ABSTRACT
Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson's disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD. We identified 12 genes with de novo mutations (MAD1L1, NUP98, PPP2CB, PKMYT1, TRIM24, CEP131, CTTNBP2, NUS1, SMPD3, MGRN1, IFI35, and RUSC2), which could be functionally relevant to PD pathogenesis. Further analyses of two independent case-control cohorts (1,852 patients and 1,565 controls in one cohort and 3,237 patients and 2,858 controls in the other) revealed that NUS1 harbors significantly more rare nonsynonymous variants (P = 1.01E-5, odds ratio = 11.3) in PD patients than in controls. Functional studies in Drosophila demonstrated that the loss of NUS1 could reduce the climbing ability, dopamine level, and number of dopaminergic neurons in 30-day-old flies and could induce apoptosis in fly brain. Together, our data suggest that de novo mutations could contribute to early onset PD pathogenesis and identify NUS1 as a candidate gene for PD.
Subject(s)
Brain/metabolism , Dopaminergic Neurons/metabolism , Mutation , Nerve Tissue Proteins/genetics , Parkinson Disease/genetics , Receptors, Cell Surface/genetics , Adult , Age of Onset , Animals , Apoptosis/genetics , Aryl Hydrocarbon Receptor Nuclear Translocator/antagonists & inhibitors , Aryl Hydrocarbon Receptor Nuclear Translocator/genetics , Aryl Hydrocarbon Receptor Nuclear Translocator/metabolism , Base Sequence , Brain/pathology , Case-Control Studies , Cohort Studies , Disease Models, Animal , Dopamine/metabolism , Dopaminergic Neurons/pathology , Drosophila Proteins/antagonists & inhibitors , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Early Diagnosis , Female , Gene Expression , Gene Regulatory Networks , Humans , Male , Nerve Tissue Proteins/metabolism , Parents , Parkinson Disease/diagnosis , Parkinson Disease/metabolism , Parkinson Disease/pathology , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Receptors, Cell Surface/metabolism , SiblingsABSTRACT
INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) has been reported to have effects on kidney diseases; however, a link between NAFLD and urinary calculi remains to be confirmed. This study was conducted on a male population based on our previous Fangchenggang Area Male Health and Examination Survey in Guangxi, China in order to estimate the frequency of urinary calculi and assess the association between NAFLD and urinary calculi while controlling for possible confounders. MATERIALS AND METHODS: This was a population-based cross-sectional study conducted in the Fangchenggang region in Guangxi, China. The diagnoses of NAFLD and urinary calculi were made by ultrasonography. Clinical and laboratory findings were analyzed to investigate whether NAFLD was a risk factor for urinary calculi. RESULTS: A total of 3719 men were enrolled (age range, 17 to 88 years). Slightly more than a quarter (26.5%) of the participants were diagnosed with NAFLD. The percentage of urinary calculi in all participants was 6.9%, and the percentage of NAFLD patients with urinary calculi (8.4%) was significantly higher than that among patients without NAFLD (6.4%, P < .05). Advanced age; high body mass index; elevated levels of blood glucose, cholesterol, triglycerides, and low-density lipoprotein cholesterol; low education; lower or higher physical activity; and NAFLD were independent risk factors for urinary calculi (P < .05). CONCLUSIONS: Our results showed that NAFLD was associated with a higher incidence of urinary calculi in this cohort and NAFLD might represent a risk factor for urinary calculi.
Subject(s)
Non-alcoholic Fatty Liver Disease/epidemiology , Urinary Calculi/epidemiology , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , China/epidemiology , Comorbidity , Cross-Sectional Studies , Educational Status , Exercise , Health Surveys , Humans , Incidence , Life Style , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/diagnostic imaging , Risk Factors , Ultrasonography , Urinary Calculi/diagnostic imaging , Young AdultABSTRACT
OBJECTIVE: This study was designed to determine the differential profiles of long non-coding RNAs (lncRNAs) between rheumatoid arthritis (RA) and gouty arthritis (GA), which may lead to the discovery of specific biomarkers for RA diagnosis and treatment in the future. METHODS: The profiles of lncRNAs were determined by Agilent microarray. Bioinformatics analyses, including Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, of the large dataset obtained from microarray experiments were performed. RESULTS: A total of 765 lncRNAs and 2,808 mRNAs were significantly and differentially expressed in RA samples as compared to GA samples. Moreover, of 2,808 differentially expressed mRNAs, 178 upregulated mRNAs and 21 downregulated mRNAs were identified to be strongly correlated with lncRNAs examined in this study. Bioinformatics analyses revealed the tumor-like phenotype of synovial cells in RA and the involvement of immune system process in GA. In addition, this study demonstrated the significantly different molecular origins of two Chinese Medicine syndrome patterns of RA patients -- blood stasis and non-blood stasis. CONCLUSIONS: Our study showed for the first time the differentially expressed lncRNA profiles in synovial tissues between RA and GA and between two clinical phenotypes of RA patients differentiated by Chinese Medicine. This study helps achieving personalized medicine in RA. Larger-scale studies are required to validate the data presented.
Subject(s)
Arthritis, Gouty/metabolism , Arthritis, Rheumatoid/metabolism , Gene Expression Regulation , RNA, Long Noncoding/biosynthesis , Adult , Arthritis, Gouty/genetics , Arthritis, Gouty/pathology , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/pathology , Female , Gene Expression Profiling , Humans , Male , Middle Aged , RNA, Long Noncoding/geneticsABSTRACT
Morus alba L. (mulberry) twig is known to have an inhibitory effect on pathogens in traditional Chinese medicine. In the present study, the dermophytic fungus, Trichophyton rubrum, was used to evaluate the inhibitory effect of total M. alba twig extract and extracts obtained using solvents with different polarities by the method of 96-well MTT colorimetry. The main active substance was isolated and identified by tracking its activity. In addition, the inhibitory effects of active extracts and a single active substance were investigated in combination with miconazole nitrate. Our data indicated that ethyl acetate extracts of mulberry twig (TEE) exhibited a desired inhibitory activity on T. rubrum with the minimum inhibitory concentration (MIC) of 1.000 mg/mL. With activity tracking, the main substance showing antimicrobial activity was oxyresveratrol (OXY), which was isolated from TEE. Its MIC for inhibiting the growth of T. rubrum was 0.500 mg/mL. The combined use of miconazole nitrate and OXY showed a synergistic inhibitory effect, as shown by a significant decrease in the MIC of both components. Based on the OXY content in TEE, the contribution rate of OXY to the inhibitory effect of TEE on T. rubrum was 80.52%, so it was determined to be the main antimicrobial substance in M. alba twig. Copyright © 2017 John Wiley & Sons, Ltd.
