A new oxime synthesized from Senecio nutans SCh. Bip (chachacoma) reduces calcium influx in the vascular contractile response in rat aorta.

Senecio nutans Sch. Bip is an endemic plant commonly employed in the Andes culture to counteract the effects of mountain sickness, and its bioactive molecules could provide new drugs for treating hypertension. The purpose was to determine whether the vascular response of the plant bioactive molecules, such as (5-acetyl-6-hydroxy-2-isopropenyl-2,3-dihydrobenzofurane; Sn-I), could be improved by a simple structural modification to synthesize oximes (Ox-Sn-I). We characterized both compounds using IR and NMR spectroscopy and Heteronuclear Multiple Quantum Coherence (HMQC). We investigated vascular relaxation mechanisms in response to Sn-I and Ox-Sn-I using rat aorta and vascular smooth muscle cells (A7r5) as experimental models. Preincubation of aortic rings with Sn-I (10-5 M) significantly (p < 0.001) decreased the contractile effect in response to phenylephrine (PE) and potassium chloride (KCl). The sensitivity (EC50) to PE significantly (p < 0.01) decreased in the presence of Sn-I (10-5 M), but not with Ox-Sn-I. Sn-I significantly (p < 0.001) reduced the PE-induced contraction under calcium-free conditions. When A7r5 cells were preincubated with Sn-I and Ox-Sn-I (10-5 M), both compounds blunted the increase in intracellular Ca2+ induced by KCl. 2,3-Dihydrobenzofurane derived from S. nutans (Sn-I) reduces the contractile response probably by blocking Ca2+ entry through voltage-gated Ca2+ channels (VGCC) in vascular smooth cells. This effect also causes relaxation in rat aorta mediated by reduction of intracellular Ca2+ concentration, rather than an increase of NO generation in endothelial vascular cells.

Calcium signaling in endothelial and vascular smooth muscle cells: sex differences and the influence of estrogens and androgens.

Calcium signaling in vascular endothelial cells (ECs) and smooth muscle cells (VSMCs) is essential for the regulation of vascular tone. However, the changes to intracellular Ca2+ concentrations are often influenced by sex differences. Furthermore, a large body of evidence shows that sex hormone imbalance leads to dysregulation of Ca2+ signaling and this is a key factor in the pathogenesis of cardiovascular diseases. In this review, the effects of estrogens and androgens on vascular calcium-handling proteins are discussed, with emphasis on the associated genomic or nongenomic molecular mechanisms. The experimental models from which data were collected were also considered. The review highlights 1) in female ECs, transient receptor potential vanilloid 4 (TRPV4) and mitochondrial Ca2+ uniporter (MCU) enhance Ca2+-dependent nitric oxide (NO) generation. In males, only transient receptor potential canonical 3 (TRPC3) plays a fundamental role in this effect. 2) Female VSMCs have lower cytosolic Ca2+ levels than males due to differences in the activity and expression of stromal interaction molecule 1 (STIM1), calcium release-activated calcium modulator 1 (Orai1), calcium voltage-gated channel subunit-α1C (CaV1.2), Na+-K+-2Cl- symporter (NKCC1), and the Na+/K+-ATPase. 3) When compared with androgens, the influence of estrogens on Ca2+ homeostasis, vascular tone, and incidence of vascular disease is better documented. 4) Many studies use supraphysiological concentrations of sex hormones, which may limit the physiological relevance of outcomes. 5) Sex-dependent differences in Ca2+ signaling mean both sexes ought to be included in experimental design.

Chemical Characterization of Phoenix dactylifera L. Seeds and their Beneficial Effects on the Vascular Response in Hypertensive Rats.

Although Phoenix dactylifera dates are traditionally consumed for their health benefits, no research has been done on the vascular response in hypertensive animals. This study evaluated the vascular relaxation of hydroalcoholic extracts from seeds of three varieties of P. dactylifera; Sukkari seed (SS), Ajwa seed (AS), and Mabroom seed (MS) on L-NAME-induced hypertension and spontaneously hypertensive rats (SHR). Results showed that all extracts (10 µg/mL) caused relaxations higher than 60% in the aortic rings precontracted with 10- 6 M phenylephrine in normotensive rats, the SS extract was the most potent. Endothelial nitric oxide (NO) pathway is involved as significantly reduced vascular relaxation in denuded-endothelium rat aorta and with an inhibitor (10- 4 M L-Nω-Nitro arginine methyl ester; L-NAME) of endothelial nitric oxide synthase (eNOS). Confocal microscopy confirmed that 10 µg/mL SS extract increases NO generation as detected by DAF-FM fluorescence in intact aortic rings. Consistent with these findings, vascular relaxation in intact aortic rings at 10 µg/mL SS extract was significantly decreased in L-NAME-induced hypertensive rats (endothelial dysfunction model), but not in SHR. In both hypertensive models, the denuded endothelium blunted the vascular relaxation. In conclusion, the hydroalcoholic extract of the seed of P. dactylifera (Sukkari, Ajwa and Mabroom varieties) presents a potent endothelium-dependent vascular relaxation, via NO, in normotensive rats as well as in two different models of hypertension. This effect could be mediated by the presence of phenolic compounds identified by UHPLC-ESI-MS/MS, such as protocatechuic acid, and caftaric acid.

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.

Lepidium meyenii Walp (red maca) Supplementation Prevents Acrylamide-Induced Oxidative Stress and Liver Toxicity in Rats: Phytochemical Composition by UHPLC-ESI-MS/MS.

Lepidium meyenii Walp (red maca) is a high Andean plant cultivated since the Incas and has innumerable therapeutic properties. The study aims to identify its phytochemical composition using UHPLC-ESI-MS/MS, and evaluate its effects on acrylamide-induced oxidative stress. The lyophilized aqueous extract of red maca (LAqE-RM) was orally administered in doses of 1 and 2 g/kg body weight for 4 weeks. Malondialdehyde (MDA) levels in erythrocytes, brain, and liver, as well as hepatic levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. Administration of acrylamide for 2 and 4 weeks significantly increased (p < 0.001) MDA levels in erythrocytes, brain, and liver. However, LAqE-RM prevented (p < 0.001) an increase in MDA levels in all tissues studied. Likewise, the groups treated with LAqE-RM presented significantly (p < 0.001) lower levels of ALT and AST compared to the control. Treatment with LAqE-RM ameliorated the acrylamide-induced oxidative stress by reducing MDA levels in erythrocytes, brain, and liver and by lowering liver levels of ALT and AST in a dose-dependent manner. Twenty-five secondary metabolites were identified and characterized from LAqE-RM based on UHPLC mass spectrophotometry. These include carbolines, alkamides, fatty acids, and macamides, which are probably involved in their antioxidant protective role.

Maca extracts and estrogen replacement therapy in ovariectomized rats exposed at high altitude.

PURPOSE: Hormone Replacement Therapy (HRT) and herbal remedies are often used to alleviate menopausal symptoms, but their effects and efficacy at high altitudes presents with several uncertainties. The purpose of this study was to evaluate whether pre-treatment with maca (Lepidium meyenii Walp) improved the tolerance to high altitude on an ovariectomized (OVX) rat model at sea level. METHOD: The animals were treated with 17ß-estradiol (200 µg/kg; E2), red and black maca (1.5 g/kg) for 28 days and exposed at high altitude or sea level. RESULT: Our findings showed that red and black maca extracts significantly (P < .001) reduced the MDA level in OVX rat serum under hypoxia in a similar way to E2. Red and black maca extracts had similar effects with E2, by significantly (P < .001) reversing and increasing the ovariectomized induced decrease in cornified endometrial cell number. Under hypoxic conditions, the black maca (P < .05) and E2 (P < .01) increased the uterine weight in OVX rats. Finally, E2 alone significantly recovered the frequency of the uterine contractile response. CONCLUSION: Aqueous extract of L. meyenii partially protects the reproductive function in hypobaric hypoxic environment, through the recovery of the cornified endometrial cells and uterine weight in a menopausal model of OVX rats.

Metabolomic Profiling of Mango (Mangifera indica Linn) Leaf Extract and Its Intestinal Protective Effect and Antioxidant Activity in Different Biological Models.

Mangifera indica Linn popularly known as mango is used in folk medicine to treat gastrointestinal disorders. The aim of this study was to identify the metabolomic composition of lyophilized extract of mango leaf (MIE), to evaluate the antioxidant activity on several oxidative stress systems (DPPH, FRAP, TBARS, and ABTS), the spasmolytic and antispasmodic activity, and intestinal protective effect on oxidative stress induced by H2O2 in rat ileum. Twenty-nine metabolites were identified and characterized based on their ultra-high-performance liquid chromatography (UHPLC) high-resolution orbitrap mass spectrometry, these include: benzophenone derivatives, xanthones, phenolic acids, fatty acids, flavonoids and procyanidins. Extract demonstrated a high antioxidant activity in in-vitro assays. MIE relaxed (p < 0.001) intestinal segments of rat pre-contracted with acetylcholine (ACh) (10-5 M). Pre-incubation of intestinal segments with 100 µg/mL MIE significantly reduced (p < 0.001) the contraction to H2O2. Similar effects were observed with mangiferin and quercetin (10-5 M; p < 0.05) but not for gallic acid. Chronic treatment of rats with MIE (50 mg/kg) for 28 days significantly reduced (p < 0.001) the H2O2-induced contractions. MIE exhibited a strong antioxidant activity, spasmolytic and antispasmodic activity, which could contribute to its use as an alternative for the management of several intestinal diseases related to oxidative stress.

Efecto oxitócico del decocto de la flor sagrada de los incas (Cantua buxifolia) sobre útero aislado de rata estrogenizada / Oxytocic effect of the deck of the sacred flower of the incas (Cantua buxifolia) on the isolated uterus of a strogenized rat

Objetivo. El objetivo de este estudio fue investigar el efecto del decocto de la flor sagrada de los incas (Cantua buxifolia) sobre útero aislado de rata estrogenizada. Materiales y métodos. La planta entera fue utilizada para preparar el decocto, obteniendo concentraciones finales 4 mg/mL. Se utilizaron seis ratas hembras procedentes del Instituto Nacional de Salud; posteriormente, se les estrogenizó con valerato de estradiol (solución 0,3%) durante tres días previos al experimento. Luego se sacrificaron mediante dislocamiento cervical y se aislaron los segmentos uterinos de las ratas; finalmente, se fijó en los baños de órgano aislado, determinándose la amplitud, frecuencia de contracción y actividad uterina en los grupos problema (Cantua buxifolia) y oxitocina. Resultados. El decocto de Cantua buxifolia 4 mg/mL evidenció incremento de la amplitud, frecuencia de la contracción y actividad uterina similar a oxitocina en concentración de 2X10-5 UI, (p=0,829; p=1,00 y p=0,762, respectivamente). Conclusión. El decocto de Cantua buxifolia tiene efecto oxitócico en útero aislado de rata estrogenizada.

Objective. The objective of this study was to investigate the effect of the decoct of the sacred flower of the Incas (Cantua buxifolia) on the isolated uterus of estrogenized rats. Materials and methods. The whole plant was used to prepare the decoct, obtaining final concentrations of 4 mg/mL. Six female rats from the National Institute of Health were used, subsequently they were estrogenized with estradiol valerate (0.3% solution) for three days prior to the experiment. Then, they were sacrificed by cervical dislocation and the uterine segments of the rats were isolated, finally it was fixed in the isolated organ baths, determining the amplitude, frequency of contraction and uterine activity in the problem groups (Cantua buxifolia) and oxytocin. Results. The decoct of Cantua buxifolia 4 mg/mL showed an increase in amplitude, frequency of contraction and uterine activity similar to oxytocin at a concentration of 2X10-5 IU, (p = 0.829; p = 1.00 and p = 0.762, respectively). Conclusion. Cantua buxifolia decoct has an oxytocic effect in the isolated uterus of estrogenized rats.

Efecto antiespasmódico de Rubus roseus y Mentha pulegium sobre íleon aislado de cobayo (Cavia porcellus) / Antispasmodic effect of Rubus roseus and Mentha pulegium on guinea pig (Cavia porcellus) isolated ileum

Objetivo. El objetivo de este estudio fue investigar el potencial efecto antiespasmódico de Rubus roseus y Mentha pulegium en íleon aislado de cobayo (Cavia porcellus) Materiales y Métodos. Los segmentos de íleon se precontrajeron con acetilcolina (ACh; 4 × 10−6 M) y cloruro de potasio (KCl; 4 × 10-4 M) luego se evaluó la respuesta de los decoctos de Rubus roseus (Rr) Mentha pulegium (Mp) en el baño de órganos aislado en concentraciones crecientes (no acumulativas), como controles positivos se utilizaron nifedipino 5 × 10-8 M (antagonista de canales de Ca2+ voltaje dependientes); atropina sulfato 5,5 × 10-9 M (antagonista muscarínico no selectivo), y N-butilbromuro de hioscina 3 x 10-3 M (antagonista muscarínico M3 selectivo). Se cuantificó la amplitud y la frecuencia de contracción (durante diez minutos) después de la administración de los decoctos. Resultados. Los decoctos de Rubus roseus y Mentha pulegium reducen las contracciones inducidas por acetilcolina (p < 0,001) y KCl (p < 0,01) similares a nifedipino (Mp: 4 y 8 mg/mL); atropina sulfato (Rr: 0,2-4 mg/mL; Mp: 0,8 y 1,6 mg/mL) y N-butilbromuro de hioscina (Mp: 2,4 y 8 mg/mL). Por otro lado, ambos decoctos reducen la frecuencia de contracción inducidas por Ach (p < 0,001) y KCl (p < 0,001). Conclusión. Los decoctos de Rubus roseus y Mentha pulegium tienen efecto antiespasmódico en íleon aislado de cobayo (Cavia porcellus).

Objective. This study aimed to investigate the potential antispasmodic effect of Rubus roseus and Mentha pulegium on isolated guinea pig (Cavia porcellus) ileum. Materials and Methods. The ileum segments were pre-contracted with acetylcholine (ACh, 4 × 10-6 M) and potassium chloride (KCl, 4 × 10-4 M) then the response of the Rubus roseus (Rr) and Mentha pulegium (Mp) decocts was evaluated in the organ bath isolated in increasing concentrations (non-cumulative), as positive controls were used nifedipine 5 × 10-8 M (antagonist of voltage dependent Ca2+ channels) atropine sulfate 5,5 × 10-9 M (non-selective muscarinic antagonist) and 3 x 10-3 M hyoscine N-butylbromide (selective M3 muscarinic antagonist). The amplitude and the frequency of contraction were quantified (during 10 minutes) after the administration of the decocts. Results. The decocts of Rubus roseus and Mentha pulegium decrease the contractions induced by acetylcholine (p < 0.001) and KCl (p <0.01) comparable to nifedipine (Mp: 4 and 8 mg/mL), atropine sulfate (Rr: 0.2 - 4 mg/mL, Mp: 0.8 and 1.6 mg/mL) and hyoscine N-butylbromide (Mp: 2.4 and 8 mg/mL). On the other hand, both decocts reduce the frequency of contraction induced by Ach (p <0.001) and KCl (p <0.001). Conclusions. The decocts of Rubus roseus and Mentha pulegium have an antispasmodic effect on isolated guinea pig ileum (Cavia porcellus).

Capacidad antioxidante in vitro del liofilizado de la pulpa y cáscara del rizoma de Zingiber officinale Roscoe (jengibre) / In vitro antioxidant capacity of freeze dried pulp and peel of the rhizome of Zingiber officinale Roscoe (ginger)

Objetivo. Evaluar la capacidad antioxidante in vitro del liofilizado de la pulpa y cáscara del rizoma de Zingiber officinale Roscoe (jengibre) mediante los ensayos DPPH, FRAP y TBARS. Materiales y métodos. Se separó la pulpa y la cáscara de los rizomas de Z. officinale, se preparó un macerado con solución hidroalcohólica (70:30 EtOH:H2O), y luego de rotaevaporar, se liofilizó. La capacidad antioxidante de los liofilizados se evaluó según porcentaje de inhibición del radical DPPH y el poder antioxidante de reducción férrica (FRAP), así como la capacidad de inhibir la peroxidación lipídica in vitro mediante el ensayo TBARS. Resultados. Los extractos liofilizados de la pulpa y cáscara evidenciaron moderada capacidad antioxidante, siendo similar según porcentaje de inhibición del radical DPPH (46,5 y 45,6% respectivamente). Sin embargo, mediante el ensayo FRAP la cáscara presentó una capacidad antioxidante de 31,09 µg/mL expresados como equivalentes de trolox (ET) en comparación a la pulpa (22,96 µg ET/mL). Además, solo el liofilizado de cáscara del rizoma de Z. officinale a bajas concentraciones (0,1, 0,2 y 0,3 mg/mL) es capaz de reducir significativamente (p < 0,01) la peroxidación lipídica in vitro. Conclusión. La cáscara del rizoma de Z. officinale posee mayor capacidad antioxidante en comparación con la pulpa según los ensayos FRAP y TBARS; sin embargo, la inhibición de radicales DPPH fue la misma tanto en la cáscara como en la pulpa.

Objective. To evaluate the in vitro antioxidant capacity of the freeze-dried pulp and peel of the rhizomes of Zingiber officinale Roscoe (ginger) using the DPPH, FRAP and TBARS assays. Materials and Methods. The pulp and peel were separated from the rhizomes of Z. officinale, then a macerate was prepared with a hydroalcoholic solution (70:30 EtOH: H2O), and after rotary evaporation, lyophilized. The antioxidant capacity of lyophilisates was evaluated according to the percentage of DPPH radical inhibition and the ferric reduction antioxidant power (FRAP), as well as the ability to inhibit lipid peroxidation in vitro using the TBARS assay. Results. Freeze-dried pulp and peel extracts showed moderate antioxidant capacity, being similar according to the percentage of DPPH radical inhibition (46.5% and 45.6% respectively). However, utilizing the FRAP assay, the peel presented an antioxidant capacity of 31.09 µg/mL expressed as Trolox Equivalents (ET) compared to the pulp (22.96 µg ET / mL). Also, only the freeze-dried peel of Z. officinale at low concentrations (0.1, 0.2 and 0.3 mg / mL) can significantly reduce p < 0.01 lipid peroxidation in vitro. Conclusion. The rhizome peel of Z. officinale has a higher antioxidant capacity compared to the pulp according to the FRAP and TBARS assays, however; DPPH radical inhibition was the same in both the peel and pulp.

Efecto del liofilizado de hojas de Mangifera indica L. "mango kent", sobre memoria espacial y la lipoperoxidación en membranas neuronales de Rattus norvegicus Sprague Dawley ovariectomizadas / Effect of lyophilized of leaves of Mangifera indica L."mango kent", on spatial memory and lipoperoxidation in neuronal membranes of Rattus norvegicus Sprague Dawley ovariectomized

Objetivos. Evaluar el efecto del liofilizado de hojas de Mangifera indica L. mango Kent, sobre memoria espacial y la lipoperoxidación en membranas neuronales de Rattus norvegicus Sprague Dawley ovariectomizadas. Materiales y métodos. Estudio experimental. Se usaron 24 especímenes hembras de 2 meses de edad, con un peso entre 150-200 g, dieciocho de ellas fueron previamente ovariectomizadas (OVX); luego fueron distribuidas (n = 6) en grupos blanco, control, problema 1 y problema 2. Al grupo control se le administró vía oral (VO) NaCl 9º/oo, a los grupos problema 1 y 2 se les administró VO el liofilizado a una concentración de 0,05 g/mL en dosis de 0,25 y 0,50 g/kg, respectivamente, la administración fue durante un periodo de 8 semanas. La memoria espacial se evaluó mediante el laberinto acuático de Morris y para determinar la lipoperoxidación en membranas neuronales según niveles de malondialdehido (MDA), se utilizó el ensayo de las especies reactivas del ácido tiobarbitúrico (TBARS) a 532 nm. Resultados. Los niveles de MDA (nmol/mL) en medianas (rango intercuartilar) fueron en el grupo control: 5,0 (2,8); blanco: 2,2 (1,7); problema 1: 3,6 (0,3); y problema 2: 4,6 (1,1). La memoria espacial evaluada a través del laberinto acuático de Morris presentó una mejora significativa (p = 0,04) en el parámetro tiempo de latencia de escape para el grupo problema 1 (32,4 ± 17,6 s) en comparación con el control (75,8 ± 18,6 s). Conclusiones. El liofilizado de hojas de Mangifera indica L. mango Kent, a dosis de 0,25 g/kg mejora la memoria espacial y presenta efecto antioxidante expresado en la disminución de los niveles de MDA; aunque no se encontraron diferencias significativas en comparación con el control.

Objectives. To evaluate the effect of the lyophilized of leaves of Mangifera indica L. mango Kent, on spatial memory and lipid peroxidation in neuronal membranes of Rattus norvegicus Sprague Dawley ovariectomized. Material and methods. Experimental research. Twenty-four female specimens of 2 months of age, with a weight between 150-200 g, were used; eighteen of them were previously ovariectomized (OVX); then they were distributed (n = 6) in groups non-intervened, control, problem 1 and problem 2. The control group was administered orally (VO) NaCl 9º/oo, the problem groups 1 and 2 were administered VO lyophilized at a concentration of 0.05 g/mL in doses of 0.25 g/kg and 0.50 g/kg respectively, administration was for a period of 8 weeks. Spatial memory was evaluated by the Morris Water Maze and to determine the lipoperoxidation in neuronal membranes according to malondialdehyde levels (MDA), the assay of thiobarbituric acid reactive species (TBARS) at 532 nm was used. Results. The median (interquartile range) MDA (nmol/mL) values were on control group: 5.0 (2.8), non-intervened group: 2.2 (1.7), problem 1 group: 3.6 (0.3) and problem 2 group: 4.6 (1.1). The spatial memory evaluated through the Morris Water Maze showed a significant improvement (p = 0.04) in the Escape Latency Time parameter for the problem group 1 (32.4 ± 17.6 s) in comparison with thecontrol (75.8 ± 18.6 s). Conclusions. The lyophilized of leaves of Mangifera indica L. mango Kent, at a dose of 0.25 g/kg improves spatial memory and presents antioxidant effect expressed in the decrease of MDA levels; instead of that, there were no significant differences between experimental groups and control.