Saffron as a source of novel acetylcholinesterase inhibitors: Molecular docking and in vitro enzymatic studies

Inhibitors of acetylcholine breakdown by acetylcholinesterase (AChE) constitute the main therapeutic modality for Alzheimer's disease. In the search for natural products with inhibitory action on AChE, this study investigated the activity of saffron extract and its constituents by in vitro enzymatic and molecular docking studies. Saffron has been used in traditional medicine against Alzheimer's disease. Saffron extract showed moderate AChE inhibitory activity (up to 30%), but IC 50 values of crocetin, dimethylcrocetin, and safranal were 96.33, 107.1, and 21.09 μM, respectively. Kinetic analysis showed mixed-type inhibition, which was verified by in silico docking studies. Safranal interacts only with the binding site of the AChE, but crocetin and dimethylcrocetin bind simultaneously to the catalytic and peripheral anionic sites. These results reinforce previous findings about the beneficial action of saffron against Alzheimer's disease and may be of value for the development of novel therapeutic agents based on carotenoid-based dual binding inhibitors. © 2012 American Chemical Society

The Effects of Long-Term Administration of Sodium Nedocromil on Bronchial Hypereactivity

The effect of long-term treatment with sodium nedocromil on airway hypereactivity was investigated in two groups of 20 patients each. Group I patients presented with allergic asthma while Group II patients presented with intrinsic asthma. For each subject of the two groups, the base FEV1 was measured and nebulized methacholine was administrated in consecutively higher concentrations until a decrease in FEV1 of >20 % was observed. Following measurement, all patients included in the study were treated with 12 mg of sodium nedocromil per day for 12 months. At the end of the treatment, bronchial hyperreactivity was evaluated for a second time by administering the same dosage of methacholine that originally produced a decline in FEV1 of >20 %. In Group I patients (allergic asthma) mean FEV1 was 3126 ml, before challenge, while after methacholine challenge FEV1 was 2400ml. Following 1-year of sodium nedocromil administration the FEV1 was 2601ml (P<0.05). Before treatment, the mean fall in FEV1, following methacholine challenge, was 23.67% while following a 1-year-long sodium nedocromil administration this value reduced to 15.70% (P<0.05). Correspondingly, PC 20 was 5.59 while after sodium nedocromil administration it increased to 11.66 (P<0.05). In Group II patients (intrinsic asthma) mean FEV1 was 2750 ml, before challenge, while after methacholine challenge FEV1 was 2066ml. Following 1-year of sodium nedocromil administration the FEV1 was 2223ml (P<0.05). Before treatment, the mean fall in FEV1, following methacholine challenge, was 27.65 % while following a 1-year-long sodium nedocromil administration this value reduced to 21.92 % (P<0.05). Correspondingly, PC 20 was 5.91 while after sodium nedocromil administration it increased to 6.19 (P<0.05). The results suggest a positive effect of long-term sodium nedocromil administration in bronchial hyperreactivity for both groups of patients

Common ABCB1 polymorphisms in Greek patients with chronic hepatitis C infection: A comparison with hyperlipidemic patients and the general population

Background Hepatitis C virus infectivity and replication efficiency appears to be dependent on the lipid content and organization of the plasma membrane of the host cell, as well as of the intracellular membranous web. As there is increasing awareness of a role played by the efflux pump ABCB1 (p-glycoprotein, P-gp) in lipid homeostasis, its function could be a determinant of chronic HCV infection. The aim of the present study was to examine and compare the distribution of common ABCB1 genotypes in patients with chronic HCV infection (n = 168), hyperlipidemic patients (n = 168) and a control group (n = 173), all from Greece. Methods Participants were genotyped for the ABCB12677G&amp;gt;T/A and 3435C&amp;gt;T polymorphisms with previously reported PCR-RFLP methods. Genotype and allele frequency distributions were compared between the three groups with the χ2 test of independence. Results The ABCB1 2677GG (ancestral) genotypes were significantly over-represented in patients with chronic hepatitis C compared to controls (39.3% vs. 26.6%, p = 0.015 according to the dominant model). A similar result was obtained when hyperlipidemic patients were compared to controls (45.2% vs. 26.6%, p &amp;lt; 0.001 according to the dominant model). Comparison of ABCB1 3435C&amp;gt;T genotype and allele distributions provided similar but not as significant differences. Genotype and allele distributions for both ABCB12677G&amp;gt;T/A and 3435C&amp;gt;T were very similar between HCV patients and hyperlipidemic patients. Conclusion Our findings imply an influence of ABCB1 polymorphisms on HCV infectivity, possibly through an effect on lipid homeostasis. © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved

Corticosteroids reduce risk of death within 28 days for patients with severe alcoholic hepatitis, compared with pentoxifylline or placebo-a meta-analysis of individual data

BACKGROUND & AIMS: We performed a meta-analysis of individual patient data from 11 randomized controlled trials comparing corticosteroids, pentoxifylline, or their combination in patients with severe alcoholic hepatitis. We compared the effects of the treatments on survival for 28 days or 6 months, and response to treatment based on the Lille model. METHODS: We searched PubMed for randomized controlled trials of pharmacologic therapy for severe alcoholic hepatitis. Our final analysis comprised 11 studies, of 2111 patients. We performed four meta-analyses of the effects of corticosteroids vs. placebo or control, corticosteroids vs. pentoxifylline, corticosteroids and pentoxifylline vs. corticosteroids and placebo or control, and pentoxifylline vs. placebo. In each meta-analysis, the effect of treatment on the primary outcome (overall survival at 28 days, defined as the period from the first day of assigned treatment to 28 days) was estimated using a Cox proportional hazards regression model, stratified by trial. RESULTS: Corticosteroid treatment significantly decreased risk of death within 28 days compared to controls (hazard ratio [HR], 0.64; 95% CI, 0.48-0.86) or to pentoxifylline (HR, 0.64; 95% CI, 0.43-0.95). In multiple imputation and complete case analyses, the effect of corticosteroids compared to controls remained significant. When we compared corticosteroids vs. pentoxifylline, the corticosteroid effect remained significant in the complete case analysis (HR, 0.66; P=.04) but not in multiple-imputation analysis (HR, 0.71; P=.08). There was no difference in 28-day mortality when patients were given a combination of corticosteroids and pentoxifylline vs. corticosteroids alone or between patients given pentoxifylline vs. control. In our analysis of secondary outcomes, we found no significant differences in 6-month mortality when any treatments or controls were compared. Corticosteroids were significantly associated with increased response to therapy compared with controls (relative risk, 1.24; 95% CI, 1.10-1.41) or pentoxifylline (relative risk, 1.43; 95% CI, 1.20-1.68). We found no difference in response to therapy between patients given a combination of corticosteroids and pentoxifylline vs. corticosteroids alone or pentoxifylline vs. controls. CONCLUSIONS: In a meta-analysis of 4 controlled trials, we found corticosteroid use to reduce risk of death within 28 days of treatment, but not in the following 6 months. This loss of efficacy over time indicates a need for new therapeutic strategies to improve medium-term outcomes

Saffron as a Source of Novel Acetylcholinesterase Inhibitors: Molecular Docking and in Vitro Enzymatic Studies

Inhibitors of acetylcholine breakdown by acetylcholinesterase (AChE) constitute the main therapeutic modality for Alzheimer’s disease. In the search for natural products with inhibitory action on AChE, this study investigated the activity of saffron extract and its constituents by in vitro enzymatic and molecular docking studies. Saffron has been used in traditional medicine against Alzheimer’s disease. Saffron extract showed moderate AChE inhibitory activity (up to 30%), but IC₅₀ values of crocetin, dimethylcrocetin, and safranal were 96.33, 107.1, and 21.09 μM, respectively. Kinetic analysis showed mixed-type inhibition, which was verified by in silico docking studies. Safranal interacts only with the binding site of the AChE, but crocetin and dimethylcrocetin bind simultaneously to the catalytic and peripheral anionic sites. These results reinforce previous findings about the beneficial action of saffron against Alzheimer’s disease and may be of value for the development of novel therapeutic agents based on carotenoid-based dual binding inhibitors

Bile Acid Profiles in Primary Sclerosing Cholangitis and their Ability to Predict Hepatic Decompensation

Postponed access: the file will be available after 2021-11-23Background and Aims: Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases, but clinical usefulness of plasma BA assessment in primary sclerosing cholangitis (PSC) remains understudied. We performed BA profiling in a large retrospective cohort of patients with PSC and matched healthy controls, hypothesizing that plasma BA profiles vary among patients and have clinical utility. Approach and Results: Plasma BA profiling was performed in the Clinical Biochemical Genetics Laboratory at Mayo Clinic using a mass spectrometry based assay. Cox proportional hazard (univariate) and gradient boosting machines (multivariable) models were used to evaluate whether BA variables predict 5-year risk of hepatic decompensation (HD; defined as ascites, variceal hemorrhage, or encephalopathy). There were 400 patients with PSC and 302 controls in the derivation cohort (Mayo Clinic) and 108 patients with PSC in the validation cohort (Norwegian PSC Research Center). Patients with PSC had increased BA levels, conjugated fraction, and primary-to-secondary BA ratios relative to controls. Ursodeoxycholic acid (UDCA) increased total plasma BA level while lowering cholic acid and chenodeoxycholic acid concentrations. Patients without inflammatory bowel disease (IBD) had primary-to-secondary BA ratios between those of controls and patients with ulcerative colitis. HD risk was associated with increased concentration and conjugated fraction of many BA, whereas higher G:T conjugation ratios were protective. The machine-learning model, PSC-BA profile score (concordance statistic [C-statistic], 0.95), predicted HD better than individual measures, including alkaline phosphatase, and performed well in validation (C-statistic, 0.86). Conclusions: Patients with PSC demonstrated alterations of plasma BA consistent with known mechanisms of cholestasis, UDCA treatment, and IBD. Notably, BA profiles predicted future HD, establishing the clinical potential of BA profiling, which may be suited for use in clinical trials.acceptedVersio