Rational design and synthesis of novel triazole- and tetrazole-fused iminosugars as potential inhibitors of amyotrophic lateral sclerosis (ALS) linked SOD1 aggregation.

In this manuscript we report the first example of an iminosugar that inhibits superoxide dismutase fibrillation associated with the amyotrophic lateral sclerosis (ALS). The present work involves synthesis of novel triazole and tetrazole embedded iminosugars, synthesized in 11-13 high yielding steps starting from readily available tri-O-benzyl-D-glucal and proceeding through a concomitant azidation - thermal intramolecular [3 + 2] cycloaddition reaction as the key step. One of these pre-designed iminosugars was found to inhibit fibrillation of SOD1 and also has shown propensity to break pre-formed fibrils. Docking and MD simulation studies suggest that the most probable interaction of this compound is a hydrogen bonding with Arg69, a loop IV residue of SOD1, which has a crucial role in stabilizing the native conformation of SOD1.

Kinetics theories to understand the mechanism of aggregation of a protein and to design strategies for its inhibition.

Protein aggregation phenomenon is closely related to the formation of amyloids which results in many neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and Amyotrophic Lateral Sclerosis. In order to prevent and treat these diseases, a clear understanding of the mechanism of misfolding and self-assembly of peptides and proteins is very crucial. The aggregation of a protein may involve various microscopic events. Multiple simulations utilizing the solutions of the master equation have given a better understanding of the kinetic profiles involved in the presence and absence of a particular microscopic event. This review focuses on understanding the contribution of these molecular events to protein aggregation based on the analysis of kinetic profiles of aggregation. We also discuss the effect of inhibitors, which target various species of aggregation pathways, on the kinetic profile of protein aggregation. At the end of this review, some strategies for the inhibition of aggregation that can be utilized by combining the chemical kinetics approach with thermodynamics are proposed.

Quercetin and Baicalein Act as Potent Antiamyloidogenic and Fibril Destabilizing Agents for SOD1 Fibrils.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that has been associated with the deposition of aggregates of superoxide dismutase 1 (SOD1). Effective therapeutics against SOD1 fibrillation is still an area of active research. Herein, we demonstrate the potential of two naturally occurring flavonoids (quercetin and baicalein) to inhibit fibrillation of wild-type SOD1 with the aid of a series of biophysical techniques. Our seeding experiments reveal that both of these flavonoids significantly affect the fibril elongation. Interestingly, our ThT binding assay, TEM, and SDS-PAGE experiments suggest that these flavonoids also disintegrate the fibrils into shorter fragments but do not completely depolymerize them into monomers. Binding parameters obtained from the analysis of UV-vis spectra suggest that these flavonoids bind moderately to native SOD1 dimer and have different binding sites. Docking of these flavonoids with a non-native monomer, non-native trimer, and oligomer derived from the 11-residue segment of SOD1 indicates that both quercetin and baicalein can bind to these species and thus can arrest the elongation of fibrils by blocking the fibrillar core regions on the intermediate species formed during aggregation of SOD1. MTT assay data revealed that both the flavonoids reduced the cytotoxicity of SOD1 fibrils. Experimental data also show the antiamyloidogenic potential of both flavonoids against A4V SOD1 mutant fibrillation. Thus, our findings may provide a direction for designing effective therapeutic agents against ALS which can act as promising antiamyloidogenic and fibril destabilizing agents.

Interventions for improving modifiable risk factor control in the secondary prevention of stroke.

BACKGROUND: People with stroke or transient ischaemic attack (TIA) are at increased risk of future stroke and other cardiovascular events. Stroke services need to be configured to maximise the adoption of evidence-based strategies for secondary stroke prevention. Smoking-related interventions were examined in a separate review so were not considered in this review. This is an update of our 2014 review. OBJECTIVES: To assess the effects of stroke service interventions for implementing secondary stroke prevention strategies on modifiable risk factor control, including patient adherence to prescribed medications, and the occurrence of secondary cardiovascular events. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (April 2017), the Cochrane Effective Practice and Organisation of Care Group Trials Register (April 2017), CENTRAL (the Cochrane Library 2017, issue 3), MEDLINE (1950 to April 2017), Embase (1981 to April 2017) and 10 additional databases including clinical trials registers. We located further studies by searching reference lists of articles and contacting authors of included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that evaluated the effects of organisational or educational and behavioural interventions (compared with usual care) on modifiable risk factor control for secondary stroke prevention. DATA COLLECTION AND ANALYSIS: Four review authors selected studies for inclusion and independently extracted data. The quality of the evidence as 'high', 'moderate', 'low' or 'very low' according to the GRADE approach (GRADEpro GDT).Three review authors assessed the risk of bias for the included studies. We sought missing data from trialists.The results are presented in 'Summary of findings' tables. MAIN RESULTS: The updated review included 16 new studies involving 25,819 participants, resulting in a total of 42 studies including 33,840 participants. We used the Cochrane risk of bias tool and assessed three studies at high risk of bias; the remainder were considered to have a low risk of bias. We included 26 studies that predominantly evaluated organisational interventions and 16 that evaluated educational and behavioural interventions for participants. We pooled results where appropriate, although some clinical and methodological heterogeneity was present.Educational and behavioural interventions showed no clear differences on any of the review outcomes, which include mean systolic and diastolic blood pressure, mean body mass index, achievement of HbA1c target, lipid profile, mean HbA1c level, medication adherence, or recurrent cardiovascular events. There was moderate-quality evidence that organisational interventions resulted in improved blood pressure control, in particular an improvement in achieving target blood pressure (odds ratio (OR) 1.44, 95% confidence interval (CI) 1.09 to1.90; 13 studies; 23,631 participants). However, there were no significant changes in mean systolic blood pressure (mean difference (MD), -1.58 mmHg 95% CI -4.66 to 1.51; 16 studies; 17,490 participants) and mean diastolic blood pressure (MD -0.91 mmHg 95% CI -2.75 to 0.93; 14 studies; 17,178 participants). There were no significant changes in the remaining review outcomes. AUTHORS' CONCLUSIONS: We found that organisational interventions may be associated with an improvement in achieving blood pressure target but we did not find any clear evidence that these interventions improve other modifiable risk factors (lipid profile, HbA1c, medication adherence) or reduce the incidence of recurrent cardiovascular events. Interventions, including patient education alone, did not lead to improvements in modifiable risk factor control or the prevention of recurrent cardiovascular events.

Levels of detection of hypertension in primary medical care and interventions to improve detection: a systematic review of the evidence since 2000.

OBJECTIVES: In England, many hypertensives are not detected by primary medical care. Higher detection is associated with lower premature mortality. We aimed to summarise recent evidence on detection and interventions to improve detection in order to inform policies to improve care. DESIGN: Data sources: systematic review of articles published since 2000. Searches of Medline and Embase were undertaken. Eligibility criteria: published in English, any study design, the setting was general practice and studies included patients aged 18 or over. EXCLUSION CRITERIA: screening schemes, studies in primary care settings other than general practice, discussion or comment pieces. PARTICIPANTS: adult patients of primary medical care services. SYNTHESIS: study heterogeneity precluded a statistical synthesis, and papers were described in summary tables. RESULTS: Seventeen quantitative and one qualitative studies were included. Detection rates varied by gender and ethnic group, but longitudinal studies indicated an improvement in detection over time. Patient socioeconomic factors did not influence detection, but living alone was associated with lower detection. Few health system factors were associated with detection, but in two studies higher numbers of general practitioners per 1000 population were associated with higher detection. Three studies investigated interventions to improve detection, but none showed evidence of effectiveness. LIMITATIONS: The search was limited to studies published from 2000, in English. There were few studies of interventions to improve detection, and a meta-analysis was not possible. CONCLUSIONS AND IMPLICATIONS: Levels of detection of hypertension by general practices may be improving, but large numbers of people with hypertension remain undetected. Improvement in detection is therefore required, but guidance for primary medical care is not provided by the few studies of interventions included in this review. Primary care teams should continue to use low-cost, practical approaches to detecting hypertension until evidence from new studies of interventions to improve detection is available.