Non-cancerous Cells Research Articles

Bromelain-facilitated GNPs: A strategic innate anticancer delivery system for methotrexate into osteosarcoma cells

Osteosarcoma is the most common malignant bone tumor in children and adolescents during rapid bone growth. Traditional chemotherapy has markedly improved patient outcomes but suffers from nonspecific side effects due to nonspecific drug distribution, highlighting the need for targeted therapies. Methotrexate, although effective, poses toxicity concerns and prompts exploration into advanced drug delivery systems like nanoparticles. Here, we developed a novel method of synthesizing gold nanoparticles using bromelain (G-BNPs) as a reducing and capping agent, and we conjugated G-BNPs with methotrexate (G-B-MNPs) via 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide (EDC/NHS) as crosslinker. Our meticulous characterization, which included UV–visible spectroscopy, Transmission electron microscopy (TEM), Dynamic light scattering (DLS), Zeta potential, and Fourier-transform infrared spectroscopy (FTIR) analyses confirmed the successful fabrication and drug conjugation of the G-BNPs. We then evaluated the cytotoxicity of the G-BNPs (sized ∼ 21 nm) and G-B-MNPs (sized ∼ 24 nm) on the osteosarcoma cell lines, Saos-2 and MG-63, as well as the non-cancerous primary osteoblast cells. Our findings revealed that G-B-MNPs significantly increased the cytotoxic impact on osteosarcoma cells compared to methotrexate alone while showing minimal toxicity toward primary osteoblast cells. Importantly, using 4`,6-diamidino-2-phenylindole(DAPI), we demonstrated that G-B-MNPs were delivered directly into the nucleus of the cells without encountering lysosomes. G-B-MNPs can be considered a potential drug delivery method for osteosarcoma treatment by improving effectiveness and reducing adverse effects, thereby enhancing patient prognosis.

Abstract Tu105: Inhibition of Queuine tRNA-Ribosyltransferase 1 Ameliorates Heaptic Lipogenesis and Atherosclerosis

Background: Atherosclerosis threatens cardiovascular health, which is featured by abnormal lipid metabolism and chronic inflammation in arterial wall. Queuine tRNA-Ribosyltransferase 1 (QTRT1) , is an enzyme responsible for tRNA modification at the wobble base. Research Questions: It is unclear whether the function of QTRT1 is involved in metabolism of non-cancer cells and tissues, especially lipid metabolism mainly orchestrated by liver. Aims: We aimed to explore the role of QTRT1 deficiency in hyperlipidemia, liver steatosis and atherosclerosis. Methods: Transgenic mice such as Qtrt1fl/flAlb-iCre+/- (Qtrt1LKO), Qtrt1fl/fl(WT), ApoE-/-, and gain of function of PCSK9 by adeno-associated virus gene transfer were used to determine the functional significance of QTRT1 in atherosclerosis. Synthesis, transportation and oxidation of lipids in livers and hepatocytes were examined by quantitative real-time polymerase chain reaction. Moreover, primary hepatocytes with overexpression and downregulation of QTRT1 were followed by RNA sequencing to identify downstream targets. Results: Deficiency of hepatic QTRT1 significantly attenuated hyperlipidemia, liver steatosis and atherosclerotic burden, but increased plaque stability in the aorta of mice. Depletion of QTRT1 markedly downregulated de novo lipogenesis (DNL) without influence on lipoprotein transportation and fatty acid oxidation. Qtrt1LKO mice on a high-carbohydrate diet displayed relatively reduced hyperlipidemia and alleviation of DNL. RNA-seq indicated that odorant binding protein 2A (OBP2A) was upregulated in Qtrt1LKO hepatocytes, which reversed the promotion of DNL by QTRT1 in hepatocytes. Conclusion: Inhibition of QTRT1 in hepatocytes ameliorates hepatic lipogenesis and atherosclerosis in mice. Targeting of QTRT1 is a promising strategy to improve therapeutic effectiveness in both hyperlipidemia and atherosclerosis.

Selective induction of senescence in cancer cells through near-infrared light treatment via mitochondrial modulation.

Photobiomodulation, utilising non-ionising light in the visible and near-infrared (NIR) spectrum, has been suggested as a potential method for enhancing tissue repair, reducing inflammation and possibly mitigating cancer-therapy-associated side effects. NIR light is suggested to be absorbed intracellularly, mainly by chromophores within the mitochondria. This study examines the impact of 734 nm NIR light on cellular senescence. Cancer (MCF7 and A549) and non-cancer (MCF10A and IMR-90) cell populations were subjected to 63 mJ/cm2 NIR-light exposure for 6 days. Senescence levels were quantified by measuring active senescence-associated beta-galactosidase. Exposure to NIR light significantly increases senescence levels in cancer (10.0%-203.2%) but not in non-cancer cells (p > 0.05). Changes in senescence were associated with significant modulation of mitochondrial homeostasis, including increased levels of reactive oxygen species (p < 0.05) and mitochondrial membrane potential (p < 0.05) post-NIR-light treatment. These results suggest that NIR light modulates cellular chemistry, arresting the proliferation of cancer cells via senescence induction while sparing non-cancer cells.

Hypermethylation of genes on chromosome 3p as a biomarker for nasopharyngeal carcinoma diagnosis: A Vietnamese case-control study.

The crucial event driving nasopharyngeal tumorigenesis is the hypermethylation of chromosome 3p-located tumor suppressor genes. This case-control study aims to investigate the methylation characteristics of RASSF1A, Blu, ADAMTS9, and DLEC1 to potentially develop effective diagnostic biomarkers for nasopharyngeal carcinoma, either individually or in combination. The methylation of RASSF1A, Blu, ADAMTS9, and DLEC1 in the collection of 93 biopsy samples and 100 healthy swab specimens were evaluated by Nested methylation-specific polymerase chain reaction. The strength of the correlation between candidate genes and nasopharyngeal carcinoma was estimated by the evaluation of odds ratios (ORs). Promoter hypermethylation of RASSF1A, Blu, ADAMTS9, and DLEC1 were found in 60.22%, 80.65%, 62.37%, and 74.19%, respectively, in nasopharyngeal carcinoma tumors. A significant association between the methylation status of candidate genes with nasopharyngeal carcinoma was reported. The methylation of candidate genes significantly increased the risk of nasopharyngeal carcinoma in cancerous samples compared with control samples (OR > 1). Based on the value of the methylation index, methylation of at least one gene was found in 95.70% of nasopharyngeal tumors. Additionally, the methylation index among 93 tumors significantly correlated with advanced stage nasopharyngeal tumors. The study explored a higher frequency of hypermethylation at least one candidate gene. Methylation of a panel of potential genes can be utilized to discriminate between nasopharyngeal carcinoma and non-cancer cells, particularly in the advanced stages of nasopharyngeal carcinoma. Thus, it could serve as a valuable marker for the diagnosis and monitoring of nasopharyngeal carcinoma.

Cheminformatics-Guided Exploration of Synthetic Marine Natural Product-Inspired Brominated Indole-3-Glyoxylamides and Their Potentials for Drug Discovery.

Marine natural products (MNPs) continue to be tested primarily in cellular toxicity assays, both mammalian and microbial, despite most being inactive at concentrations relevant to drug discovery. These MNPs become missed opportunities and represent a wasteful use of precious bioresources. The use of cheminformatics aligned with published bioactivity data can provide insights to direct the choice of bioassays for the evaluation of new MNPs. Cheminformatics analysis of MNPs found in MarinLit (n = 39,730) up to the end of 2023 highlighted indol-3-yl-glyoxylamides (IGAs, n = 24) as a group of MNPs with no reported bioactivities. However, a recent review of synthetic IGAs highlighted these scaffolds as privileged structures with several compounds under clinical evaluation. Herein, we report the synthesis of a library of 32 MNP-inspired brominated IGAs (25-56) using a simple one-pot, multistep method affording access to these diverse chemical scaffolds. Directed by a meta-analysis of the biological activities reported for marine indole alkaloids (MIAs) and synthetic IGAs, the brominated IGAs 25-56 were examined for their potential bioactivities against the Parkinson's Disease amyloid protein alpha synuclein (α-syn), antiplasmodial activities against chloroquine-resistant (3D7) and sensitive (Dd2) parasite strains of Plasmodium falciparum, and inhibition of mammalian (chymotrypsin and elastase) and viral (SARS-CoV-2 3CLpro) proteases. All of the synthetic IGAs tested exhibited binding affinity to the amyloid protein α-syn, while some showed inhibitory activities against P. falciparum, and the proteases, SARS-CoV-2 3CLpro, and chymotrypsin. The cellular safety of the IGAs was examined against cancerous and non-cancerous human cell lines, with all of the compounds tested inactive, thereby validating cheminformatics and meta-analyses results. The findings presented herein expand our knowledge of marine IGA bioactive chemical space and advocate expanding the scope of biological assays routinely used to investigate NP bioactivities, specifically those more suitable for non-toxic compounds. By integrating cheminformatics tools and functional assays into NP biological testing workflows, we can aim to enhance the potential of NPs and their scaffolds for future drug discovery and development.

Development and validation of 3D printed anthropomorphic head phantom with eccentric holes for medical LINAC quality assurance testing in stereotactic radiosurgery

Stereotactic Radiosurgery (SRS) for brain tumors using Medical Linear Accelerator (LINAC) demands high precision and accuracy. A specific Quality Assurance (QA) is essential for every patient undergoing SRS to protect nearby non-cancerous cells by ensuring that the X-ray beams are targeted according to tumor position. In this work, a water-filled generic anthropomorphic head phantom consisting of two removable parts with eccentric holes was developed using Additive Manufacturing (AM) process for performing QA in SRS. In the patient specific QA, the planned radiation dose using Treatment Planning System (TPS) was compared with the dose measured in the phantom. Also, the energy consistency of radiation beams was tested at 200 MU for different energy beams at the central and eccentric holes of the phantom using an ionization chamber. Experimentally examined results show that planned doses in TPS are reaching the target within a 5% deviation. The ratio of the dose delivered in the eccentric hole to the dose delivered to the central hole shows variations of less than 2% for the energy consistency test. The designed, low-cost water-filled anthropomorphic phantom is observed to improve positioning verification and accurate dosimetry of patient-specific QA in SRS treatment.

Green Synthesis of Silver Nanoparticles Using centratherum anthelminticum Extract against Breast Cancer Cells.

According to an international survey, the cancer occurrence in the breast is the foremost in women. Surgery and chemotherapy remain the definitive treatment for the breast cancer. The bio-green methods of synthesizing silver nanoparticles are cost-effective and eco-friendly when parallel to physical and chemical methods. In addition, they effectively control pathogenic microorganisms. Former research studies reveal that kalijiri a common name for Centratherum anthelminticum is used as a traditional medicine for various ailments including anti-bacterial, anti-fungal, antidiabetic and anticancer. Our present research study focal points on the green synthesis of silver nanoparticles using aqueous seed extract of Centratherum anthelminticum and the evaluation of their antioxidant and cytotoxic activity. An aqueous extract of seeds from Centratherum anthelminticum was prepared by boiling it with distilled water. The silver nanoparticles were synthesized from the seeds of Centratherum anthelminticum and characterized by various methods such as UV-Visible spectroscopy, FT-IR, Transmission electron microscopy, DLS and X-ray diffraction to confirm the formation of nanoparticles. The cytotoxic analysis of MDA-MB-231 cells was tested with the synthesized silver nanoparticles complex. The observed result was IC50 of 35.06±1.2 and it was not shown any toxicity to the non-cancerous cell line. In a nutshell, the synthesized silver nanoparticles from the seeds of Centratherum anthelminticum may be used for the treatment of breast cancer. Further studies are warranted to furnish the mechanism of action.

Innovative Colorimetric NQO1 Detection Strategy via Substrate Competitive and Biomimetic Cascade Reactions with a Highly Active NADH Oxidase Mimic.

NAD(P)H: quinone oxidoreductase-1 (NQO1) plays critical roles in antioxidation and abnormally overexpresses in tumors. Developing a fast and sensitive method of monitoring NQO1 will greatly promote cancer diagnosis in clinical practice. This study introduces a transformative colorimetric detection strategy for NQO1, harnessing an innovative competitive substrate mechanism between NQO1 and a new NADH oxidase (NOX) mimic, cobalt-nitrogen-doped carbon nanozyme (CoNC). This method ingeniously exploits the differential consumption of NADH in the presence of NQO1 to modulate the generation of H2O2 from CoNC catalysis, which is then quantified through a secondary, peroxidase-mimetic cascade reaction involving Prussian blue (PB) nanoparticles. This dual-stage reaction framework not only enhances the sensitivity of NQO1 detection, achieving a limit of detection as low as 0.67 μg mL-1, but also enables the differentiation between cancerous and noncancerous cells by their enzymatic activity profiles. Moreover, CoNC exhibits exceptional catalytic efficiency, with a specific activity reaching 5.2 U mg-1, significantly outperforming existing NOX mimics. Beyond mere detection, CoNC serves a dual role, acting as both a robust mimic of cytochrome c reductase (Cyt c) and a cornerstone for enzymatic regeneration, thereby broadening the scope of its biological applications. This study not only marks a significant step forward in the bioanalytical application of nanozymes but also sets the stage for their expanded use in clinical diagnostics and therapeutic monitoring.

Synthesis of furanotriterpenoids from betulin and evaluation of Tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibitory properties of new semi-synthetic triterpenoids

For the first time, a synthetic route for preparing lupane and oleanane derivatives with a hydrogenated furan ring as a cycle A of triterpene scaffold is described. Most of the synthesized compounds, furanoterpenoids and their synthetic intermediates, were non-toxic against the tested cancer and non-cancerous cell lines, and evinced significant inhibitory activity with IC50 1.0–9.0 μM in the tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibition test. Lupane derivatives – 1-oxime 7, 1,10-seco-hydroxynitrile 11 and furanoterpenoid 14 – were selected as those expected to be the most promising compounds. The results of molecular modeling evinced the strongest binding of compound 11 to the active site of Tdp1 compared to the reference drug. Simultaneously, only compound 11 at subtoxic concentration (10 μM) produced a synergetic effect on the topotecan activity against HeLa-V cells.

The Anticancer Effects and Therapeutic Potential of Kaempferol in Triple-Negative Breast Cancer.

Breast cancer is the second-leading cause of cancer death among women in the United States. Triple-negative breast cancer (TNBC), a subtype of breast cancer, is an aggressive phenotype that lacks estrogen (ER), progesterone (PR), and human epidermal growth (HER-2) receptors, which is challenging to treat with standardized hormonal therapy. Kaempferol is a natural flavonoid with antioxidant, anti-inflammatory, neuroprotective, and anticancer effects. Besides anti-tumorigenic, antiproliferative, and apoptotic effects, kaempferol protects non-cancerous cells. Kaempferol showed anti-breast cancer effects by inducing DNA damage and increasing caspase 3, caspase 9, and pAMT expression, modifying ROS production by Nrf2 modulation, inducing apoptosis by increasing cleaved PARP and Bax and downregulating Bcl-2 expression, inducing cell cycle arrest at the G2/M phase; inhibiting immune evasion by modulating the JAK-STAT3 pathway; and inhibiting the angiogenic and metastatic potential of tumors by downregulating MMP-3 and MMP-9 levels. Kaempferol holds promise for boosting the efficacy of anticancer agents, complementing their effects, or reversing developed chemoresistance. Exploring novel TNBC molecular targets with kaempferol could elucidate its mechanisms and identify strategies to overcome limitations for clinical application. This review summarizes the latest research on kaempferol's potential as an anti-TNBC agent, highlighting promising but underexplored molecular pathways and delivery challenges that warrant further investigation to achieve successful clinical translation.

DMF-DM-seq: Digital-Microfluidics Enabled Dual-Modality Sequencing of Single-Cell mRNA and microRNA with High Integration, Sensitivity, and Automation.

Multimodal measurement of single cells provides deep insights into the intricate relationships between individual molecular layers and the regulatory mechanisms underlying intercellular variations. Here, we reported DMF-DM-seq, a highly integrated, sensitive, and automated platform for single-cell mRNA and microRNA (miRNA) co-sequencing based on digital microfluidics. This platform first integrates the processes of single-cell isolation, lysis, component separation, and simultaneous sequencing library preparation of mRNA and miRNA within a single DMF device. Compared with the current half-cell measuring strategy, DMF-DM-seq enables complete separation of single-cell mRNA and miRNA via a magnetic field application, resulting in a higher miRNA detection ability. DMF-DM-seq revealed differential expression patterns of single cells of noncancerous breast cells and noninvasive and aggressive breast cancer cells at both mRNA and miRNA levels. The results demonstrated the anticorrelated relationship between miRNA and their mRNA targets. Further, we unravel the tumor growth and metastasis-associated biological processes enriched by miRNA-targeted genes, along with important miRNA-interaction networks involved in significant signaling pathways. We also deconstruct the miRNA regulatory mechanisms underlying different signaling pathways across different breast cell types. In summary, DMF-DM-seq offers a powerful tool for a comprehensive study of the expression heterogeneity of single-cell mRNA and miRNA, which will be widely applied in basic and clinical research.

A Novel Pyrazole Exhibits Potent Anticancer Cytotoxicity via Apoptosis, Cell Cycle Arrest, and the Inhibition of Tubulin Polymerization in Triple-Negative Breast Cancer Cells.

In this study, we screened a chemical library to find potent anticancer compounds that are less cytotoxic to non-cancerous cells. This study revealed that pyrazole PTA-1 is a potent anticancer compound. Additionally, we sought to elucidate its mechanism of action (MOA) in triple-negative breast cancer cells. Cytotoxicity was analyzed with the differential nuclear staining assay (DNS). Additional secondary assays were performed to determine the MOA of the compound. The potential MOA of PTA-1 was assessed using whole RNA sequencing, Connectivity Map (CMap) analysis, in silico docking, confocal microscopy, and biochemical assays. PTA-1 is cytotoxic at a low micromolar range in 17 human cancer cell lines, demonstrating less cytotoxicity to non-cancerous human cells, indicating a favorable selective cytotoxicity index (SCI) for the killing of cancer cells. PTA-1 induced phosphatidylserine externalization, caspase-3/7 activation, and DNA fragmentation in triple-negative breast MDA-MB-231 cells, indicating that it induces apoptosis. Additionally, PTA-1 arrests cells in the S and G2/M phases. Furthermore, gene expression analysis revealed that PTA-1 altered the expression of 730 genes at 24 h (198 upregulated and 532 downregulated). A comparison of these gene signatures with those within CMap indicated a profile similar to that of tubulin inhibitors. Subsequent studies revealed that PTA-1 disrupts microtubule organization and inhibits tubulin polymerization. Our results suggest that PTA-1 is a potent drug with cytotoxicity to various cancer cells, induces apoptosis and cell cycle arrest, and inhibits tubulin polymerization, indicating that PTA-1 is an attractive drug for future clinical cancer treatment.

L-proline H2SO4 catalyzed synthesis of novel coumarin-based spiroindolino-3,4-dihydropyrimidin-2(1H)-ones: in vitro cytotoxic assay and molecular docking study.

Development of environmentally benign catalyst systems, especially those derived from readily available nature's pool, in multicomponent synthesis, consolidates multiple facets of green chemistry. Here, an L-proline derived green acid catalyst in the form of L-proline⋅H2SO4 was developed and employed for multicomponent synthesis of coumarin-based spiroindolino-3,4-dihydropyrimidin-2(1H)-ones from the reaction of 4-hydroxycoumarin, isatin and urea/thiourea. Preliminary cytotoxicity studies showed that a couple of compounds (M5 and M6) have good cytotoxicity (40-50%) against in Dalton's Lymphoma (DL) cells while demonstrating minimal cytotoxicity (10-12%) for normal non-cancerous cell lines. Molecular docking simulations for the least and most cytotoxic compounds, M3 and M6 respectively, against nineteen tumor target proteins were carried out, and seven of them were identified to test against all the sixteen compounds. Based on the estimated docking score and inhibition constants (Ki), the interaction of the compounds with the tumor target protein, beta-hexosaminidase B (PDB ID: 1NOW) matched closely with in vitro cytotoxicity data.

High-confidence calling of normal epithelial cells allows identification of a novel stem-like cell state in the colorectal cancer microenvironment.

Single-cell analyses can be confounded by assigning unrelated groups of cells to common developmental trajectories. For instance, cancer cells and admixed normal epithelial cells could adopt similar cell states thus complicating analyses of their developmental potential. Here, we develop and benchmark CCISM (for Cancer Cell Identification using Somatic Mutations) to exploit genomic single nucleotide variants for the disambiguation of cancer cells from genomically normal non-cancer cells in single-cell data. We find that our method and others based on gene expression or allelic imbalances identify overlapping sets of colorectal cancer versus normal colon epithelial cells, depending on molecular characteristics of individual cancers. Further, we define consensus cell identities of normal and cancer epithelial cells with higher transcriptome cluster homogeneity than those derived using existing tools. Using the consensus identities, we identify significant shifts of cell state distributions in genomically normal epithelial cells developing in the cancer microenvironment, with immature states increased at the expense of terminal differentiation throughout the colon, and a novel stem-like cell state arising in the left colon. Trajectory analyses show that the new cell state extends the pseudo-time range of normal colon stem-like cells in a cancer context. We identify cancer-associated fibroblasts as sources of WNT and BMP ligands potentially contributing to increased plasticity of stem cells in the cancer microenvironment. Our analyses advocate careful interpretation of cell heterogeneity and plasticity in the cancer context and the consideration of genomic information in addition to gene expression data when possible.

A cell targeting and sorting approach based on the magnetophoretic capturing for early prognostics of metastatic cervical cancer cells

HeLa cervical cancer cells are immortal with telomerase activity and metastatic characteristics similar to circulating tumor cells (CTCs). Here, we report aptamer-modified multilayered magnetic beads (Apt@MBs) that efficiently targeted and captured HeLa cells up to a low concentration of freshly prepared cell suspension (500 cells/mL). Apt@MBs were functionalized with fluorophore-conjugated AS1411-aptamer on an outer layer made up of molybdenum disulfide (MoS2) to target nucleolin on the cell surface of captured HeLa cells. Moreover, this outer MoS2 layer of MBs was nanoporous and could load anticancer drugs inside its porous cavities with the possibility of killing the captured and metastatic CTCs in vivo. An internal core layer of Apt@MBs consisting of Ag–Fe3O4 magnetic particles (MPs) was designed for magnetic manifestations and cell sorting with the possibility of screening CTCs (in the patient's blood samples) for early diagnosis of metastatic cancers. The Apt@MBs after cell capture gave rise to the heavier HeLa-MBs composites to get settled down under gravitational/inertial forces to the bottom of the tube quicker than the free cells (within 10 min). The gravitational settling of HeLa-MBs was further coupled with exposing a magnetic field to effectively capture and enrich the cells at the bottom of the tube (from 91 to 98 % cells). While the fluid containing dead, non-cancerous, or uncaptured cells in the supernatant layers were easily removed by pipetting. The HeLa-MBs after sorting out were resuspended into a fresh culture medium for further incubation or cellular analysis. Moreover, both cisplatin (CP) and epirubicin (EP) loaded Apt@MBs showed the killing of about 50 % of the captured cells. Therefore, we are confident that Apt@MBs can contribute to enumerating patients' blood samples for screening CTCs to timely and efficiently detect metastatic cancers along with the ability to effectively perform prognosis, and treatment of metastatic cancers.

Synthesis, characterization and bioactivity of new pyridine-2(H)-one, nicotinonitrile, and furo[2,3-b]pyridine derivatives.

Pyridone heterocycles, such as furo[2,3-b]pyridines, have emerged as prominent scaffolds in medicinal chemistry due to their versatile pharmacological properties, including significant anticancer activity. In this study, we successfully synthesized new pyridine-2(H)-one, nicotinonitrile, and furo[2,3-b]pyridine derivatives from chalcones bearing 4-(benzyloxy)phenyl and dichlorothiophenyl subunits to explore their therapeutic potential against breast cancer. By employing a synthetic strategy involving Claisen-Schmidt condensation followed by sequential cyclizations and functional modifications, we synthesized and characterized four compounds (MI-S0, MI-S1, MI-S2, and MI-S3) using various spectroscopic methods, including FT-IR, 1H-NMR, 13C-NMR, DEPT, H,H- and C,H-COSY, and HRMS. The in vitro cytotoxic activity of these compounds was evaluated against two breast cancer cell lines, MCF-7 and MDA-MB-231, and compared with a noncancerous breast cell line, MCF-10A. All compounds exhibited potent cytotoxic activities with minimal selectivity toward normal cells. Molecular docking studies targeting the serine/threonine kinase AKT1, estrogen receptor alpha (ERα), and human epidermal growth factor receptor 2 (HER2) revealed strong binding affinities, suggesting a mechanism involving the disruption of key cellular signaling pathways. These findings underscore the potential of furo[2,3-b]pyridine derivatives as promising candidates for further development into anticancer agents, laying the groundwork for future investigations into their selective therapeutic efficacy and molecular mechanisms of action.

Investigation into the Neuroprotective and Therapeutic Potential of Plant-Derived Chk2 Inhibitors.

Nature provides us with a rich source of compounds with a wide range of applications, including the creation of innovative drugs. Despite advancements in chemically synthesized therapeutics, natural compounds are increasingly significant, especially in cancer treatment, a leading cause of death globally. One promising approach involves the use of natural inhibitors of checkpoint kinase 2 (Chk2), a critical regulator of DNA repair, cell cycle arrest, and apoptosis. Chk2's activation in response to DNA damage can lead to apoptosis or DNA repair, influencing glycolysis and mitochondrial function. In cancer therapy, inhibiting Chk2 can disrupt DNA repair and cell cycle progression, promoting cancer cell death and enhancing the efficacy of radiotherapy and chemotherapy. Additionally, Chk2 inhibitors can safeguard non-cancerous cells during these treatments by inhibiting p53-dependent apoptosis. Beyond oncology, Chk2 inhibition shows potential in treating hepatitis C virus (HCV) infections, as the virus relies on Chk2 for RNA replication in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), in which DNA damage plays a crucial role. Plant-derived Chk2 inhibitors, such as artemetin, rhamnetin, and curcumin, offer a promising future for treating various diseases with potentially milder side effects and broader metabolic impacts compared to conventional therapies. The review aims to underscore the immense potential of natural Chk2 inhibitors in various therapeutic contexts, particularly in oncology and the treatment of other diseases involving DNA damage and repair mechanisms. These natural Chk2 inhibitors hold significant promise for revolutionizing the landscape of cancer treatment and other diseases. Further research into these compounds could lead to the development of innovative therapies that offer hope for the future with fewer side effects and enhanced efficacy.

1,2,3-Triazole – [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hybrids: A switch for improvement of antibreast cancer activity targeting epidermal growth factor receptor

The development of anticancer agents targeting EGFR represents a promising strategy in the field of medicinal chemistry. Consequently, a novel series of 1,2,3-triazole – [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hybrids (7a-i &8a-f) were designed, synthesized, and screened for their in vitro anticancer activity against three human breast cancer cell lines, MCF-7, MDA-MB-231, and MDA-MB-415. Notably, hybrids 7f and 7h, featuring 4-fluorophenyl and 3,5-dichlorophenyl substitutions, respectively, exhibited superior activity against MCF-7 and MDA-MB-231 cell lines, and comparable activity against MDA-MB-415 cell line, compared to the standard drug Erlotinib. Toxicity studies on the noncancerous breast cell line MCF-10A indicate that these compounds are selective for cancer cell lines. Furthermore, these compounds demonstrated high efficacy in the in vitro EGFR inhibition assay, with IC50 values of 0.419 ± 0.05 μM and 0.312 ± 0.02 μM, respectively, in comparison to Erlotinib (IC50: 0.421 ± 0.03 μM). In silico experiments, including molecular docking studies to elucidate the interaction mode with the EGFR active site and ADMET analysis to verify drug-likeness properties, were also conducted for the potent compounds. Both experimental and in silico investigations suggest that compounds 7f and 7h hold promise as lead compounds for further drug design and development endeavors.

Molecular Mechanisms of Anticarcinogenic Potential of Hydrocotyle umbellata and Its Major Components

Despite the development of several anticancer treatments, there remains a need for new drugs that can overcome resistance and reduce side effects. While the medicinal herb Hydrocotyle umbellata (H. umbellata) has been used to relieve pain and inflammation, its antitumor properties have not yet been explored. In this study, we investigated the anticarcinogenic potential of H. umbellata extract (HUE) and its major components, as well as the underlying molecular mechanisms. Our results showed that HUE inhibited the growth of various tumor cell lines, including B16F10, without affecting non-cancer cells. Furthermore, HUE was effective in treating and preventing tumor growth in mice. Our mechanistic studies revealed that HUE inhibited cellular respiration, thereby reducing tumor cell proliferation. When combined with 2-deoxy-D-glucose, HUE demonstrated an enhanced anticancer effect by increasing the rate apoptosis. Analysis of the ethyl acetate and n-butanol fractions of HUE identified 1,3,4-trihydroxy-2-butanyl-α-d-glucopyranoside and caffeoylquinic acid derivatives as the major components responsible for the observed anticancer effects. In conclusion, our findings suggest that HUE and its two major components have the potential to be developed as effective therapeutic agents for a wide range of tumors by targeting cancer cell metabolism.

Green, facile synthesis and evaluation of unsymmetrical carbamide derivatives as antimicrobial and anticancer agents with mechanistic insights

A very practical method for the synthesis of unsymmetrical carbamide derivatives in good to excellent yield was presented, without the need for any catalyst and at room temperature. Using a facile and robust protocol, fifteen unsymmetrical carbamide derivatives (9–23) bearing different aliphatic amine moieties were designed and synthesized by the reaction of secondary aliphatic amines with isocyanate derivatives in the presence of acetonitrile as an appropriate solvent in good to excellent yields. Trusted instruments like IR, mass spectrometry, NMR spectra, and elemental analyses were employed to validate the purity and chemical structures of the synthesized compounds. All the synthesized compounds were tested as antimicrobial agents against some clinically bacterial pathogens such as Salmonella typhimurium, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans. Compounds 15, 16, 17, 19 and 22 showed potent antimicrobial activity with promising MIC values compared to the positive controls. Moreover, compounds 15 and 22 provide a potent lipid peroxidation (LPO) of the bacterial cell wall. On the other hand, we investigated the anti-proliferative activity of compounds 9–23 against selected human cancerous cell lines of breast (MCF-7), colon (HCT-116), and lung (A549) relative to healthy noncancerous control skin fibroblast cells (BJ-1). The mechanism of their cytotoxic activity has been also examined by immunoassaying the levels of key anti- and pro-apoptotic protein markers. The results of MTT assay revealed that compounds 10, 13, 21, 22 and 23 possessed highly cytotoxic effects. Out of these, three synthesized compounds 13, 21 and 22 showed cytotoxicity with IC50 values (13, IC50 = 62.4 ± 0.128 and 22, IC50 = 91.6 ± 0.112 µM, respectively, on MCF-7), (13, IC50 = 43.5 ± 0.15 and 21, IC50 = 38.5 ± 0.17 µM, respectively, on HCT-116). Cell cycle and apoptosis/necrosis assays demonstrated that compounds 13 and 22 induced S and G2/M phase cell cycle arrest in MCF-7 cells, while only compound 13 had this effect on HCT-116 cells. Furthermore, compound 13 exhibited the greatest potency in inducing apoptosis in both cell lines compared to compounds 21 and 22. Docking studies indicated that compounds 10, 13, 21 and 23 could potentially inhibit enzymes and exert promising antimicrobial effects, as evidenced by their lower binding energies and various types of interactions observed at the active sites of key enzymes such as Sterol 14-demethylase of C. albicans, Dihydropteroate synthase of S. aureus, LasR of P. aeruginosa, Glucosamine-6-phosphate synthase of K. pneumenia and Gyrase B of B. subtilis. Moreover, 13, 21, and 22 demonstrated minimal binding energy and favorable affinity towards the active pocket of anticancer receptor proteins, including CDK2, EGFR, Erα, Topoisomerase II and VEGFFR. Physicochemical properties, drug-likeness, and ADME (absorption, distribution, metabolism, excretion, and toxicity) parameters of the selected compounds were also computed.