ferrite nanoparticles have garnered significant interest for their applications in medical diagnosis and targeted drug delivery due to their unique magnetic and structural properties. In this study, we present a green synthesis approach utilizing Annona muricata extract to prepare nickel ferrite (NiFe2O4) nanoparticles, emphasizing an eco-friendly solution to overcome the limitations of conventional chemical synthesis methods. Using a sol–gel auto-combustion technique, we synthesized cerium-doped nickel ferrite nanoparticles and characterized them thoroughly to evaluate their structural, optical, magnetic, and anti-cancer properties. The characterization results showed that the nanoparticles formed a cubic spinel structure with reduced crystallite sizes and altered lattice parameters. The synthesized nanoparticles displayed agglomerated spherical morphology with high phase purity. The cerium doping caused changes in binding energies, which enhanced the magnetic properties, including increased saturation magnetization and reduced coercivity. Additionally, the anti-cancer efficacy of the nanoparticles was confirmed through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay results, showing dose-dependent cytotoxicity against Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. These findings suggest promising applications in targeted drug delivery and cancer therapy, highlighting the potential of cerium-doped nickel ferrite nanoparticles as an effective material for biomedical use.

Differential Cytotoxicity, Inflammatory Responses, and Aging Effects of Human Skin Cells in Response to Fine Dust Exposure

Airborne fine dust pollution poses a significant threat to both respiratory and skin health, yet the skin’s physiological response to such exposure has been underexplored. This study investigates the impact of fine dust on skin cells, focusing on their metabolic activity, inflammatory responses, and aging-related changes. We found that exposure to fine dust model compounds led to dose-dependent cytotoxicity, with PM2.5-Ions exhibiting higher toxicity compared to PM10-PAHs. Human epithelial keratinocytes (HEKn) showed heightened sensitivity to fine dust, marked by increased inflammation, particularly with elevated IL-8 expression in response to PM2.5-Ions. Additionally, fine dust exposure resulted in reduced cell density, slower proliferation, and decreased migration, notably at higher concentrations of PM2.5-Ions. These changes are indicative of accelerated aging processes, including compromised cell function and structural integrity. Live cell imaging and correlation analyses highlighted significant links between metabolic activity, cell morphology, and IL-8 secretion. These findings provide critical insights into the differential impacts of fine dust components on skin cells, emphasizing the potential acceleration of aging processes and underscoring the need for further research on cellular responses to environmental stress and the development of protective measures against urban fine dust exposure. Overall, this study, which contributes to addressing the skin health risks posed by air pollutants, could be actively used in environmental science, dermatology, and public health.

Fabrication of Multifunctional Green-Synthesized Copper Oxide Nanoparticles Using Rumex vesicarius L. Leaves for Enhanced Photocatalytic and Biomedical Applications

Recently, the use of plant extracts has emerged as an innovative approach for the production of various nanoparticles. Enhancing green methods for synthesizing copper oxide (CuO) nanoparticles (NPs) is a key focus in the field of nanotechnology. This study presents a novel and eco-friendly synthesis of CuO NPs using Rumex vesicarius L. leaf extracts, offering a cost-effective and efficient method. The synthesized CuO NPs were evaluated for their cytotoxic effects against human cervical carcinoma (HeLa) cells, as well as their photocatalytic and antimicrobial activities. The morphology, size, and structural properties of the CuO NPs were characterized using various analytical techniques. X-ray diffraction (XRD) analysis confirmed the pure crystalline structure of the CuO NPs with a size of 19 nm, while transmission electron microscopy (TEM) showed particle sizes ranging from 5 to 200 nm. The photocatalytic performance of the CuO NPs was assessed through the photodegradation of crystal violet (CV) and methylene blue (MB) dyes under UV light. The NPs exhibited excellent decolorization efficiency, effectively degrading dyes in aqueous solutions under irradiation. Furthermore, the green-synthesized CuO NPs displayed strong antibacterial and antifungal activities against a variety of human pathogens. They also demonstrated significant dose-dependent cytotoxicity against the HeLa cancer cell line, with an IC50 value of 8 ± 0.54 μg/mL.

Enhanced anticancer and biological activities of environmentally friendly Ni/Cu-ZnO solid solution nanoparticles

The study investigates the impact of incorporating Ni and Cu into the lattice of ZnO nanoparticles (NPs) to enhance their anticancer and antioxidant properties. Characterization techniques including pXRD, FTIR, UV–visible absorption spectroscopy, FESEM, and EDAX confirm the successful synthesis and structural modifications of Ni/Cu-ZnO NPs. Anticancer activity against breast cancer (MDA) and normal skin (BHK-21) cells reveals dose-dependent cytotoxicity, with Ni/Cu-ZnO NPs exhibiting higher efficacy against MDA cells while being less harmful to BHK-21 cells. Morphological studies corroborate these findings. Additionally, antioxidant assays using TAC, FRAP, and DPPH assay demonstrate the superior antioxidant activity of Ni/Cu-ZnO NPs matched to pure ZnO. Overall, the synergistic effect of Ni and Cu incorporation leads to improved therapeutic potential, making Ni/Cu-ZnO NPs promising candidates for cancer therapy and antioxidant applications.Molecular docking recreations were performed using Auto Dock Vina software to gain more insights and validate the observed biological activities of un-doped ZnO and bi-metal doped ZnO NPs, we investigated the interaction and binding affinities of pure ZnO and bimetallic metal co-doped ZnO for their antioxidant and anticancer studies. Ni/Cu-ZnO have shown good antioxidants and exhibited remarkable anticancer activities.

Asymmetric Janus Nanofibrous Agar-Based Wound Dressing Infused with Enhanced Antioxidant and Antibacterial Properties.

In the present study, we have developed an agar-based asymmetric Janus nanofibrous wound dressing comprising a support and an electrospun layer with antibacterial and antioxidant properties, respectively, to facilitate healing effectively. The support layer containing agar and silver nitrate was fabricated by using solvent casting for sustained release, combating the dose-dependent cytotoxicity of silver nanoparticles, where nanoparticles were synthesized using a one-pot reduction method. The electrospun layer, fabricated with a mixture of agar and polycaprolactone infused with gallic acid, was electrospun over the support layer to impart antioxidant properties. Characterizations using UV-vis spectroscopy, transmission electron microscopy, scanning electron microscopy, and Fourier transform infrared spectroscopy validated the synthesis of nanoparticles in 10-20 nm diameter and the asymmetric Janus dressing. The developed Janus nanofibrous structure exhibited 98% porosity, excellent fluid-handling properties, a moisture permeability of 1200 g/m2/day, and a water absorption of ∼250%. Moreover, the time-kill assay confirmed potent bacteriostatic effect against Gram-positive and Gram-negative bacteria, and sustained release of silver nanoparticles followed the Korsmeyer-Peppas model. With over 90% free radical scavenging efficacy, 37% degradation in 7 days, and less than 2% hemolysis, the dressings demonstrated exceptional antioxidant, biodegradable, and hemocompatible properties. The biocompatibility assessment further confirmed its cytocompatible efficacy, with more than 79% wound closure in the wound scratch assay. Most importantly, in vivo studies demonstrated the efficacy of the developed Janus dressing, promoting over 97% healing within 12 days of injury with higher epithelial formation. Overall, the in vitro and in vivo assessment of the developed Janus dressing confirmed its potential to function as a versatile and effective material for wound care applications.

Cytotoxic effects of ivermectin on Giardia lamblia: induction of apoptosis and cell cycle arrest.

Giardia lamblia is a flagellated protozoan parasite causing giardiasis, a common intestinal infection characterized by diarrhea, abdominal cramps, and nausea. Treatments employed to combat this parasitic infection have remained unchanged for the past 40 years, leading to the emergence of resistant strains and prompting the search for new therapeutic agents. This study investigated the cytotoxic effects of ivermectin (IVM) on G. lamblia trophozoites. We conducted dose-response experiments to assess IVM-induced cytotoxicity. We utilized various biochemical and ultrastructural analyses to explore the underlying mechanisms of cell death, including reactive oxygen species (ROS) production, DNA fragmentation, cell cycle arrest, and apoptosis markers. Our findings demonstrate that IVM induces dose-dependent cytotoxicity and triggers cell death pathways. We found that IVM treatment generates elevated levels of reactive oxygen species (ROS), DNA fragmentation, and arrests of trophozoites in the cell cycle's S phase. Additionally, ultrastructural analysis reveals morphological alterations consistent with apoptosis, such as cytoplasmic vacuolization, chromatin condensation, and tubulin distribution. The insights gained from this study may contribute to developing new therapeutic strategies against giardiasis, addressing the challenge posed by drug-resistant strains.

Design, synthesis, and biological evaluation of 2,4-dimorpholinopyrimidine-5-carbonitrile derivatives as orally bioavailable PI3K inhibitors.

Phosphoinositide-3-kinase (PI3K) is overexpressed in many tumors and is, thus, an ideal target for cancer treatments. Accordingly, there is an urgent need for the development of PI3K inhibitors with high potency and low toxicity. In this study, we designed and synthesized a series of 2,4-dimorpholinopyrimidine-5-carbonitrile derivatives, which were evaluated for their PI3K inhibitory potency. Compound 17p demonstrated comparable PI3Kα inhibitory activity (IC50: 31.8 ± 4.1nM) to the positive control, BKM-120 (IC50: 44.6 ± 3.6nM). In addition, 17p showed significant inhibitory activity against PI3Kδ (IC50: 15.4 ± 1.9nM) and significant isoform selectivity against PI3Kβ, PI3Kγ, and mTOR. Furthermore, 17p exhibited good antiproliferative activities against cancer cell activity and good safety in the Ames and hERG tests while having outstanding liver microsomal stability in vitro, with half-lives of 38.5min in rats and 127.9min in humans. In addition, in an apoptosis assay, 17p could induce dose-dependent cytotoxicity in the ovarian cancer cell line A2780. In a pharmacokinetic study, 17p was stable (T ½: 2.03h) and showed high bioavailability (46.2%). Collectively, these results indicate that 17p could be a promising PI3K agent for cancer treatment.

Preparation of New Liposomal Daunorubicin and Evaluation of its Anti-colorectal Cancer in HCT116 Cells

Background: Colorectal cancer (CRC) is the third most common cause of cancerrelated deaths worldwide. To develop more effective anti-CRC drugs, this research evaluated the impact of synthesized liposomal daunorubicin on HTC116 colon cancer cell line. Methods: Liposomal daunorubicin (LDNR) was synthesized by the thin layer hydration method and size was determined by dynamic light diffraction (DLS). MTT assay was used to determine the cytotoxicity and IC50 of LDNR against the HCT116 CRC cell line. Relative mRNA expression of the NF-κB gene and apoptosis were evaluated in 24 hours treatments of HCT116 cells by qRT-PCR and flow cytometry, respectively. Results: The hydrodynamic diameter of liposomes containing daunorubicin (DNR) was determined 25.2 nm. MTT assay showed a 38% decrease in HCT116 cells viability after 24-hour treatment with the DNR (0.5 μM). The lowest (0.125 μM) and highest (2 μM) dose of LDNR showed 20.4% and 71.6% cytotoxicity, respectively. LDNR showed dose-dependent cytotoxicity with the IC50 of 0.87 μM. The phase contrast microscope evaluation confirmed the LDNR cytotoxicity. The DNR and LDNR (0.87 μM) decreased relative mRNA levels of NF-κB 63% (P= 0.023) and 99.6% (P=0.003), respectively. The percentage of apoptotic cells in the DNR and LDNR increased by 27.1% (P<0.0001) and 49.7% (P<0.0001), respectively. Conclusion: DNR increases the rate of apoptosis by decreasing the NF-κB gene expression in HCT116 cells. These effects are intensified in the liposomal form. Therefore, the LDNR produced in this research can be considered in the treatment of CRC.

The Effects of Crude Alkaloid Extracts of Convolutes Arvensis on Tumour Cell Lines and Their Potential For Toxicity

General Background: Cancer remains a leading cause of mortality worldwide, and the search for effective treatments continues to intensify. Specific Background: Convolvulus arvensis has been traditionally used for medicinal purposes, but its potential as an anticancer agent is underexplored. Knowledge Gap: The cytotoxic and apoptotic mechanisms of crude alkaloids extracted from C. arvensis against specific cancer cell lines have not been fully characterized. Aims: This study investigates the antioxidant activity and cytotoxic effects of C. arvensis crude alkaloids on mouse liver cancer (HC) and human breast cancer (AMJ13) cell lines, focusing on apoptosis-related gene expression. Results: The antioxidant activity of C. arvensis was comparable to that of ascorbic acid, with inhibition rates of 92.01% at 500 µg/ml. Crude alkaloids demonstrated dose-dependent cytotoxicity, with a maximum inhibition rate of 82.65% in AMJ13 cells and 79.49% in HC cells at 500 µg/ml. Gene expression analysis revealed upregulation of caspase-9, indicating apoptosis via the intrinsic mitochondrial pathway. Novelty: This study is among the first to provide molecular evidence of C. arvensis-induced apoptosis through the intrinsic pathway, offering a novel insight into its anticancer potential. Implications: These findings suggest that C. arvensis alkaloids could be developed as a therapeutic option for cancer treatment, with future studies needed to isolate specific compounds and assess their in vivo efficacy. Highlights: C. arvensis alkaloids show antioxidant activity similar to ascorbic acid. Alkaloids inhibit liver and breast cancer cell growth dose-dependently. Apoptosis triggered via caspase-9 through the mitochondrial pathway. Keywords: Convolvulus arvensis, alkaloids, cancer, apoptosis, antioxidant

Anticancer Efficacy of Biosynthesized Zinc Oxide and Gold Nanoparticles

Abstract Introduction/Objective Introduction: Advancements in nanoscale materials have led to the exploration of metal oxides for cancer diagnosis and therapy. Zinc oxide nanoparticles (ZnO NPs) and gold nanoparticles (Au NPs) are particularly promising due to their biocompatibility and anticancer properties demonstrated across various cancer cell lines. Objectives This study aimed to isolate fungal endophytes from Eucalyptus sideroxylon leaves and utilize them for the biosynthesis of nanoparticles (ZnO NPs and Au NPs) to assess their anticancer activity. Methods/Case Report Methods: Healthy Eucalyptus sideroxylon samples were collected from a desert research center, and endophytes were isolated and cultivated. The fungal biomass was processed to synthesize ZnO NPs and Au NPs. Cell lines were propagated for cytotoxicity experiments using the MTT assay in a 96-well plate format. Results (if a Case Study enter NA) Results: Biosynthesized ZnO and Au NPs exhibited anticancer activity against HCT-116 and CACO2 cell lines. The IC50 values for ZnO NPs were 5.06 μg/mL for HCT-116 and 6.07 μg/mL for CACO2, while Au NPs showed IC50 values of 5.9 μg/mL for HCT-116 and 1.1 μg/mL for CACO2. ZnO NPs demonstrated dose-dependent toxicity on HCT-116 cells, with increasing concentrations leading to a reduction in cell viability. Similarly, Au NPs exhibited dose-dependent cytotoxicity on both cell lines. Conclusion Conclusion: This study underscores the potential of endophytic fungi for biosynthesizing metal nanoparticles with significant anticancer effects. ZnO NPs displayed superior efficacy against colon cancer cells compared to Au NPs, indicating their potential as therapeutic agents. The findings highlight the importance of exploring natural sources for nanoparticle synthesis and their application in cancer therapy.

Development of quercetin loaded biosynthesized chitosan grafted iron oxide nanoformulation and their antioxidant, antibacterial, and anti-cancer properties

In this study, we report the development and characterization of a novel nanoformulation composed of quercetin-loaded biosynthesized chitosan-grafted iron oxide nanoparticles (CH-Fe3O4 NCs). The synthesis of chitosan-grafted iron oxide nanoparticles was achieved through a green synthesis approach, utilizing chitosan derived from crustacean shells and biosynthesized iron oxide nanoparticles. Quercetin, a natural flavonoid with known antibacterial, anti-cancer, and antioxidant properties, was loaded onto the nanoparticles through physical adsorption. The optical property, crystal structure, morphology, chemical composition and surface charge were thoroughly characterized using various analytical techniques including UV–visible spectroscopy, X-ray diffractometer, scanning and transmission electron microscopy, fourier-transform infrared spectroscopy and zeta potential analyzer. The antibacterial activity of the nanoformulation was evaluated against a panel of bacterial strains using standard microbiological assays, revealing promising inhibitory effects against both Gram-positive and Gram-negative bacteria. The antibacterial activity of CH-Fe3O4 NCs was evaluated against E. coli and S. aureus bacterial species. CH-Fe3O4 NCs have a greater ability to inhibit the E.coli than S. aureus. Furthermore, the CH-Fe3O4 NCs demonstrated dose-dependent cytotoxicity and caused apoptotic cell death in the H522 cell line. Additionally, the antioxidant properties of the nanoformulation were evaluated through scavenging assays, highlighting its ability to effectively neutralize free radicals. Overall, our results suggest that the quercetin-loaded biosynthesized chitosan-grafted iron oxide nanoformulation exhibits potent antibacterial, anti-cancer, and antioxidant properties, making it a promising candidate for further development as a multifunctional therapeutic agent.

Biogenic silver nanoparticles from Simarouba glauca DC leaf extract: Synthesis, characterization, and anticancer efficacy in lung cancer cells with protective effects in Caenorhabditis elegans

This study explores the synthesis, characterization, and biomedical applications of silver nanoparticles (AgNPs) synthesized using Simarouba glauca leaf extract. The biogenic AgNPs were characterized through UV–visible spectroscopy, X-ray diffraction (XRD), particle size analysis, zeta potential analysis, energy dispersive X-ray spectroscopy (EDX), Fourier-transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), and high-resolution transmission electron microscopy (HR-TEM). The nanoparticles exhibited a distinct absorbance peak at 413.5 nm, confirming their synthesis and surface plasmon resonance. XRD and HR-TEM analyses revealed a face-centered cubic structure with an average size of 12.45 nm, while AFM indicated a mean particle size of 18.34 nm. The particles demonstrated moderate stability with a zeta potential of −41.4 mV and exhibited various elemental compositions as confirmed by EDX. In the biomedical evaluation, the anticancer potential of SG-AgNPs was tested on L-132 and A549 cell lines using MTT, live/dead, and DNA damage assays. Results showed dose-dependent cytotoxicity, with significant effects observed at higher concentrations, particularly against A549 cells. Additionally, the protective effects of SG-AgNPs were assessed in Caenorhabditis elegans using survival and paralysis assays. The nanoparticles significantly improved survival rates and reduced paralysis in worms infected with Pseudomonas aeruginosa PAO1 and Staphylococcus aureus. These findings highlight the potential of biogenic SG-AgNPs as effective agents with both anticancer and antimicrobial properties. Future research should focus on elucidating the mechanisms underlying these effects and optimizing their therapeutic applications.

‘Clickable’ polymer brush coated magnetic nanoparticles: Employing Diels-Alder and azide-alkyne cycloaddition for modular targeted drug delivery platforms

Effective methods of multi-functionalization of nanomaterials are essential for fabricating effective targeted drug delivery systems. Herein, we disclose the fabrication of polymer brush-coated magnetic nanoparticles that could be functionalized with drugs and targeting ligands through orthogonal click reactions. In particular, polymers containing electron-rich furan groups as functionalization handles are grown from the surface of magnetic nanoparticles using the ‘graft-from’ approach. Furthermore, azide groups are installed at the chain end of polymer brushes to furnish an orthogonally functionalizable system. The attachment of maleimide-containing fluorescent dyes and cytotoxic drugs using the Diels-Alder reaction is demonstrated. Drug-conjugated nanoparticles functionalized with integrin-targeting peptide using the azide-alkyne cycloaddition reaction undergo preferential uptake in cancer cells and show dose-dependent cytotoxicity. We envision that the modularly functionalizable system disclosed here could target various cancer cells using an appropriate combination of drugs and targeting groups.

510LBA (PB-510) LBA Posters: Dose-dependent cytotoxicity of arfolitixorin, a direct-acting folate, versus leucovorin with 5-fluorouracil in patient-derived colorectal cancer tumoroids (PDTs)

510LBA (PB-510) LBA Posters: Dose-dependent cytotoxicity of arfolitixorin, a direct-acting folate, versus leucovorin with 5-fluorouracil in patient-derived colorectal cancer tumoroids (PDTs)

Kalata B1 Enhances Temozolomide Toxicity to Glioblastoma Cells.

Glioblastoma (GBM) is the most aggressive cancer originating in the brain, but unfortunately combination treatments with resection, radiation, and chemotherapy are relatively ineffective. Therefore, novel methods of adjuvant therapy are critically needed. Cyclotides are plant-derived circular peptides that chemosensitize drug-resistant breast cancer to doxorubicin. We analyzed naturally occurring and synthetic cyclotides (Cycloviolacin O3, Cycloviolacin O19, natural Kalata B1, synthetic Kalata B1, and Vitri E) alone and in co-exposure treatments with the drug temozolomide (TMZ) in human glioblastoma cells. The cyclotides were identified by UPLC-PDA and HPLC-UV. The synthetic Kalata B1 sequence was verified with orbitrap LC-MS, and structural confirmation was provided by NMR spectroscopy. The cyclotides displayed dose-dependent cytotoxicity (IC50 values 2.4-21.1 µM) both alone and as chemosensitizers of U-87 MG and T 98 cells to TMZ. In fact, a 16-fold lower concentration of TMZ (100 µM) was needed for significant cytotoxicity in U-87 MG cells co-exposed to synthetic Kalata B (0.5 µM). Similarly, a 15-fold lower concentration of TMZ (75 µM) was required for a significant reduction in cell viability in T 98 cells co-exposed to synthetic Kalata B1 (0.25 µM). Kalata B1 remained stable in human serum stability assays. The data support the assertion that cyclotides may chemosensitize glioblastoma cells to TMZ.

Mechanism of non-competitive inhibition of the SARS-CoV-2 3CL protease dimerization: Therapeutic and clinical promise of the lichen secondary metabolite perlatolinic acid

In response to the COVID-19 pandemic, identifying effective treatments against SARS-CoV-2 has become of utmost importance. This study elucidates the mechanism by which perlatolinic acid, a lichen-derived secondary metabolite, non-competitively inhibits the dimerization of the SARS-CoV-2 3CL protease, a pivotal enzyme in the virus lifecycle. Utilising a combination of kinetic parameter determination, inhibition assays, and molecular docking studies, we demonstrate that perlatolinic acid effectively disrupts the enzymatic function by binding at the dimer interface with a measured Ki value of 0.67 μM, thereby impeding the protease catalytic activity essential for viral replication. Molecular docking studies further corroborate the binding specificity of perlatolinic acid to the dimer interface, which is attributed to the loss of key interactions essential for dimerization, consequently impairing catalytic activity, highlighting its potential as a scaffold for developing broad-spectrum antiviral drugs.Despite a dose-dependent cytotoxicity of perlatolinic acid, its TC50 is approximately 43 times higher than the Ki value.Our findings suggest that perlatolinic acid holds significant promise as a lead compound for the development of new therapeutics against COVID-19, warranting further investigation and clinical evaluation.In conclusion, the study sheds light on the therapeutic potential of natural compounds in combating SARS-CoV-2, paving the way for the exploration of lichen secondary metabolites as a reservoir of potential antiviral agents.

Determining the Feasibility of a Cadmium Exposure Model to Activate the Inflammatory Arm of PANoptosis in Murine Monocytes.

A prevalence of cigarette smoking can cause the accumulation of cadmium (Cd2+) in the lungs, kidneys, and blood. The effects of exposure can cause multiple chronic disease types to emerge in the affected organ systems. The only moderately effective therapeutic option is chelation therapy; the health risks associated with this therapy have caused much criticism. The disease types associated with Cd2+ toxicity have inflammatory components and greatly impact innate immunity. These factors are affected at the cellular level and cause pathways like apoptosis, pyroptosis, and necroptosis. A development in understanding these pathways stipulates that these three pathways act as one complex of pathways, known together as PANoptosis. The inflammatory mechanisms of PANoptosis are particularly interesting in Cd2+ toxicity due to its inflammatory effects. Proteins in the gasdermin family act to release inflammatory cytokines, like interleukin-1β, into the extracellular environment. Cytokines cause inflammatory disease pathologies like fibrosis and cancer. RAW 264.7 monocytes are key in the murine immune system and provide an excellent model to investigate Cd2+ toxicity. Exposure of 0-15 µM CdCl2 was sufficient to increase expression of cleaved gasdermin D (GSDMD) and gasdermin E (GSDME) in this cell type. Cd2+ also exhibits a dose-dependent cytotoxicity in this cell type.