Lanosterol Disrupts Aggregation of Human γD-Crystallin by Binding to the Hydrophobic Dimerization Interface

Cataracts are a leading cause of vision impairment, which stem from the misfolding and aggregation of crystallins in the eye lens. Despite its prevalence and severity, the detailed mechanism by which misfolded crystallins aggregate into cataracts remains elusive. Recently, <i>in vitro</i> and <i>in vivo</i> experiments demonstrated that lanosterol, a steroid-type compound found in human and animal eyes, can not only prevent cataract formation but also reverse the formation. Inspired by these experimental observations, we investigate the preventive activity of lanosterol in the aggregate formation of human γD-crystallins (HγD-Crys) using all atom molecular dynamics (MD) simulation and free energy perturbation (FEP) techniques. Our results reveal that lanosterol preferentially binds to the HγD-Crys hydrophobic dimerization interface, in particular, to the structured C-terminus (near residues 135–165) with a stronger binding affinity than the unfolded N-terminus. Furthermore, we observe that the C-terminal binding is more favorable than lanosterol self-aggregation, further attesting to lanosterol’s efficacy. Finally, we compare the binding free energy of lanosterol with cholesterol using alchemical transformation and discuss the possible correlation of the molecular geometry of steroids with binding affinity

Annual total IFs of articles published by researchers from the top five countries and China from 2000 to 2010.

<p>Annual total IFs of articles published by researchers from the top five countries and China from 2000 to 2010.</p

Number of clinical trials, RCTs, and case reports written by authors from the six countries between 2000 and 2010.

<p>Number of clinical trials, RCTs, and case reports written by authors from the six countries between 2000 and 2010.</p

Annual citations of articles related to PBC written by authors from the top five countries and China from 2000 to 2010.

<p>Annual citations of articles related to PBC written by authors from the top five countries and China from 2000 to 2010.</p

Total number of basic research, case reports, clinical research, commentaries, and reviews relating to PBC worldwide from 2000 to 2010.

<p>Total number of basic research, case reports, clinical research, commentaries, and reviews relating to PBC worldwide from 2000 to 2010.</p

Average number of citations in articles published by researchers from the different countries during the past 11 years.

<p>Average number of citations in articles published by researchers from the different countries during the past 11 years.</p

Average impact factors (IF) of articles written by authors from six countries from 2000 to 2010, based on the annual IFs of the journals published.

<p>Average impact factors (IF) of articles written by authors from six countries from 2000 to 2010, based on the annual IFs of the journals published.</p

Trends in annual numbers of articles written by researchers from the six countries from 2000 to 2010.

<p>Trends in annual numbers of articles written by researchers from the six countries from 2000 to 2010.</p

The four most popular journals for authors from five countries between 2000 and 2010.

<p>The four most popular journals for authors from five countries between 2000 and 2010.</p

The Association of 5-HT2A, 5-HTT, and LEPR Polymorphisms with Obstructive Sleep Apnea Syndrome: A Systematic Review and Meta-Analysis

<div><p>Objective</p><p>A consensus has not been reached regarding the association of several different gene polymorphisms and susceptibility to obstructive sleep apnea syndrome (OSAS). We performed a meta-analysis to better evaluate the associations between 5-HT2A, 5-HTT, and LEPR polymorphisms, and OSAS.</p><p>Method</p><p>5-HT2A, 5-HTT, and LEPR polymorphisms and OSAS were identified in PubMed and EMBASE. The pooled odd rates (ORs) with 95%CIs were estimated using a fixed-effect or random-effect models. The associations between these polymorphisms and OSAS risk were assessed using dominant, recessive and additive models.</p><p>Results</p><p>Twelve publications were included in this study. The -1438 “A” allele of 5-HT2A was identified as a candidate genetic risk factor for OSAS (OR: 2.33, 95%CI 1.49–3.66). Individuals carrying the -1438 “G” allele had a nearly 70% reduced risk of OSAS when compared with AA homozygotes (OR: 0.30, 95%CI 0.23–0.40). There was no significant association between 5-HT2A 102C/T and OSAS risk, using any model. The “S” allele of 5-HTTLPR conferred protection against OSAS (OR: 0.80, 95%CI 0.67–0.95), while the “10” allele of 5-HTTVNTR contributed to the risk of OSAS (OR: 2.08, 95%CI: 1.58–2.73). The “GG” genotype of LEPR was associated with a reduced risk of OSAS (OR: 0.39, 95%CI 0.17–0.88).</p><p>Conclusion</p><p>The meta-analysis demonstrated that 5-HTR-1438 “A” and 5-HTTVNTR “10” alleles were significantly associated with OSAS. The “S” allele of 5-HTTLPR and the “GG” genotype of LEPR conferred protection against OSAS. Further studies, such as Genome-Wide Association study (GWAS), should be conducted in a large cohort of OSAS patients to confirm our findings.</p></div