Chemical Composition, Antioxidant Activities, Antidepressant Effect, and Lipid Peroxidation of Peruvian Blueberry: Molecular Docking Studies on Targets Involved in Oxidative Stress and Depression.

Blueberries (Vaccinium corymbosum L.) are cultivated worldwide and are among the best dietary sources of bioactive compounds with beneficial health effects. This study aimed to investigate the components of Peruvian blueberry using high-performance liquid chromatography coupled to electrospray ionization and quadrupole time-of-flight mass spectrometry (HPLC-ESI-QTOF-MS/MS), identifying 11 compounds. Furthermore, we assessed in vitro the antioxidant activity and in vivo the antidepressant effect using a rat model and protective effect on lipid peroxidation (in the serum, brain, liver, and stomach). We also conducted molecular docking simulations with proteins involved in oxidative stress and depression for the identified compounds. Antioxidant activity was assessed by measuring total phenolic and flavonoid contents, as well as using 1,1-diphenyl-2-picrylhydrazin (DPPH), 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic) acid (ABTS•+), and ferric-reducing antioxidant power (FRAP) assays. Peruvian blueberries demonstrated higher antioxidant activity than Vaccinium corymbosum fruits from Chile, Brazil, the United States, Turkey, Portugal, and China. The results showed that oral administration of Peruvian blueberries (10 and 20 mg/kg) for 28 days significantly (p < 0.001) increased swimming and reduced immobility in the forced swimming test (FST). Additionally, at doses of 40 and 80 mg/kg, oxidative stress was reduced in vivo (p < 0.001) by decreasing lipid peroxidation in brain, liver, stomach, and serum. Molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions were performed. In the molecular docking studies, quercitrin and 3,5-di-O-caffeoylquinic acid showed the best docking scores for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, superoxide dismutase, and xanthine oxidase; while 3,5-dicaffeoylquinic acid methyl ester and caffeoyl coumaroylquinic acid had the best docking scores for monoamine oxidase and serotonin receptor 5-HT2. In summary, our results suggest that the antidepressant and protective effects against lipid peroxidation might be related to the antioxidant activity of Peruvian Vaccinium corymbosum L.

Antispasmodic Effect of Valeriana pilosa Root Essential Oil and Potential Mechanisms of Action: Ex Vivo and In Silico Studies.

Infusions of Valeriana pilosa are commonly used in Peruvian folk medicine for treating gastrointestinal disorders. This study aimed to investigate the spasmolytic and antispasmodic effects of Valeriana pilosa essential oil (VPEO) on rat ileum. The basal tone of ileal sections decreased in response to accumulative concentrations of VPEO. Moreover, ileal sections precontracted with acetylcholine (ACh), potassium chloride (KCl), or barium chloride (BaCl2) were relaxed in response to VPEO by a mechanism that depended on atropine, hyoscine butylbromide, solifenacin, and verapamil, but not glibenclamide. The results showed that VPEO produced a relaxant effect by inhibiting muscarinic receptors and blocking calcium channels, with no apparent effect on the opening of potassium channels. In addition, molecular docking was employed to evaluate VPEO constituents that could inhibit intestinal contractile activity. The study showed that α-cubebene, ß-patchoulene, ß-bourbonene, ß-caryophyllene, α-guaiene, γ-muurolene, valencene, eremophyllene, and δ-cadinene displayed the highest docking scores on muscarinic acetylcholine receptors and voltage-gated calcium channels, which may antagonize M2 and/or M3 muscarinic acetylcholine receptors and block voltage-gated calcium channels. In summary, VPEO has both spasmolytic and antispasmodic effects. It may block muscarinic receptors and calcium channels, thus providing a scientific basis for its traditional use for gastrointestinal disorders.

Discovery of New 2-Phenylamino-3-acyl-1,4-naphthoquinones as Inhibitors of Cancer Cells Proliferation: Searching for Intra-Cellular Targets Playing a Role in Cancer Cells Survival.

A series of 2-phenylamino-3-acyl-1,4-naphtoquinones were evaluated regarding their in vitro antiproliferative activities using DU-145, MCF-7 and T24 cancer cells. Such activities were discussed in terms of molecular descriptors such as half-wave potentials, hydrophobicity and molar refractivity. Compounds 4 and 11 displayed the highest antiproliferative activity against the three cancer cells and were therefore further investigated. The in silico prediction of drug likeness, using pkCSM and SwissADME explorer online, shows that compound 11 is a suitable lead molecule to be developed. Moreover, the expressions of key genes were studied in DU-145 cancer cells. They include genes involved in apoptosis (Bcl-2), tumor metabolism regulation (mTOR), redox homeostasis (GSR), cell cycle regulation (CDC25A), cell cycle progression (TP53), epigenetic (HDAC4), cell-cell communication (CCN2) and inflammatory pathways (TNF). Compound 11 displays an interesting profile because among these genes, mTOR was significantly less expressed as compared to control conditions. Molecular docking shows that compound 11 has good affinity with mTOR, unraveling a potential inhibitory effect on this protein. Due to the key role of mTOR on tumor metabolism, we suggest that impaired DU-145 cells proliferation by compound 11 is caused by a reduced mTOR expression (less mTOR protein) and inhibitory activity on mTOR protein.

Valeriana pilosa Roots Essential Oil: Chemical Composition, Antioxidant Activities, and Molecular Docking Studies on Enzymes Involved in Redox Biological Processes.

Valeriana pilosa is usually employed in Peruvian folk medicine in the form of infusion to treat stomach pain, and has antispasmodic, relaxing, sleep-promoting, and sedative properties, as well as is an anti-inflammatory. In this study, Valeriana pilosa essential oil (VPEO) was obtained by hydrodistillation, analyzed by GC and GC/MS, and 47 compounds were identified. Major oil components were α-patchoulene (5.8%), α-humulene (6.1%), seychellene (7.6%), and patchoulol (20.8%). Furthermore, we assessed the in vitro antioxidant activities, molecular docking, and Ligand Efficiency studies on enzymes involved in cellular redox pathways such as CYP2C9, catalase, superoxide dismutase, and xanthine oxidase. Essential oil antioxidant activities were assessed by FRAP, ABTS•+, and DPPH• radical scavenging activity. VPEO displays high antioxidant activity as compared to essential oils of Valeriana jatamansi and Valeriana officinalis oil roots. In addition, molecular docking and ADMET prediction was employed to compare the absorption, metabolism, and toxicity properties of Valeriana pilosa compounds. In the molecular docking studies, limonene, p-cimene, carvone, α-cubebene, cyclosativene, α-guaiene, allo-aromadendrene, valencene, and eremophyllene were the compounds with the best docking score on CYP2C9 and xanthine oxidase. Thus, volatile components of Valeriana pilosa could be associated with the detected antioxidant activity, acting as putative inhibitors of CYP2C9 and xanthine oxidase.

Antifungal Activity and In Silico Studies on 2-Acylated Benzo- and Naphthohydroquinones.

The high rates of morbidity and mortality due to fungal infections are associated with a limited antifungal arsenal and the high toxicity of drugs. Therefore, the identification of novel drug targets is challenging due to the several resemblances between fungal and human cells. Here, we report the in vitro antifungal evaluation of two acylphenols series, namely 2-acyl-1,4-benzo- and 2-acyl-1,4-naphthohydroquinones. The antifungal properties were assessed on diverse Candida and filamentous fungi strains through the halo of inhibition (HOI) and minimal inhibitory concentration (MIC). The antifungal activities of 2-acyl-1,4-benzohydroquinone derivatives were higher than those of the 2-acyl-1,4-naphthohydroquinone analogues. The evaluation indicates that 2-octanoylbenzohydroquinone 4 is the most active member of the 2-acylbenzohydroquinone series, with MIC values ranging from 2 to 16 µg/mL. In some fungal strains (i.e., Candida krusei and Rhizopus oryzae), such MIC values of compound 4 (2 and 4 µg/mL) were comparable to that obtained by amphotericin B (1 µg/mL). The compound 4 was evaluated for its antioxidant activity by means of FRAP, ABTS and DPPH assays, showing moderate activity as compared to standard antioxidants. Molecular docking studies of compound 4 and ADMET predictions make this compound a potential candidate for topical pharmacological use. The results obtained using the most active acylbenzohydroquinones are promising because some evaluated Candida strains are known to have decreased sensitivity to standard antifungal treatments.

Potential antioxidant effect of fruit peels for human use from northern Peru, compared by 5 different methods / Potencial efecto antioxidante de las cáscaras de frutas para uso humano del norte de Perú, comparado por 5 métodos diferentes

The objective of the work was to determine the antioxidant potential in vitro of freeze-dried peel extracts of 20 fruits from the northern region of Peru through five tests (Folin-Ciocalteu, DPPH., ABTS+., FRAP and CUPRAC). According to multivariate statistical analyzes, five groups were found: (i.) peel extracts with the highest values of antioxidant capacity (AC) from custard apple, and star fruit; (ii.) rind extracts with high AC values from quince, sweet granadilla, guava, and black grape; (iii.) husk extracts with middle values of AC from passion fruit, and red mombin; (iv.) shell extracts with low AC values from tangerine, mandarine, and bitter orange; and, (v.) coating extracts with the lowest AC values from pawpaw, red pawpaw, muskmelon, dragon fruit, yellow and red indian figs, pear, apple, and green grape. To conclude, the fruit lyophilized-husk extracts of custard apple, star fruit, quince, sweet granadilla, guava, and black grape obtained the best AC.

El objetivo del trabajo fue determinar el potencial antioxidante in vitro de extractos de cáscara liofilizada de 20 frutos de la región norte del Perú mediante cinco pruebas (Folin-Ciocalteu, DPPH., ABTS+., FRAP y CUPRAC). Según análisis estadísticos multivariados, se encontraron cinco grupos: (i.) Extractos de piel con los valores más altos de capacidad antioxidante (CA) de chirimoya y carambola; (ii.) extractos de cáscara con altos valores de CA de membrillo, granadilla dulce, guayaba y uva negra; (iii.) extractos de cáscara con valores medios de CA de maracuyá y mombina roja; (iv.) extractos de cáscara con valores bajos de CA de mandarina, mandarina y naranja amarga; y (v.) recubrir extractos con los valores de CA más bajos de papaya, papaya roja, melón, fruta del dragón, higos indios amarillos y rojos, pera, manzana y uva verde. Para concluir, los extractos de cáscara liofilizada de chirimoya, carambola, membrillo, granadilla dulce, guayaba y uva negra obtuvieron el mejor CA.

Impact of the Potential Antitumor Agent 2-(4-Hydroxyphenyl) Amino-1,4-Naphthoquinone (Q7) on Vasomotion Is Mediated by the Vascular Endothelium, But Not Vascular Smooth Muscle Cell Metabolism.

ABSTRACT: Vasomotion is defined as rhythmic oscillations in arterial diameter that regulate the blood flow and blood pressure. Because antitumor treatment may impair vascular functions and increase the blood pressure, we sought to evaluate whether a new naphthoquinone derivative, postulated as an antitumor agent, manifests adverse effects on vascular function. In this article, we evaluated the toxicity of 2-(4-hydroxyphenyl) amino-1,4-naphthoquinone (Q7) and its effects on vascular vasomotion in 3 models of vascular structure: endothelial cells, aortic ring, and smooth muscle cells. Although showing nontoxic effects, Q7 inhibited the formation of capillary-like structures of the EA.hy926 endothelial cell line grown on Matrigel. In exvivo experiments with aortic rings precontracted with phenylephrine (PE, 10-6 M), Q7 (10-5 M) significantly (P < 0.05) reduced vascular rhythmic contractions induced by the acetylcholine (ACh; 10-7-10-5 M), whereas sodium nitroprusside (a nitric oxide donor; 10-8 M) recovered the vasomotion. Furthermore, Q7 (10-5 M) did not decrease KCl-induced vascular rhythmic contractions in the aortic rings precontracted with BaCl2 (a nonselective K+ channel blocker; 10-3 M). Vascular smooth muscle cells (A7r5) preincubated with Q7 (10-5 M) for 3 hours also demonstrated a reduced glucose uptake. However, the Adenosine Triphosphate content was unaffected, suggesting that the rapid reduction in vasomotion observed in vascular reactivity experiments did not involve cellular metabolism but may be due to faster mechanisms involving endothelial nitric oxide and K+ channels leading to oscillations in intracellular Ca2+. In summary, the naphthoquinone derivative Q7 presents low cytotoxicity yet may alter the endothelial cell response and vasomotion in the absence of changes in smooth muscle cell metabolism.

La suplementación con ácido ascórbico atenúa el trastorno metabólico inducido por un derivado de juglona / Ascorbic supplementation attenuates juglone induced metabolic derangement

Los derivados de juglona, como 2-(4-hidroxifenil) amino-1,4-naftoquinona (Q7), son conocidos agentes antitumorales. Ellos generan especies reactivas de oxígeno (ROS), que podrían producir un desbalance de ROS y un metabolismo anormal de lípidos. El objetivo del estudio fue evaluar el efecto del ascorbato sobre el metabolismo de lípidos y carbohidratos en condición de estrés oxidativo inducido por Q7. A ratas Wistar macho, se les administró oralmente Q7 (10 mg/Kg) y/o ascorbato (500 mg/Kg) durante 20 días. Las ratas tratadas con Q7 mostraron un aumento de los triglicéridos en suero, del colesterol VLDL y de los niveles de peróxidación lipídica. Cuando el tratamiento con Q7 fue seguido de la administración de ascorbato (500 mg/Kg), observamos una disminución de los triglicéridos en suero, del colesterol VLDL y de la peroxidación lipídica. La administración oral de ascorbato redujo el aumento de lípidos inducido por Q7 y la glicemia postprandial. Esto podría estar asociado con la actividad redox del ascorbato, que reduce el estrés oxidativo inducido por Q7. Concluimos que el ascorbato modula el aumento del metabolismo de lípidos y carbohidratos inducido por Q7.

Juglone derivatives like 2-(4-hydroxyphenyl) amino-1,4-naphthoquinone (Q7) are used as antitumor agents, and act through reactive oxygen species (ROS) generation. Such may lead to abnormal lipid metabolism and ROS dysregulation. The objective of this study was to evaluate the effect of ascorbate on the metabolism of lipids and carbohydrates following Q7-induced oxidative stress. Male Wistar rats were administered Q7 (10 mg/Kg) and/or ascorbate (500 mg/Kg) orally for 20 days. Rats treated with Q7 showed an increase in serum triglycerides, VLDL cholesterol and lipid peroxidation levels. When Q7 treatment was followed up by ascorbate (500 mg/Kg) administration, we observed a reduction in serum triglycerides, VLDL cholesterol and lipid peroxidation. The oral administration of ascorbate reduced the Q7-induced increases in lipids, and postprandial glycemia. This could be associated with the redox activity of ascorbate that reduced the oxidative stress induced by Q7. We thus conclude that ascorbate modulates the Q7-induced increase of lipid and carbohydrate metabolism.

New 2-Acetyl-3-aminophenyl-1,4-naphthoquinones: Synthesis and In Vitro Antiproliferative Activities on Breast and Prostate Human Cancer Cells.

The reaction of 2-acyl-1,4-naphthoquinones with N,N-dimethylaniline and 2,5-dimethoxyaniline, promoted by catalytic amounts of CeCl3·7H2O under "open-flask" conditions, produced a variety of 2-acyl-3-aminophenyl-1,4-naphthoquinones structurally related to the cytotoxic 2-acetyl-3-phenyl-1,4-naphthoquinone, an inhibitor of the heat shock chaperone protein Hsp90. The members of the 2-acyl-3-aminophenyl-1,4-naphthoquinone series were isolated in good yields (63-98%). The cyclic voltammograms of the 2-acyl-3-aminophenyl-1,4-naphthoquinone exhibit two one-electron reduction waves to the corresponding radical-anion and dianion and two quasireversible oxidation peaks. The first and second half-wave potential values (E 1/2) of the members of the series are sensitive to the push-pull electronic effects of the substituents in the naphthoquinone scaffold. Furthermore, the in vitro antiproliferative properties of these new quinones were evaluated on two human cancer cells DU-145 (prostate) and MCF-7 (mammary) and a nontumorigenic HEK-293 (kidney) cell line, using the MTT colorimetric method. Two members, within the series, exhibited interesting cytotoxic activities on human prostate and mammary cancer cells.

In Vitro Inhibition of Hsp90 Protein by Benzothiazoloquinazolinequinones Is Enhanced in The Presence of Ascorbate. A Preliminary In Vivo Antiproliferative Study.

A series of benzo[g]benzothiazolo[2,3-b]quinazoline-7,12-quinones were prepared from 2-acylnaphthohydroquinones and 2-aminobenzothiazoles and were evaluated for their in vitro antiproliferative activity. After screening using the MTT reduction assay, their IC50 values were calculated on a panel of cancer cells (T24, DU-145, MCF-7). Current standard anticancer drugs were included as control, and their calculated IC50 values were 7.8 and 23.5 µM for 5-fluorouracil and tamoxifen, respectively. Non-cancer cells (AG1523) were included to assess cancer cell sensitivity and drug selectivity. Four members of the series, with IC50 values from 0.11 to 2.98 µM, were chosen for further assays. The selected quinones were evaluated regarding their effects on cancer cell proliferation (clonogenic assay) and on Hsp90 and poly(ADPribose)polymerase (PARP) protein integrity. The most active compound (i.e., 15) substantially inhibited colony forming unit (CFU) formation at 0.25 µM. In the presence of ascorbate, it induced an oxidative cleavage of Hsp90 but had no effect on PARP protein integrity. In an in vivo animal model, it discreetly increased the mean survival time (m.s.t.) of tumor-bearing mice. In light of these results, compound 15 represents a potential lead-molecule to be further developed.

Antioxidant effect and chemical composition of Ananas comosus [L.] Merr. peels from Peruvian northern / Efecto antioxidante y composición química de las cascaras de Ananas comosus [L.] Merr. del norte peruano

Pineapple peels has several beneficial properties including antioxidant activity. We investigated the antioxidant effect of five different peels of pineapple lyophilized extracts, not adsorbed and adsorbed onto Amberlite. They were examined using total phenolic contents (TPC), antioxidant effect by 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging and ferric reducing antioxidant power (FRAP). In addition, we analyzed the chemical composition by HPLC-ESI-QTOF-MS/MS. The main constituents of pineapple peels were tentatively identified as quercetin glycosides and N,N'-diferuloylspermidine. We conclude that the antioxidant activity in pineapple peels from District of Poroto, Province of Trujillo, Region of La Libertad, can be associated with the presence of flavonoid and spermidines.

Las cáscaras de piña tienen varias propiedades beneficiosas, incluida la actividad antioxidante. Investigamos el efecto antioxidante de cinco exfoliaciones diferentes de extracto liofilizado de piña, no adsorbidas y adsorbidas en Amberlita. Se examinaron utilizando los contenidos fenólicos totales (TPC), el efecto antioxidante mediante la eliminación del radical 1,1-difenil-2-picril-hidrazilo (DPPH) y el poder férrico antioxidante reductor (FRAP). Además, analizamos la composición química por HPLC-ESI-QTOF-MS/MS. Los principales constituyentes de las cáscaras de piña se identificaron tentativamente como glucósidos de quercetina y N,N'- diferuloylspermidina. Concluimos que la actividad antioxidante en las cáscaras de piña del Distrito de Poroto, Provincia de Trujillo, Región de La Libertad, puede estar asociada con la presencia de flavonoides y espermidinas.

Glaucoma y miopía agudos inducidos por el uso de topiramato / Acute glaucoma and myopia induced by the use of topiramate

El topiramato es una droga utilizada en varias enfermedades, como las neurológicas y las psiquiátricas. Entre sus efectos adversos se encuentra la producción de miopía aguda y glaucoma por cierre angular secundario en ojos previamente sanos. A pesar de que se trata de efectos adversos relativamente infrecuentes, los mismos deben tomarse en consideración puesto que su expresión clínica (cefalea y dolor periocular, entre otros) puede ser muchas veces confundida con la patología de base para la cual se estaba utilizando el topiramato (por ejemplo, para el tratamiento de la migraña). Lo anterior es importante puesto que dichos efectos adversos solo cesarán con la interrupción del uso de la droga. En este breve artículo de revisión se presentan conceptos básicos acerca de la fisiopatología y del tratamiento de la miopía y del glaucoma por cierre angular inducidos por el uso de topiramato.

Topiramate is a drug used in several diseases, such as neurological and psychiatric ones. Among its adverse effects are the production of acute myopia and glaucoma by secondary angular closure in previously healthy eyes. Although these are relatively infrequent adverse effects, they must be taken into consideration since their clinical expression (headache and periocular pain, among others) can often be confused with the pathology for which topiramate was being used (for example, for the treatment of migraine). The foregoing is important since such adverse effects will only cease with the interruption of the use of the drug. In this brief review article, we present basic concepts about the physiopathology and treatment of myopia and glaucoma by angular closure induced by the use of topiramate.

Inhibition of Escherichia coli and Bacillus subtilis FtsZ Polymerization and Bacillus subtilis Growth by Dihydroxynaphtyl Aryl Ketones.

The increasing detection of virulent and/or multidrug resistant bacterial strains makes necessary the development of new antimicrobial agents acting through novel mechanisms and cellular targets. A good choice are molecules aimed to interfere with the cell division machinery or divisome, which is indispensable for bacterial survival and propagation. A key component of this machinery, and thus a good target, is FtsZ, a highly conserved GTPase protein that polymerizes in the middle of the cell on the inner face of the cytoplasmic membrane forming the Z ring, which acts as a scaffold for the recruitment of the divisome proteins at the division site. In this work, we tested the inhibitory effect of five diaryl naphtyl ketone (dNAK) molecules on the in vitro polymerization of both Escherichia coli and Bacillus subtilis FtsZ (EcFtsZ and BsFtsZ, respectively). Among these compounds, dNAK 4 showed the strongest inhibition of FtsZ polymerization in vitro, with an IC50 of 2.3 ± 0.06 µM for EcFtsZ and 9.13 ± 0.66 µM for BsFtsZ. We found that dNAK 4 binds to GDP-FtsZ polymers but not to the monomer in GTP or GDP state. This led to the polymerization of short and curved filaments, rings, open rings forming clusters, and in the case of BsFtsZ, a novel cylindrical structure of stacked open rings. In vivo, dNAK 4 had almost no effect on the growth of E. coli in liquid culture, in contrast to the strong inhibitory effect observed over B. subtilis growth. The insensitivity of E. coli to this compound is probably related to the impermeability of dNAK 4 to the outer membrane. The low amount of this compound required to inhibit several of the bacterial strains tested and the lack of a cytotoxic effect at the concentrations used, makes dNAK 4 a very good candidate as a starting molecule for the development of a new antibiotic.

A Review of the Actions of Endogenous and Exogenous Vasoactive Substances during the Estrous Cycle and Pregnancy in Rats.

Vascular endothelium plays a key role in regulating cardiovascular homeostasis by controlling the vascular tone. Variations in sex hormones during the reproductive cycle of females affect the homeostasis of the cardiovascular system. Also, the evidence shows that estrogens show a cardioprotective effect. On this basis, this study describes some vascular responses induced by vasoactive substances during the estrous cycle in rats. We obtained the information available on this topic from the online databases that included scientific articles published in the Web of Science, PubMed, and Scielo. Many investigations have evaluated the vasoactive response of substances such as acetylcholine and norepinephrine during the estrous cycle. In this review, we specifically described the vascular response to vasoactive substances in rats during the estrous cycle, pregnancy, and in ovariectomized rats. In addition, we discussed the existence of different signaling pathways that modulate vascular function. The knowledge of these effects is relevant for the optimization and development of new treatments for some vascular pathologies.

Half-Wave Potentials and In Vitro Cytotoxic Evaluation of 3-Acylated 2,5-Bis(phenylamino)-1,4-benzoquinones on Cancer Cells.

A broad range of 3-acyl-2,5-bis(phenylamino)-1,4-benzoquinones were synthesized and their voltammetric values, as well as in vitro cancer cell cytotoxicities, were assessed. The members of this series were prepared from acylbenzoquinones and phenylamines, in moderate to good yields (47-74%), through a procedure involving a sequence of two in situ regioselective oxidative amination reactions. The cyclic voltammograms of the aminoquinones exhibit two one-electron reduction waves to the corresponding radical-anion and dianion, and two quasi-reversible oxidation peaks. The first and second half-wave potential values (E1/2) of the members of the series were sensitive to the push-pull electronic effects of the substituents around the benzoquinone nucleus. The in vitro cytotoxic activities of the 3-acyl-2,5-bis(phenylamino)-1,4-benzoquinones against human cancer cells (bladder and prostate) and non-tumor human embryonic kidney cells were measured using the MTT colorimetric method. The substitution of both aniline groups, by either methoxy (electron donating effect) or fluorine (electron withdrawal effect), decreased the cytotoxicity in the aminoquinones. Among the members of the unsubstituted phenylamino series, two of the 18 compounds showed interesting anti-cancer activities. A preliminary assay, looking for changes in the expression of selected genes, was performed. In this context, the two compounds increased TNF gene expression, suggesting an association with an inflammatory-like response.

Chemical composition by HPLC-ESI-QTOF-MS/MS: Estrogenic and antioxidant effects of Mangifera indica L. cv. "Kent" leave extracts on ovariectomized rats / Composición química por HPLC-ESI-QTOF-MS/MS: efectos estrogénicos y antioxidantes de extractos de Mangifera indica L. cv. "Kent" en ratas ovariectomizadas

The chemical composition of Mangifera indica L. cv. "Kent" leaves was determined by HPLC-ESI-QTOF-MS/MS. Polyphenolic compounds characterized as benzophenone derivatives were the main components found in extracts (1, maclurin 3-C-(2-O-galloyl)-D- glucoside isomer; 2, maclurin 3-C---D-glucoside; 3, iriflophenone 3-C---D-glucoside; 5, maclurin 3-C-(2,3-di-O-galloyl)---D-glucoside; 6, iriflophenone 3-C-(2-O-galloyl)---D-glucoside; 7, methyl-iriflophenone 3-C-(2,6-di-O-galloyl)---D-glucoside) and xanthones (4, mangiferin and 8, 6-O-galloyl-mangiferin). The estrogenic and antioxidant effects of aqueous extracts from Mangifera indica L. cv. "Kent" leaves on ovariectomized rats were determined by uterotrophic assay and malondialdehyde (MDA) levels in erythrocytes, bone, liver, and stomach. We conclude that the polyphenolic compounds from extracts act as exogenous antioxidant agents against oxidative damage in ovariectomized rats.

La composición química de las hojas de Mangifera indica L. cv. "Kent" se determinó por HPLC-ESI-QTOF-MS/MS. Compuestos polifenólicos caracterizados como derivados de benzofenona fueron los componentes principales encontrados en los extractos (1, isómero de la maclurina 3-C-(2-O-galoyil)-D-glucósido; 2, maclurina 3-C-ß-D-glucósido; 3, iriflofenona 3-C-ß-D-glucósido; 5, maclurina 3-C-(2,3-di-O-galloíl)-ß-D-glucósido; 6, iriflofenona 3-C-(2-O-galloil)-ß-D-glucósido; 7, metil-iriflofenona 3-C-(2,6-di-O- galloyl)-ß-D-glucósido) y xantonas (4, mangiferina y 8, 6-O-galoyil-mangiferina). Los efectos estrogénicos y antioxidantes de los extractos acuosos de hojas de Mangifera indica L. cv. "Kent" en ratas ovariectomizadas se determinaron mediante ensayo uterotrófico y la medición de los niveles de malondialdehído (MDA) en eritrocitos, huesos, hígado y estómago. Concluimos que los compuestos polifenólicos de los extractos actúan como agentes antioxidantes exógenos contra el daño oxidativo en ratas ovariectomizadas.

Chemical composition, in vitro cytotoxic and antioxidant activities of the essential oil of Peruvian Minthostachys mollis Griseb / Composición química, actividades citotóxicas y antioxidantes in vitro del aceite esencial de Minthostachys mollis Griseb peruano

The composition of the essential oil obtained by hydrodistillation from Minthostachys mollis Griseb (Lamiaceae) aerial parts was determined by GC and GC/MS. Menthone (13.2%), pulegone (12.4%), cis-dihydrocarvone (9.8%) and carvacrol acetate (8.8%) were the main essential oil components. The cytotoxic activity of the essential oil was in vitro measured using the MTT colorimetric assay. IC50 values were calculated on healthy non-tumor cells (HEK-293) and three human cancer cell lines (T24, DU-145 and MCF-7). In such latter cells, the estimated values were around 0.2 mg/mL. In addition, the antioxidant activity was determined by interaction with the stable free radical 2,2"-diphenyl-1-picrylhydrazyl. The essential oil was almost devoid of antioxidant activity indicating that its anti-proliferative action relies on other unknown mechanism.

La composición del aceite esencial obtenido por hidrodestilación a partir de partes aéreas de Minthostachys mollis Griseb (Lamiaceae) se determinó mediante GC y GC/MS. Mentona (13.2%), pulegona (12.4%), junto con cis-dihidrocarvona (9.8%) y acetato de carvacrol (8.8%) fueron los principales componentes del aceite esencial. La actividad citotóxica del aceite esencial se midió in vitro utilizando el ensayo colorimétrico MTT tanto en células sanas no tumorales (HEK-293) como en tres líneas celulares de cáncer humano (T24, DU-145 y MCF-7). Los valores de IC50 calculados fueron de alrededor de 0.2 mg/mL. Además, se determinó la actividad antioxidante por su interacción con el radical libre 2,2"-difenil-1-picrilhidrazilo. El aceite esencial tiene baja actividad antioxidante, lo que indica que su acción antiproliferativa depende de otro mecanismo desconocido.

Ascorbate Attenuates Oxidative Stress and Increased Blood Pressure Induced by 2-(4-Hydroxyphenyl) Amino-1,4-naphthoquinone in Rats.

Quinone derivatives like 2-(4-hydroxyphenyl) amino-1,4-naphthoquinone (Q7) are used as antitumor agents usually associated with adverse effects on the cardiovascular system. The objective of this study was to evaluate the cardioprotective effect of ascorbate on Q7-induced cardiovascular response in Wistar rats. In this study, blood pressure, vascular reactivity, and intracellular calcium fluxes were evaluated in cardiomyocytes and the rat aorta. We also measured oxidative stress through lipid peroxidation (TBARS), superoxide dismutase- (SOD-) like activity, and H2O2 generation. Oral treatment of rats with ascorbate (500 mg/kg) for 20 days significantly (p < 0.05) reduced the Q7-induced increase (10 mg/kg) in blood pressure and heart rate. The preincubation with ascorbate (2 mM) significantly (p < 0.05) attenuated the irregular beating of the atrium induced by Q7 (10-5 M). In addition, ascorbate induced endothelial vasodilation in the presence of Q7 in the intact aortic rings of a rat and reduced the cytosolic calcium levels in vascular smooth muscle cells. Ascorbate also reduced the Q7-induced oxidative stress in vivo. Ascorbate also attenuated Q7-induced SOD-like activity and increased TBARS levels. These results suggest a cardioprotective effect in vivo of ascorbate in animals treated orally with a naphthoquinone derivative by a mechanism involving oxidative stress.

In Vitro Inhibition of Helicobacter pylori Growth by Redox Cycling Phenylaminojuglones.

Infection by Helicobacter pylori increases 10 times the risk of developing gastric cancer. Juglone, a natural occurring 1,4-naphthoquinone, prevents H. pylori growth by interfering with some of its critical metabolic pathways. Here, we report the design, synthesis, and in vitro evaluation of a series of juglone derivatives, namely, 2/3-phenylaminojuglones, as potential H. pylori growth inhibitors. Results show that 5 out of 12 phenylaminojuglones (at 1.5 µg/mL) were 1.5-2.2-fold more active than juglone. Interestingly, most of the phenylaminojuglones (10 out of 12) were 1.1-2.8 fold more active than metronidazole, a known H. pylori growth inhibitor. The most active compound, namely, 2-((3,4,5-trimethoxyphenyl)amino)-5-hydroxynaphthalene-1,4-dione 7, showed significant higher halo of growth inhibitions (HGI = 32.25 mm) to that of juglone and metronidazole (HGI = 14.50 and 11.67 mm). Structural activity relationships of the series suggest that the nature and location of the nitrogen substituents in the juglone scaffold, likely due in part to their redox potential, may influence the antibacterial activity of the series.

Effects of two bisbenzylisoquinoline alkaloids, Antioquine and Tetrandrine, compared to Verapamil in Rat Thoracic Aorta.

The objective of this study was to compare two alkaloids (antioquine and tetrandrine) with verapamil; knowing that the smooth muscle respond to KCl and relationships with calcium. The effects of antioquine and tetrandrine, was studied in adults Wistar rat with modified methods used in the determination of aorta contractility and compared with verapamil effect in the same assays. The analysis of the effect of a drug or extract on aortic reactivity included maximal relaxation or maximal contraction (Cmax) (Phase 1). In our results, verapamil induced a blockade of 98.7 ± 0.7% (n = 6) in presence of endothelium and 97.9 ± 4.3% in ausence of endothelium, both in phase 1 and in phase 2 of 47.4 ± 4.1% (n = 6) in aortas in the presence of endothelium and 61.8 ± 1.1% in ausence of endothelium; Tetrandrine assays showed a phase 1 blocking effect of 63.4 ± 5.5 and 47.7 ± 2.9% (with and without endothelium, respectively) and phase 2 of 43.5 ± 6.2 and 28.5 ± 5.7%, (with and without endothelium, respectively). Antioquine presents in phase 1 and phase 2, a blockade that is not significant from the point of view of calcium antagonism. We can conclude that tetrandrine block the movement of calcium from both intracellular and extracellular deposits, with the greatest effect when aortas are in the presence of endothelium.