Morphological and Functional Analysis of Cardiac Ameliorations in Elderly Rats Supplemented with a Magnolol Extract Complex / Análisis Morfológico y Funcional de las Mejoras Cardíacas en Ratas Ancianas Suplementadas con un Complejo de Extracto de Magnolol

SUMMARY: Magnolia bark extract supplementation has an anti-oxidative role in mammalians. However, its role in physiological aged-associated heart insufficiency is not known yet. Therefore, we investigated the effects of a magnolia bark complex, including magnolol and honokiol components (MAHOC), in elderly rat hearts (24-month-old aged group). One group of aged rats was supplemented with MAHOC (400 mg/kg/d, for 12 weeks) besides the standard rat diet while the second group of elderly rats and adult rats (to 6-month- old adult-group) were only fed with the standard rat diet. The morphological analysis using light microscopy has shown marked myofibrillar losses, densely localized fibroblasts, vacuolizations, infiltrated cell accumulations, and collagen fibers in the myocardium of the elderly rats compared to the adults. We also detected a markedly increased amount of degenerated cardiomyocytes including the euchromatic nucleus. The MAHOC supplementation of the elderly rats provided marked ameliorations in these abnormal morphological changes in the heart tissue. Furthermore, electrophysiological analysis of electrocardiograms (ECGs) in the supplemented group showed significant attenuations in the prolonged durations of P-waves, QRS-complexes, QT-intervals, and low heart rates compared to the unsupplemented elderly group. The biochemical analysis also showed significant attenuations in the activity of arylesterase and total antioxidant status in the myocardium of the supplemented group. We further determined significant attenuations in the activity of a mitochondrial enzyme succinate dehydrogenase, known as a source of reactive oxygen species (ROS), and the decreased level of ATP/ADP in the heart homogenates of the supplemented group. Moreover, under in vitro conditions by using an aging-mimicked cardiac cell line induced by D-galactose, we demonstrated that MAHOC treatment could provide prevention of depolarization in mitochondria membrane potential and high-level ROS production. Overall, our data presented significant myocardial ameliorations in physiological aging-associated morphological alterations parallel to the function and biochemical attenuations with MAHOC supplementation, at most, through recoveries in mitochondria.

La suplementación con extracto de corteza de magnolia tiene un papel antioxidante en los mamíferos, sin embargo, su rol en la insuficiencia cardíaca asociada al envejecimiento fisiológico aún no se conoce. Por lo anterior, investigamos los efectos de un complejo de corteza de magnolia, incluidos los componentes magnolol y honokiol (MAHOC), en corazones de ratas seniles (grupo de edad de 24 meses). La alimentación de grupo de ratas seniles se complementó con MAHOC (400 mg/kg/d, durante 12 semanas) además de la dieta estándar, mientras que el segundo grupo de ratas seniles y ratas adultas (hasta el grupo de adultos de 6 meses) solo recibió la dieta estándar para ratas. El análisis morfológico mediante microscopía óptica ha mostrado marcadas pérdidas miofibrilares, fibroblastos densamente localizados, vacuolizaciones, acumulaciones de células infiltradas y fibras de colágeno en el miocardio de las ratas seniles en comparación con las adultas. También detectamos una cantidad notablemente mayor de cardiomiocitos degradados, incluido el núcleo eucromático. La suplementación con MAHOC de las ratas seniles proporcionó mejoras marcadas en estos cambios morfológicos anormales en el tejido cardiaco. Por otra parte, el análisis de los electrocardiogramas (ECG) en el grupo suplementado mostró atenuaciones significativas en las duraciones prolongadas de las ondas P, los complejos QRS, los intervalos QT y las frecuencias cardíacas bajas, en comparación con el grupo de ratas seniles sin suplementación alimenticia. El análisis bioquímico también mostró atenuaciones significativas en la actividad de la arilesterasa y el estado antioxidante total en el miocardio del grupo suplementado. Determinamos además atenuaciones significativas en la actividad de la enzima mitocondrial succinato deshidrogenasa, conocida como fuente de especies reactivas de oxígeno (ROS), y la disminución del nivel de ATP/ADP en los homogeneizados de corazón del grupo suplementado. Además, en condiciones in vitro mediante el uso de una línea de células cardíacas, imitando el envejecimiento inducido por D- galactosa, demostramos que el tratamiento con MAHOC podría prevenir la despolarización en el potencial de membrana de las mitocondrias y la producción de ROS de alto nivel. En general, nuestros datos presentaron mejoras miocárdicas significativas en alteraciones morfológicas asociadas con el envejecimiento fisiológico paralelas a la función y atenuaciones bioquímicas con la suplementación con MAHOC, como máximo, a través de recuperaciones en las mitocondrias.

Processing Magnoliae Officinalis Cortex with ginger juice: process optimization based on AHP-CRITIC weighting method and composition changes after processing / 中国中药杂志

The weight coefficients of appearance traits, extract yield of standard decoction, and total content of honokiol and magnolol were determined by analytic hierarchy process(AHP), criteria importance though intercrieria correlation(CRITIC), and AHP-CRITIC weighting method, and the comprehensive scores were calculated. The effects of ginger juice dosage, moistening time, proces-sing temperature, and processing time on the quality of Magnoliae Officinalis Cortex(MOC) were investigated, and Box-Behnken design was employed to optimize the process parameters. To reveal the processing mechanism, MOC, ginger juice-processed Magnoliae Officinalis Cortex(GMOC), and water-processed Magnoliae Officinalis Cortex(WMOC) were compared. The results showed that the weight coefficients of the appearance traits, extract yield of standard decoction, and total content of honokiol and magnolol determined by AHP-CRITIC weighting method were 0.134, 0.287, and 0.579, respectively. The optimal processing parameters of GMOC were ginger juice dosage of 8%, moistening time of 120 min, and processing at 100 ℃ for 7 min. The content of syringoside and magnolflorine in MOC decreased after processing, and the content of honokiol and magnolol followed the trend of GMOC>MOC>WMOC, which suggested that the change in clinical efficacy of MOC after processing was associated with the changes of chemical composition. The optimized processing technology is stable and feasible and provides references for the modern production and processing of MOC.

Sacubitril/valsartan attenuates left ventricular remodeling and improve cardiac function by upregulating apelin/APJ pathway in rats with heart failure / 中华心血管病杂志

Objective: To investigate the effect and mechanism of sacubitril/valsartan on left ventricular remodeling and cardiac function in rats with heart failure. Methods: A total of 46 SPF-grade male Wistar rats weighed 300-350 g were acclimatized to the laboratory for 7 days. Rats were then divided into 4 groups: the heart failure group (n=12, intraperitoneal injection of adriamycin hydrochloride 2.5 mg/kg once a week for 6 consecutive weeks, establishing a model of heart failure); heart failure+sacubitril/valsartan group (treatment group, n=12, intragastric administration with sacubitril/valsartan 1 week before the first injection of adriamycin, at a dose of 60 mg·kg-1·d-1 for 7 weeks); heart failure+sacubitril/valsartan+APJ antagonist F13A group (F13A group, n=12, adriamycin and sacubitril/valsartan, intraperitoneal injection of 100 μg·kg-1·d-1 APJ antagonist F13A for 7 weeks) and control group (n=10, intraperitoneal injection of equal volume of normal saline). One week after the last injection of adriamycin or saline, transthoracic echocardiography was performed to detect the cardiac structure and function, and then the rats were executed, blood and left ventricular specimens were obtained for further analysis. Hematoxylin-eosin staining and Masson trichrome staining were performed to analyze the left ventricular pathological change and myocardial fibrosis. TUNEL staining was performed to detect cardiomyocyte apoptosis. mRNA expression of left ventricular myocardial apelin and APJ was detected by RT-qRCR. ELISA was performed to detect plasma apelin-12 concentration. The protein expression of left ventricular myocardial apelin and APJ was detected by Western blot. Results: Seven rats survived in the heart failure group, 10 in the treatment group, and 8 in the F13A group. Echocardiography showed that the left ventricular end-diastolic diameter (LVEDD) and the left ventricular end-systolic diameter (LVESD) were higher (both P<0.05), while the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were lower in the heart failure group than in the control group (both P<0.05). Compared with the heart failure group, rats in the treatment group were featured with lower LVEDD and LVESD (both P<0.05), higher LVEF and LVFS (both P<0.05), these beneficial effects were reversed in rats assigned to F13A group (all P<0.05 vs. treatment group). The results of HE staining showed that the cardiomyocytes of rats in the control group were arranged neatly and densely structured, the cardiomyocytes in the heart failure group were arranged in disorder, distorted and the gap between cells was increased, the cardiomyocytes in the treatment group were slightly neat and dense, and cardiomyocytes in the F13A group were featured similarly as the heart failure group. Masson staining showed that there were small amount of collagen fibers in the left ventricular myocardial interstitium of the control group, while left ventricular myocardial fibrosis was significantly increased, and collagen volume fraction (CVF) was significantly higher in the heart failure group than that of the control group (P<0.05). Compared with the heart failure group, the left ventricular myocardial fibrosis and the CVF were reduced in the treatment group (both P<0.05), these effects were reversed in the F13A group (all P<0.05 vs. treatment group). TUNEL staining showed that the apoptosis index (AI) of cardiomyocytes in rats was higher in the heart failure group compared with the control group (P<0.05), which was reduced in the treatment group (P<0.05 vs. heart failure group), this effect again was reversed in the F13A group (P<0.05 vs. treatment group). The results of RT-qPCR and Western blot showed that the mRNA and protein levels of apelin and APJ in left ventricular myocardial tissue of rats were downregulated in heart failure group (all P<0.05) compared with the control group. Compared with the heart failure group, the mRNA and protein levels of apelin and APJ were upregulated in the treatment group (all P<0.05), these effects were reversed in the F13A group (all P<0.05 vs. treatment group). ELISA test showed that the plasma apelin concentration of rats was lower in the heart failure group compared with the control group (P<0.05); compared with the heart failure group, the plasma apelin concentration of rats was higher in the treatment group (P<0.05), this effect was reversed in the F13A group (P<0.05 vs. treatment group). Conclusion: Sacubitril/valsartan can partially reverse left ventricular remodeling and improve cardiac function in rats with heart failure through modulating Apelin/APJ pathways.

Honokiol: A naturally occurring lignan with pleiotropic bioactivities / 中国天然药物

Honokiol is the dominant biphenolic compound isolated from the Magnolia tree, and has long been considered as the active constituent of the traditional Chinese herb, 'Houpo', which is widely used to treat symptoms due to 'stagnation of qi'. Pharmacological studies have shown that honokiol possesses a wide range of bioactivities without obvious toxicity. Honokiol protects the liver, kidneys, nervous system, and cardiovascular system through reducing oxidative stress and relieving inflammation. Moreover, honokiol shows anti-diabetic property through enhancing insulin sensitivity, and anti-obese property through promoting browning of adipocytes. In vivo and in vitro studies indicated that honokiol functions as an anti-cancer agent through multiple mechanisms: inhibiting angiogenesis, promoting cell apoptosis, and regulating cell cycle. A variety of therapeutic effects of honokiol may be associated with its physiochemical properties, which make honokiol readily cross the blood brain barrier and the blood-cerebrospinal fluid barrier, with high bioavailability. In the future, more clinical researches on honokiol are needed to fully authenticate its therapeutic values.

Effect of honokiol on proliferation, migration and apoptosis of human tongue cancer CAL-27 cells / 南方医科大学学报

OBJECTIVE@#To study the effects of honokiol on proliferation, migration and apoptosis of human tongue carcinoma CAL-27 cells.@*METHODS@#Routinely cultured CAL-27 cells were treated with 20, 40, or 60 μmol/L honokiol and the changes in cell proliferation were assessed with MTT assay. The scratch wound healing assay was used to assess the migration ability of the treated cells, and the cell apoptosis was detected with Hoechst33342 fluorescence staining and annexin V-FITC/PI method. The protein expression levels of p-Pi3k, p-Fak, Fak, MMP-2, MMP-9, p-Akt, Akt, Bax, Bcl-2 and cleaved-caspase-3 in the treated cells were detected using Western blotting.@*RESULTS@#Treatment with honokiol at 20, 40, and 60 μmol/L for 24 h significantly lowered the proliferation and migration ability of CAL-27 cells. The number of apoptotic cells increased with the increase of honokiol concentration, which resulted in a cell apoptosis rate of (15.24±2.06)% at 20 μmol/L, (35.03±2.42)% at 40 μmol/L, and (48.13±4.61)% at 60 μmol/L, as compared with (6.53±1.80)% in the control group. The expressions of p-Pi3k, p-Fak, MMP-2, MMP-9, p-Akt and BCL-2 decreased and those of Bax and cleaved-caspase-3 increased significantly in the cells after the treatment ( < 0.01).@*CONCLUSIONS@#Honokiol can inhibit the proliferation and migration and induce apoptosis of CAL-27 cells possibly by regulating the expressions of p-Pi3k, p-Fak, MMP-2, MMP-9, p-Akt, Bax, Bcl-2 and cleaved-caspase-3.

Efficacy and safety of early initiation of sacubitril-valsartan therapy in patients with acute decompensated heart failure / 中华心血管病杂志

Objective: To assess the efficacy and safety of the initiation of sacubitril-valsartan （ARNI） therapy, as compared with ACEI therapy, after hemodynamic stabilization among patients hospitalized for acute decompensated heart failure （ADHF）. Methods: A total of 199 hospitalized patients for ADHF in our department from January 2017 to June 2019 were included in this retrospective analysis. According to the medication early after hemodynamic stabilization, patients were divided into ARNI group (n=92) and ACEI group (n=107). Among the included patients, 61 patients with newly diagnosed heart failure at the time of admission were also divided into ARNI group (n=30) and ACEI group (n=31) according to the applied medication. Clinical baseline data and follow-up results of enrolled patients were collected through the electronic medical records at admission, outpatient and telephone follow-up. The primary effectiveness observation index was left ventricular ejection fraction (LVEF) and left ventricular end diastolic dimension (LVEDD) measured by echocardiography; the secondary observation index was death from any causes and hospitalization for heart failure. Safety outcomes were the incidences of symptomatic hypotension, worsening renal function, hyperkalemia, and angioedema. Results: The clinical baseline characteristics were similar between ARNI group and ACEI group（all P>0.05）. The duration of follow up was (15.2±6.5) months in all patients enrolled, (12.3±5.0) months in ARNI group, and (18.2±6.5) months in ACEI group. At the end of follow-up, prevalence of an absolute LVEF increase of more than 5% was 48.9% (45/92) in ANRI group and 25.2% (27/107) in ACEI group (P=0.001). Percent of LVEF increase to more than 50% was 17.4% (16/92) in ANRI group and 3.7% (4/107) in ACEI group (P=0.001). Percent of patients with more than 10 mm LVEDD reduction was 14.1% (13/92) in ANRI group and 3.7% (4/107) in ACEI group (P=0.009). All-cause mortality rate was 5.7% (5/88) in ARNI group and 15.3% (13/85) in ACEI group (P=0.038). Rate of re-hospitalization due to heart failure was 50% (46/92) in ARNI group and 71% (76/107) in ACEI group（P=0.002）.The rates of symptomatic hypotension, worsening renal function, hyperkalemia, and angioedema were similar between ARNI group and ACEI group (all P>0.05). In patients with first diagnosed heart failure，percent of LVEF increase to more than 50% was 30% (9/30) in ANRI group and 6.5% (2/31) in ACEI group (P=0.017). Percent of more than 10 mm LVEDD reduction was 26.7%(8/30) in ANRI group and 3.2%(1/31) in ACEI group (P=0.012). Percent of an absolute LVEF increase of more than 5% was 53.3% (16/30) in ANRI group and 51.6% (16/31) in ACEI group (P=0.893). Re-hospitalization due to heart failure was 23.3% (7/30） in ARNI group and 73.3% (11/31) in ACEI group（P<0.01）. Rate of all-cause death tended to be lower in patients receiving ARNI (3.4% (1/29)) as compared to patients receiving ACEI (13.0% (3/23), P=0.197）. Conclusions: Among patients with heart failure with reduced ejection fraction hospitalized for ADHF, the initiation of ARNI therapy after hemodynamic stabilization is associated with a more significant improvement of cardiac remodeling and pump function than ACEI therapy and satisfactory safety. In ADHF patients with first diagnosed heart failure, initiation of ARNI therapy after hemodynamic stabilization can more effectively improve cardiac remodeling and pump function than treatment with ACEI.

Investigation of polysaccharide extracts from Iranian and French strains of Agaricus subrufescens against enzymes involved in Alzheimer's disease / Investigación de extractos de polisacáridos de cepas iraníes y francesas de Agaricus subrufescens contra enzimas relevantes para la enfermedad de Alzheimer

In this work, the inhibitory activity of a wide range of polysaccharide extracts from two Iranian and French strains of Agaricus subrufescens were evaluated toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, two extracts S9 and S'7 obtained from Iranian and French strains under different extraction conditions showed selective AChE inhibitory activity with IC50 values of 154.63 and 145.43 µg/mL, respectively. It should be noted that all extracts from both strains demonstrated no BChE inhibitory activity. S9 and S'7 were also tested for their effect on amyloid beta (Aß) aggregation, antioxidant activity, and neuroprotectivity. Their activity against Aß aggregation was comparable to that of donepezil as the reference drug but they induced moderate antioxidant activity by DPPH radical scavenging activity and negligible neuroprotectivity against Aß-induced damage.

En este trabajo, se evaluó la actividad inhibitoria de acetilcolinesterasa (AChE) y butirilcolinesterasa (BChE) para varios extractos de polisacáridos de dos cepas iraníes y francesas de Agaricus subrufescens. Los extractos más potentes mostraron valores de IC50 de 154,63 y 145 µg/ml para las cepas iraní (S9) y francesa (S'7), respectivamente, las cuales se obtuvieron de diferentes condiciones de extracción; sin embargo, todos los extractos no mostraron actividad inhibitoria de BChE. Además, S9 y S'7 se probaron para determinar su efecto sobre la agregación de beta-amiloide (Aß), así como su actividad antioxidante y neuroprotectora. Su actividad inhibitoria de la agregación de Aß fue comparable con donepezil, fármaco de referencia, pero indujeron una actividad antioxidante moderada, medida mediante la captación de radicales DPPH, y una neuroprotectora insignificante contra el daño inducido por Aß.

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.

Geo-herbalism study of Magnoliae Officinalis Cortex / 中国中药杂志

Magnoliae Officinalis Cortex( MOC),the stem bark of Magnolia officinalis( MO) and M. officinalis var. biloba( MOB),is a main ingredient in more than 200 types of Chinese formulae commonly used in clinics. MO and MOB are widely distributed in China,from Sichuan of the west to Zhejiang province of the east and from Shannxi province in the north to Guangxi province in the south. This review summarizes new findings on geo-heralism of MOC concerning textual research,plants taxonomy,genetic study,chemical study,and pharmacological activity,resulting in the following views. ①The original plants of MOC are suggested to be divided into three geographic clans according to the form of leave and the result of genetic research; ②Concentrations of magnolol,honokiol,magnoloside A,magnoloside B,magnoflorine,and β-eudesmol in samples collected from different geographic areas are varied;③Samples of MOC produced in Hubei and Sichuan were traditionally regarded as Dao-di herbs,which were called Chuanpo,and the pure haplotype of MOC produced in Hubei may become a genetic index.

Two symmetrical unsaturated acids isolated from Viscum album / 中国天然药物

In the present study, two new acetylene conjugate compounds, dibutyl (2Z, 6Z)-octa-2, 6-dien-4-yne dioate (1), and dibutyl (2E, 6E)- octa-2, 6-dien-4-yne dioate (2), were isolated from the dry stem leaves of Viscum album, along with nine known compounds (3 - 11). Their structures were confirmed on the basis of spectroscopic data. Compounds 1 and 8 showed antioxidant activity against xanthine oxidase (XOD) and 1,1-diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydroxyl (DPPH), with the IC of 1.22 and 1.33 μmol·L, and the SC of 4.34 and 8.22 μmol·L, respectively.

Un novedoso agente en el tratamiento de la insuficiencia cardiaca con función sistólica deprimida / A novel agent in the treatment of heart failure with depressed systolic function

Resumen Introducción: Se revisará la evolución del tratamiento farmacológico de la insuficiencia cardiaca (IC) en los últimos 25 an˜os, desde el concepto de tratamiento con vasodilatadores, pasando por el bloqueo o inhibición del sistema renina-angiotensina-aldosterona y la inhibición betaadrenérgica y su importante contribución en la disminución de la morbimortalidad por IC, el papel de los péptidos natriuréticos y, finalmente, se conocerá uno de los estudios más importantes en el área cardiológica y específicamente en el manejo de la IC, en el cual se demuestra un enfoque modulador de los sistemas neuro humorales que se activan en estos pacientes. Objetivos: La IC constituye la etapa final de la mayoría de las enfermedades cardiovasculares, con una alta tasa de hospitalización y de morbimortalidad cardiovascular, siendo, por lo tanto, de interés constante la necesidad de encontrar un agente terapéutico innovador que disminuya significativamente estas complicaciones y también que mejore la calidad de vida de los que la presentan. Metodología: Se realizará una descripción del PARADIGM-HF Clinical Trial, que utilizó un compuesto sacubitrilo/valsartán para el manejo de la IC con un mecanismo modulador diferente del concepto de bloqueador de sistemas deletéreos que se activan cuando un paciente presenta síntomas y signos de IC. Conclusiones: La muerte por causas cardiovasculares u hospitalización por IC (el punto final primario) se produjo en 914 pacientes (21.8%) en el grupo sacubitrilo/valsartán y 1,117 pacientes (26.5%) en el grupo de enalapril (razón de riesgo en el grupo sacubitrilo/valsartán, 0.80; intervalo de confianza (IC) del 95%: 0.73 a 0.87; p < 0.001 (exacta p = 4.0 × 10 - 7)). De los pacientes que recibieron sacubitrilo/valsartán, 537 (12.8%) fueron hospitalizados por IC, en comparación con los 658 pacientes (15.6%) que recibieron enalapril (razón de riesgo, 0.79; IC del 95%, 0.71 a 0.89; p < 0.001). Un total de 711 pacientes (17.0%) en el grupo sacubitrilo/valsartán y 835 pacientes (19.8%) en el grupo de enalapril murió (razón de riesgo de muerte por cualquier causa, 0.84; IC del 95%, 0.76 a la 0.93; p < 0.001).

Abstract Introduction: A review is presented on the evolution of the pharmacological treatment of heart failure (HF) in the last 25 years, from the concept of treatment with vasodilators to the blocking or inhibition of the renin angiotensin aldosterone system. Beta-adrenergic inhibition and its important contribution in the reduction of morbidity and mortality due to HF will be discussed along with the role of the natriuretic peptides. One of the most important studies in the cardiology area, and specifically in the management of HF, is presented, in which an approach is demonstrated of the modulator of the neurohumoral systems that are activated in these patients. Objectives: HF is the final stage of most cardiovascular diseases, and has a high rate of hospital admission, as well as cardiovascular morbidity and mortality. Therefore, there is constant interest in the need to find an innovative therapeutic agent that significantly reduces these complications and that improves the quality of life of those who suffer from it. Methods: A description will be presented of the PARADIGM-HF Clinical Trial using a sacubitril/valsartán compound for the management of HF with a modulating mechanism different from the concept of a deleterious system blocker that is activated when a patient has symptoms and signs of heart failure. Conclusions: Death due to cardiovascular causes, or hospital admission due to heart failure (the primary endpoint) occurred in 914 patients (21.8%) in the Sacubitril / valsartán group, and 1117 patients (26.5%) in the enalapril group (risk ratio in the sacubitril / valsartán group, 0.80, with a 95% confidence interval [CI]: 0.73 to 0.87, P<0.001 ;exact P= 4.0 × 10 --7;). Of the patients receiving sacubitril / valsartán, 537 (12.8%) were hospitalised due to heart failure, compared with 658 patients (15.6%) receiving enalapril (hazard ratio 0.79, 95% CI: 0.71 to 0.89, P<.001). A total of 711 patients (17.0%) in the sacubitril / valsartán group, and 835 patients (19.8%) in the enalapril group, died (all-cause death rate, 0.84, 95% CI: 0.76 to 0.93, P<.001)

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.

Assessment of the antibacterial, cytotoxic and antioxidant activities of Morus nigra L. (Moraceae) / Avaliação das atividades antibacteriana, citotóxica e antioxidante de Morus nigra L. (Moraceae)

Abstract This study was carried out to assess the antibacterial, cytotoxic and antioxidant activities of extracts of Morus nigra L. HPLC was used to determine the fingerprint chromatogram of the crude ethanolic extract (Mn-EtOH). The antibacterial effect was assessed through the method of microdilution. The cytotoxicity was tested against human tumour cell lines using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The total phenolic and flavonoid contents were also assessed through the Folin-Ciocalteu and aluminum chloride methods, respectively. Antioxidant activities of the extracts were evaluated by using 2,2-diphenyl-1-picrylhydrazil (DPPH) radical scavenging and β-carotene-linoleic acid bleaching methods. The presence of phenolic compounds in Mn-EtOH was confirmed using HPLC. The extracts showed activity against most microorganisms tested. The extracts did not show any expressive antiproliferative effect in the assessment of cytotoxicity. The most significant total phenolic content was 153.00 ± 11.34 mg of gallic acid equivalent/g to the ethyl acetate extract (AcOEt). The total flavonoid content was 292.50 ± 70.34 mg of catechin equivalent/g to the AcOEt extract, which presented the best antioxidant activity (IC50 50.40 ± 1.16 μg/mL) for DPPH scavenging. We can conclude that this species shows strong antibacterial and antioxidant activities, as well as weak cytotoxic effects.

Resumo Este estudo foi realizado para avaliar as atividades antibacteriana, citotóxica e antioxidante de extratos de Morus nigra L. HPLC foi utilizado para determinar o perfil de compostos fenólicos do extrato etanólico bruto (Mn-EtOH). O efeito antibacteriano foi avaliado através do método de microdiluição. A citotoxicidade foi testada contra linhagens celulares de tumores humanos utilizando o ensaio do brometo de 3-(4,5-dimetil-2-tiazolil)-2,5-difenil-2H-tetrazólio (MTT). O conteúdo total de compostos fenólicos e flavonoides também foi avaliado por meio dos métodos de Folin-Ciocalteu e cloreto de alumínio, respectivamente. A atividade antioxidante dos extratos foi avaliada por meio do sequestro do radical livre 2,2-difenil-1-picrilhidrazil (DPPH) e co-oxidação do sistema β-caroteno-ácido linoleico. A presença de compostos fenólicos em Mn-EtOH foi confirmada utilizando HPLC. Os extratos mostraram atividade contra a maioria dos microrganismos testados. Os extratos não mostraram qualquer efeito antiproliferativo expressivo na avaliação da citotoxicidade. O conteúdo fenólico total mais significativo foi de 153,00 ± 11,34 mg de equivalente de ácido gálico/g para o extrato acetato de etila (AcOEt). O conteúdo de flavonoides totais foi de 292,50 ± 70,34 mg de equivalente de catequina/g para o extrato AcOEt, que apresentou a melhor atividade antioxidante (IC50 50,40 ± 1,16 mg/mL) para o sequestro do DPPH. Podemos concluir que esta espécie apresenta forte atividade antibacteriana e antioxidante, bem como fraca atividade citotóxica.

Chemical composition, antimicrobial and antioxidant potential of the essential oil of Guarea kunthiana A. Juss / Composição química, potencial antimicrobiano e antioxidante do óleo essencial de Guarea kunthiana A. Juss

Abstract The essential oils are extracted from plant compounds and can present activities antimicrobial and antioxidant properties. The goals of the present study were: (a) to determine the chemical composition of the essential oil of Guarea kunthiana A. Juss using the method of gas chromatography coupled to mass spectrometry (GC-MS); (b) to evaluate the antimicrobial potential of this oil using the broth microdilution method against different microorganisms: five Gram-negative bacteria, four Gram-positive bacteria and a yeast and (c) to determine the antioxidant activity of the oil using the DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical assay. The GC-MS analyses allowed identifying 13 constituents, representing 96.52% of the essencial oil composition. The main compounds identified were α-zingiberene (34.48%), β-sesquiphellandrene (22.90%), and α-curcumene (16.17%). With respect to the antimicrobial activity, the essential oil was effective against all the microorganisms tested, except for the bacteria E. coli and K. pneumoniae, which were resistant to the action of the oil. From a general point of view, Gram-positive bacteria were more susceptible to the action of the essential oil than Gram-negative bacteria. The essential oil exhibited antioxidant potential.

Resumo Os óleos essenciais são compostos extraídos de plantas e podem apresentar propriedades antimicrobianas e antioxidantes. O objetivo deste trabalho foi (a) determinar a composição química do óleo essencial de Guarea kunthiana A. Juss pelo método de cromatografia gasosa acoplada à espectrometria de massas (CG-EM); (b) avaliar o potencial antimicrobiano deste óleo pelo método de microdiluição em caldo frente a diferentes micro-organismos, sendo cinco bactérias Gram-negativas, quatro Gram-positivas uma levedura e (c) por fim, determinar a atividade antioxidante do óleo pelo método de captura do radical livre 2,2-difenil-1-picril hidrazil (DPPH). As análises de CG-EM resultaram na identificação de 13 constituintes, representando 96,52% da composição do óleo essencial. Os principais compostos identificados foram α-Zingibereno (34,48%), β-Sesquifelandreno (22,90%) e α-Curcumeno (16,17%). Em relação à atividade antimicrobiana, o óleo essencial foi efetivo frente a todos os micro-organismos testados exceto para as bactérias E. coli e K. pneumoniae, as quais se apresentaram resistentes à ação do óleo. Em geral, as bactérias Gram-positivas foram mais suscetíveis à ação do óleo essencial em relação às Gram-negativas. O óleo essencial apresentou potencial.

Avaliação do efeito antiproliferativo da apocinina e diapocinina em células de osteossarcoma humano / Evaluation of the antiproliferative effect of apocynin and diapocynin on human osteosarcoma cells

O osteossarcoma (OS) é o tumor maligno primário mais comum do tecido ósseo, caracterizado pela formação de osteócitos anormais. Apesar do avanço nas terapias convencionais (quimioterapia e retirada do tumor), essas não conseguem eliminar totalmente as células tumorais e impedir a progressão da doença. Recentemente, agentes derivados de fontes naturais ganharam considerável atenção por causa de sua segurança, eficácia e disponibilidade imediata. Nesse sentido, a apocinina, inibidor do complexo NADPH-oxidase, vem sendo estudada como agente antitumoral em alguns tipos de câncer como: pâncreas, próstata, pulmão e mama. Apocinina é um pró-fármaco e sua ação parece estar relacionada à sua conversão produzindo a diapocinina, a qual se mostrou mais efetiva do que a apocinina. Portanto, o objetivo desse estudo é avaliar, in vitro, o potencial antitumoral da apocinina e diapocinina em células de osteossarcoma humano. Para isso, foram utilizados osteoblastos humanos normais (HOb) e osteossarcoma humano imortalizadas (SaOS-2) tratados ou não com apocinina e diapocinina em diversas concentrações. Foram realizados os ensaios de viabilidade celular, alterações morfológicas, apoptose celular, produção de espécies reativas de oxigênio (EROs), formação de colônias, migração, invasão e expressão do fator indutor de hipóxia-1alfa (HIF-1). Também foram conduzidos ensaios para verificar a atividade de metaloproteinase de matriz (MMP) 2 e 9. Os resultados em SaOS-2 mostraram que o tratamento com apocinina nas concentrações de 1,5 e 3 mM; e diapocinina nas concentrações de 0,75 e 1,5 mM reduziram a viabilidade; aumentaram o número de células em apoptose e diminuíram a produção de EROs; sem causar danos às células HOb. Além disso, essas mesmas concentrações inibiram a migração e invasão celular; diminuíram a expressão de HIF-1; e reduziram a atividade de MMP-2 em SaOS-2. Considerando os resultados obtidos, concluímos que a apocinina e diapocinina podem atuar como possíveis moduladores de células tumorais, sendo que a diapocinina mostrou ser mais efetiva nos parâmetros testados.(AU)

Osteosarcoma (OS) is the most common primary malignant tumor of bone tissue, characterized by the formation of abnormal osteocytes. Despite advances in conventional therapies (chemotherapy and surgery) they cannot completely eliminate tumor cells and prevent the progression of the disease. Recently, agents derived from natural sources have achieved considerable attention because of their safety, efficacy and immediate availability of therapies. In this way, apocynin, an inhibitor of the NADPH-oxidase complex, has been studied as an antitumor agent in some types of cancer, such as pancreas, prostate, lung and breast. Apocynin is a prodrug and its action indicate to be related to its conversion to diapocynin, which has been shown to be more efficient than apocynin itself. Thus, the aim of this study is to evaluate, in vitro, the antitumor potential of apocynin and diapocynin in human osteosarcoma cells. For this, normal human osteoblasts (HOb) and immortalized human osteosarcoma cells (SaOS-2) were treated or no-treated with apocynin and diapocynin in various concentrations. Cell viability assay, morphological alterations, cellular apoptosis, reactive oxygen species (ROS) production, colony formation, migration, invasion and expression of hypoxia-inducible factor-1 alpha (HIF-1) were performed. We also performed assays to verify the activity of matrix metalloproteinase (MMP) 2 and 9. The results in SaOS-2 showed that treatment with apocynin at concentrations of 1,5 e 3 mM; and diapocynin at concentrations of 0,75 e 1,5 mM reduced cell viability; increased the number of cells in apoptosis and decreased the production of ROS; without damaging HOb cells. Moreover, these same concentrations inhibited cell migration and invasion; decreased HIF-1 expression; and reduced MMP 2 activity in SaOS-2. Considering the results, we suggest that apocynin and diapocynin may act as possible modulators of tumor cells, and diapocynin has been shown to be more effective.(AU)

Light curing resin cements containing iodonium salts promote suitable apical bonding of posts to radicular dentin

Abstract The aim of this study was to analyze the efficiency of experimental light-curing resin cements (ERCs) with a ternary photo-initiator system containing diphenyliodonium hexafluorphosphate (DPI) and different amines on retention of glass-fiber posts to dentin (GFP). ERCs formulations: a 1:1 mass ratio of 2,2-bis[4-(2-hydroxy-3-methacryloxypropoxy)phenylpropane and triethyleneglycol dimethacrylate. Camphorquinone was used as initiator. Six experimental groups were established according to the amine used: [ethyl-4-(dimethylamino)benzoate-EDMAB or 2-(dimethylamino)ethyl methacrylate-DMAEMA] and the concentration of DPI (0, 0.5 mol%, 1 mol%). The resin cements Variolink II (dual- and light-cured versions) were used as commercial reference. Eighty recently extracted bovine incisors (n = 10) were selected for this study. The roots were prepared and the fiber posts were cemented with the resin cement specified for each experimental group. Specimens from coronal, middle, and apical thirds of the root were subjected to push-out bond strength test 24 hours after bonding. Data were subjected to split-plot ANOVA and the Tukey test (p = 0.05). ERCs containing DPI showed statistically significant higher bond strengths compared with ERCs without DPI. ERCs containing DPI were statistically similar to VARIOLINK II - dual-cured and superior to VARIOLINK II - light-cured (except for EDMAB - 1DPI in the medium third and DMAEMA - 1DPI in the coronal third). Different amines did not influence post retention. The apical root region showed the lowest bond strength for the groups EDAB-0DPI, DMAEMA-0DPI and VARIOLINK II light-cured. Light-cured ERCs containing DPI were efficient for GFP retention to radicular dentin, with similar behaviour to that of dual-curing commercial resin cement.

Effects of Honokiol on cognitive function in mice with kainic acid-induced epilepsy / 浙江大学学报·医学版

OBJECTIVE@#To investigate the effects of Honokiol on cognitive function in mice with epilepsy.@*METHODS@#Kainic acid (38 mg/kg) was intraperitoneally injected in 5 weeks old male ICR mice to induce epilepsy. Honokiol at dose of 3, 10, 30 mg/kg was given to epilepic mice by intraperitoneal injection for 10 days. Fluoro-Jade B staining was used to assess neuronal death; Morris water maze and Y maze tests were used to measure cognitive function such as learning and memory; Western blot was performed to detect the expression of acetylated superoxide dismutase (SOD), microtubule associated protein 1 light chain 3-Ⅱ (LC3-Ⅱ) and P62 in hippocampus tissue; thiobarbituric acid and WST-1 methods were used to detect malondialdehyde (MDA) and SOD.@*RESULTS@#Compared with control group, the levels of acetylated-SOD, MDA, LC3-Ⅱ, P62 and neuronal death increased, cognitive function and SOD decreased in model group (<0.05 or <0.01). Honokiol at the dose of 10 mg/kg and 30 mg/kg decreased SOD acetylation, MDA content, expression of LC3-Ⅱ and P62, as well as neuronal death, and the cognitive function was improved (<0.05 or <0.01), especially in 30 mg/kg Honokiol group.@*CONCLUSIONS@#Honokiol alleviates oxidative stress and autophagy degradation disorder, decreases neuronal death, and therefore improves cognitive function in epilepsy mice.

Effects of honokiol on particulate matter 2.5-induced lung injury in asthmatic mice and its mechanisms / 中南大学学报(医学版)

To explore the therapeutic effect of honokiol on particulate matter 2.5 (PM2.5)-induced lung injury in asthmatic mice and the possible mechanisms.
 Methods: A total of 32 BALB/C mice were randomly divided into four groups: a normal saline group, a model group, a PM2.5 group and a honokiol group (n=8 in each group). The asthma mouse model was established by ovalbumin treatment. The mice were treated with physiological saline, ovalbumin, PM2.5 and honokiol, respectively. Lung tissues and serum were collected. The pathological changes of lung tissues were evaluated. The levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and serum were measured and the expressions of Toll like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), retinoid-related orphan receptor gamma-t (RORγt) and forkhead box protein 3 (Foxp3) in lung tissues were detected.
 Results: 1) The lung tissues of mice in the asthma group showed obvious pathological changes and inflammatory state, suggesting that the asthma model was established successfully. PM2.5 could aggravate the pathological condition of inflammatory injury in lung tissues in asthmatic mice. 2) Compared to the PM2.5 group, the pathological symptoms in the lung tissues were alleviated in the honokiol group and the percentage of inflammatory cells in BALF and the levels of inflammatory cytokines in BALF and serum were significantly reduced (all P<0.05). 3) Compared to the PM2.5 group, the expressions of TLR4, NF-κB (p-p65) and RORγt in lung tissues were significantly decreased, while the expression of Foxp3 was increased; the ratio of RORγt/Foxp3 was also decreased in the honokiol group (all P<0.05).
 Conclusion: Honokiol can resist lung injury induced by PM2.5 in asthmatic mice. These effects are through inhibiting TLR4-NF-κB pathway-mediated inflammatory response or regulating the balance of Th17/Treg cells.

Honokiol attenuates lipopolysaccharide-induced acute respiratory distress syndrome via activation of mitochondrion-dependent Sirt3/AMPK pathway / 中南大学学报(医学版)

To explore the effects of honokiol (HKL) on pulmonary microvascular endothelial cells in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) and the underlying mechanisms.
 Methods: In animal experiment, a total of 40 C57BL/6J mice were randomly divided into a control group (Con group), a LPS intervention group (LPS group), a LPS+honokiol (HKL) intervention group (HKL group) and a LPS+HKL+nicotinamide (NAM) intervention group (NAM group) (n=10 in each group). In the cell experiment, the experiment cells were divided into a control group (Con group), a LPS intervention group (LPS group), a LPS+HKL intervention group (HKL group), a LPS+HKL+NAM intervention group (NAM group), and a LPS+HKL+compound C (CMC) intervention group (CMC group). The pathological changes of the lung tissues were evaluated by hematoxylin and eosin (HE) staining; the protein concentration, total cells and neutrophils in the bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) activity in the lung tissues were detected; the changes of pulmonary microvascular permeability were determined by Evans blue assay; the effect of HKL on the vitality of human pulmonary microvascular endothelial cells were examined by cell counting kit-8 (CCK-8); the inhibitors including NAM and CMC were applied to explore the molecular mechanism of the protective effects of HKL. The expression levels of Sirt3, caspase-3, cleaved caspase-3, Bcl-2, Bax, p-adenosine monophosphate activated protein kinase (p-AMPK) and AMPK in lung tissues or cells were detected by Western blot.
 Results: In animal models, compared with the Con group, the mice in the LPS group displayed typical ARDS pathological changes, and the ratio of lung wet/dry weight (W/D) and MPO activity in the lung tissues, protein concentration, total cells and neutrophils in BALF, Evans blue leaking index (ELI), expression levels of cleaved caspase-3 were significantly increased (all P<0.05), while the expression levels of Sirt3 was obviously decreased (P<0.05). Compared with the LPS group, the above changes in the LPS group were significantly improved in the HKL group (all P<0.05); Compared with the HKL group, the curative effect of HKL intervention could be partly inhibited in the NAM group (P<0.05). In cell experiments, compared with the LPS group, the HPMECs viability in the HKL group was markedly improved (P<0.05), while the expression levels of Bcl-2 and Sirt3 were significantly upregulated (P<0.05), and the expression levels of Bax and cleaved caspase-3 were significantly downregulated (P<0.05), accompanied by the activation of AMPK pathway (P<0.05) in the HKL group. Compared with the HKL group, the curative effect of HKL intervention was partly inhibited in the CMC group (P<0.05).
 Conclusion: HKL can significantly attenuate LPS-induced lung injury and inhibit the apoptosis of pulmonary microvascular endothelial cells through regulation of Sirt3/AMPK pathway.