Extrapolation of cytotoxic masked effects in planar in vitro assays.

The masking of specific effects in in vitro assays by cytotoxicity is a commonly known phenomenon. This may result in a partial or complete loss of effect signals. For common in vitro assays, approaches for identifying and quantifying cytotoxic masking are partly available. However, a quantification of cytotoxicity-affected signals is not possible. As an alternative, planar bioassays that combine high-performance thin layer chromatography with in vitro assays, such as the planar yeast estrogen screen (p-YES), might allow for a quantification of cytotoxically affected signals. Affected signals form a typical ring structure with a supressed or completely lacking centre that results in a double peak chromatogram. This study investigates whether these double peaks can be used for fitting a peak function to extrapolate the theoretical, unaffected signals. The precision of the modelling was evaluated for four individual peak functions, using 42 ideal, undistorted peaks from estrogenic model compounds in the p-YES. Modelled ED50-values from bisphenol A (BPA) experiments with cytotoxically disturbed signals were 13 times higher than for the apparent data without compensation for cytotoxicity (320 ± 63 ng versus 24 ± 17 ng). This finding has a high relevance for the modelling of mixture effects according to concentration addition that requires unaffected, complete dose-response relationships. Finally, we applied the approach to results of a p-YES assay on leachate samples of an elastomer material used in water engineering. In summary, the fitting approach enables the quantitative evaluation of cytotoxically affected signals in planar in vitro assays and also has applications for other fields of chemical analysis like distorted chromatography signals.

In-vitro and in silco analysis and antitumor studies of novel Cu(II) and V(V) complexes of N-p-Tolylbenzohydroxamic acid.

Copper(L2Cu) and vanadium(L2VOCl) complexes of N-p-tolylbenzohydroxamic acid (LH) ligand have been investigated for DNA binding efficacy by multiple analytical, spectral, and computational techniques. The results revealed that complexes as groove binders as evidenced by UV absorption. Fluorescence studies including displacement assay using classical intercalator ethidium bromide as fluorescent probe also confirmed as groove binders. The viscometric analysis too supports the inferences as strong groove binders for both the complexes. Molecular docking too exposed DNA as a target to the complexes which precisely binds L2Cu, in the minor groove region while L2VOCl in major groove region. Molecular dynamic simulation performed on L2Cu complex revealing the interaction of complex with DNA within 20 ns time. The complex stacked into the nitrogen bases of oligonucleotides and the bonding features were intrinsically preserved for longer simulation times. In-vitro cytotoxicity study was undertaken employing MTT assay against the breast cancer cell line (MCF-7). Potential cytotoxic activities were observed for L2Cu and L2VOCl complexes with IC50 values of showing 71 % and 74 % of inhibition respectively.

Phytochemical characterization by GC-MS and in vitro evaluation of antiproliferative and antimigratory studies of Leucas aspera leaf extracts on MDA-MB-231 cell line.

Breast cancer is the most recurrently identified and one of women's prominent causes of death. Currently, researchers have turned their focus on natural chemicals from synthetic chemicals due to their environmental, economic, and health benefits. Considering this, the medicinal plant Leucas aspera was chosen for the current study. The aim of this study was to isolate and characterize secondary metabolites from L. aspera and determine the antiproliferative and antimigratory activities in the MDA-MB-231 cell line under in vitro conditions. Phytochemicals from L. aspera were isolated through sequential extraction using hexane, dichloromethane, and ethyl acetate. These extracts were qualitatively screened, subjected to FT-IR, and analyzed using GC-MS. The antiproliferative activity was determined through the MTT assay. Scratch assay was utilized to determine the antimigratory activity of the plant extracts. The phytochemical analysis revealed the presence of steroids, alkaloids, phenols, flavonoids, galactose, tannins, saponins, and amino acids in the extracts. The results of the cell viability assay indicated that the crude dichloromethane and ethyl acetate extracts inhibited cell proliferation, with inhibitory concentrations of 5 and 3 µg/ml, respectively. In contrast, the crude hexane extract did not exhibit any cytotoxicity. Furthermore, the scratch assay results showed that the plant extracts had cell migration inhibitory properties. The outcomes of the current study conclude that L. aspera possesses active therapeutic agents with strong anticancer potential, effectively impeding the proliferation and invasion of MDA-MB-231. Further studies are needed to identify the potential active agents that contribute to these activities.

Rosellichalasins A-H, cytotoxic cytochalasans from the endophytic fungus Rosellinia sp. Glinf021.

Eight new cytochalasans rosellichalasins A-H (1-8), as well as two new shunt metabolites rosellinins A (9) and B (10) before intramolecular Diels-Alder cycloaddition reaction in cytochalasan biosynthesis, along with nine known cytochalsans (11-19) were isolated from the endophytic fungus Rosellinia sp. Glinf021, which was derived from the medicinal plant Glycyrrhiza inflata. Their structures were characterized by extensive analysis of 1D and 2D NMR as well as HRESIMS spectra and quantum chemical ECD calculations. The cytotoxic activities of these compounds were evaluated against four human cancer cell lines including HCT116, MDA-MB-231, BGC823, and PANC-1 with IC50 values ranging from 0.5 to 58.2 µM.

Treatment advances in high-grade gliomas.

High-grade gliomas (HGG) pose significant challenges in modern tumour therapy due to the distinct biological properties and limitations of the blood-brain barrier. This review discusses recent advancements in HGG treatment, particularly in the context of immunotherapy and cellular therapy. Initially, treatment strategies focus on targeting tumour cells guided by the molecular characteristics of various gliomas, encompassing chemotherapy, radiotherapy and targeted therapy for enhanced precision. Additionally, technological enhancements are augmenting traditional treatment modalities. Furthermore, immunotherapy, emphasising comprehensive tumour management, has gained widespread attention. Immune checkpoint inhibitors, vaccines and CAR-T cells exhibit promising efficacy against recurrent HGG. Moreover, emerging therapies such as tumour treating fields (TTFields) offer additional treatment avenues for patients with HGG. The combination of diverse treatments holds promise for improving the prognosis of HGG, particularly in cases of recurrence.

Granzymes in health and diseases: the good, the bad and the ugly.

Granzymes are a family of serine proteases, composed of five human members: GA, B, H, M and K. They were first discovered in the 1980s within cytotoxic granules released during NK cell- and T cell-mediated killing. Through their various proteolytic activities, granzymes can trigger different pathways within cells, all of which ultimately lead to the same result, cell death. Over the years, the initial consideration of granzymes as mere cytotoxic mediators has changed due to surprising findings demonstrating their expression in cells other than immune effectors as well as new intracellular and extracellular activities. Additional roles have been identified in the extracellular milieu, following granzyme escape from the immunological synapse or their release by specific cell types. Outside the cell, granzyme activities mediate extracellular matrix alteration via the degradation of matrix proteins or surface receptors. In certain contexts, these processes are essential for tissue homeostasis; in others, excessive matrix degradation and extensive cell death contribute to the onset of chronic diseases, inflammation, and autoimmunity. Here, we provide an overview of both the physiological and pathological roles of granzymes, highlighting their utility while also recognizing how their unregulated presence can trigger the development and/or worsening of diseases.

Cytotoxic and Antibacterial Meroterpenoids Isolated from the Marine-Derived Fungus Talaromyces sp. M27416.

Three novel meroterpenoids, taladrimanins B-D (1-3), were isolated from the marine-derived fungus Talaromyces sp. M27416, alongside three biogenetically related compounds (4-6). We delineated taladrimanin B's (1) structure using HRESIMS and NMR, confirmed its configuration via quantum chemical NMR analysis and DP4+ methodology, and verified it through X-ray crystallography. ECD calculations determined the absolute configuration of compound 1, while comparative NMR and ECD analyses elucidated the absolute configurations of 2 and 3. These compounds are drimane-type meroterpenoids with a C10 polyketide unit (8R-configuration). We proposed a biosynthetic pathway and noted that compound 1 showed cytotoxic activity against MKN-45 and 5637 cell lines and selective antibacterial effects against Staphylococcus aureus CICC 10384.

New Solasodine-type Glycoalkaloids Isolated from Solanum nigrum and Their Cytotoxic Activity.

Three undescribed solalodine-type glycoalkaloids, named  solanigrinoside A-C (1-3), and six known compounds (4-9) were isolated from the whole plants of Solanum nigrum. Their structures were elucidated based on analysis of HR-ESI-MS, 1D- and 2D-NMR spectral data, and comparison with those reported in literatures. The solanigrinoside A-C (1-3), solasodine (4), and 3-acetoxysolasodine (5) exhibited cytotoxic effects against LU-1, Hep-G2, and MCF-7 cells with IC50 values in range from 4.6 µM to 56.2 µM. Compound 2 showed the significant cytotoxic activity with corresponding IC50 values of 5.7 µM, 7.9 µM, and 4.6 µM, respectively.

Rational Design and Synthesis of Isatin-Chalcone Hybrids Integrated with 1H-1,2,3-Triazole: Anti-proliferative Profiling and Molecular Docking Insights.

In this study, a series of isatin-chalcone linked triazoles were synthesized using Cu-promoted Azide-Alkyne Cycloaddition (CuAAC) reaction and evaluated for their cytotoxicity against various cancer cell lines. The most potent compound displayed approximately 2.5 times greater activity compared to both reference compounds against ovarian cancer cell lines. These findings were supported by caspase-mediated apoptosis and molecular docking analyses. Docking revealed comparable VEGFR-2 affinities for 5b and 5-FU but highlighted stronger interaction of 5b with EGFR, evident from its lower docking score. Overall, these results signify the notable anti-proliferative potential of most synthesized hybrids, notably emphasizing the efficacy of compound 5b in suppressing cancer cell growth.

Design, synthesis, insilco study and biological evaluation of new isatin-sulfonamide derivatives by using mono amide linker as possible as histone deacetylase inhibitors.

OBJECTIVE: Aim: To evaluate the cytotoxic activity of newly synthesized a series of novel HDAC inhibitors comprising sulfonamide as zinc binding group and Isatin derivatives as cap group joined by mono amide linker as required to act as HDAC inhibitors. PATIENTS AND METHODS: Materials and Methods: The utilization of sulfonamide as zinc binding group joined by N-alkylation reaction with ethyl-bromo hexanoate as linker group that joined by amide reaction with Isatin derivatives as cap groups which known to possess antitumor activity in the designed of new histone deacetylase inhibitors and using the docking and MTT assay to evaluate the compounds. RESULTS: Results: Four compounds have been synthesized and characterized successfully by ART-FTIR, NMR and ESI-Ms. the compounds were synthesized and characterized by successfully by ART-FTIR, NMR and ESI- Ms. Assessed for their cytotoxic activity against human colon adenocarcinoma MCF-7 (IC50, I=105.15, II=60.00, III=54.11, IV=56.57, vorinostat=28.41) and hepatoblastoma HepG2 (IC50, I=63.91, II=135.18, III=118.85, IV=51.46, vorinostat=37.50). Most of them exhibited potent HDAC inhibitory activity and significant cytotoxicity. CONCLUSION: Conclusions: The synthesized compounds (I, II, III and IV) showed cytotoxicity toward MCF-7 and HepG2 cancer cell lines and their docking analysis provided a preliminary indication that they are viable [HDAC6] candidates.

BCL2A1 neoepitopes-elicited cytotoxic T lymphocytes are a promising individualized immunotherapy of pancreatic cancer.

Conventional treatments have shown a limited efficacy for pancreatic cancer, and immunotherapy is an emerging option for treatment of this highly fatal malignancy. Neoantigen is critical to improving the efficacy of tumor-specific immunotherapy. The cancer and peripheral blood specimens from human leukocyte antigen (HLA)-A0201 positive pancreatic cancer patient were subjected to next-generation sequencing and bioinformatics analyses were performed to screen high-affinity and highly stable neoepitopes. The activation of cytotoxic T lymphocytes (CTLs) by the mutBCL2A111-20 neoepitope targeting B-cell lymphoma 2-related protein A1 (BCL2A1) mutant epitope was investigated, and the cytotoxicity of mutBCL2A111-20 neoepitope-specific CTLs to pancreatic cancer cells was evaluated. The mutBCL2A111-20 neoepitope was found to present a high immunogenicity and induce CTLs activation and proliferation, and was cytotoxic to mutBCL2A111-20 neoepitope-loaded T2 cells and pancreatic cancer PANC-1-Neo and A2-BxPC-3-Neo cells that overexpressed mutBCL2A111-20 neoepitopes, appearing a targeting neoepitope specificity. In addition, high BCL2A1 expression correlated with a low 5-year progress free interval (PFI) among pancreatic cancer patients. Our findings provide experimental supports to individualized T-cell therapy targeting mutBCL2A111-20 neoepitopes, and provide an option of immunotherapy for pancreatic cancer.

Surviving the Storm: The Role of Poly- and Depolyploidization in Tissues and Tumors.

Polyploidization and depolyploidization are critical processes in the normal development and tissue homeostasis of diploid organisms. Recent investigations have revealed that polyaneuploid cancer cells (PACCs) exploit this ploidy variation as a survival strategy against anticancer treatment and for the repopulation of tumors. Unscheduled polyploidization and chromosomal instability in PACCs enhance malignancy and treatment resistance. However, their inability to undergo mitosis causes catastrophic cellular death in most PACCs. Adaptive ploid reversal mechanisms, such as multipolar mitosis, centrosome clustering, meiosis-like division, and amitosis, counteract this lethal outcome and drive cancer relapse. The purpose of this work is to focus on PACCs induced by cytotoxic therapy, highlighting the latest discoveries in ploidy dynamics in physiological and pathological contexts. Specifically, by emphasizing the role of "poly-depolyploidization" in tumor progression, the aim is to identify novel therapeutic targets or paradigms for combating diseases associated with aberrant ploidies.

Edema progression in proximity to traumatic microbleeds: evolution of cytotoxic and vasogenic edema on serial MRI.

Introduction: Although cerebral edema is common following traumatic brain injury (TBI), its formation and progression are poorly understood. This is especially true for the mild TBI population, who rarely undergo magnetic resonance imaging (MRI) studies, which can pick up subtle structural details not visualized on computed tomography, in the first few days after injury. This study aimed to visually classify and quantitatively measure edema progression in relation to traumatic microbleeds (TMBs) in a cohort of primarily mild TBI patients up to 30 days after injury. Researchers hypothesized that hypointense lesions on Apparent Diffusion Coefficient (ADC) detected acutely after injury would evolve into hyperintense Fluid Attenuated Inversion Recover (FLAIR) lesions. Methods: This study analyzed the progression of cerebral edema after acute injury using multimodal MRI to classify TMBs as potential edema-related biomarkers. ADC and FLAIR MRI were utilized for edema classification at three different timepoints: ≤48 hours, ~1 week, and 30 days after injury. Hypointense lesions on ADC (ADC+) suggested the presence of cytotoxic edema while hyperintense lesions on FLAIR (FLAIR+) suggested vasogenic edema. Signal intensity Ratio (SIR) calculations were made using ADC and FLAIR to quantitatively confirm edema progression. Results: Our results indicated the presence of ADC+ lesions ≤48 hours and ~1 week were associated with FLAIR+ lesions at ~1 week and 30 days, respectively, suggesting some progression of cytotoxic edema to vasogenic edema over time. Ten out of 15 FLAIR+ lesions at 30 days (67%) were ADC+ ≤48 hours. However, ADC+ lesions ≤48 hours were not associated with FLAIR+ lesions at 30 days; 10 out of 25 (40%) ADC+ lesions ≤48 hours were FLAIR+ at 30 days, which could indicate that some lesions resolved or were not visualized due to associated atrophy or tissue necrosis. Quantitative analysis confirmed the visual progression of some TMB lesions from ADC+ to FLAIR+. FLAIR SIRs at ~1 week were significantly higher when lesions were ADC+ ≤48 hours (1.22 [1.08-1.32] vs 1.03 [0.97-1.11], p=0.002). Conclusion: Awareness of how cerebral edema can evolve in proximity to TMBs acutely after injury may facilitate identification and monitoring of patients with traumatic cerebrovascular injury and assist in development of novel therapeutic strategies.

Determination of chemical components of the endemic species Allium turcicum L. plant extract by LC-MS/MS and evaluation of medicinal potentials.

The Allium turcicum L. (Zuzubak) plant as a cultivated vegetable have various health benefits and consumed as a food. Due to the shortcoming evidence in literature and the importance of this plant in folk medicine, in the present study, for the first time, we evaluated the bioactive profile of components (using LC-MS/MS), cytotoxicity, anticancer, antioxidant, and antibacterial prospectives of Zuzubak methanol extract. Reported results show that the extract is rich in bioactive compounds and has anticancer activity with breast cancer cells (MCF-7), human prostate cancer cells (DU-145), and Human osteosarcoma cancer Cell lines of (IC50) in dose dependent manner in the concentration range of 31.25 µg/mL and 2000 µg/mL for 24 and 48 h. Western blotting results determined that the extract significantly suppressed the growth of U2OS, MCF-7, and DU-145 cancer cells by down expression of Ang-1 (angiogenic protein) and Beclin-1 (autophagy protein) and overexpression of Bax (a proapoptotic protein). The oxidative stress indices showed a reduction in RPE-1 and MCF-7 cells and an upsurge in U2OS and DU-145 cells. Additionally, the antimicrobial assay showed suppression of the growth of various pathogenic microorganisms in 4.00-8.00 µg/concentrations of Zuzubak extract using the microdilution method. The phytochemicals identified showed promising anticancer, antioxidant effects, and antimicrobial properties, representing a valuable herbal source for drug development studies.

Hericium VN, an undescribed compound isolated from Hericium erinaceus and its cytotoxic activity on human brain astrocytoma.

Hericium erinaceus is a species of mushroom with high nutritional value that is used mainly as food in tropical countries. Phytochemical study of H. erinaceus led to the isolation of an undescribed compound, named as hericium VN (1), together with nine known compounds, 1-(2-formyl-1-pyrrolyl)butanoic acid (2), herierin III (3), 5'-(methylthio)adenosine (4), adenosine (5), nicotinic acid (6), (22E,24R)-5α,8α-epidioxyergosta-6,9(11),22-trien-3ß-ol (7), 5α,8α-peroxycerevisterol (8), (22E,24R)-5α,8α-epidioxy-egosta-6,22-diene 3-O-ß-D-glucopyranoside (9), and cerevisterol (10) based on extensive analyses of HR-ESI-MS, 1D and 2D NMR spectra. The absolute configuration of compound 1 was determined by experimental combined with calculated electronic circular dichroism spectra. Compound 7 exhibited cytotoxic effects against brain tumor cell line CCF-STTG1 with the IC50 value of 15.50 µM, compared to that of the positive control compound, doxorubicin, which showed IC50 value of 15.84 µM.

The ethnomedicine, phytochemistry, and pharmacological properties of the genus Bersama: current review and future perspectives.

Bersama (Melianthaceae) has been used in traditional medicine for a wide range of ailments, including blood purifier, immune booster, psychotropic medication, and treatment for malaria, hepatitis, infertility, diabetes, impotency, meningitis, and stroke. This review gathers fragmented information from the literature on ethnomedicinal applications, phytochemistry, pharmacology, and toxicology of the Bersama genus. It also explores the therapeutic potential of the Bersama genus in ethnophytopharmacology, allowing for further investigation. All the available information published in the English language on Bersama genus was compiled from electronic databases such as Academic Journals, Ethnobotany, Google Scholar, PubMed, Science Direct, Web of Science, and library search using the following keywords: "Bersama genus," "traditional use," "phytochemistry," "pharmacological effects," and "toxicology". The ethnomedical applications of the Bersama genus have been recorded, and it has been used traditionally for more than 30 different types of ailments. Thus far, more than 50 compounds have been isolated from the genus. Cardiac glycosides and terpenoids are the main compounds isolated from the Bersama genus. Different plant parts of Bersama genus extracts demonstrated a wide range of pharmacological properties, including antioxidant, antimalarial, antidiabetic, antiviral, anti-inflammatory, and cytotoxic activity. Exemplary drug leads from the genus include mangiferin and quercetin-3-O-arabinopyranoside, both of which have antioxidant activities. Bersama genus has long been used to cure a wide range of ailments. Bersama genus extracts and phytochemicals have been found to have promising pharmacological activities. Further study on promising crude extracts and compounds is required to develop innovative therapeutic candidates.

Advanced cervix cancer patient with chemotherapy-induced grade IV myelosuppression achieved complete remission with cadonilimab: A case report.

BACKGROUND: The prognosis for patients with advanced metastatic cervix cancer (MCC) is poor, and this disease continues to pose a considerable therapeutic challenge. Despite the administration of first-line regimens consisting of cisplatin, paclitaxel, and bevacizumab, survival rates for patients with metastasis remain poor. The emergence of bispecific antibodies (BsAbs) offers a novel treatment option for patients diagnosed with MCC. CASE SUMMARY: In this report, we present a patient with MCC who was treated with cadonilimab monotherapy at a dose of 6 mg/kg every two weeks after chemotherapy was proven to be intolerable. The patient exhibited a sustained complete response for a duration of 6 months, demonstrating an optimistic outlook. CONCLUSION: This case illustrates the considerable efficacy of cadonilimab for treating advanced MCC. Therefore, BsAb therapy is a promising strategy for effectively treating patients with advanced MCC and should be considered as an option when patients are intolerant to standard chemotherapy.

Synthesis and cytotoxic evaluation of glycosyl derivatives of icaritin.

A series of glycosyl alkyl/triazol-linked icaritin derivatives have been designed and synthesised. The target glycosyl derivatives were evaluated for their anticancer activity against three human cancer cell lines. The results of preliminary anticancer tests in vitro revealed that mannose derivatives 10a-10c (100 µM) with different aliphatic chain lengths exhibited increased cytotoxicity against HepG2 and SK-OV-3 cells compared with the parent compound icaritin. The data indicated that the kind of glycosyl groups and linkers affected the anticancer potency significantly. The ADME analysis of derivatives 10a-10c was also performed.

Utilising UPLC-QTOF-MS/MS to determine the phytochemical profile and in vitro cytotoxic potential of Ziziphora capitata L. with molecular docking simulation.

Ziziphora capitata (Lamiaceae family) aerial parts extract contains 57 metabolites, including flavonoids, phenolic acids, anthocyanins, and coumarins, as assessed by UPLC-QTOF-MS/MS. Successive extracts (hexane, chloroform, ethyl acetate, ethanol 95%, and water) were tested in vitro cytotoxic activity against HepG-2, MCF-7, HCT-116, A549, and PC3 cell lines. The results revealed that hexane extract exhibited the most potent cytotoxic activity among PC3 and A549 cell lines, IC50 = 47.1 ± 1.75 and 49.2 ± 1.08 µg/mL compared to Vinblastine IC50 = 42.47 ± 1.95 and 24.64 ± 1.18 µg/mL, respectively, and had a moderate impact on the remaining cell lines. Moreover, the chloroform and ethyl acetate extracts exhibited moderate affinity among all tested cell lines. Furthermore, the total phenolic and flavonoid contents were assessed. The molecular docking simulation was performed inside the effective sites of VEGFR-2 and TS as anticancer targets for the top ten phytochemicals. The results showed higher binding energy values for VEGFR-2 than for TS compared to vinblastine and co-crystallized ligands.

Two new triterpenoid saponins and two new goodyerosides isolated from the whole plant of Tournefortia sibirica.

Two new triterpenoid saponins (oleanolic acid 2ß-hydroxyl-3-O-ß-D-glucuronopyranoside-6'-O-buthyl ester (1) and oleanolic acid 2ß-hydroxyl-3-O-[ß-D-glucuronopyranosyl-6'-O-methylester]-28-O-ß-D-glucopyranoside (2)) and two new goodyerosides (4-methylenefuran-2(5H)-one (6'-O-vanilloyl)-ß-D-glucopyranoside (3), 3-hydroxy-2(5H)-furanone, 4-(6'-O-vanilloyl)-ß-D-glucopyranoside (4)), together with seven known compounds (5-11) were isolated from the whole plant of Tournefortia sibirica L. The chemical structures of the compounds were determined by spectroscopic analysis (1D and 2D NMR) and HR-ESI-MS. Compounds 1, 6 and 9 showed significant cytotoxicity towards A549, SK-Hep1 and HeLa cells, with IC50 values ranging from 1.68 ± 0.09 to 6.87 ± 0.13 µM.