Quantitative and causal analysis for inflammatory genes and the risk of Parkinson's disease.

Background: The dysfunction of immune system and inflammation contribute to the Parkinson's disease (PD) pathogenesis. Cytokines, oxidative stress, neurotoxin and metabolism associated enzymes participate in neuroinflammation in PD and the genes involved in them have been reported to be associated with the risk of PD. In our study, we performed a quantitative and causal analysis of the relationship between inflammatory genes and PD risk. Methods: Standard process was performed for quantitative analysis. Allele model (AM) was used as primary outcome analysis and dominant model (DM) and recessive model (RM) were applied to do the secondary analysis. Then, for those genes significantly associated with the risk of PD, we used the published GWAS summary statistics for Mendelian Randomization (MR) to test the causal analysis between them. Results: We included 36 variants in 18 genes for final pooled analysis. As a result, IL-6 rs1800795, TNF-α rs1799964, PON1 rs854560, CYP2D6 rs3892097, HLA-DRB rs660895, BST1 rs11931532, CCDC62 rs12817488 polymorphisms were associated with the risk of PD statistically with the ORs ranged from 0.66 to 3.19 while variants in IL-1α, IL-1ß, IL-10, MnSOD, NFE2L2, CYP2E1, NOS1, NAT2, ABCB1, HFE and MTHFR were not related to the risk of PD. Besides, we observed that increasing ADP-ribosyl cyclase (coded by BST1) had causal effect on higher PD risk (OR[95%CI] =1.16[1.10-1.22]) while PON1(coded by PON1) shown probably protective effect on PD risk (OR[95%CI] =0.81[0.66-0.99]). Conclusion: Several polymorphisms from inflammatory genes of IL-6, TNF-α, PON1, CYP2D6, HLA-DRB, BST1, CCDC62 were statistically associated with the susceptibility of PD, and with evidence of causal relationships for ADP-ribosyl cyclase and PON1 on PD risk, which may help understand the mechanisms and pathways underlying PD pathogenesis.

Efficacy of CPAP duration and adherence for cognitive improvement in patients with obstructive sleep apnea: a meta-analysis of randomized controlled trials.

PURPOSE: Obstructive sleep apnea (OSA) can impair cognition. Continuous positive airway pressure (CPAP) is a recommended treatment for OSA but its effectiveness on cognitive improvement is uncertain, a finding which may be biased by various durations and adherence to treatment with CPAP. In a meta-analysis assessing high-quality randomized controlled trials (RCTs), we estimated whether or not CPAP benefits cognition in patients with OSA. METHODS: PRISMA criteria were followed in the performance of this meta-analysis. The weighted mean difference (WMD) and 95% confidence interval (CI) of six neuropsychological scores covering eight cognitive domains were used to evaluate the benefit between CPAP and non-CPAP interventions. Subgroups of different therapeutic durations and adherence, which were divided into short-term (< 8 weeks) and long-term (≥ 12 weeks) durations, and poor (nighttime < 4 h/night) and good (nighttime ≥ 4 h/night) adherence were also analyzed. RESULTS: Among 16 RCTs, 1529 participants with OSA were included. Comparing the CPAP group and the control group for all treatment durations and adherence, a mild improvement for digit span forward which reflected short-term memory was observed (WMD[95%CI] = 0.67[0.03,1.31], p = 0.04). Trail making test-part B, which reflected executive function was improved for participants with OSA who had good adherence to CPAP (WMD[95%CI] = - 6.24[- 12.60,0.12], p = 0.05). Patients with OSA who received short-term CPAP treatment (WMD[95%CI] = - 7.20[- 12.57, - 1.82], p = 0.009) had a significant improvement in executive function when compared with controls. There was no statistical difference for all scales between long-term (≥ 12 weeks) CPAP treatment group and control group. CONCLUSION: The effectiveness of CPAP on cognitive improvement in patients with OSA is limited, although good adherence to CPAP can mildly benefit executive function with short-term effectiveness.

Polymorphism of neurodegeneration-related genes associated with Parkinson's disease risk.

BACKGROUND: Neurodegenerative genes are critical in neuronal loss in Parkinson's disease (PD). We performed a systematic meta-analysis including all the studies published on PD risk related to genes encoding enzymes vital for dopamine metabolism and neuron survival. METHODS: We included neurodegeneration-related genes which were divided into four groups according to their functions: main enzymes in dopamine metabolism, receptors and transporters for dopamine or other metabolites, neuroprotective factors for dopaminergic neurons, and genes associated with dopaminergic neurons survival reported in other neurological diseases. We collected original articles from PubMed, Embase, and Web of Science databases. Revman 5.3 software was used to analyze data. The allele model (AM) was used to test the effect size of the effect allele between the case group and the control group and secondary analysis using the dominant model (DM) and recessive model (RM) to analyze the contributions from heterozygote and homozygote to the allele risk. Odds ratio (OR) and 95% confidence interval (CI) were used to present the pooled results. RESULTS: We included 31 variants in 20 genes for the final pooled analysis. Consequently, SLC6A4/5-HTT HTTLPR, BDNF rs56164415, FGF20 rs1721100, PARK16 rs823128, rs823156, rs947211, APOE e2, A2M rs669, RIT2 rs12456492, MAPT intron 9 H1H2, and STH rs62063857 variants were statistically associated with PD risk while researched variants in COMT, DBH, MAO, DAT/SLC6A3, DRD2, GRIN2B, GSK3ß, ATP13A2, LINGO1, PICALM, and GRN were not related to PD risk. CONCLUSION: Several variants from neurodegeneration-related genes are associated with PD risk, which may help deepen the understanding of PD pathogenesis and improve clinical treatment strategies.

Hinokitiol impedes tumor drug resistance by suppressing protein kinase B/mammalian targets of rapamycin axis.

Chemotherapy is a treatment method commonly used for cancer and that patients showing low to no response to the treatment often developed drug resistance via multiple mechanisms. Natural products have been shown to reduce tumor drug resistance. Hinokitiol, a natural tropolone derivative, has potential as an antitumor agent. To improve the efficacy and safety of hinokitiol, a further understanding of hinokitiol interactions with the tumor microenvironment is necessary. The presence of plasma membrane multidrug resistance protein P-glycoprotein (P-gp) is favorable for tumor cells to elicit chemotherapeutic resistance. Here, we showed that hinokitiol dose-dependently decreased P-gp expression and suppressed the P-gp-driven efflux activity based on Rhodamine 123 assay. The protein expression levels of phosph-protein kinase B (P-AKT), phosph-mammalian targets of rapamycin (P-mTOR), and phosph-p70 ribosomal s6 kinase (P-p70s6K) in tumor cells were likewise reduced after hinokitiol treatment. The transfection of cells with active P-AKT rescued hinokitiol-induced downregulation of P-gp, suggesting the involvement of Akt/mTOR/p70s6K signaling in P-gp expression. Our results showed that hinokitiol can chemosensitize cancer cells. These findings indicate that hinokitiol could enhance 5-Fluorouracil therapeutic effects in murine B16F10 and CT26 tumor cells via downregulation of the AKT/mTOR pathway.