Monocyte chemoattractant protein-1 (MCP-1, also known as chemokine CCL2) is a vital chemokine that mediates inflammation in Alzheimer's disease (AD). We analyzed the associations between the baseline ...plasma MCP-1 level, longitudinal cognitive changes, and genetic effects of CCL2 rs1024611 and its receptor, CC-chemokine receptor 2 (CCR2) rs1799864, in AD. In total, 310 AD patients and 66 mild cognitive impairment (MCI) patients were followed for 2 years, and 120 controls were recruited at baseline for comparison. After adjusting for covariates using one-way analysis of covariance, AD patients had higher plasma MCP-1 levels compared with MCI patients and controls, and severe AD patients had the highest levels. After adjusting for covariates using generalized estimating equation analysis, the results showed that the baseline MCP-1 level was significantly correlated with changes in the two-year Mini-Mental Status Examination (p = 0.046). The A allele of CCR2 rs1799864 was associated with a higher MCP-1 level in AD and MCI patients. In conclusion, plasma MCP-1 might reflect the risk and disease course of AD. A higher plasma MCP-1 level is associated with greater severity and faster cognitive decline. Additionally, the CCR2 polymorphism may play a role in the regulation of MCP-1/CCR2 signaling in AD.
Objective
To evaluate human glymphatics and meningeal lymphatics noninvasively.
Methods
This prospective study implemented 3‐dimensional (3D) isotropic contrast‐enhanced T2 fluid‐attenuated inversion ...recovery (CE‐T2‐FLAIR) imaging with a 3T magnetic resonance machine to study cerebral glymphatics and meningeal lymphatics in patients with reversible cerebral vasoconstriction syndrome (RCVS) with (n = 92) or without (n = 90) blood–brain barrier (BBB) disruption and a diseased control group with cluster headache (n = 35). The contrast agent gadobutrol (0.2mmol/kg 0.2ml/kg) was administered intravenously in all study subjects.
Results
In total, 217 patients (182 RCVS, 35 cluster headache) were analyzed and separated into 2 groups based on the presence or absence of visible gadolinium (Gd) leakage. Para‐arterial tracer enrichment was clearly depicted in those with overt BBB disruption, while paravenous and parasinus meningeal contrast enrichment was evident in both groups. Paravenous and parasinus contrast enrichment remained in RCVS patients in the remission stage and in cluster headache patients, suggesting that these meningeal lymphatic channels were universal anatomical structures rather than being phase‐ or condition‐specific. Additionally, we demonstrated nodular leptomeningeal enhancement in 32.3% of participants, which might represent potential lymphatic reservoirs. Four selected RCVS patients who received consecutive contrasted 3D isotropic FLAIR imaging after gadobutrol administration showed that the Gd persisted for at least 54 minutes and was completely cleared within 18 hours.
Interpretation
This large‐scale in vivo study successfully demonstrated the putative human para‐arterial glymphatic transports and meningeal lymphatics by clear depiction of para‐arterial, parasinus, and paravenous meningeal contrast enrichment using high‐resolution 3D isotropic CE‐T2‐FLAIR imaging noninvasively; this technique may serve as a basis for further studies to delineate clinical relevance of glymphatic clearance. ANN NEUROL 2021;89:111–124
Obesity has been associated with cognition in observational studies; however, whether its effect is confounding or a reverse causality remains inconclusive. This study aimed to investigate the causal ...relationships of overall obesity, measured by body mass index (BMI), and abdominal adiposity, measured by waist-hip ratio adjusted for BMI (WHRadjBMI), and cognition across European and Asian populations using Mendelian randomization (MR) analysis.
We used publicly available genome-wide association study (GWAS) summary data of European ancestry, including BMI (n = 322,154) and WHRadjBMI (n = 210,088) from the GIANT consortium, and cognition performance (n = 257,828) from the UK Biobank and COGENT consortium. Data for individuals of Asian ancestry were retrieved from Taiwan Biobank to perform GWAS for BMI (n = 65,689), WHRadjBMI (n = 65,683), and Mini-Mental State Examination (MMSE, n = 21,273). MR analysis was carried out using the inverse-variance weighted method for the main results. Further, we examined the overall pleiotropy by MR-Egger intercept, and detected and adjusted for possible outliers using MR PRESSO.
No causal effect of BMI on cognition performance (beta 95% CI = 0.00 -0.07, 0.07, p value = 0.91) was found for Europeans; however, a 1-SD increase in WHRadjBMI was associated with a 0.07 standardized score decrease in cognition performance (beta 95% CI = -0.07 -0.12, -0.02, p value = 0.006). Further, no causal effect of BMI on MMSE (beta 95% CI = 0.01 -0.08, 0.10, p = 0.91) was found for Asians; however, a 1-SD increase in WHRadjBMI was associated with a 0.17 standardized score decrease in MMSE (beta 95% CI = -0.17 -0.30, -0.03, p = 0.02). In both populations, overall pleiotropy was not detected, and outliers did not affect the robustness of the main findings.
This trans-ethnic MR study reveals that abdominal adiposity, as measured by WHR adjusted for BMI, impairs cognition, whereas weak evidence suggests that BMI impairs cognition.
Background and Purpose
Atherosclerosis, resulting from lipid dysregulation and vascular inflammation, causes atherosclerotic cardiovascular disease (ASCVD), which contributes to morbidity and ...mortality worldwide. Chalcone and its derivatives possess beneficial properties, including anti‐inflammatory, antioxidant and antitumour activity with unknown cardioprotective effects. We aimed to develop an effective chalcone derivative with antiatherogenic potential.
Experimental Approach
Human THP‐1 cells and HUVECs were used as in vitro models. Western blots and real‐time PCRs were performed to quantify protein, mRNA and miRNA expressions. The cholesterol efflux capacity was assayed by 3H labelling of cholesterol. LDL receptor knockout (Ldlr−/−) mice fed a high‐fat diet were used as an in vivo atherogenesis model. Haematoxylin and eosin and oil red O staining were used to analyse plaque formation.
Key Results
Using ATP‐binding cassette transporter A1 (ABCA1) expression we identified the chalcone derivative, 1m‐6, which enhances ABCA1 expression and promotes cholesterol efflux in THP‐1 macrophages. Moreover, 1m‐6 stabilizes ABCA1 mRNA and suppresses the expression of potential ABCA1‐regulating miRNAs through nuclear factor erythroid 2‐related factor 2 (Nrf2)/haem oxygenase‐1 (HO‐1) signalling. Additionally, 1m‐6 significantly inhibits TNF‐α‐induced expression of adhesion molecules, vascular cell adhesion molecule 1 (VCAM‐1) and intercellular adhesion molecule 1 (ICAM‐1), plus production of proinflammatory cytokines via inhibition of JAK/STAT3 activation and the modulation of Nrf2/HO‐1 signalling in HUVECs. In atherosclerosis‐prone mice, 1m‐6 significantly reduces lipid accumulation and atherosclerotic plaque formation.
Conclusion and Implications
Our study demonstrates that 1m‐6 produces promising atheroprotective effects by enhancing cholesterol efflux and suppressing inflammation‐induced endothelial dysfunction, which opens a new avenue for treating ASCVD.
LINKED ARTICLES
This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc
We found that GroEL in Porphyromonas gingivalis accelerated tumor growth and increased mortality in tumor‐bearing mice; GroEL promoted proangiogenic function, which may be the reason for promoting ...tumor growth. To understand the regulatory mechanisms by which GroEL increases the proangiogenic function of endothelial progenitor cells (EPCs), we explored in this study. In EPCs, MTT assay, wound‐healing assay, and tube formation assay were performed to analyze its activity. Western blot and immunoprecipitation were used to study the protein expression along with next‐generation sequencing for miRNA expression. Finally, a murine tumorigenesis animal model was used to confirm the results of in vitro. The results indicated that thrombomodulin (TM) direct interacts with PI3K/Akt to inhibit the activation of signaling pathways. When the expression of TM is decreased by GroEL stimulation, molecules in the PI3K/Akt signaling axis are released and activated, resulting in increased migration and tube formation of EPCs. In addition, GroEL inhibits TM mRNA expression by activating miR‐1248, miR‐1291, and miR‐5701. Losing the functions of miR‐1248, miR‐1291, and miR‐5701 can effectively alleviate the GroEL‐induced decrease in TM protein levels and inhibit the proangiogenic abilities of EPCs. These results were also confirmed in animal experiments. In conclusion, the intracellular domain of the TM of EPCs plays a negative regulatory role in the proangiogenic capabilities of EPCs, mainly through direct interaction between TM and PI3K/Akt to inhibit the activation of signaling pathways. The effects of GroEL on tumor growth can be reduced by inhibiting the proangiogenic properties of EPCs through the inhibition of the expression of specific miRNAs.
The aim of this study was to investigate the functional networks in subjects with reversible cerebral vasoconstriction syndrome (RCVS) using resting-state functional magnetic resonance imaging ...(rs-fMRI).
We prospectively recruited patients with RCVS and healthy controls (HCs) between February 2017 and April 2021. The rs-fMRI data were analyzed using graph theory methods. We compared node-based global and regional topological metrics (Bundle 1) and network-based intranetwork and internetwork connectivity (Bundle 2) between RCVS patients and HCs. We also explored the associations of clinical and vascular (ie, the Lindegaard index, LI) parameters with significant rs-fMRI metrics.
A total of 104 RCVS patients and 93 HCs were included in the final analysis. We identified significantly decreased local efficiency of the left dorsal anterior insula (dAI; p = 0.0005) in RCVS patients within 30 days after disease onset as compared to HCs, which improved 1 month later. RCVS patients also had increased global efficiency (p = 0.009) and decreased average degree centrality (p = 0.045), clustering coefficient (p = 0.033), and assortativity values (p = 0.003) in node-based analysis. In addition, patients with RCVS had increased internetwork connectivity of the default mode network (DMN) with the salience (p = 0.027) and dorsal attention (p = 0.016) networks. Significant correlations between LI and regional local efficiency in left dAI (r
= -0.418, p = 0.042) was demonstrated.
The significantly lower local efficiency of the left dAI, suggestive of impaired central autonomic modulation, was negatively correlated with vasoconstriction severity, which is highly plausible for the pathogenesis of RCVS. ANN NEUROL 2023.
Genome-wide association studies (GWASs) have been mostly conducted in populations of European ancestry, which currently limits the transferability of their findings to other populations. Here, we ...show, through theory, simulations and applications to real data, that adjustment of GWAS analyses for polygenic scores (PGSs) increases the statistical power for discovery across all ancestries. We applied this method to analyze seven traits available in three large biobanks with participants of East Asian ancestry (n = 340,000 in total) and report 139 additional associations across traits. We also present a two-stage meta-analysis strategy whereby, in contributing cohorts, a PGS-adjusted GWAS is rerun using PGSs derived from a first round of a standard meta-analysis. On average, across traits, this approach yields a 1.26-fold increase in the number of detected associations (range 1.07- to 1.76-fold increase). Altogether, our study demonstrates the value of using PGSs to increase the power of GWASs in underrepresented populations and promotes such an analytical strategy for future GWAS meta-analyses.
Therapeutic elevation of high-density lipoprotein (HDL) is thought to minimize atherogenesis in subjects with dyslipidemia. However, this is not the case in clinical practice. The function of HDL is ...not determined by its concentration in the plasma but by its specific structural components. We previously identified an index for the prediction of HDL functionality, relative HDL (rHDL) index, and preliminarily explored that dysfunctional HDL (rHDL index value > 2) failed to rescue the damage to endothelial progenitor cells (EPCs). To confirm the effectiveness of the rHDL index for predicting HDL functions, here we evaluated the effects of HDL from patients with different rHDL index values on the endothelial–mesenchymal transition (EndoMT) of EPCs. We also analyzed the lipid species in HDL with different rHDL index values and investigated the structural differences that affect HDL functions. The results indicate that HDL from healthy adults and subjects with an rHDL index value < 2 protected transforming growth factor (TGF)-β1-stimulated EndoMT by modulating Smad2/3 and Snail activation. HDL from subjects with an rHDL index value > 2 failed to restore the functionality of TGF-β1-treated EPCs. Lipidomic analysis demonstrated that HDL with different rHDL index values may differ in the composition of triglycerides, phosphatidylcholine, and phosphatidylinositol. In conclusion, we confirmed the applicability of the rHDL index value to predict HDL function and found structural differences that may affect the function of HDL, which warrants further in-depth studies.
Previous studies have shown an increase of insulin-like growth factor-2 (IGF2) in animal models of neuropathic pain. We aimed to examine the hypothesis that reducing the expression of IGF2 using ...intrathecal IGF2 small-interfering RNA (siRNA) would attenuate the development of neuropathic pain in rats after spared nerve injury (SNI). Male Wistar rats were divided into three groups: sham-operated group, in which surgery was performed to cut the muscles without injuring the nerves; SNI group, in which SNI surgery was performed to sever the nerves; and SNI + siRNA IGF2 group, in which SNI surgery was performed, and IGF2-siRNA was administered intrathecally 1 day after SNI. The rats were assessed for mechanical allodynia and cold allodynia 1 day before surgery (baseline), and at 2, 4, 6, 8, and 10 days after siRNA treatment. The rat spinal cord was collected for quantitative polymerase chain reaction and western blot analysis. Compared with the SNI group, rats that received IGF2 siRNA showed a significantly increased SNI-induced paw-withdrawal threshold to metal filament stimulation from Day 4 to Day 10 after SNI surgery. IGF2 siRNA significantly decreased the response duration from the acetone test from Day 2 to Day 10 following SNI surgery. SNI increased IGF2 mRNA expression on Day 2 and increased IGF2 protein expression on Day 8 and Day 10 in the spinal cord of the SNI rats. However, the above-mentioned effects of IGF2 mRNA and protein expression were significantly inhibited in the SNI + IGF2 siRNA group. We demonstrated that intrathecal administration of IGF2 siRNA provided significant inhibition of SNI-induced neuropathic pain via inhibition of IGF2 expression in the spinal cord. The analgesic effect lasted for 10 days. Further exploration of intrathecal IGF2 siRNA administration as a potential therapeutic strategy for neuropathic pain is warranted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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