Search Results (453)

Background/Objectives: Gut microbiota research has gained momentum in recent years broadening knowledge of microbial components and their potential effects on health and well-being. Strong association between explicit microbes and metabolic diseases associated with obesity and type 2 diabetes mellitus, gastrointestinal disorders, neurodegenerative diseases, and even cancers have been established. Akkermansia muciniphila is a budding next-generation probiotic that plays an important role in systemic metabolism, intestinal health, and immune regulation, establishing strong implications for its use as a potent therapeutic intervention in diverse diseases. This project aimed at evaluating whether bacterial cell extracts of VH Akkermansia muciniphila (Vidya Strain; VS) can stimulate insulin secretion in INS-1 pancreatic beta cells and GLP-1 secretion in NCI-H716 human L-cells, both established in vitro models for studying metabolic regulation. Methods: Cultured VH Akkermansia muciniphila extracts were administered in a dose-dependent manner on INS-1 cells, and glucose-stimulated insulin secretion (GSIS) was measured via ELISA. Treated Human L-cell lines (NCI-H716) were analyzed for GLP-1 secretion. Results: Our study demonstrated that VH Akkermansia muciniphila extracts modestly increase insulin secretion from INS-1 beta cells and, more notably, induce a robust, dose-dependent rise in GLP-1 secretion from NCI-H716 L-cells, with the highest dose achieving over a 2000% increase comparable to glutamine. Conclusions: These findings suggest that VH A. muciniphila extracts may offer metabolic benefits by enhancing GLP-1 release, highlighting their potential for managing type 2 diabetes and obesity. Full article

Background: Natural products play a crucial role in cancer treatment due to their ability to selectively target cancer cells. Andrographolide, a major constituent of Andrographis paniculata, exhibits potential anticancer properties. Considering the pharmacological importance of nitrogen-based heteroaromatic scaffolds, particularly pyrazole motifs, this study aimed to integrate the pyrazole pharmacophore with the andrographolide scaffold to develop novel therapeutic candidates. Methods: Twenty novel 3,19-(N-phenyl-3-aryl-pyrazole) acetals of andrographolide and isoandrographolide were synthesized and characterized using UV-Vis, FT-IR, NMR, and HRMS. Initial anticancer screening was conducted by the National Cancer Institute (NCI), USA, against 60 human cancer cell lines. The most promising compound, 1f (R = 4-F), was selected for further biological evaluation in the MDA-MB-231 breast cancer cell line. Results: The MTT assay results demonstrated that compound 1f exhibited strong, dose-dependent anti-proliferative effects. The apoptosis analysis of 1f revealed a time-dependent increase in apoptotic cells, and cell cycle studies indicated S phase arrest in MDA-MB-231 cells. Antioxidant activity via the DPPH assay identified compounds 1b (R = 3-NO₂) and 2b (R = 3-NO₂) as the most effective radical scavengers. The most active compounds were also evaluated for drug-likeness using in silico Lipinski’s rule assessments. Conclusions: The synthesized 3,19-(N-phenyl-3-aryl-pyrazole) acetals of andrographolide and isoandrographolide exhibited promising anticancer and antioxidant properties. Among them, compound 1f showed the most significant activity, supporting its potential as a lead candidate for further anticancer drug development. Full article

Anthracyclines have been clinically well established in cancer chemotherapy for decades. The main limitations of this drug class are the development of resistance and severe side effects. In the present investigation, we analyzed 30 anthracyclines in a panel of 59 cell lines of the National Cancer Institute, USA. The log₁₀IC₅₀ values varied from −10.49 M (3′-deamino-3′-(4″-(3″-cyano)morpholinyl)-doxorubicin, 1) to −4.93 M (N,N-dibenzyldaunorubicin hydrochloride, 30). Multidrug-resistant NCI-ADR-Res ovarian cancer cells revealed a high degree of resistance to established anthracyclines (between 18-fold to idarubicin (4) and 166-fold to doxorubicin (13) compared to parental, drug-sensitive OVCAR8 cells). The resistant cells displayed only low degrees of resistance (1- to 5-fold) to four other anthracyclines (7, 18, 28, 30) and were even hypersensitive (collaterally sensitive) to two compounds (1, 26). Live cell time-lapse microscopy proved the cross-resistance of the three chosen anthracyclines (4, 7, 9) on sensitive CCRF/CEM and multidrug-resistant CEM/ADR5000 cells. Structure–activity relationships showed that the presence of tertiary amino functions is helpful in avoiding resistance, while primary amines rather increased resistance development. An α-aminonitrile function as in compound 1 was favorable. Investigating the mRNA expression of 49 ATP-binding cassette (ABC) transporter genes showed that ABCB1/MDR1 encoding P-glycoprotein was the most important one for acquired and inherent resistance to anthracyclines. Molecular docking demonstrated that all anthracyclines bound to the same binding domain at the inner efflux channel side of P-glycoprotein with high binding affinities. Kaplan–Meier statistics of RNA sequencing data of more than 8000 tumor biopsies of TCGA database revealed that out of 23 tumor entities high ABCB1 expression was significantly correlated with worse survival times for acute myeloid leukemia, multiple myeloma, and hepatocellular carcinoma patients. This indicates that ABCB1 may serve as a prognostic marker in anthracycline-based chemotherapy regimens in these tumor types and a target for the development of novel anthracycline derivatives. Full article

Parietaria judaica L. (alfavaca-de-cobra) was investigated as a potential source of anticancer compounds. Leaf extracts obtained using solvents of different polarities were evaluated for their phytochemical profiles and cytotoxic activities against a panel of human cancer cell lines (glioblastoma LN-229, lung NCI-H1563, breast MDA-MB-231, liver HepG2, renal 769-P, cervical HeLa, and melanoma A-375) and a noncancerous HEK-293 cell line. LC-ESI-MS/MS analysis confirmed that the extracts are rich in polyphenols, including phenolic acids and flavonoids. Cytotoxicity was assessed via MTT and SRB assays, demonstrating dose-dependent antiproliferative effects. Among the extracts, the ethanolic fraction (PJ-E) exhibited the strongest cytotoxicity, with an IC₅₀ of 11.82 µg/mL against HeLa cells, while displaying a significantly higher IC₅₀ (139.42 µg/mL) against HEK-293, indicating tumor selectivity. The water extract (PJ-W) showed selective activity against lung cancer cells (IC₅₀ = 87.69 µg/mL), with minimal toxicity toward normal cells. The methanol/acetone extract (PJ-M) displayed intermediate activity, whereas the hexane extract (PJ-H) was the least effective. These findings highlight P. judaica, particularly its ethanolic extract, as a promising source of natural anticancer agents. Further research focusing on the isolation of active constituents, formulation development, and in vivo validation is warranted to support its therapeutic potential. Full article

Glucagon-like peptide-1 (GLP-1) is a hormone secreted from enteroendocrine cells that can promote weight loss and blood glucose improvement. We screened probiotic strains that effectively stimulate GLP-1 secretion from human enteroendocrine cells and then investigated the efficacy of this strain in a high-fat diet (HFD)-induced mouse model of obesity. Lactiplantibacillus plantarum GB104 greatly induced GLP-1 secretion by increasing expression of the proglucagon gene (GCG), but not the proprotein convertase subtilisin/kexin type 1 gene (PCSK1) in the human enteroendocrine cell line NCI-H716. In an HFD-induced mouse model of obesity, GB104 inhibited weight gain and improved blood glucose levels by increasing blood GLP-1 levels. It also tended to attenuate the HFD-induced changes in blood levels of other hormones and suppressed fat accumulation in the liver and adipose tissues. In white adipose tissue, GB104 suppressed inflammation by reducing pro-inflammatory M1 macrophages and increasing anti-inflammatory M2 macrophages and regulatory T cells. Probiotic strains that promote GLP-1 secretion, such as GB104, may serve as a promising candidate for dietary intervention against obesity and metabolic diseases. Full article

In this study, a novel 4-methylbenzoylhydrazide·dimethyl sulfoxide·dichloro platinum(II) complex (Pt2) was synthesized and characterized, and its anti-tumor activity and action mechanism were explored. The molecular structure and spatial configuration of the complex were determined using X-ray diffraction. The results obtained using fluorescence spectroscopy demonstrate that this complex can effectively bind to DNA and affect its fluorescence properties. The experimental results show that Pt2 exhibited significant inhibitory effects on a variety of tumor cell lines (MCF-7, HepG-2, NCI-H460, T24, and A549), and its IC50 values were lower than those of cisplatin (DDP), indicating stronger anti-tumor activity. In addition, the complex not only significantly induced the apoptosis of MCF-7 cells but also inhibited cell cycle arrest at the G₂ phase, with the proportion of G₂-phase cells as high as 49.47%. In conclusion, the 4-methylbenzoylhydrazide platinum(II) complex exhibits good anti-tumor activity by inducing apoptosis and inhibiting the cell cycle, providing an important experimental basis for the development of novel platinum-based anti-tumor drugs. Full article

Background/Objectives: This study investigates the phytochemical composition and anticancer activity of Melaleuca quinquenervia leaf essential oil (MQLEO) from Egypt. Methods: Chemical profiling was performed using GC/MS. Anticancer activity was assessed through cytotoxicity screening against multiple cancer cell lines, with a subsequent evaluation of cell migration, apoptosis, and cell cycle analysis on the most sensitive line (A549). Network pharmacology and molecular docking analyses were employed to identify potential molecular targets and pathways. Results: GC/MS analysis revealed a unique profile dominated by 1,8-cineole (31.57%), α-pinene isomers (both 1R and 1S forms, collectively 21.26%), and sesquiterpene alcohols (viridiflorol: 13.65%; ledol: 4.55%). These results diverge from prior studies, showing a 25.63% decrease in 1,8-cineole and no detectable α-terpineol, suggesting environmental, genetic, or methodological impacts on biosynthesis. In vitro tests revealed selective cytotoxicity against A549 lung cancer cells (IC₅₀ = 18.09 μg/mL; selectivity index = 4.30), meeting NCI criteria. Staurosporine was used as a positive control to validate the assays, confirming the reliability of the methods. MQLEO also inhibited cell migration (62–68% wound closure reduction) and induced apoptosis (24.32% vs. 0.7% in controls). Cell cycle arrest at the G₀-G₁ phase implicated cyclin-dependent kinase regulation. Network pharmacology identified ESR1, CASP3, PPARG, and PTGS2 as key targets, with MQLEO components engaging apoptosis, inflammation (TNF, IL-17), and estrogen pathways. Conclusions: MQLEO demonstrates promising anticancer activity through multiple mechanisms including apoptosis induction, cell cycle arrest, and migration inhibition. The multi-target activity profile highlights its potential as a therapeutic candidate for lung cancer, warranting further in vivo validation and pharmacokinetic studies to advance clinical translation. Full article

The dinuclear platinum(IV) compound {Pt(CH₃)₃}₂(μ-I)₂(μ-adenine) (abbreviated Pt₂ad), obtained by treating cubic [Pt^IV(CH₃)₃(μ₃-I)]₄ with two equivalents of adenine, was isolated and structurally characterized by single crystal X-ray diffraction. The National Cancer Institute Developmental Therapeutics Program’s in vitro sulforhodamine B assays showed Pt₂ad to be particularly cytotoxic against the central nervous system cancer cell line SF-539, and the human renal carcinoma cell line RXF-393. Furthermore, Pt₂ad displayed some degree of cytotoxicity against non-small cell lung cancer (NCI-H522), colon cancer (HCC-2998, HCT-116, HT29, and SW-620), melanoma (LOX-IMVI, Malme-3M, M14, MDA-MB-435, SK-MEL-28, and UACC-62), ovarian cancer (OVCAR-5), renal carcinoma (A498), and triple negative breast cancer (BT-549, MDA-MB-231, and MDA-MB-468) cells. Although anticancer studies involving some adenine platinum(II) compounds have been reported, this study marks the first assessment of the anticancer activity of an adenine platinum(IV) complex. Full article

Tricyclic and tetracyclic lactone derivatives of thieno[2,3-b]pyrazine or thieno[2,3-b]quinoline, and 2H-pyrones were prepared using different methodologies. Pd/Cu-catalyzed Sonogashira coupling using Et₃N as a base, of methyl 7-bromothieno[2,3-b]pyrazine-6-carboxylate and (het)arylalkynes to yield the Sonogashira ester products, gave also the corresponding tricyclic lactones as minor products. However, the major products did not cyclize with TFA. Tricyclic lactones were then obtained by a tandem one-pot Sonogashira coupling and 6-endo-dig lactonization of 7-bromothieno[2,3-b]pyrazine-6-carboxylic acid with (het)arylalkynes, in good yields. Halogenated tricyclic lactones were synthesized by halocyclization using CuX and NXS. Tetracyclic lactones were synthesized through a Rh(III)-catalyzed formal [4+2] cycloaddition, between thieno[2,3-b]quinoline-2-carboxylic acid and internal alkynes, triggered by C-H activation, with the carboxylic group acting as a directing group. Using the SRB assay, the antitumor activity of both Sonogashira products and lactones was evaluated across five human cancer cell lines (CaCo-2, MCF-7, AGS, HeLa, NCI-H460). The best-performing compound was a Sonogashira product showing a GI₅₀ < 10 µM in all tumor cell lines and low toxicity in PLP2 cells. Additionally, antiparasitic testing against Trypanosoma brucei and Leishmania infantum revealed some compounds with IC₅₀ < 11 µM, though some level of cytotoxicity was observed in THP-1—derived macrophages. Full article

Background/Objectives: Antibody-based therapies often exhibit limited distribution within solid tumors due to the “binding-site barrier” (BSB). Our group has developed and validated the use of anti-idiotypic distribution enhancers (AIDEs), which transiently block antibody binding, improving intra-tumoral distribution and efficacy. This study evaluated 1HE and LG1, model anti-trastuzumab AIDEs, in combination with trastuzumab–PE24, a highly potent immunotoxin. Methods: The effects of 1HE on the whole-body disposition of radiolabeled trastuzumab were assessed in NCI-N87 tumor-bearing mice. Mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modeling was employed to explore how AIDE binding kinetics influence antibody intra-tumoral distribution and immunotoxin potency. Trastuzumab–PE24 was developed by site-specific conjugation, enabled by self-splicing split intein, with cytotoxicity tested on various cell lines in vitro. The impact of 1HE and LG1 coadministration on trastuzumab–PE24 efficacy was evaluated in NCI-N87 xenograft-bearing mice. Results: 1HE coadministration decreased trastuzumab tumor maximum concentration, reducing tumor terminal slope by 8% and overall tumor exposure by 2.6%, without negatively affecting selectivity. Modeling predicted the optimal AIDE dissociation rate constant for trastuzumab–PE24 to be between 0.015 and 0.3 h⁻¹. The coadministration of trastuzumab–PE24 with 1HE and LG1 improved anti-tumor efficacy and extended median survival to 60 days (p = 0.0002). Conclusions: AIDE coadministration led to minimal negative impacts on overall tumor exposure, consistent with model simulations. AIDE coadministration improved the efficacy of trastuzumab–PE24 in NCI-N87 xenografts. Modeling further predicted that repeated AIDE administration with trastuzumab–PE24 could induce complete tumor regression. These findings highlight the advantages of the AIDE strategy, particularly when coadministered with highly potent immunotoxins. Full article

Three new complexes of copper(II) and chromone-2-carboxylic acid, a ligand from the group of hydroxypyrones, were synthesised according to the principles of green chemistry. The complexes were characterised by FT–IR and NMR spectroscopy, thermal and electrochemical analysis, and their structures are proposed. The results show the formation of mononuclear (1) and dinuclear hydroxo-bridged dinuclear copper(II) complexes (2 and 3). The results of cyclic voltammetry show that the copper in all complexes is in the +2-oxidation state. The antiproliferative activity was determined by MTT assay on 2D cell models in vitro on seven cell lines. The activity spectrum of complexes 1–3 ranged from the highest to the lowest value in the tumour cell lines tested, in the following order: Hep G2 > NCI-H358 > HT-29 > KATO III > MDA-MB 231 > Caco-2. The most effective concentration was 10⁻⁵ mol dm⁻³, which suppressed the growth of Hep G2 cells as follows: 69.5% (1), 64.8% (2) and 64% (3). The calculated selectivity index clearly shows that Hep G2 is the most sensitive cell line to copper complexes (SI = 1.623 (1); 1.557 (2), 1.431 (3). Full article

The Vinca alkaloid vindoline was coupled at position 17 with several trisubstituted phosphine derivatives and their in vitro anticancer activities on 60 human tumor cell lines (NCI60) were investigated. This phosphonium-type ionic side chain is beneficial because it allows therapeutic molecules to pass through the cell membrane. Thus, the candidates coupled to it can exert their activities in the mitochondria. The coupling of vindoline with the trisubstituted phosphines was achieved through flexible or rigid linkers. Instead of the ionic phosphonium structural part, a neutral moiety, namely the triphenylmethyl group, was also added to the side chain, being sterically similar but without a charge and phosphorus atom. In addition, the triphenylphosphine element was also built at position 10 of vindoline. Most of the derivatives showed low micromolar growth inhibition (GI₅₀) values against most cell lines. Among them, conjugate 9e was outstanding: it exhibited nanomolar anticancer activity on the RPMI-8226 leukemia cell line (GI₅₀ = 20.0 nM). Compound 9g elicited cell cycle disturbance and apoptosis on A2780 ovary cancer cells and inhibited their migration at subantiproliferative concentrations. The selectivity of the conjugates was determined by their effects on non-tumor Chinese hamster ovary (CHO) cells in the CellTiter-Glo Luminescent Cell Viability Assay. Compound 9e showed an estimated half-maximal inhibitory concentration (IC₅₀) value of 1.36 µM, suggesting good selectivity on cancer cells. These results open new perspectives of novel phosphonium-based vindoline derivatives as anticancer compounds. Full article

This work focuses on the extraction of cynthichlorine from the ascidian Cynthia savignyi, a molecule that has potential promise as an anticancer agent. The main objective was to optimize the extraction conditions and evaluate the cytotoxic activity of cynthichlorine in tumor cell lines. Two extraction methods, maceration and Soxhlet extraction, were compared, with maceration showing a significantly higher yield (2.2 ± 0.2%) compared to Soxhlet extraction (1.0 ± 0.2%). An optimization of the factors influencing the extraction was performed using the Box–Behnken method, showing that the extraction temperature and time have a negative impact on the yield, with the optimal conditions of temperature being below 25 °C and those of extraction time being below 12 h. Cytotoxic activity assessment revealed the marked inhibition of cell growth in all tested lines (U87-MG, U2OS, NCI-N87, HCT116, and A2780), with IC₅₀ values ranging from 0.162 µg/mL in U87-MG to 0.576 µg/mL in NCI-N87. Finally, computational analysis showed that cynthichlorine exhibits high electronic stability and notable affinity for some biological targets, including NM23-H2, suggesting its potential as a targeted therapy in cancer treatment. These results pave the way for future studies on the therapeutic use of cynthichlorine. Full article

This study describes the synthesis of O-alkylated benzaldehydes 1–8, Schiff bases 9–28, and benzoxazole derivatives 29–48 using microwave, ultrasound, and mechanochemical reactions, as well as reactions in deep eutectic solvents in excellent yields, and their antiproliferative and antibacterial activities. The in vitro evaluation of antiproliferative activity for the newly synthesised benzoxazole derivatives 29–48 against a diverse panel of human cancer cell lines, such as LN-229, Capan-1, HCT-116, NCI-H460, DND-41, HL-60, K-562, and Z-138 demonstrated that the majority of these benzoxazole derivatives displayed promising anticancer activity, particularly against non-small cell lung cancer (NSCLC) cells (NCI-H460). Notably, several derivatives showed enhanced activity compared to the included reference drug, etoposide. Considering the influence of substituents at position 5 of the benzoxazole ring and positions 3 and 4 of the phenyl ring on the antiproliferative activity, it is evident that derivatives 41–48 bearing a methoxy group at position 3 generally exhibit higher activity compared to compounds 29–40, which lack substitution at position 3. Furthermore, derivatives substituted at position 4 with a morpholine substituent, as well as those with an N,N-diethyl group, exhibited higher activity compared to other evaluated benzoxazole derivatives. The in vitro antibacterial evaluation against Gram-positive and Gram-negative bacteria revealed that benzoxazole derivative 47 exhibited notable activity, against the Gram-negative bacterium Pseudomonas aeruginosa (MIC = 0.25 μg/mL) and the Gram-positive bacterium Enterococcus faecalis (MIC = 0.5 μg/mL). The results point out that this class of benzoxazoles can be efficiently synthesized using eco-friendly methods and represent promising candidates for further design and optimization aimed at developing potent antiproliferative agents. Full article

Despite the wealth of data related to the advantages of formulating a wide range of compounds as salts to ameliorate their biological properties, there is scant information regarding the therapeutic potential of selenium (Se) salts. In this work, we have formulated six antibiotics as hydroselenite salts in order to compare their in vitro antibacterial and anticancer effects and evaluate if this approach could enhance their water solubility. In this regard, in almost all the cases, their solubility was increased by one order of magnitude. All the compounds were screened against a panel of three Gram-positive and three Gram-negative bacteria. Likewise, their antiproliferative activity was evaluated in breast, prostate, glioblastoma, and pancreatic cancer cell lines. Normal human dermal fibroblasts (NHDF) were used to determine their selectivity indexes (SI). Additionally, these novel hydroselenite salts were submitted to the National Cancer Institute (NCI) to study their antitumoral potential. Compounds SLT-2 and SLT-6 showed potent cytotoxicity against the glioblastoma cancer cell line, and their ability to induce apoptosis and reactive oxygen species (ROS) was further assessed. To conclude, we have demonstrated that the formulation of several antibiotics as hydroselenite salts could be a feasible approach to obtain biologically active compounds with an enhanced effect. Full article