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This research explores the health-promoting properties of the pectin–polyphenol complex extracted from alperujo, a by-product of olive oil production. This study investigates the chemical composition and antioxidant activity of the extracts, revealing their high antioxidant activity in vitro. Cell viability assays conducted on colon carcinoma cells (Caco-2) demonstrate the inhibitory effect of the extracts on cell proliferation. However, the extracts do not affect the viability of differentiated Caco-2 cells, suggesting a selective antiproliferative action. Additionally, the extracts reduce intracellular reactive oxygen species (ROS) and nitrite (NO) production in LPS-stimulated murine peritoneal macrophages. Furthermore, the extracts exhibit anti-inflammatory effects by downregulating the secretion of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in these macrophages. These findings highlight the potential of pectin–polyphenol complexes as functional ingredients with significant health benefits, demonstrating antioxidant, antiproliferative, and anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

Nineteen isosteviol derivatives were designed and synthesized by C-16, C-19 and D-ring modifications of isosteviol. These compounds were screened for their cytotoxic activities against Hela and A549 cells in vitro. Among them, the inhibitory effect of compounds 3b and 16 on Hela cells was comparable to that of the positive control gefitinib, and the compounds 3b (IC50=7.84 ± 0.84 μM) and 7a (IC50=6.89 ± 0.33 μM) exhibited significant cytotoxicity superior to gefitinib (IC50=11.02 ± 3.27 μM) against A549 cells. [ABSTRACT FROM AUTHOR]

Plantago ovata seed is comprises two distinct layers: a non-adherent outer layer that can easily extracted by gentle agitation, and an adherent inner layer, which is extremely difficult to separate from the seed coat. This study aims to develop and optimize an efficient method for extracting adherent and non-adherent mucilage from P. ovata seeds and to evaluate its biological activities. The extraction process variables were optimized using the response surface methodology (RSM) based on Box-behnken Design with three factors at three levels, to test different experimental conditions and achieve the highest yield. Our results demonstrate that ultrasound treatment was an efficient method for the rapid extraction of both mucilage layers. The aqueous treatment involved a seed-to-water ratio of 1:60, an extraction time of 1.4 h with constant stirring at 45 °C and pH 8, followed by sonication at 100% amplitude for 60 min with pulses of 10 s ON and 20 s OFF for non-adherent mucilage extraction. For the adherent mucilage, the extraction time was adjusted to 1 h with constant stirring at 45 °C and a seed-to-water ratio of 1:50. This process facilitated the recovery of nearly all P. ovata seed mucilage, estimated at approximately 40 mg/g of seeds (39.85% ~ 40%). Evaluation of antioxidant activity in vitro showed that aqueous extracts of P.ovata mucilage had antiradical activity (IC50 = 202 µg/ml), ferric reducing power (IC50 = 310 µg/ml), important total antioxidant activity (16.84 mg EAG/g MS), inhibitory effect on alpha amylase (IC50 = 2.13 mg/ml), and exhibits strong antiproliferative effects on Caco2 cells (IC50 = 90 µg/ml). [ABSTRACT FROM AUTHOR]

This research explores the health-promoting properties of the pectin–polyphenol complex extracted from alperujo, a by-product of olive oil production. This study investigates the chemical composition and antioxidant activity of the extracts, revealing their high antioxidant activity in vitro. Cell viability assays conducted on colon carcinoma cells (Caco-2) demonstrate the inhibitory effect of the extracts on cell proliferation. However, the extracts do not affect the viability of differentiated Caco-2 cells, suggesting a selective antiproliferative action. Additionally, the extracts reduce intracellular reactive oxygen species (ROS) and nitrite (NO) production in LPS-stimulated murine peritoneal macrophages. Furthermore, the extracts exhibit anti-inflammatory effects by downregulating the secretion of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in these macrophages. These findings highlight the potential of pectin–polyphenol complexes as functional ingredients with significant health benefits, demonstrating antioxidant, antiproliferative, and anti-inflammatory properties.

Introduction: Schisandra chinensis is a plant species whose fruits have been well known for its multiple pharmacological effects. In the current work, aqueous extract of S. chinensis fruits is used to produce Copper nanoparticles (CuNPs) through green-synthesis method. Physical and biological essays characterized the nanoparticles obtained. Aim: To produce Copper nanoparticles through a greensynthesis method using the aqueous extract of S. chinensis fruits and to characterize this material using spectroscopic methods, including UV-Vis, FTIR (Fourier Transform Infrared Spectra), X-ray diffraction, and SEM (Scanning electron microscopy). Subsequently, the nanoparticulate material is evaluated against three tumor cell lines: A549 human lung cancer cell line (CRM-CCL-185TM), HT29 human colorectal adenocarcinoma cell line (ATCC® HTB-38TM) and MCF7 breast cancer cell line (ATCC® HTB-22TM). Results: Through a green synthesis method, Copper nanoparticles were synthesized from aqueous extract of S. chinensis fruits, demonstrating a spherical morphology with a size close to 26 nanometers by means of spectral methods. Furthermore, results suggest that the S. chinensis reduced CuNPs were able to induce mainly early apoptotic cell death in cancer cells in a concentration-dependent manner. Conclusions: The results proved that S. chinensis fruit aqueous extract could be applied for a greener synthesis of copper nanoparticles with potential anti-proliferative effect. [ABSTRACT FROM AUTHOR]

With the growing issues of food spoilage, microbial resistance, and high mortality caused by cancer, the aim of this study was to evaluate T. zygis essential oil (TZEO) as a potential solution for these challenges. Here, we first performed GC/MS analysis which showed that the tested TZEO belongs to the linalool chemotype since the abundance of linalool was found to be 38.0%. Antioxidant activity assays showed the superiority of TZEO in neutralizing the ABTS radical cation compared to the DPPH radical. The TZEO was able to neutralize 50% of ABTS•+ at the concentration of 53.03 ± 1.34 μg/mL. Antimicrobial assessment performed by employing disc diffusion and minimal inhibitory concentration assays revealed TZEO as a potent antimicrobial agent with the highest inhibition activity towards tested gram-negative strains. The most sensitive on the treatment with TZEO was Enterobacter aerogenes showing an MIC 50 value of 0.147 ± 0.006 mg/mL and a MIC 90 value of 0.158 ± 0.024 mg/mL. Additionally, an in situ analysis showed great effects of TZEO in inhibiting gram-negative E. coli, P. putida, and E. aerogenes growing on bananas and cucumbers. Treatment with the TZEO vapor phase in the concentration of 500 μg/mL was able to reduce the growth of these bacteria on the food models to the extent > 90%, except for E. coli growth on the cucumber, which was reduced to the extent of 83.87 ± 4.76%. Furthermore, a test on the antibiofilm activity of the tested essential oil revealed its biofilm prevention effects against Salmonella enterica which forms biofilms on plastic and stainless-steel surfaces. Performed tests on the TZEO effects towards cell viability showed no effects on the normal MRC-5 cell line. However, the results of MTT assay of TZEO effects on three cancer cell lines (MDA-MB-231, HCT-116, and K562) suggest that TZEO exerted the strongest effects on the inhibition of the viability of MDA-MB-231 cells, especially after long-term treatment in the highest concentration applied with reducing the viability of the cells to 57%. Additionally, results of NBT and Griess assays suggest that TZEO could be a convenient candidate for future testing for developing novel antitumor therapies. [ABSTRACT FROM AUTHOR]

Two new -biotics concepts, such as paraprobiotics and postbiotics were introduced, with beneficial effects beyond the viability of probiotic. In this study, the effect of individual (thermal, ohmic heating, high pressure, and ultrasound) and combined (ohmic, high pressure and ultrasound in combination with heating) treatments on the inactivation kinetics of Lactiplantibacillus plantarum was investigated. Different inactivation rates were obtained, up to 8.18 after 10 min at 90 °C, 2.07 after 15 min at a voltage gradient of 20 V/cm, 6.62 after 10 min at 600 MPa and 3.6 after ultrasound treatment for 10 min at 100 % amplitude. The experimental data were fitted to Weibullian model proposed by Peleg, allowing to estimate the inactivation rate coefficient (b) and the shape of the inactivation curves (n). At lower concentration, the samples showed both cytocompatibility and antiproliferative effect, stimulating the cell proliferation on both murine fibroblast and human colorectal adenocarcinoma cell lines.

In recent years, small peptide and non-peptide AVPI-/Smac-mimetics have been developed as IAP antagonists and are in clinical trials to overcome resistance to apoptosis in various cancer types. In this study, we present molecular modeling studies and in vitro biological evaluation of a set of AVPI-mimetics, including parent AVPI, tetrapeptide AVPI-mimetics and AVPI-conjugates.Combined molecular modeling studies and HYDE analyses provided valuable information regarding the protein–ligand interactions within the binding site of cIAP1-BIR3 and XIAP-BIR3 domains, showing that the binding part of both domains (cIAP1- and XIAP-BIR3) are formed from 22 amino acid residues, and their active part of 11 AAs. Moreover, 5 amino acids are defined common for both targets, namely Lys299, Gly306, Leu307, Trp310, and Trp323. Based on the observed docking models, six amino acid residues for cIAP1-BIR3 and five amino acids for XIAP-BIR3 are recognized actively involved in the formation of H-bonds with the respective ligand. The amino acid sequence 308 (Arg308 in cIAP1-BIR3, Thr308 in XIAP-BIR3), simultaneously forming two H-hydrogen bonds, seems to plays a key role in improvement of binding affinity.Apart from docking results the synthesized set of AVPI-mimetics was tested in vitro using cell biology (MTT assay) and parallel artificial membrane permeability assay (PAMPA). The results showed that the double modification of AVPI via substitution of Pro3 with Hyp3, as well as elongation of AVPI’s C-terminus by its conjugation with RGD-analogs, significantly increase the antiproliferative effects of AVPI-conjugates on all tested cancer cell lines (MDA-MB-231, MCF-7, HepG2 and HT-29 cells) compared to the parent AVPI peptide. SARs analysis defined this modification beneficial for the overall biological activity of the AVPI-mimetics and pointed out AVHypI-AgbGD as the most active conjugate with an IC50 of 348 µM for MDA-MB-231, 457 µM for MCF-7, 399 µM for HepG2, and 578 µM for HT-29 cells. Though the calculated IC50 values were still high, we consider AVHypI-AgbGD peptide as a good basis for further modifications. In addition, PAMPA results showed that substitution of Pro with Hyp improved the BBB permeability of AVHypI peptide compared to its parent molecule.

The volatile oils hydrodistilled from the aerial parts and roots of O. carduchorum C.C Towns. (Fabaceae) have been chemically characterized for the first time. A total of 43 constituents with an abundance >0.03% were identified and quantified in the two oils by GC/MS and GC/FID analyses. They comprise 38 components (98.58%) of the oil isolated from the aerial parts (OCA) and 34 components (93.33%) of the oil from the roots (OCR). Six constituents, α-pinene (23.11 ± 0.1%), β-elemene (17.33 ± 0.1%), 1,8-cineole (12.15 ± 0.2%), furfural (7.91 ± 0.1%), terpineol-4-ol (6.32 ± 0.2%), and limonene (4.13 ± 0.1%), accounted for about 75% of the total OCA oil. On the other hand, 1,8-cineole (15.79 ± 0.1%), furfural (10.44 ± 0.1%), β-elemene (10.14 ± 0.2%), α-terpineol (7.74 ± 0.1%), linalool (7.45 ± 0.1%), and α-pinene (4.76 ± 0.1%) made up about 60% of the OCR oil. The IC50 values of the scavenging activities of the OCA and OCR oils towards the DPPH radical and H2O2 were 79.8 ± 0.5 and 153.3 ± 0.6 μg/mL and 394.09 ± 0.2 and 311.67 ± 0.4 μg/mL, respectively. In addition, in the MTS assay, the OCA and OCR oils showed significant antiproliferative effects against T47D, MDA-MB-453, BG-1, and A549 human cancer cells that were more powerful than those against two normal human cell lines, HEK-293 and HFF-1. The abundant presence of β-elemene as an antiproliferative component of the two oils suggested the existence of a new chemotype of O. carduchorum. [ABSTRACT FROM AUTHOR]

With the growing issues of food spoilage, microbial resistance, and high mortality caused by cancer, the aim of this study was to evaluate T. zygis essential oil (TZEO) as a potential solution for these challenges. Here, we first performed GC/MS analysis which showed that the tested TZEO belongs to the linalool chemotype since the abundance of linalool was found to be 38.0%. Antioxidant activity assays showed the superiority of TZEO in neutralizing the ABTS radical cation compared to the DPPH radical. The TZEO was able to neutralize 50% of ABTS•+ at the concentration of 53.03 ± 1.34 μg/mL. Antimicrobial assessment performed by employing disc diffusion and minimal inhibitory concentration assays revealed TZEO as a potent antimicrobial agent with the highest inhibition activity towards tested gram-negative strains. The most sensitive on the treatment with TZEO was Enterobacter aerogenes showing an MIC 50 value of 0.147 ± 0.006 mg/mL and a MIC 90 value of 0.158 ± 0.024 mg/mL. Additionally, an in situ analysis showed great effects of TZEO in inhibiting gram-negative E. coli, P. putida, and E. aerogenes growing on bananas and cucumbers. Treatment with the TZEO vapor phase in the concentration of 500 μg/mL was able to reduce the growth of these bacteria on the food models to the extent > 90%, except for E. coli growth on the cucumber, which was reduced to the extent of 83.87 ± 4.76%. Furthermore, a test on the antibiofilm activity of the tested essential oil revealed its biofilm prevention effects against Salmonella enterica which forms biofilms on plastic and stainless-steel surfaces. Performed tests on the TZEO effects towards cell viability showed no effects on the normal MRC-5 cell line. However, the results of MTT assay of TZEO effects on three cancer cell lines (MDA-MB-231, HCT-116, and K562) suggest that TZEO exerted the strongest effects on the inhibition of the viability of MDA-MB-231 cells, especially after long-term treatment in the highest concentration applied with reducing the viability of the cells to 57%. Additionally, results of NBT and Griess assays suggest that TZEO could be a convenient candidate for future testing for developing novel antitumor therapies.

Due to the great variations in altitude, humidity, hours of exposure to the sun, chemical and microbiological composition of the soil, the Andean and Amazon regions of Peru have a great diversity of microclimates, thus allowing the development of a wide variety of species of plants producing edible fruits. In addition to their nutritional value, these fruits are characterized by the presence of high levels of compounds beneficial to health, particularly polyphenols, such as flavonoids, lignans, phenolic acids, and stilbenes, and natural pigments, such as betalains. Several studies have shown that these compounds have antioxidant, antimicrobial, antitumor, and immunogenic activities and, therefore, can contribute to the prevention of diseases such as cancer, diabetes, and hypertension. Given the accumulated evidence, we believe that the consumption of fresh fruits from these regions, or even those preserved through industrial processes that maintain their properties, should be strongly encouraged. This manuscript aims to present and discuss the literature relevant to the benefits of consuming fruits from the Amazon and Andean regions of Peru for health maintenance. [ABSTRACT FROM AUTHOR]

Guanine-based purines (GBPs) exert numerous biological effects at the central nervous system through putative membrane receptors, the existence of which is still elusive. To shed light on this question, we screened orphan and poorly characterized G protein-coupled receptors (GPRs), selecting those that showed a high purinoreceptor similarity and were expressed in glioma cells, where GBPs exerted a powerful antiproliferative effect. Of the GPRs chosen, only the silencing of GPR23, also known as lysophosphatidic acid (LPA) 4 receptor, counteracted GBP-induced growth inhibition in U87 cells. Guanine (GUA) was the most potent compound behind the GPR23-mediated effect, acting as the endpoint effector of GBP antiproliferative effects. Accordingly, cells stably expressing GPR23 showed increased sensitivity to GUA. Furthermore, while GPR23 expression was low in a hypoxanthine-guanine phosphoribosyl-transferase (HGPRT)-mutated melanoma cell line showing poor sensitivity to GBPs, and in HGPRT-silenced glioma cells, GPR23-induced expression in both cell types rescued GUA-mediated cell growth inhibition. Finally, binding experiments using [³H]-GUA and U87 cell membranes revealed the existence of a selective GUA binding (KD = 29.44 ± 4.07 nM; Bmax 1.007 ± 0.035 pmol/mg prot) likely to GPR23. Overall, these data suggest GPR23 involvement in modulating responses to GUA in tumor cell lines, although further research needs to verify whether this receptor mediates other GUA effects. [ABSTRACT FROM AUTHOR]

Copyright of General Practitioner / Lekarz POZ is the property of Termedia Publishing House and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Phytochemical study on the stems and leaves of Artocarpus tonkinensis led to the isolation of a new 2-arylbenzofuran, artocartone ( 1 ), as well as seven known 2-arylbenzofurans ( 2-8 ). The chemical structure of 1 was established by means of comprehensive spectroscopic analyses and the known compounds were determined by comparing their MS and NMR data with those reported data in literature. The antiproliferative activities of all isolates 1-8 against five human cancer cell lines: HL-60, SMMC-7721, A-375, MCF-7 and SW480 in vitro were evaluated. As a result, compounds 1- 8 displayed notable antiproliferative activities against various human cancer cell lines with IC 50 values in the range of 0.28 ± 0.05-26.89 ± 0.18 μM.

Guanine-based purines (GBPs) exert numerous biological effects at the central nervous system through putative membrane receptors, the existence of which is still elusive. To shed light on this question, we screened orphan and poorly characterized G protein-coupled receptors (GPRs), selecting those that showed a high purinoreceptor similarity and were expressed in glioma cells, where GBPs exerted a powerful antiproliferative effect. Of the GPRs chosen, only the silencing of GPR23, also known as lysophosphatidic acid (LPA) 4 receptor, counteracted GBP-induced growth inhibition in U87 cells. Guanine (GUA) was the most potent compound behind the GPR23-mediated effect, acting as the endpoint effector of GBP antiproliferative effects. Accordingly, cells stably expressing GPR23 showed increased sensitivity to GUA. Furthermore, while GPR23 expression was low in a hypoxanthine-guanine phosphoribosyl-transferase (HGPRT)-mutated melanoma cell line showing poor sensitivity to GBPs, and in HGPRT-silenced glioma cells, GPR23-induced expression in both cell types rescued GUA-mediated cell growth inhibition. Finally, binding experiments using [3H]-GUA and U87 cell membranes revealed the existence of a selective GUA binding (KD = 29.44 ± 4.07 nM; Bmax 1.007 ± 0.035 pmol/mg prot) likely to GPR23. Overall, these data suggest GPR23 involvement in modulating responses to GUA in tumor cell lines, although further research needs to verify whether this receptor mediates other GUA effects.

Highlights on the development of ferrocene biochemistry in Russia since the 1950s are given. Here, avoiding high‐toxic precursors, ferrocene‐based imidazoles and benzimidazoles (16 compounds) were synthesized in good to high yields via the reaction of the α‐(hydroxy)alkyl ferrocenes with modified heterocycles using oxalyl chloride to activate imidazole system. Mild conditions (room temperature, chloroform, stirring for up to 1.5 h) allowed preparing a number of various ferrocene‐containing imidazoles, which are promising as antitumor agents. The analytical HPLC method was successfully applied to enantioseparation of the resulting ferrocene enantiomers (Chiralcel OD column). Antitumor activities of the preparing compounds against murine solid tumours such as Acatol adenocarcinoma and Ca755 carcinoma have been studied in vivo. Some of the tested compounds have been strong effective against Acatol adenocarcinoma. The value of the tumour growth inhibition coefficient was about 90% versus control in this strain. [ABSTRACT FROM AUTHOR]

Summary: The aim of this study was to evaluate the antiproliferative activity of bioaccessible fractions (BFs) obtained by the internationally standardized INFOGEST static digestion method to Sicilian honeys of three distinct floral origins (Sulla, Thistle and Dill) and the Manuka honey (gold standard), and to compare their effects based on total polyphenol content (TPC). Differentiated CaCo‐2 cells (intestinal‐like) and non‐differentiated CaCo‐2 and HCT‐116 colonic tumour‐like cells were incubated for 24 h with BFs of honeys to test viability, apoptosis, mitochondrial membrane potential (MMP), ROS and cell cycle. TPC after digestion ranked in the following order: Dill > Thistle > Sulla > Manuka. No decrease in cell viability in differentiated CaCo‐2 cells was observed, while a reduction to 25–85% (CaCo‐2) and 20–80% (HCT‐116) of viability was obtained. This descent in viability was caused by a cell cycle block with an increase in apoptosis through dissipation of MMP and raise in ROS levels, being Thistle and Dill the most effective honeys followed by Sulla and finally Manuka, in agreement with TPC after digestion. [ABSTRACT FROM AUTHOR]

Red‐fleshedapples are preferredbecause of their high content of phenolics and antioxidants in peel and pulp. Herein, we evaluated the mechanisms of apple peel polyphenolic extracts (APP) and apple flesh polyphenolic extracts (AFP) from the new red‐fleshed apple in inhibiting cell proliferation and inducing apoptosis on human breast cancer MDA‐MB‐231 cells. The antiproliferative activities were determined by the CCK8 assay. The expression of proteins was determined using Western blot. We found that the content of polyphenols and flavonoids in APP was significantly higher than that in AFP, and 14 main phenolic compounds in APP and AFP were quantified using UPLC–MS/MS techniques. Besides, the significant inhibition effects of APP and AFP were achieved through Akt pathway by inducing apoptosis (significantly upregulating reactive oxygen species [ROS] levels, and downregulating expression of pAkt, pBad, Bcl‐2, promoting Cytochrome c release, activating Cle‐Caspase 9, and inducing expressions of Cle‐Caspase 3 and Cle‐PARP), and inducing G0/G1 cell cycle arrest (increased expressions of p‐p53 and p21 and decreased expressions of PCNA and Cyclin D1). And the inhibition effect of APP was stronger than that of AFP. These results suggest that AFP and APP may be excellent sources of natural chemicals for treating triple‐negative breast cancer MDA‐MB‐231 cells. Practical Application: The effects of antiproliferation of phenolic extracts from red‐fleshed apple peels and flesh on human breast cancer MDA‐MB‐231 cells were evaluated. The data may clarify the functional parts of red‐fleshed apple and provide some basis for scientific researchers and consumers to recognize and exploit red‐fleshed apple. [ABSTRACT FROM AUTHOR]

Uterine myomas/fibroids are one of the most common benign tumors of the reproductive system in women. Given pleiotropic effects of statins, the aim of this study is to evaluate the therapeutic effects of atorvastatin on uterine fibroids in women of reproductive age. This randomized clinical study included 90 women aged 35–45 years with uterine fibroids. The patients were randomly allocated into the intervention group (received one tablet, 20 mg of atorvastatin every day for three months) and placebo. Ultrasound was performed every month, and the change in the size of fibroids was recorded for each patient. At the end of the study, the data obtained were analyzed using SPSSv22 and a p value <.05 was considered statistically significant. The mean age in the placebo and intervention group was 39.63 ± 36.3 and 40.35 ± 3.32 years, respectively. The number and location of the tumor was comparable for the two groups. We observed a statically significant reduction in fibroid size from the treatment initiation until completion of three months, (41.06 ± 6.68 mm3 vs 35.16 ± 6.67 mm3) p =.0001. However, the decrease in fibroid size from 1st month to the 3rd month was not statistically significant, p =.189 (36.71 ± 5.54 mm3 vs 35.16 ± 6.67 mm3). This study shows that treatment with atorvastatin might positively reduce the size of fibroids. The decrease was only statistically significant during the first month. Further studies with a detailed analysis of the intervention's clinical impact are required to consider statins as a therapeutic tool. [ABSTRACT FROM AUTHOR]

PurposeProliferative vitreoretinopathy (PVR) is the most common cause of poor visual outcomes in association with retinal detachment surgeries and ocular trauma. Daunorubicin (DNR) has shown the strongest efficacy in proliferation inhibition in vitro. However, clinical studies have shown only mild effect owing to limitations of narrow therapeutic window and short vitreous half-life.MethodsThree milligrams of DNR-loaded particles were intravitreally injected into 18 pigmented rabbits, and vitreous samples were collected up to 84 days for analysis. Thirty-seven rabbits were used for a dose-escalation (1, 3, 6 mg) safety and efficacy study in a rabbit PVR model using a pretreatment design.ResultsLoading efficiency of DNR was 108.55 ± 12 μg per 1 mg particles. Eighty-four days of follow-up did not reveal any adverse reaction. Pharmacokinetic analysis demonstrated a vitreous half-life of 29 days with a maximum DNR concentration of 178 ng/mL and a minimum concentration of 29 ng/mL at day 84. Daunorubicin-loaded porous silicon (pSi) particles were dosed 8 to 9 weeks before PVR induction, and PVR severity score was dose dependent (Spearman ρ = -0.25, P = 0.0005). Proliferative vitreoretinopathy with tractional retinal detachment was 88% in the control group, 63% in the low-dose group, 14% in the medium-dose group, and 0% in the high-dose group (Cochran-Armitage Trend Test, Z = 8.99, ρ = -0.67, P < 0.0001).ConclusionsDaunorubicin-loaded pSi particles can safely reside in the vitreous for at least 3 months. The pSi-based delivery expanded the therapeutic window of DNR by a factor of 862 and drove down the minimum effective concentration by a factor of 175.

The endocannabinoid system has been associated with antiproliferative effects in several types of tumors through cannabinoid receptor–mediated cell death mechanisms. Oleamide (ODA) is a CB1/CB2 agonist associated with cell growth and migration by adhesion and/or ionic signals associated with Gap junctions. Antiproliferative mechanisms related to ODA remain unknown. In this work, we evaluated the effects of ODA on cell viability and morphological changes in a rat RG2 glioblastoma cell line and compared these effects with primary astrocyte cultures from 8-day postnatal rats. RG2 and primary astrocyte cultures were treated with ODA at increasing concentrations (25, 50, 100, and 200 μM) for different periods of time (12, 24, and 48 h). Changes in RG2 cell viability and morphology induced by ODA were assessed by viability/mitochondrial activity test and phase contrast microscopy, respectively. The ratios of necrotic and apoptotic cell death, and cell cycle alterations, were evaluated by flow cytometry. The roles of CB1 and CB2 receptors on ODA-induced changes were explored with specific receptor antagonists. ODA (100 μM) induced somatic damage, detachment of somatic bodies, cytoplasmic polarization, and somatic shrinkage in RG2 cells at 24 and 48 h. In contrast, primary astrocytes treated at the same ODA concentrations exhibited cell aggregation but not cell damage. ODA (100 μM) increased apoptotic cell death and cell arrest in the G1 phase at 24 h in the RG2 line. The effects induced by ODA on cell viability of RG2 cells were independent of CB1 and CB2 receptors or changes in intracellular calcium transient. Results of this novel study suggest that ODA exerts specific antiproliferative effects on RG2 glioblastoma cells through unconventional apoptotic mechanisms not involving canonical signals. [ABSTRACT FROM AUTHOR]

Citrus fruits are one of the principal fruits used to produce juices. Over the years, these fruits have been recognized as new health-promoting agents. In this work, food wastes derived from autochthonous citrus fruits of Southern Italy, named Limone di Rocca Imperiale, Arancia Rossa Moro, and Arancia Bionda Tardivo from Trebisacce, were analyzed. After fresh-squeezing juice, peel and pomace were employed to obtain six different extracts using an ultrasound-assisted method in a hydroalcoholic solvent. The extracts were analyzed in terms of qualitative composition, antioxidant properties, and antiproliferative activity on MCF-7, MDA-MB-231, and BJ-hTERT cell lines. GC-MS and LC-ESI-MS analyses showed different compounds: of note, limonin-hexoside, neodiosmin, obacunone glucoside, and diacetyl nomilinic acid glucoside have been identified as limonoid structures present in all the samples, in addition to different polyphenols including naringenin-glucoside, hesperetin-O-hexoside-O-rhamnoside-O-glucoside, diferuloyl-glucaric acid ester, chlorogenic acid, and the presence of fatty acids such as palmitic, myristic, and linoleic acids. These extracts were able to exert antioxidant activity as demonstrated by DPPH and ABTS assays and, although at higher doses, to reduce the cell viability of different solid tumor cell lines, as shown in MTT assays.

The M2 isoform of pyruvate kinase (PKM2) is a potential antitumor therapeutic target. In this study, we designed and synthesised a series of 2, 3-didithiocarbamate substituted naphthoquinones as PKM2 inhibitors based on the lead compound 3k that we previously reported. Among them, compound 3f (IC50 = 1.05 ± 0.17 µM) and 3h (IC50 = 0.96 ± 0.18 µM) exhibited potent inhibition of PKM2, and their inhibitory activities are superior to compound 3k (IC50 = 2.95 ± 0.53 µM) and the known PKM2 inhibitor shikonin (IC50 = 8.82 ± 2.62 µM). In addition, we evaluated in vitro antiproliferative effects of target compounds using MTS assay. Most target compounds exhibited dose-dependent cytotoxicity with IC50 values in nanomolar concentrations against HCT116, MCF7, Hela, H1299 and B16 cells. These small molecule PKM2 inhibitors not only provide candidate compounds for cancer therapy, but also offer a tool to probe the biological effects of PKM2 inhibition on cancer cells.

This is the first study to report the green synthesis of Lobelia trigona Roxb‐ mediated silver nanoparticles (LTAgNPs). The optical and structural properties of the synthesised LTAgNPs were analysed using ultraviolet–visible spectroscopy, scanning electron microscopy, Fourier transform infrared, dynamic light scattering and energy dispersive X‐ray. LTAgNps were evaluated for their anti‐bacterial and anti‐fungal properties against 18 pathogens and exhibited significant inhibition against all the strains tested. LTAgNPs had potential scavenging effects on the DPPH, • OH, O2•− free radical scavenging assays and reducing power assay. LTAgNps possess strong anti‐cancer activity against five human cancer cell lines (A549, MCF‐7, MDA‐MB‐231, HeLa and KB) in a dose‐dependent manner. The antiproliferative, anti‐inflammatory and genotoxicity effects of LTAgNPs were further confirmed by the lactate dehydrogenase release assay, nitric oxide inhibitory assay and comet assay. Furthermore, the incision, excision and burn wound‐healing activity of formulated LTAgNPs ointment was assessed in rats. All the wounds had significant healing in groups treated with LTAgNPs ointment compared to the groups treated with the commonly prescribed ointment (SilverexTM). This study shows and suggests that the previously unreported LTAgNPs could be used as a nanomedicine with significant biological applications. [ABSTRACT FROM AUTHOR]

Twenty-five novel 2,4,6-trisubstituted triazines were synthesized and biologically evaluated. Most of the compounds synthesized showed good antiproliferative activity against HCT-116 and MCF-7. Compounds B18 and B19 showed the best antiproliferative activity. Further study showed B18 and B19 inhibited four phosphoinositide 3-kinase isoforms and mammalian target of rapamycin with good potency. These results demonstrate that 2,4,6-trisubstituted triazines are potentially useful phosphoinositide 3-kinase inhibitors for the development of new anticancer drugs. [ABSTRACT FROM AUTHOR]

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The goals of the present investigation were the development of two independent synthetic approaches, the original spectroscopic characterisation, the identification of in vitro antitumour activities and the correlation of determined retention factors with in silico pharmacokinetic descriptors of two novel classes of potential antimetabolites based on the privileged 7,8-dihydroimidazo[2,1- c ][1,2,4]triazin-4(6 H)-one scaffold. Well-established, scalable and optimised synthetic approaches leading to two novel classes of the desired compounds (7–12 and 13–17) were developed. These original fused azaisocytosine-like congeners were screened in vitro with the purpose of identifying molecules with better biological profiles that are suitable for further more detailed drug development studies. All the synthesised compounds proved to be strongly antiproliferative active against human neoplastic cell lines (A549, HeLa, T47D and TOV112D) and revealed higher cytotoxic effects in A549, HeLa and T47D cells than the known antitumour agent – pemetrexed. Four potent fused azaisocytosine-like congeners (10 , 12 , 15 and 16) proved to be the most promising lead structures as they reveal the explicitly lower cytotoxicity for non-tumoural cells. These molecules could be employed for novel effective anticancer strategies directed towards designing more selective and safer cytotoxic agents. In addition, a number of compounds (that target epithelial cancer cells and inhibit their growth) have been preselected because they present optimum lipophilicity ranges significantly correlated with in silico bioactivity descriptors (such as % F , Caco-2, P e,jejunum , log BB, f u,brain , log P HSA) important for the optimal pharmacokinetic profile in vivo. [ABSTRACT FROM AUTHOR]

Food proteins from different sources can provide beneficial effects on human health by releasing the bioactive peptides that are integral part of their native structure. In this study, we tested the biological potential of hempseed protein hydrolysates (HPHs) obtained from hempseed cake protein isolate. The HPHs were prepared by enzyme hydrolysis using three different proteases of microbial origin: Alcalase®, Neutrase® and Protamex®. The antioxidant activity of the obtained hydrolysates was determined by oxygen radical absorbance capacity (ORAC) assay, while the proliferative effects on normal (HaCaT) and cancer (HeLa) cells were determined by the CellTiter 96® AQueous One Solution Reagent (MTS) assay. HPHs showed dose-dependent antiproliferative effects on HeLa cells and stimulatory effects on the proliferation of HaCaT cells. HPH obtained by Neutrase® (HPH-N) showed the highest antioxidant activity expressed as an ORAC value. The protective effect of HPH-N on H2O2-induced oxidative stress in normal and cancer cells was evaluated and 1 mg/mL of HPH-N significantly reduced the formation of intracellular reactive oxygen species (ROS) in both cell lines. The obtained results indicate the benefits of HPHs as potential natural antioxidants for the food industry and contribute to the growing trend of utilizing hempseed by-products. [ABSTRACT FROM AUTHOR]

Resveratrol, a natural plant phytoalexin, is produced in response to fungal infection or− UV irradiation. It exists as an isomeric pair with cis- and trans-conformation. Whereas multiple physiological effects of the trans-form, including a pronounced anti-tumoral activity, are nowadays elucidated, much less knowledge exists concerning the cis-isomer. In our work, we analyzed the antiproliferative and cytotoxic properties of cis-resveratrol in four different human tumor entities in direct comparison to trans-resveratrol. We used human cell lines as tumor models for hepatocellular carcinoma (HCC; HepG2, Hep3B), colon carcinoma (HCT-116, HCT-116/p53(−/−)), pancreatic carcinoma (Capan-2, MiaPaCa-2), and renal cell carcinoma (A498, SN12C). Increased cytotoxicity in all investigated tumor cells was observed for the trans-isomer. To verify possible effects of the tumor suppressor p53 on resveratrol-induced cell death, we used wild type and p53-deleted or -mutated cell lines for every tested tumor entity. Applying viability and cytotoxicity assays, we demonstrated a differential, dose-dependent sensitivity towards cis- or trans-resveratrol among the respective tumor types.

Epilobium hirsutum is extensively used as a traditional remedy in folk medicine, especially against prostate inflammation. Therefore, we evaluated the chemical profiles and biopharmaceutical potentials of different extracts of E. hirsutum aerial parts and roots. Metabolomic, antioxidant, and enzyme inhibitory profiles were investigated. Human prostate cancer PC3 cells were exposed to the extracts to evaluate antiproliferative effects. Gene expression and bioinformatics analyses were performed to investigate anti-inflammatory mechanisms. Oenothein B and myricetin were prominent compounds in the extracts. In scavenging/reducing assays, the methanol, infusion, and methanol/water extracts exhibited similar activities. We also observed the reduction of PC3 viability occurring following exposure to methanol and methanol/water extracts. According to bioinformatics analysis, myricetin was predicted to interact with COX-2 and TNFα. The interaction between TNFα and oxo-dihydroxy-octadecenoic acid was predicted as well. Intriguingly, the gene expression of COX-2 and TNFα was reduced in PC3 cells after exposure to methanol and methanol/water extracts. These effects were paralleled by the decreased gene expression of IL-8 and NFkB and the inhibition of PGE2 release. Therefore, the present findings suggest the potential use of E. hirsutum for the management of the burden of inflammation and oxidative stress occurring in lower urinary tract diseases, including prostatitis.

Grape pomace is an abundant/accessible food industry by-product that contains a wide range of phenolic compounds, which have been related to several health benefits and bioactivities. The aim of this study was to mimic the gastrointestinal digestion and the colonic fermentation of Merlot grape pomace, in order to unravel possible phytochemical contents reductions and the processes associated with them, as a tentative to relate the phenolic compound profiles of the extracts with their biological properties. LC-DAD-ESI/MS suggested that the in vitro digestion process promoted drastic qualitative and quantitative reductions in the phenolic compounds profile of the Merlot grape pomace crude extract. Such alterations could be related to the decreases of some bioactivities of the extract, which seems to be the case of antioxidant and antibacterial properties, although not in a directly proportional manner. However, the simulated colonic fermentation seems to have a positive effect over the extract's antiproliferative potential.

Aim: Stilbenes are well-known phytoalexins present in vine and wine. Stilbene glucosides have been identified in wine; however, other than piceid, these compounds have never been reported to be present in the woody parts of grapevine. The aims of this study were to investigate the presence of stilbene glucosides in the woody parts of the vine and to evaluate their cytotoxic activity, in comparison with that of resveratrol, in human hepatoma HepG2 cells. Methods and results: Stilbene glucosides were isolated from a Vitis vinifera root extract. The extract was partitioned with ethyl acetate and fractionated by polyamide gel column chromatography. Pure compounds were obtained by semipreparative high-performance liquid chromatography. These were then identified by mass spectrometry and nuclear magnetic resonance (NMR) analyses, including analysis of two-dimensional NMR spectra. In addition to resveratrol, five stilbene glucosides were found: resveratroloside, resveratrol rutinoside, trans-ε-viniferin diglucoside, cis-ε-viniferin diglucoside and piceid. Of these, the first four showed cytotoxic effects against HepG2 cells when the crystal violet assay was used to determine cell viability. Conclusion: In addition to resveratrol and piceid, this is the first report of the presence of four glucosylated derivatives of resveratrol (resveratroloside, resveratrol rutinoside, and trans- and cis-ε-viniferin diglucosides) in the woody parts of vine. These compounds showed significant cytotoxicity against HepG2 cells. Significance and impact of the study: Stilbenes are well-known biological compounds. Grapevine is one of the main sources of this family of polyphenols. Other than piceid, stilbene glucosides have been identified in wine but never in the woody parts of vine. This is the first study in which five glucosylated derivatives of resveratrol were isolated from woody parts of vine. They were also shown to exert antiproliferative effects in human hepatoma HepG2 cells.

Two new -biotics concepts, such as paraprobiotics and postbiotics were introduced, with beneficial effects beyond the viability of probiotic. In this study, the effect of individual (thermal, ohmic heating, high pressure, and ultrasound) and combined (ohmic, high pressure and ultrasound in combination with heating) treatments on the inactivation kinetics of Lactiplantibacillus plantarum was investigated. Different inactivation rates were obtained, up to 8.18 after 10 min at 90 °C, 2.07 after 15 min at a voltage gradient of 20 V/cm, 6.62 after 10 min at 600 MPa and 3.6 after ultrasound treatment for 10 min at 100 % amplitude. The experimental data were fitted to Weibullian model proposed by Peleg, allowing to estimate the inactivation rate coefficient ( b ) and the shape of the inactivation curves (n). At lower concentration, the samples showed both cytocompatibility and antiproliferative effect, stimulating the cell proliferation on both murine fibroblast and human colorectal adenocarcinoma cell lines., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

A class of vanadium complexes were prepared and investigated for their antiproliferative effects by MTT assay. The structure-activity relationship was extensively studied through the ligand variation. The results showed that the synthetic vanadium complexes demonstrated moderate to good antiproliferative activities against the four cancer cell lines including MGC803, EC109, MCF7 and HepG2, respectively. Of note was that most of the complexes showed preferential growth inhibitory activity to some degree toward gastric cancer line MGC803. Among them, complex 19 exhibited the most and broad-spectrum proliferative inhibition against the tested cell lines. In addition, mechanism studies illustrated that complex 19 could prevent the colony formation, migration and EMT process, as well as induce apoptosis of MGC803 cells. Furthermore, Western blot experiments revealed that the expression of apoptosis-related proteins changed, including up-regulation of Bax, PARP and caspase-3/9, as well as down-regulation of Bcl-2. Image 1 • A library of vanadium complexes showed moderate to good growth inhibition against the tested cancer cells. • Complex 19 demonstrated the best as well as selective proliferation inhibition toward MGC-803 cells. • Complex 19 inhibited the cell colony formation, migration and EMT process of MGC803. • Complex 19 induced the apoptosis of MGC-803 cells, and led to the expression changes of key proteins related to apoptosis. [ABSTRACT FROM AUTHOR]

>bold<>italic/italic<>/bold< Pirfenidone (PFD), which is an antifibrotic agent used for treatment of idiopathic pulmonary fibrosis, induces G0/G1 cell cycle arrest in fibroblasts. We hypothesized that PFD-induced G0/G1 cell cycle arrest might be achieved in other types of cells, including cancer cells. Here we investigated the effects of PFD on the proliferation of pancreatic cancer cells (PCCs) in vitro. >bold<>italic/italic<>/bold< Human skin fibroblasts ASF-4-1 cells and human prostate stromal cells (PrSC) were used as fibroblasts. PANC-1, MIA PaCa-2, and BxPC-3 cells were used as human PCCs. Cell cycle and apoptosis were analyzed using flow cytometer. >bold<>italic/italic<>/bold< First, we confirmed that PFD suppressed cell proliferation of ASF-4-1 cells and PrSC and induced G0/G1 cell cycle arrest. Under these experimental conditions, PFD also suppressed cell proliferation and induced G0/G1 cell cycle arrest in all PCCs. In PFD-treated PCCs, expression of p21 was increased but that of CDK2 was not clearly decreased. Of note, PFD did not induce significant apoptosis among PCCs. >bold<>italic/italic<>/bold< These results demonstrated that the antifibrotic agent PFD might have antiproliferative effects on PCCs by inducing G0/G1 cell cycle arrest. This suggests that PFD may target not only fibroblasts but also PCCs in the tumor microenvironment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Abstract In this study, synthesis, structural characterization, molecular docking studies, and antiproliferative effects in four different cell lines of several novel 16-arylidene-4-azaandrost-5-ene compounds are reported. These compounds were prepared by oxidative cleavage of the enone system of androstenedione followed by an azacyclization reaction and an aldol condensation with various aldehydes at C16. In the androgen-dependent LNCaP cells, the most relevant antiproliferative effects were observed with the 16-phenyl, 16- p -tolyl, and 16- p -nitrophenyl derivatives. Compound 16 E -[(4-methylphenyl)methylidene]-4-azaandrost-5-ene-3,17-dione was the most potent in these cells (IC 50 = 28.28 μM), having lower antiproliferative effects in the androgen-independent PC-3 cells (IC 50 = 45.31 μM). In addition, an interesting selectivity toward cancer cell lines was found for all compounds because a generally low cytotoxicity was detected in healthy human fibroblasts. Furthermore, the 16- p -tolylazaandrostene steroid induced a reduction of viability in LNCaP cells similar to that observed with finasteride, a clinically used 5α-reductase inhibitor. Moreover, molecular docking studies predicted that these 4-azaandrostene derivatives can interact with 5β-reductase, which has a high level of similarity to 5α-reductase enzyme, and with other common targets of steroidal drugs, particularly the enzyme 17α-hydroxylase/17,20-lyase. [ABSTRACT FROM AUTHOR]

The M2 isoform of pyruvate kinase (PKM2) is a potential antitumor therapeutic target. In this study, we designed and synthesised a series of 2, 3-didithiocarbamate substituted naphthoquinones as PKM2 inhibitors based on the lead compound 3k that we previously reported. Among them, compound 3f (IC50 = 1.05 ± 0.17 µM) and 3h (IC50 = 0.96 ± 0.18 µM) exhibited potent inhibition of PKM2, and their inhibitory activities are superior to compound 3k (IC50 = 2.95 ± 0.53 µM) and the known PKM2 inhibitor shikonin (IC50 = 8.82 ± 2.62 µM). In addition, we evaluated in vitro antiproliferative effects of target compounds using MTS assay. Most target compounds exhibited dose-dependent cytotoxicity with IC50 values in nanomolar concentrations against HCT116, MCF7, Hela, H1299 and B16 cells. These small molecule PKM2 inhibitors not only provide candidate compounds for cancer therapy, but also offer a tool to probe the biological effects of PKM2 inhibition on cancer cells. [ABSTRACT FROM AUTHOR]

Acridine derivatives were first used as antibacterial and antiparasitic agents, later as antimalarial and anti-HIV drugs, and now as potentially anticancer agents due to their high cytotoxic activity. Due to their serious adverse effects, new synthetic derivatives were introduced and tested based on modified naturally occurring substances, such as acridone derivatives, which also exhibit potential anti-tumor activity. Most of them are DNA-damaging substances, causing relatively strong and selective destruction of tumor cells. We have tested in vitro anti-proliferative effects of newly-synthesized tetrahydroacrid derivatives, namely tacrine-coumarin hybrid molecules, on various human and mouse cancer cell lines. Our results showed that tacrine-coumarin hybrids with seven, eight, and nine methylene groups in spacer reduce proliferation of cancer cells. A hybrid with nine methylene groups had the most significant anti-cancer effect. [ABSTRACT FROM AUTHOR]

Coronilla species, belonging to the Coronilla genus (Fabaceae), have long been used in traditional medicine for treating cold, diabetes, pain, and as cardiotonics. The goal of the present study was to explore the phytochemical composition and pharmaco-toxicological properties of C. minima. In this regard, phenolic content, scavenging/reducing properties and antimicrobial activity toward pathogen bacterial (Escherichia coli, Pseudomonas aeruginosa, Bacillus cereus, Staphylococcus aureus) and fungal strains (Candida albicans, C. tropicalis, Aspergillus tubigensis and A. minutus) were investigated. Extract effects on human colon cancer HCT116 cell viability were also assayed. Finally, a bioinformatics approach was conducted with the aim to identify putative microbial and human protein targets underlying antibacterial, antimycotic, and antiproliferative effects. Phytochemical investigation suggested that water extract is richer in terms of total flavonoid and phenol content, whereas the hydroalcoholic extract was revealed to be more potent as antioxidant agent. According to bioinformatics analysis, the antibacterial activity of the hydroalcoholic extract could be related to its content in resveratrol. The presence of resveratrol could also explain the hydroalcoholic extract efficacy in reducing HCT116 cell viability. In conclusion, the present study represents the first phytochemical and bio-pharmacological investigation about C. minima. Like other plants belonging to the Fabaceae family, C. minima revealed a good source of resveratrol, which could explain, albeit partially, the efficacy of the hydroalcoholic extract as antimicrobial, antioxidant, and antiproliferative agent.

Photodynamic therapy is a medical modality developed for the treatment of several diseases of oncological and non-oncological etiology that requires the presence of a photosensitizer, light and molecular oxygen, which combined will trigger physicochemical reactions responsible for reactive oxygen species production. Given the scarcity of photosensitizers that exhibit desirable characteristics for its potential application in this therapeutic strategy, the main aims of this work were the study of the photophysical and photochemical properties and the photobiological activity of several dicyanomethylene squaraine cyanine dyes. Thus, herein, the study of their aggregation character, photobleaching and singlet oxygen production ability, and the further application of the previously synthesized dyes in Caco-2 and HepG2 cancer cell lines, to evaluate their phototherapeutic effects, are described. Dicyanomethylene squaraine dyes exhibited moderate light-stability and, despite the low singlet oxygen quantum yields, were a core of dyes that exhibited relevant in vitro photodynamic activity, as there was an evident increase in the toxicity of some of the tested dyes exclusive to radiation treatments.

In present study, we described the synthesis and biological evaluation of a new class of EGFR inhibitors containing 2,9-disubstituted 8-phenylthio/phenylsulfinyl-9 H -purine scaffold. Thirty-one compounds were synthesized. Among them, compound C9 displayed the IC 50 of 29.4 nM against HCC827 cell line and 1.9 nM against EGFR L858R . Compound C12 showed moderate inhibitory activity against EGFR L858R/T790M/C797S (IC 50  = 114 nM). Western bolt assay suggested that compound C9 significantly inhibited EGFR phosphorylation. In vivo test, compound C9 remarkably exhibited inhibitory effect on tumor growth at 5.0 mg/kg by oral administration in established nude mouse HCC827 xenograft model. These results indicate that the 2,9-disubstituted 8-phenylsulfinyl/phenylsulfinyl-9 H -purine derivatives can act as potent EGFR(L858R) inhibitors and effective anticancer agents. Additionally, optimization of compound C12 may result in discovering the fourth-generation EGFR-TKIs. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol 3-kinase (PI3K) signaling pathway has diverse functions, including the regulation of cellular survival, proliferation, cell cycle, migration, angiogenesis and apoptosis. Among class I PI3Ks (PI3Kα, β, γ, δ), the PIK3CA gene encoding PI3K p110α is frequently mutated and overexpressed in a large portion of human cancers. Therefore, the inhibition of PI3Kα has been considered as a promising target for the development of a therapeutic treatment of cancer. In this study, we designed and synthesized a series of 4-aminoquinazoline derivatives and evaluated their antiproliferative activities against six cancer cell lines, including HCT-116, SK-HEP-1, MDA-MB-231, SNU638, A549 and MCF-7. Compound 6b with the most potent antiproliferative activity and without obvious cytotoxicity to human normal cells was selected for further biological evaluation. PI3K kinase assay showed that 6b has selectivity for PI3Kα distinguished from other isoforms. The western blot assay and PI3K kinase assay indicated that 6b effectively inhibited cell proliferation via suppression of PI3Kα kinase activity with an IC 50 of 13.6 nM and subsequently blocked PI3K/Akt pathway activation in HCT116 cells. In addition, 6b caused G1 cell cycle arrest owing to the inhibition of PI3K signaling and induced apoptosis via mitochondrial dependent apoptotic pathway. Our findings suggested that 6b has a therapeutic value as an anticancer agent via PI3Kα inhibition. [ABSTRACT FROM AUTHOR]

The overexpression of EGFR correlates with rapidly progressive disease, resistance to chemotherapy and poor prognosis. In certain human cancers, PI3K works synergistically with EGFR to promote proliferation, survival, invasion and metastasis. Development of dual-target drugs against EGFR and PI3K has therapeutic advantage and was an attractive approach against tumors. In this work, based on the molecular docking and previous studies, a series of 4-aminoquinazolines derivatives containing 6-sulfonamide substituted pyridyl group were rationally designed and identified as potent EGFR and PI3K dual inhibitors. The cytotoxicity experiment results showed that this series of compounds could effectively inhibit cell growth. The kinase assay demonstrated that 6c and 6i had high inhibition for EGFR and selectivity for PI3Kα distinguished from other isoforms. Further experiments showed that 6c could induce cell cycle arrest in G1 phase and apoptosis in BT549 cells. The western blot assay indicated that 6c inhibited the proliferation of BT549 cell through EGFR and PI3Kα/Akt signaling pathway. Our study suggested that compound 6c was a potential dual inhibitors of EGFR and PI3Kα. [ABSTRACT FROM AUTHOR]

The marine sponge Raspailia bouryesnaultae, collected in South Brazil, was selected for detailed investigation considering the results of a screening that pointed to an in vitro antiproliferative effect against non-small cells of human lung cancer (A549) and anti-herpes activity against Herpes Simplex virus type 1 (KOS and 29R strains) of ethanolic extracts. The fractionation and chemical investigation of the sponge’s hexanic fraction led to the isolation and structural elucidation of six clerodane diterpenes. The main component was identified as the already-reported raspailol (1), isolated from a sponge of the same genus collected in New Zealand. The structure of a new diterpene (2) with a rearranged skeleton was established by high-resolution mass spectrometry (HRMS) and 1D and 2D Nuclear magnetic resonance spectroscopy (NMR) experiments, and named here as raspadiene. Furthermore, four diterpenes were elucidated as isomers of clerodane diterpenes previously obtained from plants, namely kerlinic acid (3), kerlinic acid methyl ester (4), annonene (5), and 6-hydroxyannonene (6). They differ in their stereochemistry, since these diterpenes are characterized by a trans ring fusion at the decalin moiety and the relative configuration of the two methyl groups at C-8 and C-9 in a cis relationship (type trans/cis). The Raspailia diterpenes have a cis ring fusion at the decalin moiety, and the two methyl groups at C-8 and C-9 are in a trans relationship (type cis/trans). The isolated compounds were evaluated for their potential antiproliferative effects on human cancer cell line A549, and it was observed that the diterpenes bearing a hydroxyl group at C-6 exhibited moderate cytotoxic activity, with 50% inhibitory concentration (IC50) values lower than 25 μM. The evaluation of the potential anti-herpes activity against Herpes Simplex Virus type 1 (HSV-1, KOS and 29R strains) showed that the more promising results were observed for the new compound 2, since it inhibited HSV-1 (KOS and 29R strains) replication by 83% and 74%, respectively.

In recent years, the green microalgae Neochloris oleoabundans have demonstrated to be an interesting natural source of carotenoids that could be used as potential food additive. In this work, different N. oleoabundans extracts obtained by pressurized liquid extraction (PLE) have been analyzed in depth to evaluate the influence of different culture conditions (effect of nitrogen, light intensity or carbon supplied) not only on the total carotenoid content but also on the carotenoid composition produced by these microalgae. Regardless of the cultivation conditions, lutein and carotenoid monoesters were the most abundant carotenoids representing more than 60% of the total content in all extracts. Afterwards, the effect of the different N. oleoabundans extracts and the dose-effect of the most potent algae extracts (namely, N9, PS and CO 2 (−)) on the proliferation of human colon cancer cells lines (HT-29 and SW480) and a cell line established from a primary colon cancer cell culture (HGUE-C-1) were evaluated by an MTT assay whereas a stepwise multiple regression analysis was performed to get additional evidences on the relationship between carotenoid content and the antiproliferative activity. Results revealed that, as a general trend, those extracts with high total carotenoid content showed comparably antiproliferative activity being possible to establish a high correlation between the cell proliferation values and the carotenoid constituents. Monoesters showed the highest contribution to cell proliferation inhibition whereas lutein and violaxanthin showed negative correlation and diesters and zeaxanthin showed a positive significant contribution to cell proliferation. [ABSTRACT FROM AUTHOR]

Grape pomace is an abundant/accessible food industry by-product that contains a wide range of phenolic compounds, which have been related to several health benefits and bioactivities. The aim of this study was to mimic the gastrointestinal digestion and the colonic fermentation of Merlot grape pomace, in order to unravel possible phytochemical contents reductions and the processes associated with them, as a tentative to relate the phenolic compound profiles of the extracts with their biological properties. LC-DAD-ESI/MS suggested that the in vitro digestion process promoted drastic qualitative and quantitative reductions in the phenolic compounds profile of the Merlot grape pomace crude extract. Such alterations could be related to the decreases of some bioactivities of the extract, which seems to be the case of antioxidant and antibacterial properties, although not in a directly proportional manner. However, the simulated colonic fermentation seems to have a positive effect over the extract's antiproliferative potential. [ABSTRACT FROM AUTHOR]

A new 5-dehydroxyflavan, namely Albiziaflavan B or (+)-(2R, 3S, 4R)-3′,4′, 7-trihydroxy-4-methoxy-2,3-trans-flavan-3,4-trans-diol (1)was isolated from the root bark ofAlbizia glaberrima, together with six known compounds including three flavans: (+)-mollisacacidin (2), (+)-fustin(3) and butin (4); two steroids: chondrillasterol (5)and chondrillasterone (6), and a triterpenoid: lupeol (7). The structure of1was established by detailed analysis of its spectroscopic data, especially 1D and 2D NMR spectra, HRESIMS and CD data. Compounds1–6were assayed for their antiproliferative effects on two human cancer cells, HeLa at 50 μM (n = 2) and HL60 at 20 μM (n = 2). Compound3and4were the most active on HL60 with IC50of 8.1 and 8.3 μM, respectively. Compound6was the most active with an IC50of 4.6 μM on HeLa. [ABSTRACT FROM PUBLISHER]

Reaction of various sulphur ligands L (SEt − , SPh − , SC 6 F 4 H-4 − , SEt 2 , S t Bu 2 , S n Bu 2 , DMSO, DPSO) with the precursors [(COD)M(R)Cl] (COD = 1,5-cyclooctadiene, M = Pd or Pt; R = methyl (Me) or benzyl (Bn); DMSO = dimethyl sulfoxide; DPSO = diphenyl sulfoxide) allowed isolation and characterisation of mononuclear neutral (n = 0) or cationic (n = 1) complexes [(COD)Pt(R)(L)] n+ . Reaction of l -cysteine (HCys) with [(COD)Pt(Me)Cl] under similar conditions gave the binuclear cationic complex in [{(COD)Pt(Me)} 2 (μ-Cys)]Cl. Detailed NMR spectroscopy and single crystal X-ray diffraction in the case of [(COD)Pt(Me)(SEt 2 )][SbF 6 ] and [(COD)Pt(Me)(DMSO)][SbF 6 ] reveal markedly labilised Pt–S bonds as a consequence of the highly covalent Pt–C bonds of the R coligands in these organometallic species. Cationic charge (n = 1) seems to lower the Pt–S bond strength further. Consequently, most of these complexes are not stable long-term in aqueous DMF ( N , N -dimethylformamide) solutions. This made the evaluation of their antiproliferative properties towards HT-29 colon carcinoma and MCF-7 breast adenocarcinoma cell lines impossible. Only the two complexes [(COD)Pt(R)(SC 6 F 4 H-4)] with R = Me or SC 6 F 4 H-4 coligands could be tested with the R = Me complex showing promising activity (in the range of cisplatin), while the R = SC 6 F 4 H-4 derivative is largely inactive, as were the phosphane complexes [(dppe)Pt(SC 6 F 4 H-4) 2 ] (dppe = 1,2-bis(diphenylphosphino)ethane), cis -[(PPh 3 ) 2 Pt(SC 6 F 4 H-4) 2 ] and cis -[(PPh 3 ) 2 PtCl 2 ] which were tested for comparison. In turn, our findings might pave the way to new Pt anti-cancer drugs with largely reduced unwanted depletion of incorporated drugs and reduced side-effects from binding to S-containing biomolecules. [ABSTRACT FROM AUTHOR]