Small molecules interacting with α-synuclein: antiaggregating and cytoprotective properties

Curcumin, a dietary polyphenol, has shown a potential to act on the symptoms of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, as a consequence of its antioxidant, anti-inflammatory and anti-protein aggregation properties. Unfortunately, curcumin undergoes rapid degradation at physiological pH into ferulic acid, vanillin and dehydrozingerone, making it an unlikely drug candidate. Here, we evaluated the ability of some curcumin by-products: dehydrozingerone (1), its O-methyl derivative (2), zingerone (3), and their biphenyl analogues (4–6) to interact with α-synuclein (AS), using CD and fluorescence spectroscopy. In addition, the antioxidant properties and the cytoprotective effects in rat pheochromocytoma (PC12) cells prior to intoxication with H₂O₂, MPP+ and MnCl₂ were examined while the Congo red assay was used to evaluate the ability of these compounds to prevent aggregation of AS. We found that the biphenyl zingerone analogue (6) interacts with high affinity with AS and also displays the best antioxidant properties while the biphenyl analogues of dehydrozingerone (4) and of O-methyl-dehydrozingerone (5) are able to partially inhibit the aggregation process of AS, suggesting the potential role of a hydroxylated biphenyl scaffold in the design of AS aggregation inhibitors.     

Maternal Antiretroviral Therapy for the Prevention of Mother-To-Child Transmission of HIV in Malawi: Maternal and Infant Outcomes Two Years after Delivery

Background

Optimized preventive strategies are needed to reach the objective of eliminating pediatric AIDS. This study aimed to define the determinants of residual HIV transmission in the context of maternal antiretroviral therapy (ART) administration to pregnant women, to assess infant safety of this strategy, and to evaluate its impact on maternal disease.

Methodology/Principal Findings

A total of 311 HIV-infected pregnant women were enrolled in Malawi in an observational study and received a nevirapine-based regimen from week 25 of gestation until 6 months after delivery (end of breastfeeding period) if their CD4+ count was > 350/mm³ at baseline (n = 147), or indefinitely if they met the criteria for treatment (n. 164). Mother/child pairs were followed until 2 years after delivery. The Kaplan-Meier method was used to estimate HIV transmission, maternal disease progression, and survival at 24 months. The rate of HIV infant infection was 3.2% [95% confidence intervals (CI) 1.0-5.4]. Six of the 8 transmissions occurred among mothers with baseline CD4+ count > 350/mm³. HIV-free survival of children was 85.8% (95% CI 81.4-90.1). Children born to mothers with baseline CD4+ count < 350/mm³ were at increased risk of death (hazard ratio 2.6, 95% CI 1.1-6.1). Among women who had stopped treatment the risk of progression to CD4+ count < 350/mm³ was 20.6% (95% CI 9.2-31.9) by 18 months of drug discontinuation.

Conclusions

HIV transmission in this cohort was rare however, it occurred in a significative proportion among women with high CD4+ counts. Strategies to improve treatment adherence should be implemented to further reduce HIV transmission. Mortality in the uninfected exposed children was the major determinant of HIV-free survival and was associated to maternal disease stage. Given the considerable proportion of women reaching the criteria for treatment within 18 months of drug discontinuation, life-long ART administration to HIV-infected women should be considered.     

Hypothermia during Carotid Endarterectomy: A Safety Study

BackgroundCEA is associated with peri-operative risk of brain ischemia, due both to emboli production caused by manipulation of the plaque and to potentially noxious reduction of cerebral blood flow by carotid clamping. Mild hypothermia (34–35°C) is probably the most effective approach to protect brain from ischemic insult. It is therefore a substantial hypothesis that hypothermia lowers the risk of ischemic brain damage potentially associated with CEA. Purpose of the study is to test whether systemic endovascular cooling to a target of 34.5–35°C, initiated before and maintained during CEA, is feasible and safe.MethodsThe study was carried out in 7 consecutive patients referred to the Vascular Surgery Unit and judged eligible for CEA. Cooling was initiated 60–90 min before CEA, by endovascular approach (Zoll system). The target temperature was maintained during CEA, followed by passive, controlled rewarming (0.4°C/h). The whole procedure was carried out under anesthesia.ResultsAll the patients enrolled had no adverse events. Two patients exhibited a transient bradycardia (heart rate 30 beats/min). There were no significant differences in the clinical status, laboratory and physiological data measured before and after CEA.ConclusionsSystemic cooling to 34.5–35.0°C, initiated before and maintained during carotid clamping, is feasible and safe.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02629653","term_id":"NCT02629653"}}NCT02629653     

Common dandelion: a review of its botanical,phytochemical and pharmacological profiles

Phytochemistry Reviews - Phytoalimurgy is a term that derives from Greek and Latin by combination of the words φυτόν, which meaning plant, and alimenta urgentia, indicating...     

Identification and characterization of carbapenem binding sites within the RND-transporter AcrB

Understanding the molecular determinants for recognition, binding and transport of antibiotics by multidrug efflux systems is important for basic research and useful for the design of more effective antimicrobial compounds. Imipenem and meropenem are two carbapenems whose antibacterial activity is known to be poorly and strongly affected by MexAB-OprM, the major efflux pump transporter in Pseudomonas aeruginosa. However, not much is known regarding recognition and transport of these compounds by AcrAB-TolC, which is the MexAB-OprM homologue in Escherichia coli and by definition the paradigm model for structural studies on efflux pumps. Prompted by this motivation, we unveiled the molecular details of the interaction of imipenem and meropenem with the transporter AcrB by combining computer simulations with biophysical experiments. Regarding the interaction with the two main substrate binding regions of AcrB, the so-called access and deep binding pockets, molecular dynamics simulations revealed imipenem to be more mobile than meropenem in the former, while comparable mobilities were observed in the latter. This result is in line with isothermal titration calorimetry, differential scanning experiments, and binding free energy calculations, indicating a higher affinity for meropenem than imipenem at the deep binding pocket, while both sharing similar affinities at the access pocket. Our findings rationalize how different physico-chemical properties of compounds reflect on their interactions with AcrB. As such, they constitute precious information to be exploited for the rational design of antibiotics able to evade efflux pumps.     

Localization of liver myofibroblasts and hepatic stellate cells in normal and diseased rat livers: distinct roles of (myo-)fibroblast subpopulations in hepatic tissue repair

Previous in vitro studies indicated that hepatic stellate cells (HSC) and rat liver myofibroblasts (rMF) have to be regarded as different cell populations of the myofibroblastic lineage with fibrogenic potential. Employing the discrimination features defined by these studies the localization of HSC and rMF was analyzed in diseased livers. Normal and acutely as well as chronically carbon tetrachloride-injured livers were analyzed by immunohistochemistry and by in situ hybridization. In normal livers HSC [desmin/glial fibrillary acid protein (GFAP)-positive cells] were distributed in the hepatic parenchyma, while rMF (desmin/smooth muscle alpha actin-positive, GFAP-negative cells colocalized with fibulin-2) were located in the portal field, the walls of central veins, and only occasionally in the parenchyma. Acute liver injury was characterized almost exclusively by an increase in the number of HSC, while the amount of rMF was nearly unchanged. In early stages of fibrosis, HSC and rMF were detected within the developing scars. In advanced stages of fibrosis, HSC were mainly present at the scar–parenchymal interface, while rMF accounted for the majority of the cells located within the scar. At every stage of fibrogenesis, rMF, in contrast to HSC, were only occasionally detected in the hepatic parenchyma. HSC and rMF are present in normal and diseased livers in distinct compartments and respond differentially to tissue injury. Acute liver injury is followed by an almost exclusive increase in the number of HSC, while in chronically injured livers not only HSC but also rMF are involved in scar formation. Accepted: 16 September 1999     

IFN-gamma production in rabbits: behavioral and endocrine correlates

Freely interacting male rabbits were studied to establish the effect of exogenous testosterone on interferon-gamma (IFN-gamma) production in peripheral blood mononuclear cells (PBMCs) and to evaluate if this effect is related to season, social rank, plasma corticosterone and glucocorticoid receptors (GcR) in PBMCs. Dominance behavior increases after testosterone propionate (TP) administration only in rank 1 animals, while submission behavior increases after TP only in rank 4 animals, indicating a reinforcing effect of TP on the behavior. Corticosterone and IFN-gamma production are higher and GcR binding capacity is lower in spring than in autumn, suggesting that seasonal fluctuations in the immune system may be related to the pattern of secretion of immunomodulatory hormones. In autumn, corticosterone decreases after TP treatment and increases after social interaction, while GcR binding capacity decreases after TP treatment and social interaction. IFN-gamma production decreases in spring and increases in autumn after TP treatment plus social interaction, indicating that the modulating action of testosterone is related to the current immune status. The relationship between dominance, testosterone and the immune system in spring is suggested by the finding that GcR binding capacity after TP treatment is directly related to social rank, as confirmed by the positive correlation with dominance behavior frequency. The dominance index is positively correlated with GcR binding capacity and negatively with IFN-gamma production before TP treatment, indicating that high receptor activity in immunocompetent cells and low immunoreactivity could be prerequisites for dominance behavior. The immunosuppressive effect of corticosterone and the mechanism of down-regulation on GcR are confirmed by the negative correlations with IFN-gamma production and GcR binding capacity.