Chemical Constituents from Agave applanata and Its Antihyperglycemic, Anti-inflammatory, and Antimicrobial Activities Associated with Its Tissue Repair Capability.

Agave applanata is a Mexican agave whose fresh leaves are employed to prepare an ethanol tonic used to relieve diabetes. It is also applied to skin to relieve varicose and diabetic foot ulcers, including wounds, inflammation, and infections. In this study, the chemical composition of this ethanol tonic is established and its association with antihyperglycemic, anti-inflammatory, antimicrobial, and wound healing activities is discussed. The fresh leaves of A. applanata were extracted with ethanol : H2O (85 : 15). A fraction of this extract was lyophilized, and the remainder was partitioned into CH2Cl2, n-BuOH, and water. CH2Cl2 and n-BuOH fractions were subjected to a successive open column chromatography process. The structure of the isolated compounds was established using nuclear magnetic resonance and mass spectrometry spectra. The antihyperglycemic activity was evaluated through in vivo sucrose and glucose tolerance experiments, as well as ex vivo intestinal absorption and hepatic production of glucose. Wound healing and edema inhibition were assayed in mice. The minimum inhibitory concentrations (MICs) of the hydroalcoholic extract, its fractions, and pure compounds were determined through agar microdilution against the most isolated pathogens from diabetic foot ulcers. Fatty acids, ß-sitosterol, stigmasterol, hecogenin (1: ), N-oleyl-D-glucosamine, ß-daucosterol, sucrose, myo-inositol, and hecogenin-3-O-α-L-rhamnopyranosyl-(1 → 3)-ß-D-xylopyranosyl-(1 → 2)-[ß-D-xylopyranosyl-(1 → 3)-ß-D-glucopyranosyl-(1 → 3)]-ß-D-glucopyranosyl-(1 → 4)-ß-D-galactopyranoside (2: ) were characterized. This research provides evidence for the pharmacological importance of A. applanata in maintaining normoglycemia, showing anti-inflammatory activity and antimicrobial effects against the microorganisms frequently found in diabetic foot ulcers. This plant plays an important role in wound healing and accelerated tissue reparation.

Beneficio clínico del tratamiento con cannabinoides para el dolor crónico no oncológico / Clinical benefit of cannabinoids to treat chronic non-cancer pain / Benefício clínico do tratamento com canabinoide para dor crônica não oncológica

Introducción: los cannabinoides pueden ser una opción válida para el tratamiento del dolor crónico no oncológico de acuerdo a los estudios publicados hasta el momento y a nuestra experiencia clínica. Objetivo: valorar el beneficio clínico de preparados de cannabis medicinal (CM) para dolor crónico no oncológico en pacientes que consultaron en la Clínica de Endocannabinología del Uruguay (CEDU). Material y método: estudio descriptivo, observacional, longitudinal, de una población atendida en un centro privado de salud. Se trata de una cohorte de 438 pacientes que consultaron espontáneamente en CEDU desde septiembre de 2016 a marzo de 2020. El motivo de consulta fue dolor crónico no oncológico que no respondió al tratamiento estándar. Resultados: en la cohorte estudiada predominaron las mujeres (74%), promedio 69 años, que se asisten en el sistema privado de salud en el 95% de los casos, en su mayoría con instrucción secundaria. El tipo de dolor más frecuente fue el dolor osteoarticular. El quimiotipo de CM más usado fue cannabidiol (CBD) al 5%, con buena respuesta al tratamiento en el descenso del nivel del dolor y suspensión o disminución de uso de opioides (y derivados) y antiinflamatorios no esteroideos (AINES). Se observaron escasos y leves efectos adversos (EA) en la gran mayoría de los pacientes. Abandonaron el tratamiento 12 pacientes (menos del 3%). Conclusiones: esta investigación retrospectiva mostró una caída del nivel del dolor de 3,14 (valor p ≤ 0,0001), indicando que el CM puede ser una opción para el tratamiento del dolor crónico no oncológico. Se requieren más estudios para demostrar la efectividad y seguridad de los cannabinoides. Esto depende de muchos factores (leyes que faciliten la accesibilidad a variedad de productos de CM de grado médico, incentivos a la ciencia e investigación). De todas formas, podemos afirmar que los resultados presentados son prometedores en relación con su potencial terapéutico.

Introduction: Cannabinoids can be a valid option for the treatment of chronic non-cancer pain, according to the studies published to date and our clinical experience. Objectives: To evaluate the clinical benefit of medicinal cannabis preparations (MCPs) for chronic non-cancer pain in patients seen at the Endocannabinology Clinic of Uruguay (CEDU). Method: Descriptive, observational, longitudinal study of a population treated at a private healthcare center. This involves a cohort of 438 patients who spontaneously consulted at CEDU from September 2016 to March 2020. The reason for consultation was chronic non-cancer pain that did not respond to standard treatment. Results: in the studied cohort, women prevailed and accounted for 74% of patients. Average age was 69 years old and 95% of them sought care within the private healthcare system. Most women had completed secondary school education. The most frequent type of pain was osteoarticular pain. The most used chemovar of Medicinal Cannabis (MC) was 5% cannabidiol (CBD), showing a favorable treatment response in reducing pain levels and the discontinuation or reduction of opioid and non-steroidal anti-inflammatory drug (NSAID) usage. Few and mild adverse effects (AE) were observed in the vast majority of patients. Twelve patients (less than 3%) discontinued the treatment. Conclusions: This retrospective study demonstrated a reduction in pain level of 3.14 (p-value ≤ 0.0001) indicating that MC could be an option for the treatment of non-oncological chronic pain. Further studies are needed to demonstrate the effectiveness and safety of cannabinoids. This depends on many factors (laws facilitating accessibility to a variety of medical-grade MC products, incentives for science and research). Nevertheless, we can assert that the presented results are promising in consideration of their therapeutic potential.

Introdução: os canabinoides podem ser uma opção válida para o tratamento da dor crônica não oncológica de acordo com estudos publicados até o momento e nossa experiência clínica. Objetivos: avaliar o benefício clínico das preparações de Cannabis Medicinal (CM) para dor crônica não oncológica em pacientes que consultaram a Clínica de Endocanabinologia do Uruguai (CEDU). Método: estudo descritivo, observacional, longitudinal de uma população atendida em um centro de saúde privado. Esta é uma coorte de 438 pacientes que consultaram espontaneamente no CEDU no período setembro de 2016 - março de 2020. O motivo da consulta foi dor crônica não oncológica que não respondeu ao tratamento padrão. Resultados: na coorte estudada, 74% eram mulheres, a idade média foi 69 anos, 95% frequentam a rede privada de saúde e a maioria com ensino médio. O tipo de dor mais frequente foi a osteoarticular. O quimiotipo de MC mais utilizado foi o Canabidiol 5% (CBD), com boa resposta ao tratamento em termos de redução do nível de dor e suspensão ou redução do uso de opioides (e derivados) e anti-inflamatórios não esteroides (AINEs). A grande maioria dos pacientes apresentou poucos e leves efeitos adversos (EAs). Menos de 3% dos 12 pacientes abandonou o tratamento. Conclusões: Esta investigação retrospectiva mostrou uma queda no nível de dor de 3,14 (valor de p ≤ 0,0001), indicando que o MC pode ser uma opção para o tratamento da dor crônica não oncológica. São necessários mais estudos para demonstrar a eficácia e segurança dos canabinoides. Isso depende de muitos fatores (leis que facilitem o acesso a uma variedade de produtos CM de grau médico, incentivos para ciência e pesquisa). De qualquer forma, podemos afirmar que os resultados apresentados são promissores em relação ao seu potencial terapêutico.

Elevated asleep blood pressure and non-dipper 24h patterning best predict risk for heart failure that can be averted by bedtime hypertension chronotherapy: A review of the published literature.

Several prospective studies consistently report elevated asleep blood pressure (BP) and blunted sleep-time relative systolic BP (SBP) decline (non-dipping) are jointly the most significant prognostic markers of cardiovascular disease (CVD) risk, including heart failure (HF); therefore, they, rather than office BP measurements (OBPM) and ambulatory awake and 24 h BP means, seemingly are the most worthy therapeutic targets for prevention. Published studies of the 24 h BP pattern in HF are sparse in number and of limited sample size. They report high prevalence of the abnormal non-dipper/riser 24 h SBP patterning. Despite the established clinical relevance of the asleep BP, past as do present hypertension guidelines recommend the diagnosis of hypertension rely on OBPM and, when around-the-clock ambulatory BP monitoring (ABPM) is conducted to confirm the elevated OBPM, either on the derived 24 h or "daytime" BP means. Additionally, hypertension guidelines do not advise the time-of-day when BP-lowering medications should be ingested, in spite of known ingestion-time differences in their pharmacokinetics and pharmacodynamics. Between 1976 and 2020, 155 unique trials of ingestion-time differences in the effects of 37 different single and 14 dual-combination hypertension medications, collectively involving 23,972 patients, were published. The vast majority (83.9%) of them found the at-bedtime/evening in comparison to upon-waking/morning treatment schedule resulted in more greatly enhanced: (i) reduction of asleep BP mean without induced sleep-time hypotension; (ii) reduction of the prevalence of the higher CVD risk non-dipper/riser 24 h BP phenotypes; (iii) improvement of kidney function, reduction of cardiac pathology, and with lower incidence of adverse effects. Most notably, no single published randomized trial found significantly better BP-lowering, particularly during sleep, or medical benefits of the most popular upon-waking/morning hypertension treatment-time scheme. Additionally, prospective outcome trials have substantiated that the bedtime relative to the upon-waking, ingestion of BP-lowering medications not only significantly reduces risk of HF but also improves overall CVD event-free survival time.

Chemical profile, antimicrobial activity, and leaf anatomy of Adenophyllum porophyllum var. cancellatum.

Adenophyllum porophyllum var. cancellatum, known as "árnica del monte" in Mexico, is an aromatic annual plant belonging to the Asteraceae family that grows from southern Arizona to central Mexico. The aerial parts of the plant are used in traditional medicine to treat skin diseases such as irritations, infections, and wounds. In this study, the essential oil of this plant was characterized, and its antimicrobial activity was evaluated. This species has large glands in its leaves; therefore, for quality control purposes, an anatomical study of the leaves was performed. The essential oil was isolated from the aerial parts of the plant through hydro-distillation and analyzed using a gas chromatography/mass spectrometry (GC/MS) system. Its anti-yeast activity was evaluated against three Candida species and ten bacterial strains using the disk diffusion technique. The minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), and minimum bactericidal concentration (MBC) were determined using broth microdilution. Anatomical study was performed on the middle part of the leaf. A yield of 0.5% of the essential oil was obtained from the herb, and Eighteen compounds in the essential oil were identified, within them trans pinocamphone (29.5%), limonene (24.7%), pinocarvone (21.8%), and cis pinocamphone (8.0%) were the main components. The inhibition zones were between 10 mm and 20 mm, and the MIC and MFC against the three Candida species ranged from 60 to 500 µg/ml. The leaf anatomy showed anisocytic stomata, simple and glandular trichomes of different types, and large and elliptical-shaped lysigenous glands, which can be used for taxonomic identification. The A. porophyllum var. cancellatum essential oil can serve as an alternative source of natural antimicrobial agents as an affordable approach to control infectious diseases. This is the first study that reports the chemical composition and antimicrobial activity of the essential oil, as well as the leaf anatomy of this species.

UPLC-QTOF-MS analysis of cytotoxic and antibacterial extracts of Hechtia glomerata Zucc.

Hechtia glomerata, a Mexican medicinal plant employed against bacterial infections and as food, is taxonomically related to the genus Tillandsia which has anticancer activity. Organic and aqueous extracts of H. glomerata leaves were prepared and tested for cytotoxic and antibacterial activity. UPLC-QTOF-MS analysis determined the chemical composition of active extracts to find cytotoxic and antibacterial compounds. Hexane extract was cytotoxic against HepG2, Hep3B and MCF7 (IC50: 24-28 µg/mL), whereas CHCl3/MeOH extract against PC3 and MCF7 (IC50: 25 and 32 µg/mL). CHCl3/MeOH extract showed antibacterial activity against Staphylococcus aureus and Enterococcus faecium (MIC: 125 and 62.5 µg/mL). Hexane extract cytotoxic compounds were ß-sitosterol, stigmasterol, phytol and ursolic acid. CHCl3/MeOH extract antibacterial and/or cytotoxic compounds were daucosterol, oleanolic acid, resveratrol, quercetin, kaempferol, apigenin, cyanidin, p-coumaric acid and caffeic acid. This plant could be useful against bacterial infections and cancer. However, in vivo studies are needed to determine its toxicity and therapeutic efficacy.

Metabolomic Profile and Cytotoxic Activity of Cissus incisa Leaves Extracts.

Cissus incisa leaves have been traditionally used in Mexican traditional medicine to treat certain cancerous illness. This study explored the metabolomic profile of this species using untargeted technique. Likewise, it determined the cytotoxic activity and interpreted all data by computational tools. The metabolomic profile was developed through UHPLC-QTOF-MS/MS for dereplication purposes. MetaboAnalyst database was used in metabolic pathway analysis and the network topological analysis. Hexane, chloroform/methanol, and aqueous extracts were evaluated on HepG2, Hep3B, HeLa, PC3, A549, and MCF7 cancer cell lines and IHH immortalized hepatic cells, using Cell Titer proliferation assay kit. Hexane extract was the most active against Hep3B (IC50 = 27 ± 3 µg/mL), while CHCl3/MeOH extract was the most selective (SI = 2.77) on the same cell line. A Principal Component Analysis (PCA) showed similar profiles between the extracts, while a Venn diagram revealed 80 coincident metabolites between the bioactive extracts. The sesquiterpenoid and triterpenoid biosynthesis pathway was the most significant identified. The Network Pharmacology (NP) approach revealed several targets for presqualene diphosphate, phytol, stearic acid, δ-tocopherol, ursolic acid and γ-linolenic acid, involved in cellular processes such as apoptosis. This work highlights the integration of untargeted metabolomic profile and cytotoxic activity to explore plant extracts, and the NP approach to interpreting the experimental results.

Indicadores de calidad en el cuidado humanizado de personas con sufrimiento psíquico en etapa aguda / Quality indicators in the humanized care of users with psychic suffering in the acute stage / Indicadores de qualidade no atendimento humanizado a usuários com sofrimento psíquico na fase aguda

La práctica de enfermería, incorpora el cuidado humanizado como una vía para valorar además de aspectos físicos en las personas, los elementos mentales y emocionales implicados en el contexto de la enfermedad. Los indicadores de calidad han funcionado como aspectos que son objeto de evaluación sanitaria hacia el restablecimiento de la salud afectada. Estos indicadores suelen proveer información fundamental para el desarrollo de una práctica asistencial de calidad y al mismo tiempo refieren procesos para alcanzar los objetivos trazados en la atención de los centros sanitarios. La práctica de enfermería dirigida a superar el sufrimiento psíquico en etapa aguda, requiere la valoración holística, con lo cual alcanzar un mayor impacto en la salud de la persona. El cuidado humanizado de éstas personas que sufren de forma aguda, influye sobre el afrontamiento de esta realidad compleja, el sentirse escuchados, atendidos, e impulsando su participación y autonomía en el tratamiento, propicia un mejor afrontamiento a la realidad particular de cada persona. Aunque muchos profesionales de enfermería aplican un cuidado humanizado enmarcado en la religión o política, es fundamental redireccionar acciones para empoderar a la persona. El objetivo central del artículo está dirigido a efectuar un análisis reflexivo sobre los indicadores de calidad en el cuidado humanizado de las personas con sufrimiento psíquico en etapa aguda, para valorar el trabajo desarrollado de los profesionales de enfermería y su impacto en la salud de los mismos.

Nursing practice incorporates humanized care as a way to assess, in addition to physical aspects in people, the mental and emotional elements involved in the context of the disease. The quality indicators have functioned as aspects that are object of sanitary evaluation towards the reestablishment of the affected health. These indicators usually provide fundamental information for the development of a quality care practice and at the same time refer to processes to achieve the objectives set in the care of health centers. Nursing practice aimed at overcoming mental suffering in the acute stage requires holistic assessment, thereby achieving a greater impact on the health of the person. The humanized care of these people who suffer acutely, influences the coping with this complex reality, feeling heard, cared for, and promoting their participation and autonomy in the treatment, fosters a better coping with the particular reality of each person. Although many nursing professionals apply humanized care framed in religion or politics, it is essential to redirect actions to empower the person. The main objective of the article is aimed at carrying out a reflective analysis on the quality indicators in the humanized care of people with mental suffering in the acute stage, to assess the work carried out by nursing professionals and its impact on their health.

A prática de enfermagem incorpora o cuidado humanizado como forma de avaliar, além dos aspectos físicos nas pessoas, os elementos mentais e emocionais envolvidos no contexto da doença. Os indicadores de qualidade têm funcionado como aspectos que são objeto de avaliação sanitária para o restabelecimento da saúde afetada. Esses indicadores costumam fornecer informações fundamentais para o desenvolvimento de uma prática assistencial de qualidade e, ao mesmo tempo, referem-se a processos para atingir os objetivos traçados na assistência aos centros de saúde. A prática de enfermagem voltada para a superação do sofrimento mental na fase aguda requer avaliação holística, alcançando assim um maior impacto na saúde da pessoa. O cuidado humanizado a essas pessoas que sofrem agudamente, influencia no enfrentamento dessa realidade complexa, sentindo-se ouvido, cuidado e promovendo sua participação e autonomia no tratamento, favorece um melhor enfrentamento da realidade particular de cada pessoa. Embora muitos profissionais de enfermagem apliquem o cuidado humanizado enquadrado pela religião ou pela política, é fundamental redirecionar as ações para empoderar a pessoa. O objetivo principal do artigo é realizar uma análise reflexiva sobre os indicadores de qualidade no cuidado humanizado à pessoa com sofrimento mental na fase aguda, para avaliar o trabalho desenvolvido pelos profissionais de enfermagem e seu impacto na saúde.

Verbesina crocata: A pharmacognostic study for the treatment of wound healing.

ETHNOPHARMACOLOGICAL RELEVANCE: Verbesina crocata (Cav.) Less. (Arnica or Capitaneja) is an endemic plant from Mexico restricted to the western part of the country. The aerial parts are used in traditional medicine for the treatment of wounds and burns. The objective of this investigation was to carry out a pharmacognostic study of V. crocata and establish markers that allow for the recognition of the characteristics of the plant and validate its traditional use. The study includes anatomical and chemical characteristics of the plant as well as evaluations of its antioxidant capacity and wound healing ability in a murine model. MATERIALS AND METHODS: An anatomical study of V. crocata was performed on the middle part of the leaf and stem. A methanolic extract of this species (VcME) was obtained by methanolic maceration of the aerial parts. Subsequently, a partition of the VcME was made to obtain a hexanic fraction (VcH). The phytochemical preliminary screening and characterization by high-performance liquid chromatography/mass spectrometry (HPLC-ESI/MS) of the VcME and VcH were performed. The antioxidant activity and total phenolic content were quantified. The wound healing capacity of the methanolic extract was determined in CD-1 mice by the healing rate, the tensiometric method, and histological analysis. RESULTS: The anatomical study of V. crocata showed the presence of two types of secretory structures and their position on the leaves. In addition, the characteristics of the middle vein and trichomes are potentially useful for recognition of the species. Chemical compounds detected by HPLC-ESI/MS reveal the presence of sitosterol glycoside and catechin derivatives as principal constituents of V. crocata. The VcME showed low antioxidant capacity and total phenolic. V. crocata had a similar healing effect to Recoveron® in the tensiometric method, but the rate of healing was higher. According to the histological analysis, the treatment of V. crocata promoted the remodelling phase 15 days after the incisional wound. CONCLUSION: This is the first pharmacognostic study of this species that covers the plant anatomy, chemical content and biological properties related to its traditional use. V. crocata favours wound healing according to physical and histological evaluations. In addition, the characteristics of the middle vein, trichomes and catechin glycosides are potentially useful for the recognition of this species.

Antibacterial and cytotoxic activities of new sphingolipids and other constituents isolated from Cissus incisa leaves.

Cissus incisa is used in traditional Mexican medicine to treat certain ailments, infectious or cancerous diseases. Excepting for our previous research, this species had no scientific reports validating its traditional use. In this study, we evaluated the antibacterial and cytotoxic properties of the sphingolipids and others phytocompounds isolated from C. incisa leaves to increase the scientific knowledge of the Mexican flora. The antibacterial activity was evaluated against Gram-positive and Gram-negative bacteria by the Microdilution method. Meanwhile, the cytotoxic potential was determined on six human cancer cells: PC3, Hep3B, HepG2, MCF7, A549, and HeLa; using an aqueous solution cell proliferation assay kit. A cell line of immortalized human hepatocytes (IHH) was included as a control of non-cancerous cells. Selectivity index (SI) was determined only against the hepatocellular carcinoma cell lines. The phytochemical investigation of C. incisa leaves resulted in the isolation and characterization of five compounds: 2-(2'-hydroxydecanoyl amino)-1,3,4-hexadecanotriol-8-ene (1), 2,3-dihydroxypropyl tetracosanoate (2), ß-sitosterol-D-glucopyranoside (3), α-amyrin-3-O-ß-D-glucopyranoside (4), and a mixture of cerebrosides (5). Until now, this is the first report of the sphingolipids (1), (5-IV) and (5-V). Only the compound (4) and cerebrosides (5) exhibited antibacterial activity reaching a MIC value of 100 µg/mL against Pseudomonas aeruginosa resistant to carbapenems. While, the acetylated derivate of (3), compound (3Ac) showed the best cytotoxic result against PC3 (IC50 = 43 ± 4 µg/mL) and Hep3B (IC50 = 49.0 ± 4 µg/mL) cancer cell lines. Likewise, (3Ac) achieved better SI values on HepG2 and Hep3B cell lines. This research reveals the importance of study medicinal plants, to identify bioactive molecules as sources of potential drugs. The presence of these compounds allows us to justify the use of this plant in traditional Mexican medicine.

Does Timing of Antihypertensive Medication Dosing Matter?

PURPOSE OF REVIEW: Current hypertension guidelines do not provide recommendation on when-to-treat. Herein, we review the current evidence on ingestion-time differences of hypertension medications in blood pressure (BP)-lowering effects and prevention of cardiovascular disease (CVD) events. RECENT FINDINGS: The vast (81.6%) majority of the 136 published short-term treatment-time trials document benefits, including enhanced reduction of asleep BP and increased sleep-time relative BP decline (dipping), when hypertension medications and their combinations are ingested before sleep rather than upon waking. Long-term outcome trials further document bedtime hypertension therapy markedly reduces risk of major CVD events. The inability of the very small 18.4% of the published trials to substantiate treatment-time difference in effects is mostly explained by deficiencies of study design and conduct. Our comprehensive review of the published literature reveals no single study has reported better benefits of the still conventional, yet scientifically unjustified, morning than bedtime hypertension treatment scheme.

The Hygia Project and Hygia Chronotherapy Trial: insights of we clinical investigators on the impact of the embedded continuing medical education on primary-care practice and improved patient cardiovascular health.

The participating doctors of the Hygia Chronotherapy Trial (HCT) are aware of the criticisms of its published findings, which have been unjustifiably misrepresented in letters to the editors and commentaries, perhaps because of lack of understanding of the foundations of the Hygia Project, in which the HCT is nested. Thus, our purpose through this communication is to highlight the unique features of the Hygia Project and HCT in terms of: (i) organization, management, and quality control, (ii) physician training/continuing medical education, and (iii) impact on every-day primary-care clinical practice specifically improved patient care through 48 h ambulatory blood pressure monitoring to diagnose and optimally manage by bedtime hypertension chronotherapy true arterial hypertension to markedly improve the cardiovascular health of our patients.

Bedtime hypertension chronotherapy best reduces cardiovascular disease risk as corroborated by the Hygia Chronotherapy Trial. Rebuttal to European Society of Hypertension officials.

Reinhold Kreutz and colleagues in a recent editorial claim the Hygia Chronotherapy Trial lacks credibility because of deficient methods, thereby dismissing both the plausibility and clinical significance of its reported findings. They misstate and misrepresent crucial information, findings and conclusions unambiguously detailed in the published report of the Hygia Chronotherapy Trial. The purpose of this communication is to provide a complete rebuttal to each and every one of the misleading and scientifically unsupported claims by Kreutz et al. that calls into question their expertise to decry the merits, advantages, limitations and validity of correctly designed and conducted ambulatory blood pressure monitoring-based chronotherapy trials.

New perspectives on the definition, diagnosis, and treatment of true arterial hypertension.

INTRODUCTION: Office blood pressure measurements (OBPM), still used today for diagnosis and management of hypertension, fail to reveal clinically important features of the mostly predictable blood pressure (BP) 24 h pattern, and lead to >45% of individuals being misclassified. Current hypertension guidelines do not provide recommendation on when-to-treat, despite multiple prospective clinical trials documenting improved normalization of 24 h BP pattern and significant reduction in cardiovascular disease (CVD) events when hypertension medications are ingested at bedtime rather than upon waking. AREAS COVERED: In this review, the authors discuss current evidence on the: (i) most relevant attributes of the 24 h BP pattern deterministic of CVD risk; (ii) asleep systolic BP (SBP) mean as the most significant therapeutic target for CVD risk reduction; (iii) ingestion-time differences in pharmacodynamics of BP-lowering medications as reported with high consistency in multiple clinical trials; and (iv) enhanced prevention of CVD events achieved by bedtime hypertension chronotherapy. EXPERT OPINION: Several prospective trials consistently document asleep SBP mean and sleep-time relative SBP decline (dipping) constitute highly significant CVD risk factors, independent of OBPM. Bedtime, compared to customary upon-waking, hypertension chronotherapy reduces risk of major CVD events. Collectively, these findings call for new definition of true hypertension and, accordingly, its proper diagnosis and management.

Glaucacetalin E and galphimidin B from Galphimia glauca and their anxiolytic activity.

ETHNOPHARMACOLOGICAL RELEVANCE: Galphimia glauca is a Mexican medicinal plant used to treat anxiety, fear, phobia and stress as it possesses sedative properties which produce a calming effect. Although some chemical and pharmacological studies have already been carried out on G. glauca, there are still new chemical entities from this plant whose anxiolytic activity should be established. AIM OF THE STUDY: To validate the use of G. glauca growing in Cuernavaca, Morelos, as an anti-stress agent, through the purification and structural identification of its extracts' chemical constituents; the analysis of the biogenetic relationship of its chemical compounds, and its biological evaluation to demonstrate its traditional use as anxiolytic agents. MATERIALS AND METHODS: The structures of all isolated compounds were established based on their spectroscopic and spectrometric data. The structure of compound 2 was corroborated through X-Ray. The anxiolytic and sedative-like activities were assessed by the open-field, hole-board and exploration cylinder test. RESULTS: The nor-triterpenes glaucacetalin E (1) and galphimidin B (2) were isolated for the first time along with seven other known compounds, one of them galphimidin (3), from the CHCl3 fraction of the aerial parts of Galphimia glauca. The biogenesis of the natural nor-triterpenes isolated from Galphimia glauca is delineated for the first time starting from the taraxasteryl cation. Oral administration of CHCl3 fraction and 1-3 compounds produced significant attenuation in the anxiety-response in cylinder activity, decrease in the ambulatory activity and in head dipping when compared to the vehicle. However, only the extract enhanced the pentobarbital-induced hypnosis. Diazepam was used as a positive control. CONCLUSION: Our results suggest that G. glauca growing in Cuernavaca, Morelos, exerts anxiolytic-like activity due to the presence of the nor-triterpenes 1-3. These results reinforce the potential use of this species in the treatment of anxiety.

Effect of Coffee Cascara Dietary Fiber on the Physicochemical, Nutritional and Sensory Properties of a Gluten-Free Bread Formulation.

This study aimed to assess the physicochemical, nutritional and sensory properties of gluten-free breads containing isolated coffee cascara dietary fiber (ICCDF) as a food ingredient. ICCDF was obtained by aqueous extraction. The oil and water holding capacity and the nutritional profile of the novel ingredient were determined. Its safety was certificated by analysis of ochratoxin A, caffeine and gluten. Gluten-free bread formulations were prepared enriching a commercial bakery premix in rice protein (8%) and ICCDF (3% and 4.5%). Nutritional profile of the novel gluten-free breads (dietary fiber, protein, amino acids, lipids, fatty acid profile and resistant starch), as well as bread volume, crumb density, moisture, firmness, elasticity and color intensity were determined. A sensory quantitative descriptive analysis of the breads was conducted using eight trained panelists. New breads showed significantly higher (p < 0.05) content of dietary fiber and protein than the control bread. The addition of ICCDF allowed increasing dough yield, a less crumb firmness and a higher crumb elasticity. The nutrition claims "source of protein and high in dietary fiber" were assigned to the new formulations. In conclusion, a certificated gluten-free bread with improved nutritional and physicochemical properties and good sensorial profile was obtained.

Metabolic Profile and Evaluation of Biological Activities of Extracts from the Stems of Cissus trifoliata.

Cissus trifoliata (L.) L belongs to the Vitaceae family and is an important medicinal plant used in Mexico for the management of infectious diseases and tumors. The present study aimed to evaluate the metabolic profile of the stems of C. trifoliata and to correlate the results with their antibacterial and cytotoxic activities. The hexane extract was analyzed using gas chromatography coupled with mass spectrometry (GC-MS) and the CHCl3-MeOH and aqueous extracts by ultraperformance liquid chromatography quadrupole time of fly mass spectrometry (UPLC-QTOF-MS). The antibacterial activity was determined by broth microdilution and the cytotoxicity was evaluated using MTS cell proliferation assay. Forty-six metabolites were putatively identified from the three extracts. Overall, terpenes, flavonoids and stilbenes characterize the metabolic profile. No antibacterial activity was found in any extract against the fifteen bacteria strains tested (MIC >500 µg/mL). However, high cytotoxic activity (IC50 ≤ 30 µg/mL) was found in the hexane and aqueous extracts against hepatocarcinoma and breast cancer cells (Hep3B, HepG2 and MCF7). This is the first report of the bioactive compounds of C. trifoliata stems and their antibacterial and cytotoxic properties. The metabolic profile rich in anticancer compounds correlate with the cytotoxic activity of the extracts from the stems of C. trifoliata. This study shows the antitumor effects of this plant used in the traditional medicine and justifies further research of its anticancer activity.

Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial.

AIMS: The Hygia Chronotherapy Trial, conducted within the clinical primary care setting, was designed to test whether bedtime in comparison to usual upon awakening hypertension therapy exerts better cardiovascular disease (CVD) risk reduction. METHODS AND RESULTS: In this multicentre, controlled, prospective endpoint trial, 19 084 hypertensive patients (10 614 men/8470 women, 60.5 ± 13.7 years of age) were assigned (1:1) to ingest the entire daily dose of ≥1 hypertension medications at bedtime (n = 9552) or all of them upon awakening (n = 9532). At inclusion and at every scheduled clinic visit (at least annually) throughout follow-up, ambulatory blood pressure (ABP) monitoring was performed for 48 h. During the 6.3-year median patient follow-up, 1752 participants experienced the primary CVD outcome (CVD death, myocardial infarction, coronary revascularization, heart failure, or stroke). Patients of the bedtime, compared with the upon-waking, treatment-time regimen showed significantly lower hazard ratio-adjusted for significant influential characteristics of age, sex, type 2 diabetes, chronic kidney disease, smoking, HDL cholesterol, asleep systolic blood pressure (BP) mean, sleep-time relative systolic BP decline, and previous CVD event-of the primary CVD outcome [0.55 (95% CI 0.50-0.61), P < 0.001] and each of its single components (P < 0.001 in all cases), i.e. CVD death [0.44 (0.34-0.56)], myocardial infarction [0.66 (0.52-0.84)], coronary revascularization [0.60 (0.47-0.75)], heart failure [0.58 (0.49-0.70)], and stroke [0.51 (0.41-0.63)]. CONCLUSION: Routine ingestion by hypertensive patients of ≥1 prescribed BP-lowering medications at bedtime, as opposed to upon waking, results in improved ABP control (significantly enhanced decrease in asleep BP and increased sleep-time relative BP decline, i.e. BP dipping) and, most importantly, markedly diminished occurrence of major CVD events. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00741585.

Coffee Silverskin Extract: Nutritional Value, Safety and Effect on Key Biological Functions.

This study aimed to complete the scientific basis for the validation of a coffee silverskin extract (CSE) as a novel food ingredient according to European legislation. Nutritional value, safety, effects on biochemical biomarkers and excretion of short chain fatty acids (SCFAs) in vivo of CSE were assessed. Proteins, amino acids, fat, fatty acids, fiber, simple sugars and micronutrients were analyzed. For the first time, toxicological and physiological effects were evaluated in vivo by a repeated-dose study in healthy Wistar rats. Hormone secretion, antioxidant (enzymatic and no-enzymatic) and anti-inflammatory biomarkers, and dietary fiber fermentability of CSE (analysis of SCFAs in feces) were studied in biological samples. This unique research confirms the feasibility of CSE as a human dietary supplement with several nutrition claims: "source of proteins (16%), potassium, magnesium, calcium and vitamin C, low in fat (0.44%) and high in fiber (22%)". This is the first report demonstrating that its oral administration (1 g/kg) for 28 days is innocuous. Hormone secretion, antioxidant or anti-inflammatory biomarkers were not affected in heathy animals. Total SCFAs derived from CSE fiber fermentation were significantly higher (p < 0.05) in male treated rats compared to male control rats. All the new information pinpoints CSE as a natural, sustainable and safe food ingredient containing fermentable fiber able to produce SCFAs with beneficial effects on gut microbiota.

Hechtia glomerata Zucc: Phytochemistry and Activity of Its Extracts and Major Constituents Against Resistant Bacteria.

Hechtia glomerata Zucc. is used both as a source of food and in ethnomedicine to treat various diseases derived from bacterial infections such as bronchitis, laryngitis, nephritis, whooping cough, urethritis, and sepsis. There are no previous reports about its chemistry and biological activities. Therefore, the aims of this study were to identify components from organic and aqueous extracts of H. glomerata and test the extracts and major isolate compounds against resistant bacteria. Hexane, CHCl3/MeOH, and aqueous extracts were prepared and analyzed by different chromatographic techniques. Structural elucidation was carried out by NMR spectroscopy and X-ray diffraction. The antibacterial activities of extracts, phytochemicals, and semisynthetic derivatives against resistant bacteria were determined by the broth micro-dilution method. From the hexane extract nonacosane (1), hexatriacontanyl stearate (2), hexacosanol (3), oleic acid (4), and ß-sitosterol (5) were isolated and characterized. From the CHCl3/MeOH extract, p-coumaric acid (6), margaric acid (7), caffeic acid (8), daucosterol (9), and potassium chloride (10) were isolated and characterized. A total of 58 volatile compounds were identified by GC-MS from the hexane extract and two solids were isolated from the CHCl3/MeOH extract. The UPLC-QTOF-MS analysis of the aqueous extract allowed the identification of 55 polar compounds. Hexane and aqueous extracts showed antibacterial activity against ESBL Escherichia coli, and three strains of Klebsiella pneumoniae ESBL, NDM-1 +, and OXA-48 with MIC values of 500 µg/mL. The CHCl3/MeOH extract was devoid of activity. The activity of phytocompounds and their semisynthetic derivatives toward resistant bacteria was weak. The most active compound was ß-sitosterol acetate, with a MIC value of 100 µg/mL against carbapenem-resistant A. baumannii. This is the first report of the secondary metabolites of H. glomerata Zucc. and the activity of its extracts and major pure compounds against resistant bacterial strains.