Cytochrome P450 (CYP, P450) is the collective term for a superfamily of heme-containing membrane proteins responsible for the metabolism of approximately 70 - 80 % of clinically used drugs. Besides ...the liver and other peripheral organs, P450 isoforms are expressed in glial cells and neurons of the brain. To enlighten their function and significance is a topic of high interest, as most of the neuroactive drugs used in therapy today are not only substrates, but also inducers of brain P450s with far reaching consequences. First of all, brain P450s are regulated differentially from those in liver. The availability of the prosthetic heme group appears to be essential for correct membrane insertion and enzymatic functionality of brain P450s. Furthermore, although not contributing to body's overall drug metabolism, brain P450s fulfil particular functions within specific cell types of the brain. In astrocytes of brain's border lines P450 isoforms are expressed at very high level. They form a metabolic barrier regulating drugs' influx, modulate blood-flow regulation, and act as signalling enzymes in inflammation. In neurons, however, P450s apparently have different function. In specified brain regions such as hypothalamus, hippocampus and striatum they provide signalling molecules like steroids and fatty acids necessary for neuronal outgrowth and maintenance. Induction of these P450s by neuroactive drugs can alter steroid hormone signalling directly in drug target cells, which may cause clinically relevant side effects like reproductive disorders and sexual or mental dysfunction. The understanding of brain P450 function appears to be of major interest in long-term drug mediated therapy of neurological diseases.
Summary
Objective
Weight management pharmacotherapies can improve metabolic diseases through weight‐dependent and weight‐independent effects. Lorcaserin is a selective 5‐hydroxytryptamine 2C receptor ...agonist. The objective of this analysis is to quantify the relative contribution of weight loss to the treatment effects of lorcaserin 10 mg twice a day on key metabolic parameters.
Methods
This retrospective analysis evaluated 6,897 patients with overweight or obesity (with or without diabetes mellitus) across three randomized, placebo‐controlled, double‐blind, 52‐week clinical trials that evaluated lorcaserin 10 mg twice daily (BID; NCT00395135, NCT00603902, and NCT00603291); 509 patients from only one of the studies had type 2 diabetes mellitus. A mediation analysis was applied to help rank the relative contribution of weight loss to metabolic study outcomes.
Results
According to this mediation analysis, lorcaserin 10 mg BID improved a spectrum of adiposopathic metabolic abnormalities with varying contributions attributable to weight loss. Improvements in waist circumference and blood pressure were almost exclusively attributable to weight loss. Less than 50% of the improvement in glucose parameters (fasting blood glucose and haemoglobin A1c) were attributable to weight loss.
Conclusions
Across Phase III clinical trials, lorcaserin 10 mg BID improved multiple cardiometabolic parameters through both weight‐loss dependent and independent mechanisms.
Abstract Cell transplantation is a promising therapeutic approach that has the potential to replace damaged host striatal neurons and, thereby, slow down or even reverse clinical signs and symptoms ...during the otherwise fatal course of Huntington's disease (HD). Open-labeled clinical trials with fetal neural transplantation for HD have demonstrated long-term clinical benefits for HD patients. Here we report a postmortem analysis of an individual with HD 6 months after cell transplantation and demonstrate that cells derived from grafted fetal striatal tissue had developed into graft-derived neurons expressing dopamine-receptor related phosphoprotein (32 kDa) (DARPP-32), neuronal nuclear antigen (NeuN), calretinin and somatostatin. However, a fully mature phenotype, considered by the expression of developmental markers, is not reached by engrafted neurons and not all types of interneurons are being replaced at 6 months, which is the earliest time point human fetal tissue being implanted in a human brain became available for histological analysis. Host-derived tyrosine hydroxylase (TH) fibers had already heavily innervated the transplants and formed synaptic contacts with graft-derived DARPP-32 positive striatal neurons. In parallel, the transplants contained a considerable number of immature neuroepithelial cells (doublecortin+, Sox2+, Prox-1+, ß3-tubulin+) that exhibited a pronounced migration into the surrounding host striatal tissue and considerable mitotic activity. Graft-derived astrocytes could also be found. Interestingly, the immunological host response in the grafted area showed localized increase of immunocompetent host cells within perivascular spaces without deleterious effects on engrafted cells under continuous triple immunosuppressive medication. Thus this study provides for a better understanding of the developmental processes of grafted human fetal striatal neurons in HD and, in addition, has implications for stem cell–based transplantation approaches in the CNS.
Background
NAP, an 8-amino acid peptide (NAPVSIPQ=Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln) derived from activity-dependent neuroprotective protein (ADNP), plays an important role in neuronal differentiation ...and the survival of neurons in different pathological situations. We already discovered that NAP increases the survival of retinal ganglion cells (RGC) in vitro, and supports neurite outgrowth in retinal explants at femtomolar concentrations. The aim of this study was to investigate the effects of NAP on RGC survival after transient retinal ischemia and optic nerve crush.
Methods
RGC of male Wistar rats were labelled retrogradely with 6 l FluoroGold injected stereotactically into both superior colliculi. Seven days later, retinal ischemia was induced by elevating the intraocular pressure to 120 mm Hg for 60 minutes or by crushing one optic nerve for 10 s after a partial orbitotomy. NAP was either injected intraperitoneally in the concentration of 100 mg/kg 1 day before, directly after, and on the first and the second days after damage, or intravitreally (0.05 or 0.5 μg/eye) directly after the optic nerve crush. Controls received the same concentrations of a control peptide. Densities of surviving RGC and activated microglial cells (AMC) were quantified in a masked fashion 10 days after damage by counting FluoroGold-labelled cells.
Results
After retinal ischemia, intraperitoneal injections of NAP increased the number of surviving RGC by 40% (
p
< 0.005) compared to the control group. After optic nerve crush, NAP raised the number of surviving RGC by 31% (
p
= 0.07) when injected intraperitoneally and by 54% (
p
< 0.05) when administered intravitreally.
Conclusions
NAP acts neuroprotectively in vivo after retinal ischemia and optic nerve crush, and may have potential in treating optic nerve diseases.
Onion downy mildew is a major production constraint. Weather-based decision support has been an important tool for the rational use of fungicides. The present study established a chemical management ...strategy of the disease based on temperature and relative humidity. We defined daily severity values (DSV) according to temperature range (08–13.9 °C; 14–21.9 °C; 22–29 °C) and relative humidity ≥90% to carry out the spraying. The treatments mancozeb/copper oxychloride or metalaxyl-M/chlorothalonil were applied when the summations of the DSV reached the 6–11 range, or 12–17 range, or ≥18, besides weekly sprays using these fungicides or water. The area under disease progress curve (AUDPC) and yield of commercial bulbs were calculated. In both years evaluated (2014, 2015), we managed to reduce the number of metalaxyl-M/chlorothalonil sprays without compromising commercial yield. In 2014, the yield values for all treatments using metalaxyl-M/chlorothalonil were significantly higher than those which used mancozeb/copper oxychloride and control. In fact, with one spray less the routine weekly application, yield was 48.203 tons per hectare, while following the routine weekly application it was 42.411 tons per hectare. In 2015, we have reduced the number of metalaxyl-M/chlorothalonil sprays by 20%, while maintaining the same levels of AUDPC and yield. For both years, treatments with mancozeb/copper oxychloride did not differ from the control (water weekly). The rational use of fungicides is a key element for establishing an integrated production system of onion.
•A chemical management of onion downy mildew, based on temperature and relative humidity, is feasible.•It was possible to keep yield and plant health reducing the fungicide use.•For this decision support, systemic fungicides were efficient to control downy mildew.
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