Resveratrol for Alzheimer's disease Sawda, Christine; Moussa, Charbel; Turner, R. Scott
Annals of the New York Academy of Sciences,
September 2017, Letnik:
1403, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The amyloid hypothesis suggests that the progressive accumulation and deposition of central nervous system (CNS) amyloid with aging is the proximate cause of Alzheimer's disease (AD). Thus, targeting ...molecular mechanisms of aging may be a viable treatment approach. Caloric restriction prevents diseases of aging, including AD, in animal models, perhaps by activation of sirtuins. The sirtuins (e.g., mammalian SIRT1) are deacetylases that link energy balance (NAD+/NADH) to regulation of gene transcription. Resveratrol is a potent activator of SIRT1, and thus may mimic caloric restriction to prevent diseases of aging. We conducted a randomized, double‐blind, placebo‐controlled, phase II trial of resveratrol for individuals with mild‐to‐moderate AD. Resveratrol (1) is detectable in cerebrospinal fluid (at low nanomolar levels), (2) is safe and well tolerated, (3) alters AD biomarker trajectories, (4) preserves blood–brain barrier integrity, and (5) modulates the CNS immune response. Further studies are needed to determine the safety and efficacy of resveratrol and the validity of this approach in the treatment and prevention of AD and other diseases of aging.
Recent historic observed lows in Arctic sea ice extent, together with climate model projections of additional ice reductions in the future, have fueled speculations of potential new trans-Arctic ...shipping routes linking the Atlantic and Pacific Oceans. However, numerical studies of how projected geophysical changes in sea ice will realistically impact ship navigation are lacking. To address this deficiency, we analyze seven climate model projections of sea ice properties, assuming two different climate change scenarios representative concentration pathways (RCPs) 4.5 and 8.5 and two vessel classes, to assess future changes in peak season (September) Arctic shipping potential. By midcentury, changing sea ice conditions enable expanded September navigability for common open-water ships crossing the Arctic along the Northern Sea Route over the Russian Federation, robust new routes for moderately ice-strengthened (Polar Class 6) ships over the North Pole, and new routes through the Northwest Passage for both vessel classes. Although numerous other nonclimatic factors also limit Arctic shipping potential, these findings have important economic, strategic, environmental, and governance implications for the region.
This review summarizes the characterization and quantification of interactions between dissolved organic matter (DOM) and estrogens as well as the effects of DOM on aquatic estrogen removal. DOM ...interacts with estrogens via binding or sorption mechanisms like π-π interaction and hydrogen bonding. The binding affinity is evaluated in terms of organic-carbon-normalized sorption coefficient (Log KOC) which varies with types and composition of DOM. DOM has been suggested to be a more efficient sorbent compared with other matrices, such as suspended particulate matter, sediment and soil; likely associated with its large surface area and concentrated carbon content. As a photosensitizer, DOM enhanced estrogen photodegradation when the concentration of DOM was below a threshold value, and when above, the acceleration effect was not observed. DOM played a dual role in affecting biodegradation of estrogens depending on the recalcitrance of the DOM and the nutrition status of the degraders. DOM also acted as an electron shuttle (redox mediator) mediating the degradation of estrogens. DOM hindered enzyme-catalyzed removal of estrogens while enhanced their transformation during the simultaneous photo-enzymatic process. Membrane rejection of estrogens was pronounced for hydrophobic DOM with high aromaticity and phenolic moiety content. Elimination of estrogens via photolysis, biodegradation, enzymolysis and membrane rejection in the presence of DOM is initiated by sorption, accentuating the role of DOM as a mediator in regulating aquatic estrogen removal.
Display omitted
•Dissolved organic matter interacts with estrogens via binding or sorption.•Binding mechanisms include π-π electron donor-acceptor interaction and hydrogen bonding.•The interactions were primarily associated with dissolved organic carbon quality.•Methods to characterize and quantify binding or sorption affinity were summarized.•The regulatory effects of dissolved organic matter on estrogen elimination were discussed.
The oxazolidinone antibacterial linezolid has been in clinical use for over 20 years, yet knowledge of the contributions of specific cytochrome (CYP) 450 enzymes to the metabolic clearance of this ...drug were mostly unknown. In this investigation, it was revealed that three P450 enzymes that had not been previously explored in linezolid metabolism, CYP2J2, CYP4F2, and CYP1B1, catalyzed the 2-hydroxylation and de-ethyleneation of the morpholine moiety of linezolid. The intrinsic clearance for linezolid metabolism in pooled human liver microsomes was low at 0.51 μL/min/mg protein, consistent with its in vivo clearance in humans, and the K
was high (>200 μM). In recombinant human P450 enzymes, a rank order of intrinsic clearance values for linezolid 2-hydroxylation were CYP2J2 ≫ CYP4F2 > CYP2C8 > CYP1B1 ≈ CYP2D6 ≈ CYP3A4 > CYP1A1 > CYP3A5, with nine other P450 enzymes showing no linezolid metabolism. The effect of selective inhibitors for these eight P450 enzymes on linezolid metabolism in pooled human liver microsomes was evaluated to provide estimates of the relative fractional contributions of these enzymes to linezolid metabolism. These experiments suggest that CYP2J2 and CYP4F2 contribute about 50% each to linezolid hepatic metabolism. It is proposed that the oxidative metabolic clearance of linezolid is primarily catalyzed by these two unusual P450 enzymes and that this explains the lack of observation of meaningful effects of common perpetrators of drug interactions on linezolid pharmacokinetics. SIGNIFICANCE STATEMENT: Linezolid is an important antibacterial drug, but the enzymes involved in its oxidative metabolism were unknown. In this study, evidence is shown that supports an important role for two enzymes not frequently associated with the metabolism of drugs: cytochrome P450 2J2 and cytochrome P450 4F2. These observations offer insight to understand the results of clinical drug-drug interaction studies conducted on linezolid.
Temporally regulated microRNAs have been identified as master regulators of developmental timing in both animals and plants. In plants, vegetative development is regulated by a temporal decrease in ...miR156 level, but how this decreased expression is initiated and then maintained during shoot development remains elusive. Here, we show that miR159 is required for the correct timing of vegetative development in Arabidopsis thaliana. Loss of miR159 increases miR156 level throughout shoot development and delays vegetative development, whereas overexpression of miR159 slightly accelerated vegetative development. The repression of miR156 by miR159 is predominantly mediated by MYB33, an R2R3 MYB domain transcription factor targeted by miR159. Loss of MYB33 led to subtle precocious vegetative phase change phenotypes in spite of the significant downregulation of miR156. MYB33 simultaneously promotes the transcription of MIR156A and MIR156C, as well as their target, SPL9, by directly binding to the promoters of these three genes. Rather than acting as major players in vegetative phase change in Arabidopsis, our results suggest that miR159 and MYB33 function as modifiers of vegetative phase change; i.e., miR159 facilitates vegetative phase change by repressing MYB33 expression, thus preventing MYB33 from hyperactivating miR156 expression throughout shoot development to ensure correct timing of the juvenile-to-adult transition in Arabidopsis.
Metabolism represents the most prevalent mechanism for drug clearance. Many drugs are converted to metabolites that can retain the intrinsic affinity of the parent drug for the pharmacological ...target. Drug metabolism redox reactions such as heteroatom dealkylations, hydroxylations, heteroatom oxygenations, reductions, and dehydrogenations can yield active metabolites, and in rare cases even conjugation reactions can yield an active metabolite. To understand the contribution of an active metabolite to efficacy relative to the contribution of the parent drug, the target affinity, functional activity, plasma protein binding, membrane permeability, and pharmacokinetics of the active metabolite and parent drug must be known. Underlying pharmacokinetic principles and clearance concepts are used to describe the dispositional behavior of metabolites in vivo. A method to rapidly identify active metabolites in drug research is described. Finally, over 100 examples of drugs with active metabolites are discussed with regard to the importance of the metabolite(s) in efficacy and safety.
Abstract
No previous infectious disease outbreak, including the Spanish Flu, has affected the stock market as forcefully as the COVID-19 pandemic. In fact, previous pandemics left only mild traces on ...the U.S. stock market. We use text-based methods to develop these points with respect to large daily stock market moves back to 1900 and with respect to overall stock market volatility back to 1985. We also evaluate potential explanations for the unprecedented stock market reaction to the COVID-19 pandemic. The evidence we amass suggests that government restrictions on commercial activity and voluntary social distancing, operating with powerful effects in a service-oriented economy, are the main reasons the U.S. stock market reacted so much more forcefully to COVID-19 than to previous pandemics in 1918–1919, 1957–1958, and 1968.
Post-stroke depression: A 2020 updated review Medeiros, Gustavo C.; Roy, Durga; Kontos, Nicholas ...
General hospital psychiatry,
September-October 2020, 2020-09-00, 20200901, Letnik:
66
Journal Article
Recenzirano
Post-stroke depression (PSD) is common and associated with higher mortality, poorer recovery, more pronounced cognitive deficits, and lower quality of life than is stroke without depression. This ...manuscript will conduct an updated, comprehensive and clinically-useful review of the risk factors, pathophysiology, assessment, prevention, and treatment of PSD.
This narrative review summarizes articles obtained on PubMed, Medline, EMBase, Google Scholar and the Cochrane Database. This review prioritized articles with a more robust level of evidence, such as original articles with longitudinal data and/or larger samples, randomized controlled trials, systematic reviews, and metaanalyses.
One hundred twenty-four articles were reviewed, of which 44 (35%) were published before 2016 and 80 (65%) that were published since 2016.
Rates of PSD range from 18 to 33%, yet it is vastly underdiagnosed and undertreated. Risk factors for PSD include female sex, history of psychiatric illness, large or multiple strokes, injuries in frontal/anterior areas or in the basal ganglia, stroke occurrence within the past year, poor social support, and pronounced disability. The pathophysiology of PSD is multifactorial and likely involves decreased levels of monoamines, abnormal neurotrophic response, increased inflammation with dysregulation of hypothalamic-pituitary-adrenal axis, and glutamate-mediated excitotoxicity. The evidence for preventive interventions for PSD is somewhat inconsistent and modest. The best treatment for PSD consists of the combination of pharmacological, psychosocial and stroke-focused interventions.
PSD is a common, treatable condition that is associated with several negative outcomes. Early detection and proper management are critical to obtain better outcomes in individuals with PSD.
•Post-stroke depression (PSD) is common and associated with several poor outcomes•PSD is vastly underdiagnosed and undertreated•The evidence for preventive interventions for PSD is inconsistent and modest•Management includes pharmacological, psychosocial and stroke-focused interventions•Repetitive transcranial magnetic stimulation is an emerging therapy for PSD
PDF
