Synthesis of 6,8-diaminopurines acid-induced cascade cyclization of 5-aminoimidazole precursors and preliminary anticancer evaluation.

Inspired by the pharmacological interest generated by 6-substituted purine roscovitine for cancer treatment, 5-aminoimidazole-4-carboxamidine precursors containing a cyanamide unit were prepared by condensation of 5-amino--cyanoimidazole-4-carbimidoyl cyanides with a wide range of primary amines. When these amidine precursors were combined with acids, a fast cascade cyclization occurred at room temperature, affording new 6,8-diaminopurines with the N-3 and N-6 substituents changed relatively to the original positions they occupied in the amidine and imidazole moieties of precursors. The efficacy and wide scope of this method was well demonstrated by an easy and affordable synthesis of 22 6,8-diaminopurines decorated with a wide diversity of substituents at the N-3 and N-6 positions of the purine ring.

Ursolic Acid Impairs Cellular Lipid Homeostasis and Lysosomal Membrane Integrity in Breast Carcinoma Cells.

Cancer is one of the leading causes of death worldwide, thus the search for new cancer therapies is of utmost importance. Ursolic acid is a naturally occurring pentacyclic triterpene with a wide range of pharmacological activities including anti-inflammatory and anti-neoplastic effects. The latter has been assigned to its ability to promote apoptosis and inhibit cancer cell proliferation by poorly defined mechanisms.

Can dietary flavonoids be useful in the personalized treatment of colorectal cancer?

Activating mutations in the oncogenes , and define molecular colorectal cancer (CRC) subtypes because they play key roles in promoting CRC development and in determining the efficacy of chemotherapeutic agents such as 5-fluorouracil and anti-epidermal growth factor receptor monoclonal antibodies. Survival of patients with cancers displaying these molecular profiles is low. Given the limited efficacy of therapeutic strategies for CRC presenting mutational activations in mitogen-activated protein kinase and/or PI3K pathways, developing combination therapies with natural flavonoids or other phytochemicals with demonstrated effects on these pathways (and little or no toxic effects) may constitute a valuable path forward.

flower and berry extracts for food and therapeutic applications: effect of gastrointestinal digestion on and bioactivity and toxicity.

The bioavailability of natural compounds should be assessed through different perspectives. Studying the behaviour of the extracts after digestion is often overlooked but is crucial for success in the development of active food ingredients. Thus, the bioaccessibility of (flower and berry) extracts after gastrointestinal digestion and their effect on toxicity and bioactive potential were studied.

Chemical Characterization of L. Flowers Aqueous Extract and Its Biological Implications.

The main goal of this study was to chemically characterize an aqueous flower extract and validate it as a bioactive agent. The elderflower aqueous extraction was performed at different temperatures (50, 70 and 90 °C). The extract obtained at 90 °C exhibited the highest phenolic content and antiradical activity.

Ohmic Heating Extract of Vine Pruning Residue Has Anti-Colorectal Cancer Activity and Increases Sensitivity to the Chemotherapeutic Drug 5-FU.

Vine pruning residues are by-products of the wine industry that have not received much attention in the past, in spite of being rich in bioactive compounds. In this study, we aimed to test whether an ohmic extract of vine pruning residue (VPE) has anti-colorectal cancer (CRC) properties, and whether responses differ according with cell's mutation profile. VPE decreased human CRC cell proliferation, accompanied by DNA effects and cell cycle modulation.

In Vitro Modulation of Gut Microbiota and Metabolism by Cooked Cowpea and Black Bean.

Legumes are a rich source of a wide range of compounds that may represent an important tool to overcome gut dysbiosis. In this work, the prebiotic potential of two cooked legumes (cowpea and black bean) was investigated in comparison with potato:beef mixture, as substrates in batch faecal culture fermentation. Prior to the fermentation, all the samples were in vitro digested, passing through three phases, namely mouth, gastric and small intestine simulation, and then in vitro fermented for 6, 24 and 48 h.

Ohmic heating polyphenolic extracts from vine pruning residue with enhanced biological activity.

Vine Pruning residue was submitted to conventional heating and ohmic heating (OH) for the extraction of bioactive compounds and analyzed for total phenolic content (TPC), polyphenolic profile, antioxidant activity, antimicrobial activity and anticancer activity. The OH extracts were obtained using Low electric field (496.0 V/cm) or Intermediate electric field - IEF (840.

Colon Cancer Chemoprevention by Sage Tea Drinking: Decreased DNA Damage and Cell Proliferation.

Salvia officinalis and some of its isolated compounds have been found to be preventive of DNA damage and increased proliferation in vitro in colon cells. In the present study, we used the azoxymethane model to test effects of S. officinalis on colon cancer prevention in vivo.

Effects on Liver Lipid Metabolism of the Naturally Occurring Dietary Flavone Luteolin-7-glucoside.

Disruptions in whole-body lipid metabolism can lead to the onset of several pathologies such as nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVDs). The present study aimed at elucidating the molecular mechanisms behind the lipid-lowering effects of the flavone luteolin-7-glucoside (L7G) which we previously showed to improve plasma lipid profile in rats. L7G is abundant in plant foods of Mediterranean diet such as aromatic plants used as herbs.

Novel structurally similar chromene derivatives with opposing effects on p53 and apoptosis mechanisms in colorectal HCT116 cancer cells.

In the present work, novel chromene derivatives fused with the imidazo[1,2-a]pyridine nucleus were tested for their anticancer potential in the human colorectal cancer HCT116 cells. Compounds 2a and 2c showed significant growth inhibitory activity with GI50 of 15 μM and 11 μM, respectively. Compound 2c, the most potent, has a carbamate group in position 8 of the pyridine ring, and showed significant cell cycle arrest and induction of cell death by apoptosis, even at 5 μM.

Redox-dependent induction of antioxidant defenses by phenolic diterpenes confers stress tolerance in normal human skin fibroblasts: Insights on replicative senescence.

Mild stress-induced hormesis represents a promising strategy for targeting the age-related accumulation of molecular damage and, therefore, for preventing diseases and achieving healthy aging. Fruits, vegetables, and spices contain a wide variety of hormetic phytochemicals, which may explain the beneficial health effects associated with the consumption of these dietary components. In the present study, the induction of cellular antioxidant defenses by the phenolic diterpenes carnosic acid (CA) and carnosol (CS) were studied in normal human skin fibroblasts, and insights into the aging process at the cellular level investigated.

Superior anticancer activity of halogenated chalcones and flavonols over the natural flavonol quercetin.

A series of chalcone and flavonol derivatives were synthesized in good yield by an eco-friendly approach. A pharmacological evaluation was performed with the human colorectal carcinoma cell line HCT116 and revealed that the anticancer activity of flavonols was higher when compared with that of the respective chalcone precursors. The antiproliferative activity of halogenated derivatives increases as the substituent in the 3- or 4-positon of the B-ring goes from F to Cl and to Br.

Development of a new application of the comet assay to assess levels of O6-methylguanine in genomic DNA (CoMeth).

O(6)-methylguanine (O(6)meG) is one of the most premutagenic, precarcinogenic, and precytotoxic DNA lesions formed by alkylating agents. Repair of this DNA damage is achieved by the protein MGMT, which transfers the alkyl groups from the O(6) position of guanine to a cysteine residue in its active center. Because O(6)meG repair by MGMT is a stoichiometric reaction that irreversibly inactivates MGMT, which is subsequently degraded, the repair capacity of O(6)meG lesions is dependent on existing active MGMT molecules.

Water extracts of tree Hypericum sps. protect DNA from oxidative and alkylating damage and enhance DNA repair in colon cells.

Diet may induce colon carcinogenesis through oxidative or alkylating DNA damage. However, diet may also contain anticarcinogenic compounds that contribute to cancer prevention. DNA damage prevention and/or induction of repair are two important mechanisms involved in cancer chemoprevention by dietary compounds.

Ursolic acid induces cell death and modulates autophagy through JNK pathway in apoptosis-resistant colorectal cancer cells.

Colorectal carcinomas (CRCs) with P53 mutations have been shown to be resistant to chemotherapy with 5-fluorouracil (5-FU), the most widely used chemotherapeutic drug for CRC treatment. Autophagy is emerging as a promising therapeutic target for drug-resistant tumors. In the present study, we tested the effects of ursolic acid (UA), a natural triterpenoid, on cell death mechanisms and its effects in combination with 5-FU in the HCT15 p53 mutant apoptosis-resistant CRC cell line.

Protection by Salvia extracts against oxidative and alkylation damage to DNA in human HCT15 and CO115 cells.

DNA damage induced by oxidative and alkylating agents contributes to carcinogenesis, leading to possible mutations if replication proceeds without proper repair. However, some alkylating agents are used in cancer therapy due to their ability to induce DNA damage and subsequently apoptosis of tumor cells. In this study, the genotoxic effects of oxidative hydrogen peroxide (H₂O₂) and alkylating agents N-methyl-N-nitrosourea (MNU) and 1,3-bis-(2-chloroethyl)-1-nitosourea (BCNU) agents were examined in two colon cell lines (HCT15 and CO115).

Hypericum androsaemum water extract inhibits proliferation in human colorectal cancer cells through effects on MAP kinases and PI3K/Akt pathway.

MAP kinase and PI3K/Akt signalling pathways are commonly altered in colorectal carcinoma (CRC) leading to tumor growth due to increased cell proliferation and inhibition of apoptosis. Several species of the genus Hypericum are used in Portugal to prepare herbal teas to which digestive tract effects are attributed. In the present study, the antiproliferative and proapoptotic effects of the water extracts of H.

Quercetin enhances 5-fluorouracil-induced apoptosis in MSI colorectal cancer cells through p53 modulation.

Purpose: Colorectal tumors (CRC) with microsatellite instability (MSI) show resistance to chemotherapy with 5-fluorouracil (5-FU), the most widely used pharmacological drug for CRC treatment. The aims of this study were to test the ability of quercetin (Q) and luteolin (L) to increase the sensitivity of MSI CRC cells to 5-FU and characterize the dependence of the effects on cells' p53 status.

Methods: Two MSI human CRC-derived cell lines were used: CO115 wild type (wt) for p53 and HCT15 that harbors a p53 mutation.

Rosmarinic acid, major phenolic constituent of Greek sage herbal tea, modulates rat intestinal SGLT1 levels with effects on blood glucose.

Scope: Previous results suggested that the effects of Salvia fruticosa tea (SFT) drinking on glucose regulation might be at the intestinal level. Here we aim to characterize the effects of SFT treatment and of its main phenolic constituent--rosmarinic acid (RA)--on the levels and localization of the intestinal Na+/glucose cotransporter-1 (SGLT1), the facilitative glucose transporter 2 and glucagon-like peptide-1 (GLP-1).

Methods And Results: Two models of SGLT1 induction in rats were used: through diabetes induction with streptozotocin (STZ) and through dietary carbohydrate manipulation.

Curcumin induces heme oxygenase-1 in normal human skin fibroblasts through redox signaling: relevance for anti-aging intervention.

Scope: Curcumin, a component of the spice turmeric, was tested for its potential hormetic anti-aging effects as an inducer of mild stress.

Methods And Results: Early passage young human skin fibroblasts treated with low doses of curcumin (below 20 μM) showed a time- and concentration-dependent induction of heme oxygenase-1 (HO-1), followed by compensatory increase in glutathione-S-transferase activity, GSH levels and GSH/GSSG ratio. These effects were preceded by induction of oxidative stress (increased levels of reactive oxygen species and DNA damage) and impairment of cells' GSH redox state.

Protective effects of ursolic acid and luteolin against oxidative DNA damage include enhancement of DNA repair in Caco-2 cells.

Consumption of fruits and vegetables is associated with a reduced risk of developing a wide range of cancers including colon cancer. In this study, we evaluated the effects of two compounds present in fruits and vegetables, ursolic acid, a triterpenoid, and luteolin, a flavonoid, on DNA protection and DNA repair in Caco-2 cells using the comet assay. Ursolic acid and luteolin showed a protective effect against H(2)O(2)-induced DNA damage.

Polyphenolic compounds from Salvia species protect cellular DNA from oxidation and stimulate DNA repair in cultured human cells.

DNA damage can lead to carcinogenesis if replication proceeds without proper repair. This study evaluated the effects of the water extracts of three Salvia sp., Salvia officinalis (SO), Salvia fruticosa (SF), and Salvia lavandulifolia (SL), and of the major phenolic constituents, rosmarinic acid (RA) and luteolin-7-glucoside (L-7-G), on DNA protection in Caco-2 and HeLa cells exposed to oxidative agents and on DNA repair in Caco-2 cells.

Ursolic acid and luteolin-7-glucoside improve lipid profiles and increase liver glycogen content through glycogen synthase kinase-3.

In the present study, two phytochemicals - ursolic acid (UA) and luteolin-7-glucoside (L7G) - were assessed in vivo in healthy rats regarding effects on plasma glucose and lipid profile (total cholesterol, HDL and LDL), as well as liver glycogen content, in view of their importance in the aetiology of diabetes and associated complications. Both UA and L7G significantly decreased plasma glucose concentration. UA also significantly increased liver glycogen levels accompanied by phosphorylation of glycogen synthase kinase-3 (GSK3).

Sage tea drinking improves lipid profile and antioxidant defences in humans.

Salvia officinalis (common sage) is a plant with antidiabetic properties. A pilot trial (non-randomized crossover trial) with six healthy female volunteers (aged 40-50) was designed to evaluate the beneficial properties of sage tea consumption on blood glucose regulation, lipid profile and transaminase activity in humans. Effects of sage consumption on erythrocytes' SOD and CAT activities and on Hsp70 expression in lymphocytes were also evaluated.