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To evaluate whether the polygenic profile modifies the development of sporadic Alzheimer's disease (sAD) and pathological biomarkers in cerebrospinal fluid (CSF), 462 sAD patients and 463 age-matched cognitively normal (CN) controls were genotyped for 35 single-nucleotide polymorphisms (SNPs) that are significantly associated with sAD. Then, the alleles found to be associated with sAD were used to build polygenic risk score (PRS) models to represent the genetic risk. Receiver operating characteristic (ROC) analyses and the Cox proportional hazards model were used to evaluate the predictive value of PRS for the sAD risk and age at onset. We measured the CSF levels of Aβ42, Aβ42/Aβ40, total tau (T-tau), and phosphorylated tau (P-tau) in a subgroup (60 sAD and 200 CN participants), and analyzed their relationships with the PRSs. We found that 14 SNPs, including SNPs in the APOE, BIN1, CD33, EPHA1, SORL1, and TOMM40 genes, were associated with sAD risk in our cohort. The PRS models built with these SNPs showed potential for discriminating sAD patients from CN controls, and were able to predict the incidence rate of sAD and age at onset. Furthermore, the PRSs were correlated with the CSF levels of Aβ42, Aβ42/Aβ40, T-tau, and P-tau. Our study suggests that PRS models hold promise for assessing the genetic risk and development of AD. As genetic risk profiles vary among populations, large-scale genome-wide sequencing studies are urgently needed to identify the genetic risk loci of sAD in Chinese populations to build accurate PRS models for clinical practice.
ABSTRACT
BACKGROUND@#Recent studies suggest that a healthy diet helps to prevent the development of Alzheimer disease (AD). This study aimed to investigate whether spicy food consumption is associated with cognition and cerebrospinal fluid (CSF) biomarkers of AD in the Chinese population.@*METHODS@#We enrolled 55 AD patients and 55 age- and gender-matched cognitively normal (CN) subjects in a case-control study, as well as a cohort of 131 participants without subjective cognitive decline (non-AD) in a cross-sectional study. Spicy food consumption was assessed using the Food Frequency Questionnaire (FFQ). Associations of FFQ scores with cognition and CSF biomarkers of AD were analyzed.@*RESULTS@#In the case-control study, spicy food consumption was lower in AD patients than that in CNs (4.0 [4.0-8.0] vs. 8.0 [4.5-10.0], P < 0.001); FFQ scores were positively associated with Mini-Mental Status Examination scores in the total sample (r = 0.218, P = 0.014). In the cross-sectional study, the association between spicy food consumption and cognition levels was verified in non-AD subjects (r = 0.264, P = 0.0023). Moreover, higher FFQ scores were significantly associated with higher β-Amyloid (1-42) (Aβ42) levels and lower phospho-tau/Aβ42 and total tau/Aβ42 ratios in the CSF of non-AD subjects (P < 0.05).@*CONCLUSION@#Spicy food consumption is closely related to higher cognition levels and reversed AD biomarkers in the CSF, suggesting that a capsaicin-rich diet might have the potential to modify the cognitive status and cerebral pathologies associated with AD.
Subject(s)
Humans , Alzheimer Disease , Amyloid beta-Peptides , Biomarkers , Case-Control Studies , Cognition , Cross-Sectional Studies , Peptide Fragments , tau ProteinsABSTRACT
<p><b>OBJECTIVE</b>To investigate the silencing effect of gene encoding peroxisome proliferator-activated receptor gamma (PPARgamma) on the expression of tumor necrosis factor alpha (TNFalpha) by constructing vectors for RNA interference in RAW264.7 cells.</p><p><b>METHODS</b>The pSUPER-EGFP vectors were used to transcribe functional small interfering RNA (siRNA). Four pairs of oligonucleotides (64 nt) targeting PPARgamma gene were inserted into the downstream of the H1 promotor, with their veracity confirmed by double digestion and sequencing. Western blotting and immunofluorescence assay were used to examine the silencing effect of PPARgamma gene in RAW264.7 cells. Meanwhile, the TNFalphalevel was determined by Sandwich ELISA.</p><p><b>RESULTS</b>Compared with other recombinant pSUPER-EGFP vectors (R-pSUPER.EGFP), R-pSUPER.EGFP2 induced the best silencing effect on the expression of PPARgamma in RAW264.7 cells, which played an obvious inhibitory role in down-regulating the TNFalphaexpression after the curcumin and lipopolysaccharide (LPS) stimulation.</p><p><b>CONCLUSIONS</b>PPARgamma-pSUPER-EGFP inducing a silencing effect on the expression of PPARgamma can efficiently play a negative role in controlling the inflammatory responses of RAW264.7 cells.</p>
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Objective To investigate the changes of sympathovagal balance and the effects of va- gus stimulation on sympathovagal balance in endotoxemia rats.Methods Twenty-four Spragne Dawley rats were randomly divided into four groups.The frequency domain of heart rate variability(HRV)com- ponent was analyzed at 0 min,2 ,4 and 6 hours after intravenous injection of lipopolysaccharide(LPS, 5mg/kg)or physiologic saline,and cervical vagal nerve was stimulated(5mv,2ms,1Hz,5 min lasted, 20 min interval)when LPS or physiologic saline was injected.The levels of Noepinephine(NE)and Ace- tylcholin(ACh)were measured in liver tissues.Results Normalized low frequency(LFnm),hormali- zed high frequency(HFnm),very low frequency(VLF),LF/HF values and liver ACh were significantly increased(P＜0.05)and the level of liver NE was significantly decreased (P＜0.05)after LPS admin- istration.Vagal nerve stimulation markedly increased HFnm but decreased LFnm,VLF,LF/HF values, and the liver ACh also significant increased(P＜0.05 ).Conclusion The results suggest that the ac- tivity of sympathetic and vagal nerve was increased during endotoxemia,but the sympathetic activity was more excitable than that of vagal nerve.Vagal nerve stimulation increased the tone of vagus nerve while the tone of sympathetic nerve was decreased in this study.This may be beneficial for anti-inflammatory activity of vagal nerve.
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Objective To investigate the effect of cardiopulmonary bypass (CPB) on vascular endothelial cell injury and plasma endothelin-1 and nitric oxide equilibrium in patients undergoing cardiovascular operation with CPB. Methods A total of 20 patients with congenital heart disease (Group Ⅰ) and 20 with valvular problem (group Ⅱ) were operated on under CPB respectively. Blood samples were collected from central vein before skin incision, before CPB, 30 min after CPB, at the end of CPB, and end of operation, the first morning and third morning after operation. The levels of plasma thrombomodulin(TM), endothelin-1(ET-1) and nitric oxide(NO) were measured. Results The plasma TM level was significantly elevated during CPB (P<0.01, P<0.05) and 1 d after operation, reached its peak as (4.88±1.12) ng/ml in Group Ⅰand (8.34±1.84) ng/ml in group Ⅱ at the end of surgery and came back to the level as before operation. The plasma level of ET-1 was also increased significantly after CPB and reached peak as (129.04±22.29) in Group Ⅰ and (156.62±29.66) in Group Ⅱ at the end of operation. And the level was still higher than before operation in 2 groups 3 d after operation. No change was found on the level of NO in 2 groups. Conclusion CPB may cause extensive acute endothelial cells damage for about 24-48 h and recovered about 72 h and it may also cause an imbalance of ET-1 and NO.
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Objective To investigate the effect of cardiopulmonary bypass (CPB) on vascular endothelial cell injury and plasma endothelin-1 and nitric oxide equilibrium in patients undergoing cardiovascular operation with CPB. Methods A total of 20 patients with congenital heart disease (Group Ⅰ) and 20 with valvular problem (group Ⅱ) were operated on under CPB respectively. Blood samples were collected from central vein before skin incision, before CPB, 30 min after CPB, at the end of CPB, and end of operation, the first morning and third morning after operation. The levels of plasma thrombomodulin(TM), endothelin-1(ET-1) and nitric oxide(NO) were measured. Results The plasma TM level was significantly elevated during CPB (P<0.01, P<0.05) and 1 d after operation, reached its peak as (4.88±1.12) ng/ml in Group Ⅰand (8.34±1.84) ng/ml in group Ⅱ at the end of surgery and came back to the level as before operation. The plasma level of ET-1 was also increased significantly after CPB and reached peak as (129.04±22.29) in Group Ⅰ and (156.62±29.66) in Group Ⅱ at the end of operation. And the level was still higher than before operation in 2 groups 3 d after operation. No change was found on the level of NO in 2 groups. Conclusion CPB may cause extensive acute endothelial cells damage for about 24-48 h and recovered about 72 h and it may also cause an imbalance of ET-1 and NO.