New Drug Design Avenues Targeting Alzheimer's Disease by Pharmacoinformatics-Aided Tools.

Neurodegenerative diseases (NDD) have been of great interest to scientists for a long time due to their multifactorial character. Among these pathologies, Alzheimer's disease (AD) is of special relevance, and despite the existence of approved drugs for its treatment, there is still no efficient pharmacological therapy to stop, slow, or repair neurodegeneration. Existing drugs have certain disadvantages, such as lack of efficacy and side effects. Therefore, there is a real need to discover new drugs that can deal with this problem. However, as AD is multifactorial in nature with so many physiological pathways involved, the most effective approach to modulate more than one of them in a relevant manner and without undesirable consequences is through polypharmacology. In this field, there has been significant progress in recent years in terms of pharmacoinformatics tools that allow the discovery of bioactive molecules with polypharmacological profiles without the need to spend a long time and excessive resources on complex experimental designs, making the drug design and development pipeline more efficient. In this review, we present from different perspectives how pharmacoinformatics tools can be useful when drug design programs are designed to tackle complex diseases such as AD, highlighting essential concepts, showing the relevance of artificial intelligence and new trends, as well as different databases and software with their main results, emphasizing the importance of coupling wet and dry approaches in drug design and development processes.

Validation of a Histologic Scoring Index for C3 Glomerulopathy.

RATIONALE & OBJECTIVE: A previous study that evaluated associations of kidney biopsy findings with disease progression in patients with C3 glomerulopathy (C3G) proposed a prognostic histologic index (C3G-HI) that has not yet been validated. Our objective was to validate the performance of the C3G-HI in a new patient population. STUDY DESIGN: Multicenter, retrospective cohort study. SETTING & PARTICIPANTS: 111 patients fulfilling diagnostic criteria of C3G between January 1995 and December 2019, from 33 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN). PREDICTORS: Demographic, clinical parameters, C3G-HI total activity score, and the C3G-HI total chronicity score. OUTCOME: Time to kidney failure. ANALYTICAL APPROACH: Intraclass correlation coefficients and κ statistic were used to summarize inter-rater reproducibility for assessment of histopathology in kidney biopsies. The nonlinear relationships of risk of kidney failure with the total activity score and total chronicity score were modeled using Cox proportional hazards analysis that incorporated cubic splines. RESULTS: The study group included 93 patients with C3 glomerulonephritis and 18 with dense-deposit disease. Participants had an overall meanage of 35±22 (SD) years. Forty-eight patients (43%) developed kidney failure after a mean follow-up of 65±27 months. The overall inter-rater reproducibility was very good for the total activity score (intraclass correlation coefficient [ICC]=0.63) and excellent for total chronicity score (ICC=0.89). Baseline estimated glomerular filtration rate (eGFR), 24-hour proteinuria, and treatment with immunosuppression were the main determinants of kidney failure in a model with only clinical variables. Only tubular atrophy and interstitial fibrosis were identified as predictors in a model with histological variables. When the total activity score and total chronicity score were added to the model, only the latter was identified as an independent predictor of kidney failure. LIMITATIONS: Only a subset of the kidney biopsies was centrally reviewed. Residual confounding. CONCLUSIONS: We validated the performance of C3G-HI as a predictor of kidney failure in patients with C3G. The total chronicity score was the principal histologic correlate of kidney failure.

Influence of polysulphone-derived dialysis membranes on the interaction of circulating mononuclear cells with the endothelium.

PURPOSE: Cardiovascular morbidity in hemodialysis (HD) patients may be influenced by the activation of circulating mononuclear cells (MCs) with subsequently increased endothelium interaction. The use of more biocompatible membranes would reduce this monocyte activation. We compare monocyte activation after using two different high-flux polymers, polysulphone and polyethersulphone. METHODS: The first part of the study was done with 10 patients who successively received dialysis for 2 weeks with polysulphone and polyethersulphone. The second part with 30 patients dialyzed for 3 months with polysulphone or polyethersulphone. Blood samples were taken before (pre-HD) and after (post-HD) the first HD session with each membrane to evaluate the effect of a single HD session. To assess acute and chronic effects of membranes, blood samples were taken pre-HD, after 2 weeks (first part of study) and after 3 months (second part of study). MCs were isolated from blood and then incubated with cultured human endothelial cells to evaluate MC adhesion, MC-dependent endothelial toxicity, and endothelial protein expressions of nitric oxide synthase and endothelin-converting enzyme-1 (ECE-1). RESULTS: One single HD session did not induce any changes. Dialysis for 2 weeks (first part of study) with polyethersulphone reduced MC adhesion to endothelium, cellular toxicity, and ECE-1 protein expression compared to polysulphone or basal conditions. Dialysis for 3 months (second part of study) increased MC adhesion to endothelium, whereas cellular toxicity was decreased with both dialyzers compared to the basal situation. CONCLUSIONS: Although polyethersulphone HD decreased the interaction of MC with the endothelium in short-term experiments, both membranes were comparable in the long-term.