The main purpose of this commentary is to update, based on our extensive review of the published literature of the past 45 yrs, the differential therapeutic effects of hypertension medications of various classes and their combinations when ingested in the evening/at-bedtime versus in the morning/upon-awakening. Interestingly, revision of the currently available evidence on the differential circadian-time-dependent effects of hypertension medications of six different classes and their combinations indicates among the 137 published hypertension medication trials that evaluated blood pressure (BP)-lowering efficacy according to treatment-time, 112 (81.75%) documented significant better benefits by evening/bedtime compared to morning/awakening-scheduled therapy. The remaining 25 published trials found no treatment-time difference in effects; indeed, no single study has reported better benefits of the still conventional, but scientifically unjustified, morning than evening/at-bedtime treatment scheme.
Objective: In hypertension, ingesting blood pressure (BP)-lowering medications at bedtime, compared to upon awakening, is usually associated with significantly improved reduction of sleep-time BP mean, a sensitive prognostic marker of cardiovascular disease (CVD) risk. The Hygia Project, a research network presently composed of 292 investigators of 40 clinical sites, was specifically designed to test the hypothesis that bedtime chronotherapy entailing the entire daily dose of >1 conventional hypertension medications exerts better ambulatory BP control and CVD risk reduction than all such medications ingested upon awakening. Design and method: We conducted a prospective, randomized, open-label, blinded endpoint trial of 15,674 hypertensive patients (8,682 men/6,992 women, 60.4 ± 13.7 years of age) according to ambulatory BP (ABPM) criteria. Participants were randomized to ingest all their prescribed hypertension medications upon awakening (n = 7,848) or the entire daily dose of at least one of them at bedtime (n = 7,826). Among the later, 3,918 participants were ingesting all medications at bedtime and the remaining 3,908 ingested some medications at bedtime and others upon awakening. At inclusion and at every scheduled clinic visit for ABPM (at least annually) during follow-up, BP was assessed for 48 h. The primary CVD-outcome was the composite of CVD death, myocardial infarction, coronary revascularization, heart failure, and stroke. Results: During a median 5.1-year follow-up, we documented 1,154 major CVD events. Patients of the bedtime, compared with the upon-waking, treatment group showed significantly lower hazard ratio of CVD events, adjusted for significant influential characteristics of age, sex, type 2 diabetes, chronic kidney disease, cigarette smoking, HDL-cholesterol, asleep systolic BP (SBP) mean, sleep-time relative SBP decline, and previous CVD event (0.47 [95%CI 0.42–0.54], P < 0.001). CVD risk was further reduced among patients who ingested not just some, but all their BP-lowering medications at bedtime (0.27 [0.21–0.34], P < 0.001, compared with ingestion of all medications upon awakening). Conclusions: In hypertensive patients, ingestion of some (preferably all) BP-lowering medications at bedtime, compared with ingestion of all such medications upon-awakening, results in improved ambulatory BP control (significantly enhanced decrease of asleep BP and increase of sleep-time relative BP decline) and, most importantly, markedly reduced risk of major CVD events.
Conventional time-unspecified single measurements of blood pressure and heart rate may be misleading since they may be influenced, among other factors, by the patient's emotional state, position and diet, and by external stimuli. The evaluation of predictable variability in blood pressure and heart rate by (1) the use of fully ambulatory devices, and (2) the proper processing of the time series thus obtained, can be useful in assessing early cardiovascular disease risk in pregnancy. We have used this approach to examine characteristics of blood pressure variability during pregnancy with a view of an early recognition of blood pressure elevation. A total of 193 pregnant women provided 301 profiles of blood pressure sampled mostly hourly for about 48 hours with an ambulatory device. Circadian parameters of blood pressure were first computed for each single profile of measurement by the least-squares fit of a 24-hour cosine curve, and then used for assessing circadian rhythm characteristics for each group of subjects (complicated vs. uncomplicated) in each trimester of pregnancy. Results indicate that, on a group basis, as compared to uncomplicated pregnancies, a statistically significant elevation of blood pressure is found in pregnancies with gestational hypertension or preeclampsia in all trimesters. These differences occur with values for systolic and diastolic blood pressure well within the currently accepted range of physiological variation. These results provide sensitive parameters for use in early risk assessment and as a guide to preventive intervention during pregnancy.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">></ETX>
The concept of homology lies at the root of evolutionary biology. Since the seminal work of Fitch (1970), three main categories of homology relationships have been defined at the molecular level: orthology, paralogy, and xenology. In brief, if two gene copies arose by duplication they are paralogs, whereas if they arose through speciation they are orthologs. If one of them was transferred from a contemporaneous species, we call them xenologs (Supplementary Fig. S1 in Supplementary Material online, available at http://dx.doi.org/10.5061/dryad.87k57; see Gray and Fitch (1983); Fitch (2000)). Indeed, these terms were coined under a phylogenetic framework in which species were represented by single individuals, and as such they have remained very much intact during the last four decades—although particular cases within these categories have received specific names (Mindell and Meyer 2001). However, advances in sequencing technology have changed the field, and it is now very common to collect data sets containing multiple gene loci and/or multiple individuals per species. In general, such genome-wide data sets not only have unveiled extensive phylogenomic incongruence (Jeffroy et al. 2006; Salichos and Rokas 2013) but have brought back to the spotlight the consideration of how ancestral polymorphisms sort within populations (Edwards 2009). Altogether, phylogenomic data make imperative the explicit distinction between organismal and gene histories. Let us consider phylogenetic relationships at three different levels: species, loci, and gene copies (Fig. 1). The distinction between species/population trees and gene trees has been known for decades (Goodman et al. 1979; Pamilo and Nei 1988; Takahata 1989), whereas the introduction of locus trees into these models is very recent (Rasmussen and Kellis 2012). In brief, a species tree depicts the evolutionary history of the sampled organisms. In this case, the nodes represent speciation events, connected by branches that reflect the population history along these periods, and where their widths represent effective population size (Ne) and their lengths represent time (usually in years or number of generations). Apart from speciations, only evolutionary processes that affect species as a whole are represented at this level, like hybridization. Note that species trees are equivalent to population trees when the organismal units of interest are conspecific populations. In this case, the nodes of the population trees represent isolation events. In general, we will refer to “species” as any diverging, interbreeding group of individuals regardless of its taxonomic rank. On the other hand, a locus tree represents the evolutionary history of the sampled loci for a given gene family (see Rasmussen and Kellis 2012). Since the loci exist inside individuals evolving as part of a population, the locus tree is embedded within the species tree. In a locus tree, the nodes depict either genetic divergence due to speciation in the embedding species tree or locus-level events such as duplication, losses, or horizontal gene transfers, whereas the branch lengths and widths represent time and Ne, respectively. Here, we assume that the locuslevel events get immediately fixed in the population, so these Ne are equivalent to those in the species tree and are the same for every locus. Finally, a gene tree represents the evolutionary history of the sampled gene copies that evolve inside the locus tree. Gene tree nodes indicate coalescent events, which looking forward in time correspond to the process of DNA replication and divergence, and that can occur around the speciation time, well before (deep coalescence) or afterwards (migration in population trees). The branches of the gene tree usually represent amount of substitutions per site, and can also represent number of generations or other measures of time. Importantly, these three historical layers do not necessarily coincide. True species/population trees can differ from true locus trees due to gene duplications, losses, and/or horizontal gene transfers, whereas true gene trees can differ from their embedding locus and species trees if there is incomplete lineage sorting (ILS) (Maddison 1997; Page and Charleston 1997) (and migration in the case of population trees). In this regard,
The risk plastic pollution poses to organisms depends on multiple factors such as particle size and additive composition. In some cases, additives account for up to 30% by weight, and it is well known that some of these additives generate adverse effects on organisms. Bisphenol A (BPA) is a widely used synthetic chemical found in various industries, including plastic. It is prevalent in aquatic environments, with concentrations reaching over 10 μg L⁻¹, and is recognized as a weak estrogenic endocrine disruptor (eEDC). BPA has been identified as a substance of concern due to its reproductive toxicity and has been added to the European Union's "Candidate List" for possible regulation under the REACH framework.The primary stablished mode of action of BPA is its binding to nuclear estrogen receptors, affecting the transcription of estrogen-responsive genes. However, its effects vary among species, often causing mild or inconsistent outcomes, which complicates regulatory measures.In vertebrates, BPA is primarily metabolized in the liver by the enzyme uridyl glucuronyl transferase (UGT). However, under specific conditions, UGT availability may be compromised, activating alternative secondary pathways. One such pathway involves the CYP450 enzyme, leading to the formation of the metabolite MBP. We have tested the estrogenic effects of MBP in the marine fish Cyprinodon variegatus, demonstrating elevated estrogenicity at both protein and gene expression levels, and have explored approaches to simulate in vivo scenarios of UGT deficiency.
Calvo, C; Hermida, R C; Ayala, D E; Lopez, J E; Dominguez, M J; Covelo, M; Mojon, A; Fernandez, J R Author Information
Marine-associated fungal strains act as a valuable reservoir of bioactive diverse secondary metabolites including alkaloids which are highly popular by their biological activities. This review highlighted the chemistry and biology of alkaloids isolated from twenty-six fungal genera associated with marine organisms and marine sea sediments. The selected fungi are from different marine sources without focusing on mangroves. The studied fungal genera comprises Acrostalagmus, Arthrinium, Chaetomium, Cladosporium, Coniothyrium, Curvularia, Dichotomomyces, Eurotium, Eutypella, Exophiala, Fusarium, Hypocrea, Microsphaeropsis, Microsporum, Neosartorya, Nigrospora, Paecilomyces, Penicillium, Pleosporales, Pseudallescheria, Scedosporium, Scopulariopsis, Stagonosporopsis, Thielavia, Westerdykella, and Xylariaceae. Around 347 alkaloid metabolites were isolated and identified via chromatographic and spectroscopic techniques comprising 1D and 2D NMR (one and two dimensional nuclear magnetic resonance) which were further confirmed using HR-MS (high resolution mass spectrometry) and Mosher reactions for additional ascertaining of the stereochemistry. About 150 alkaloids showed considerable effect with respect to the tested activities. Most of the reported bioactive alkaloids showed considerable biological activities mainly cytotoxic followed by antibacterial, antifungal, antiviral, antioxidant; however, a few showed anti-inflammatory and antifouling activities. However, the rest of the compounds showed weak or no activity toward the tested biological activities and required further investigations for additional biological activities. Thus, alkaloids isolated from marine-associated fungi can afford an endless source of new drug entities that could serve as leads for drug discovery combating many human ailments.
