Multicenter Validation of lncRNA and Target mRNA Diagnostic and Prognostic Biomarkers of Acute Ischemic Stroke From Peripheral Blood Leukocytes.

BACKGROUND: Long noncoding RNA (lncRNA) and mRNA profiles in leukocytes have shown potential as biomarkers for acute ischemic stroke (AIS). This study aimed to identify altered lncRNA and target mRNA profiles in peripheral blood leukocytes as biomarkers and to assess the diagnostic value and association with AIS prognosis. METHODS AND RESULTS: Differentially expressed lncRNAs (DElncRNAs) and differentially expressed target mRNAs (DEmRNAs) were screened by RNA sequencing in the discovery set, which consisted of 10 patients with AIS and 20 controls. Validation sets consisted of a multicenter (311 AIS versus 303 controls) and a nested case-control study (351 AIS versus 352 controls). The discriminative value of DElncRNAs and DEmRNAs added to the traditional risk factors was estimated with the area under the curve. NAMPT-AS, FARP1-AS1, FTH1, and NAMPT were identified in the multicenter case-control study (P<0.05). LncRNA NAMPT-AS was associated with cis-target mRNA NAMPT and trans-target mRNA FTH1 in all validation sets (P<0.001). Similarly, AIS cases exhibited upregulated lncRNA FARP-AS1 and FTH1 expression (P<0.001) in the nested case-control study (P<0.001). Furthermore, lncRNA FARP1-AS1 expression was upregulated in AIS patients at discharge with an unfavorable outcome (P<0.001). Positive correlations were found between NAMPT expression level and NIHSS scores of AIS patients (P<0.05). Adding 2 lncRNAs and 2 target mRNAs to the traditional risk factor model improved area under the curve by 22.8% and 5.2% in the multicenter and the nested case-control studies, respectively. CONCLUSIONS: lncRNA NAMPT-AS and FARP1-AS1 have potential as diagnostic biomarkers for AIS and exhibit good performance when combined with target mRNA NAMPT and FTH1.

Interactive effect of increased high sensitive C-reactive protein and dyslipidemia on cardiovascular diseases: a 12-year prospective cohort study.

BACKGROUND: Dyslipidemia and inflammation are significant factors for the onset of cardiovascular diseases (CVD); however, studies regarding their interactions on the risk of CVD are scarce. This study aimed to assess the interaction of dyslipidemia and high-sensitivity C-reactive protein (hs-CRP) on CVD. METHODS: This prospective cohort enrolled 4,128 adults at baseline in 2009 and followed them up until May 2022 for collecting CVD events. Cox-proportional hazard regression analysis estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) of the associations of increased hs-CRP (≥ 1 mg/L) and dyslipidemia with CVD. The additive interactions were explored using the relative excess risk of interaction (RERI) and the multiplicative interactions were assessed with HRs (95% CI) while the multiplicative interactions were assessed by the HRs (95% CI) of interaction terms. RESULTS: The HRs of the association between increased hs-CRP and CVD were 1.42 (95% CI: 1.14-1.79) and 1.17 (95% CI: 0.89-1.53) among subjects with normal lipid levels and subjects with dyslipidemia, respectively. Stratified analyses by hs-CRP levels showed that among participants with normal hs-CRP (< 1 mg/L), TC ≥ 240 mg/dL, LDL-C ≥ 160 mg/dL, non-HDL-C ≥ 190 mg/dL, ApoB < 0.7 g/L, and LDL/HDL-C ≥ 2.02 were associated with CVD [HRs (95%CIs): 1.75 (1.21-2.54), 2.16 (1.37-3.41), 1.95 (1.29-2.97), 1.37 (1.01-1.67), and 1.30 (1.00-1.69), all P < 0.05, respectively]. While in the population with increased hs-CRP, only ApoAI > 2.10 g/L had a significant association with CVD [HR (95% CI): 1.69 (1.14-2.51)]. Interaction analyses showed that increased hs-CRP had multiplicative and additive interactions with LDL-C ≥ 160 mg/dL and non-HDL-C ≥ 190 mg/dL on the risk of CVD [HRs (95%CIs): 0.309 (0.153-0.621), and 0.505 (0.295-0.866); RERIs (95%CIs): -1.704 (-3.430-0.021 and - 0.694 (-1.476-0.089), respectively, all P < 0.05]. CONCLUSION: Overall our findings indicate negative interactions between abnormal blood lipid levels and hs-CRP on the risk of CVD. Further large-scale cohort studies with trajectories measurement of lipids and hs-CRP might verify our results as well explore the biological mechanism behind that interaction.

Sex and age differences in the association between high sensitivity C-reactive protein and all-cause mortality: A 12-year prospective cohort study.

To explore the influence of age on hs-CRP among men and women and investigate the impact of hs-CRP on all-cause death, this prospective cohort enrolled 4128 community adults from 2009 to 2022 for all-cause death. Age and sex-specific hs-CRP percentile curves were generated using the GAMLSS method. Cox-proportional hazard regression analysis was applied to estimate the hazard ratios (HRs) and 95 % confidence intervals (CIs). During the follow-up with a median of 12.59 years, 701 cases of all-cause death were identified. Among men, the smoothed centile curves of hs-CRP gradually increased from age 35 onwards whereas, the smoothed centile curves of hs-CRP continuously increased as age increased among women. Compared with the reference group, the adjusted HR of the association between elevated hs-CRP and all-cause death was 1.33 (95 % CI: 1.11-1.61). The adjusted HRs of the associations between elevated hs-CRP and all-cause death were higher in women [1.40 (95 % CI: 1.07-1.83)] than men [1.28 (95 % CI: 0.99-1.65) and in subjects aged < 65 years [1.77 (95 % CI: 1.19-2.62)] than in subjects aged ≥ 65 years [1.27 (95 % CI: 1.03-1.57)]. Our findings highlight the need of investigating sex and age differences in biological pathways that link inflammation and mortality.

The relationship between lipid risk score and new-onset hypertension in a prospective cohort study.

Background: Dyslipidemia and hypertension are both important risk factors for atherosclerotic cardiovascular diseases. However, the relationship between dyslipidemia and incident hypertension remains to be elucidated comprehensively. The main purpose of this study was to construct the lipid risk score to explore the risk prediction effect of integrated lipid indices on new-onset hypertension. Methods: This prospective cohort study with 2116 non-hypertensive subjects was conducted from 2009 to 2020. New hypertension events during the follow-up period were recorded and verified. The lipid risk score was calculated by summing coded total cholesterol, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol weighted with corresponding effect sizes. Cox regression analysis was used to estimate the association between the lipid risk score or lipid indices and incident hypertension in the subgroup of age (< 55 and≥ 55 years at baseline). Results: After a median of 10.75-year follow-up, 637 incident hypertension cases were identified. The restricted cubic spline showed that the lipid risk score had a positive linear correlation with hypertension (P< 0.001). Among people< 55 years, with every increase of 0.94 in lipid risk score, the risk of hypertension increased by 37% (adjusted HR [95%CI]: 1.369 [1.164-1.610]). This association was not modified by overweight or obesity. Conclusions: The integrated lipid risk score, independent of traditional risk factors, has a significantly predictive effect on hypertension in people younger than 55 years. This finding may aid in identifying high-risk individuals for hypertension, as well as facilitating early intervention and management to reduce adverse cardiovascular events. Comprehensive lipid management should be attached importance in the prevention and control of hypertension.

Interaction Analysis of Abnormal Lipid Indices and Hypertension for Ischemic Stroke: A 10-Year Prospective Cohort Study.

Background: Dyslipidemia and hypertension are two important independent risk factors for ischemic stroke (IS); however, their combined effect on IS remains uncertain. Objectives: This present study aimed to evaluate the interaction effect of hypertension and abnormal lipid indices on IS in a 10-year prospective cohort in Chinese adults. Methods: The cohort study of 4,128 participants was conducted in May 2009 and was followed up to July 2020. All qualified participants received a questionnaire survey, physical examination, and blood sample detection. Cox regression was used to evaluate the association of dyslipidemia and hypertension with IS, and calculate the hazard ratio (HR) and 95% confidence interval (CI). The relative excess risk of interaction (RERI) and the HR (95%CI) of interaction terms were used to examine additive and multiplicative interactions. Results: In the hypertensive population, Non-HDL-C ≥190 mg/dl, LDL-C/HDL-C ≥2 and HDL-C ≥60 mg/dl were statistically associated with IS, and after adjusting for covariates, HRs (95%CIs) were 1.565 (1.007-2.429), 1.414 (1.034-1.933) and 0.665 (0.450-0.983), respectively. While in the non-hypertension population, no significant association of Non-HDL-C ≥190 mg/dl, LDL-C/HDL-C ≥2, and HDL-C ≥60 was detected with IS (P > 0.05). There was a significant association between TC/HDL-C ≥ 3.6 and the decreased risk of IS in the non-hypertension population, and the HR (95%CI) was 0.479 (0.307-0.750). Whereas, a similar association was not observed in the hypertensive population. HDL-C ≥ 60 mg/dl, Non-HDL-C ≥ 190 mg/dl, TC/HDL-C ≥ 3.6, and TG/HDL-C ≥ 1 have additive and multiplicative interactions with hypertension (P < 0.05). The RERIs (95% CIs) of the additive interaction are -0.93 (-1.882-0.044), 1.394 (0.38-2.407), 0.752 (0.354-1.151) and 0.575 (0.086-1.065), respectively. The HRs (95% CIs) of the multiplicative interaction terms were 0.498 (0.272-0.911), 4.218 (1.230-14.464), 2.423 (1.437-4.086) and 1.701 (1.016-2.848), respectively. Conclusion: High concentration of HDL-C reduces the impact of hypertension on IS, while the high concentration of Non-HDL-C, TC/HDL-C, and TG/HDL-C positively interact with hypertension affecting the incidence of IS. This study provides useful evidence for the combined effects of dyslipidemia and hypertension in predicting IS.

Inokosterone Is A Potential Drug Target of Estrogen Receptor 1 in Rheumatoid Arthritis Patients: Analysis from Active Ingredient of Cyathula Officinalis.

OBJECTIVE: To elucidate the active compounds and the molecular mechanism of Cyathula Officinalis as a drug treatment for rheumatoid arthritis (RA). METHODS: The target genes of active ingredients from Cyathula Officinalis were obtained from bioinformatics analysis tool for the molecular mechanism of traditional Chinese medicine. The protein-protein interaction between the target genes were analyzed using STRING and Genemania. The transcriptome of RA patients compared to healthy people (GSE121894) were analyzed using R program package Limma. The relative expression of the target genes was obtained from the RNA-seq datasets. The molecular docking analyses were processed based on the molecular model of estrogen receptor 1 (ESR1) binding with estradiol (PDB ID:1A52). The binding details were analyzed by SYBYL. RESULTS: Inokosterone, ecdysterone, and cyaterone were the 3 active ingredients from Cyathula Officinalis that bind to target genes. Of all the significantly changed genes from RA patients, ESR1, ADORA1, and ANXA1 were significantly increased in mRNA samples of RA patients. CONCLUSION: ESR1, the transcription factor that binds inokosterone in the molecular binding analysis, is the target protein of Cyathula Officinalis.