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Neuroscience Jun 2024N6-methyladenosine (m6A) is one of the most extensive RNA methylation modifications in eukaryotes and participates in the pathogenesis of numerous diseases including...
BACKGROUND
N6-methyladenosine (m6A) is one of the most extensive RNA methylation modifications in eukaryotes and participates in the pathogenesis of numerous diseases including ischemic stroke. Peripheral blood neutrophils are forerunners after ischemic brain injury and exert crucial functions. This study aims to explore the transcriptional profiles of m6A modification in neutrophils of patients with ischemic stroke.
RESULTS
We found that the expression levels of m6A regulators FTO and YTHDC1 were notably decreased in the neutrophils following ischemic stroke, and FTO expression was negatively correlated with neutrophil counts and neutrophil-to-lymphocyte ratio (NLR). The m6A mRNA&lncRNA epigenetic transcriptome microarray identified 416 significantly upregulated and 500 significantly downregulated mRNA peaks in neutrophils of ischemic stroke patients. Moreover, 48 mRNAs and 18 lncRNAs were hypermethylated, and 115 mRNAs and 29 lncRNAs were hypomethylated after cerebral ischemia. Gene ontology (GO) analyses identified that these m6A-modified mRNAs were primarily enriched in calcium ion transport, long-term synaptic potentiation, and base-excision repair. The signaling pathways involved were EGFR tyrosine kinase inhibitor resistance, ErbB, and base excision repair signaling pathway. MeRIP-qPCR validation results showed that NRG1 and GDPD1 were significantly hypermethylated, and LIG1, CHRND, lncRNA RP11-442J17.2, and lncRNA RP11-600P1.2 were significantly hypomethylated after cerebral ischemia. Moreover, the expression levels of major m6A regulators Mettl3, Fto, Ythdf1, and Ythdf3 were obviously declined in the brain and leukocytes of post-stroke mouse models.
CONCLUSION
This study explored the RNA m6A methylation pattern in the neutrophils of ischemic stroke patients, indicating that it is an intervention target of epigenetic regulation in ischemic stroke.
PubMed: 38945353
DOI: 10.1016/j.neuroscience.2024.06.014 -
The Journal of Heart and Lung... Jun 2024There are limited data depicting the prevalence and ramifications of acute limb ischemia (ALI) among cardiogenic shock (CS) patients.
BACKGROUND
There are limited data depicting the prevalence and ramifications of acute limb ischemia (ALI) among cardiogenic shock (CS) patients.
METHODS
We employed data from the Cardiogenic Shock Working Group (CSWG), a consortium including 33 sites. We constructed a multi-variable logistic regression to examine the association between clinical factors and ALI, we generated another logistic regression model to ascertain the association of ALI with mortality.
RESULTS
There were 7,070 patients with CS and 399 (5.6%) developed ALI. Patients with ALI were more likely to be female (40.4% versus 29.4%) and have peripheral arterial disease (13.8% versus 8.3%). Stratified by maximum SCAI shock stage, the rates of ALI were stage B 0.0%, stage C 1.8%, stage D 4.1%, and stage E 10.3%. Factors associated with higher risk for ALI included: peripheral vascular disease OR 2.24 (95% CI: 1.53 - 3.23; p < 0.01) and ≥ 2 mechanical circulatory support (MCS) devices OR 1.66 (95% CI: 1.24 - 2.21, p < 0.01). ALI was highest for VA-ECMO patients (11.6%) or VA-ECMO + IABP/Impella CP (16.6%) yet use of distal perfusion catheters was less than 50%. Mortality was 38.0% for CS patients without ALI but 57.4% for CS patients with ALI. ALI was significantly associated with mortality, adjusted OR 1.40 (95% CI 1.01 - 1.95, p < 0.01).
CONCLUSIONS
The rate of ALI was 6% among CS patients. Factors most associated with ALI include peripheral vascular disease and multiple MCS devices. The downstream ramifications of ALI were dire with a considerably higher risk of mortality.
PubMed: 38944132
DOI: 10.1016/j.healun.2024.06.012 -
Journal of Imaging Informatics in... Jun 2024To assess the effectiveness of the vViT model for predicting postoperative renal function decline by leveraging clinical data, medical images, and image-derived...
Predicting EGFR Status After Radical Nephrectomy or Partial Nephrectomy for Renal Cell Carcinoma on CT Using a Self-attention-based Model: Variable Vision Transformer (vViT).
OBJECTIVE
To assess the effectiveness of the vViT model for predicting postoperative renal function decline by leveraging clinical data, medical images, and image-derived features; and to identify the most dominant factor influencing this prediction.
MATERIALS AND METHODS
We developed two models, eGFR10 and eGFR20, to identify patients with a postoperative reduction in eGFR of more than 10 and more than 20, respectively, among renal cell carcinoma patients. The eGFR10 model was trained on 75 patients and tested on 27, while the eGFR20 model was trained on 77 patients and tested on 24. The vViT model inputs included class token, patient characteristics (age, sex, BMI), comorbidities (peripheral vascular disease, diabetes, liver disease), habits (smoking, alcohol), surgical details (ischemia time, blood loss, type and procedure of surgery, approach, operative time), radiomics, and tumor and kidney imaging. We used permutation feature importance to evaluate each sector's contribution. The performance of vViT was compared with CNN models, including VGG16, ResNet50, and DenseNet121, using McNemar and DeLong tests.
RESULTS
The eGFR10 model achieved an accuracy of 0.741 and an AUC-ROC of 0.692, while the eGFR20 model attained an accuracy of 0.792 and an AUC-ROC of 0.812. The surgical and radiomics sectors were the most influential in both models. The vViT had higher accuracy and AUC-ROC than VGG16 and ResNet50, and higher AUC-ROC than DenseNet121 (p < 0.05). Specifically, the vViT did not have a statistically different AUC-ROC compared to VGG16 (p = 1.0) and ResNet50 (p = 0.7) but had a statistically different AUC-ROC compared to DenseNet121 (p = 0.87) for the eGFR10 model. For the eGFR20 model, the vViT did not have a statistically different AUC-ROC compared to VGG16 (p = 0.72), ResNet50 (p = 0.88), and DenseNet121 (p = 0.64).
CONCLUSION
The vViT model, a transformer-based approach for multimodal data, shows promise for preoperative CT-based prediction of eGFR status in patients with renal cell carcinoma.
PubMed: 38940889
DOI: 10.1007/s10278-024-01180-0 -
Arteriosclerosis, Thrombosis, and... Jun 2024Despite being in an oxygen-rich environment, endothelial cells (ECs) use anaerobic glycolysis (Warburg effect) as the primary metabolic pathway for cellular energy...
BACKGROUND
Despite being in an oxygen-rich environment, endothelial cells (ECs) use anaerobic glycolysis (Warburg effect) as the primary metabolic pathway for cellular energy needs. PFKFB (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase)-3 regulates a critical enzymatic checkpoint in glycolysis and has been shown to induce angiogenesis. This study builds on our efforts to determine the metabolic regulation of ischemic angiogenesis and perfusion recovery in the ischemic muscle.
METHODS
Hypoxia serum starvation (HSS) was used as an in vitro peripheral artery disease (PAD) model, and hind limb ischemia by femoral artery ligation and resection was used as a preclinical PAD model.
RESULTS
Despite increasing PFKFB3-dependent glycolysis, HSS significantly decreased the angiogenic capacity of ischemic ECs. Interestingly, inhibiting PFKFB3 significantly induced the angiogenic capacity of HSS-ECs. Since ischemia induced a significant in PFKFB3 levels in hind limb ischemia muscle versus nonischemic, we wanted to determine whether glucose bioavailability (rather than PFKFB3 expression) in the ischemic muscle is a limiting factor behind impaired angiogenesis. However, treating the ischemic muscle with intramuscular delivery of D-glucose or L-glucose (osmolar control) showed no significant differences in the perfusion recovery, indicating that glucose bioavailability is not a limiting factor to induce ischemic angiogenesis in experimental PAD. Unexpectedly, we found that shRNA-mediated PFKFB3 inhibition in the ischemic muscle resulted in a numerical increase in perfusion recovery and significantly higher vascular density compared with control shRNA (consistent with the increased angiogenic capacity of PFKFB3 silenced HSS-ECs). Based on these data, we hypothesized that inhibiting HSS-induced PFKFB3 in ischemic ECs activates alternative metabolic pathways that revascularize the ischemic muscle in experimental PAD. A comprehensive glucose metabolic gene qPCR arrays in PFKFB3 silenced HSS-ECs, and PFKFB3-inhibited ischemic muscle versus respective controls identified UGP2 (uridine diphosphate-glucose pyrophosphorylase 2), a regulator of protein glycosylation and glycogen synthesis, is induced upon PFKFB3 inhibition in vitro and in vivo. Antibody-mediated inhibition of UGP2 in the ischemic muscle significantly impaired perfusion recovery versus IgG control. Mechanistically, supplementing uridine diphosphate-glucose, a metabolite of UGP2 activity, significantly induced HSS-EC angiogenic capacity in vitro and enhanced perfusion recovery in vivo by increasing protein glycosylation (but not glycogen synthesis).
CONCLUSIONS
Our data present that inhibition of maladaptive PFKFB3-driven glycolysis in HSS-ECs is necessary to promote the UGP2-uridine diphosphate-glucose axis that enhances ischemic angiogenesis and perfusion recovery in experimental PAD.
PubMed: 38934117
DOI: 10.1161/ATVBAHA.124.320665 -
Frontiers in Molecular Neuroscience 2024Stroke is a devastating disease with high morbidity, disability, and mortality, among which ischemic stroke is more common. However, there is still a lack of effective... (Review)
Review
Stroke is a devastating disease with high morbidity, disability, and mortality, among which ischemic stroke is more common. However, there is still a lack of effective methods to improve the prognosis and reduce the incidence of its complications. At present, there is evidence that peripheral organs are involved in the inflammatory response after stroke. Moreover, the interaction between central and peripheral inflammation includes the activation of resident and peripheral immune cells, as well as the activation of inflammation-related signaling pathways, which all play an important role in the pathophysiology of stroke. In this review, we discuss the mechanisms of inflammatory response after ischemic stroke, as well as the interactions through circulatory pathways between peripheral organs (such as the gut, heart, lung and spleen) and the brain to mediate and regulate inflammation after ischemic stroke. We also propose the potential role of meningeal lymphatic vessels (MLVs)-cervical lymph nodes (CLNs) as a brain-peripheral crosstalk lymphatic pathway in ischemic stroke. In addition, we also summarize the mechanisms of anti-inflammatory drugs in the treatment of ischemic stroke.
PubMed: 38932932
DOI: 10.3389/fnmol.2024.1400808 -
Microorganisms Jun 2024Exposure to passive heat (acclimation) and exercise under hot conditions (acclimatization), known as heat acclimation (HA), are methods that athletes include in their... (Review)
Review
Exposure to passive heat (acclimation) and exercise under hot conditions (acclimatization), known as heat acclimation (HA), are methods that athletes include in their routines to promote faster recovery and enhance physiological adaptations and performance under hot conditions. Despite the potential positive effects of HA on health and physical performance in the heat, these stimuli can negatively affect gut health, impairing its functionality and contributing to gut dysbiosis. Blood redistribution to active muscles and peripheral vascularization exist during exercise and HA stimulus, promoting intestinal ischemia. Gastrointestinal ischemia can impair intestinal permeability and aggravate systemic endotoxemia in athletes during exercise. Systemic endotoxemia elevates the immune system as an inflammatory responses in athletes, impairing their adaptive capacity to exercise and their HA tolerance. Better gut microbiota health could benefit exercise performance and heat tolerance in athletes. This article suggests that: (1) the intestinal modifications induced by heat stress (HS), leading to dysbiosis and altered intestinal permeability in athletes, can decrease health, and (2) a previously acquired microbial dysbiosis and/or leaky gut condition in the athlete can negatively exacerbate the systemic effects of HA. Maintaining or improving the healthy gut microbiota in athletes can positively regulate the intestinal permeability, reduce endotoxemic levels, and control the systemic inflammatory response. In conclusion, strategies based on positive daily habits (nutrition, probiotics, hydration, chronoregulation, etc.) and preventing microbial dysbiosis can minimize the potentially undesired effects of applying HA, favoring thermotolerance and performance enhancement in athletes.
PubMed: 38930542
DOI: 10.3390/microorganisms12061160 -
Journal of Clinical Medicine Jun 2024Myokines have been demonstrated to be associated with cardiovascular diseases; however, they have not been studied as biomarkers for peripheral artery disease (PAD). We...
Myokines have been demonstrated to be associated with cardiovascular diseases; however, they have not been studied as biomarkers for peripheral artery disease (PAD). We identified interleukin-7 (IL-7) as a prognostic biomarker for PAD from a panel of myokines and developed predictive models for 2-year major adverse limb events (MALEs) using clinical features and plasma IL-7 levels. A prognostic study was conducted with a cohort of 476 patients (312 with PAD and 164 without PAD) that were recruited prospectively. Their plasma concentrations of five circulating myokines were measured at recruitment, and the patients were followed for two years. The outcome of interest was two-year MALEs (composite of major amputation, vascular intervention, or acute limb ischemia). Cox proportional hazards analysis was performed to identify IL-7 as the only myokine that was associated with 2-year MALEs. The data were randomly divided into training (70%) and test sets (30%). A random forest model was trained using clinical characteristics (demographics, comorbidities, and medications) and plasma IL-7 levels with 10-fold cross-validation. The primary model evaluation metric was the F1 score. The prognostic model was used to classify patients into low vs. high risk of developing adverse limb events based on the Youden Index. Freedom from MALEs over 2 years was compared between the risk-stratified groups using Cox proportional hazards analysis. Two-year MALEs occurred in 28 (9%) of patients with PAD. IL-7 was the only myokine that was statistically significantly correlated with two-year MALE (HR 1.56 [95% CI 1.12-1.88], = 0.007). For the prognosis of 2-year MALEs, our model achieved an F1 score of 0.829 using plasma IL-7 levels in combination with clinical features. Patients classified as high-risk by the predictive model were significantly more likely to develop MALEs over a 2-year period (HR 1.66 [95% CI 1.22-1.98], = 0.006). From a panel of myokines, IL-7 was identified as a prognostic biomarker for PAD. Using a combination of clinical characteristics and plasma IL-7 levels, we propose an accurate predictive model for 2-year MALEs in patients with PAD. Our model may support PAD risk stratification, guiding clinical decisions on additional vascular evaluation, specialist referrals, and medical/surgical management, thereby improving outcomes.
PubMed: 38930112
DOI: 10.3390/jcm13123583 -
Life (Basel, Switzerland) May 2024Acute limb ischaemia (ALI) is of great clinical importance due to its consequent serious complications and high comorbidity and mortality rates. The purpose of this...
Acute limb ischaemia (ALI) is of great clinical importance due to its consequent serious complications and high comorbidity and mortality rates. The purpose of this study was to compare the acute success and complication rates of CDT performed via transradial, transbrachial, and transfemoral access sites in patients with acute lower limb vascular occlusion and to investigate the 1-year outcomes of CDT and MT for ALI. Between 2008 and 2019, 84 consecutive patients with ALI were treated with CDT in a large community hospital. Data were collected and retrospectively analysed. The primary ("safety") endpoints encompassed major adverse events (MAEs), major adverse limb events (MALEs), and the occurrence of complications related to the access site. Secondary ("efficacy") endpoints included both technical and clinical achievements, treatment success, fluoroscopy time, radiation dose, procedure time, and the crossover rate to an alternative puncture site. CDT was started with radial ( = 17), brachial ( = 9), or femoral ( = 58) access. CDT was technically successful in 74/84 patients (88%), but additional MT and angioplasty and/or stent implantation was necessary in 17 (20.2%) and 45 cases (53.6%), respectively. Clinical success was achieved in 74/84 cases (88%). The mortality rate at 1 year was 14.3%. The cumulative incidence of MAEs and MALEs at 12 months was 50% and 40.5%, respectively. After conducting multivariate analysis, history of Rutherford stage IIB (hazard ratio [HR], 3.64; 95% confidence interval [CI], 1.58-8.41; = 0.0025), occlusion of the external iliac artery (HR, 27.52; 95% CI, 2.83-267.33; = 0.0043), being a case of clinically unsuccessful thrombolysis (HR, 7.72; 95% CI, 2.48-23.10; = 0.0004), and the presence of diabetes mellitus (HR, 2.18; 95% CI, 1.01-4.71; = 0.047) were independent predictors of a high MAE mortality rate at 12 months. For MALEs, statistically significant differences were detected with the variables history of Rutherford stage IIB (HR, 4.30; 95% CI, 1.99-9.31; = 0.0002) and external iliac artery occlusion (HR, 31.27; 95% CI, 3.47-282.23; = 0.0022). Based on the short-term results of CDT, acute limb ischaemia can be successfully, safely, and effectively treated with catheter-directed thrombolytic therapy with radial, brachial, or femoral access. However, radial access is associated with fewer access site complications. A history of Rutherford stage IIB, occlusion of external iliac artery, unsuccessful thrombolysis, and the presence of diabetes mellitus were independently associated with an increased risk of MAEs. A history of Rutherford stage IIB and external iliac artery occlusion are independent predictors of MALEs.
PubMed: 38929649
DOI: 10.3390/life14060666 -
Biomedicines Jun 2024Critical limb ischemia (CLI) is the end stage of peripheral artery disease (PAD), and around 30% of CLI patients are ineligible for current treatments. The angiogenic...
BACKGROUND
Critical limb ischemia (CLI) is the end stage of peripheral artery disease (PAD), and around 30% of CLI patients are ineligible for current treatments. The angiogenic benefits of c-Kit have been reported in the ischemia scenario; however, the present study demonstrates the effects of specific endothelial c-Kit signaling in arteriogenesis during hindlimb ischemia.
METHODS
We created conditional knockout mouse models that decrease c-Kit (c-Kit VE-Cadherin CreERT2-c-Kit) or its ligand (SCF VE-Cadherin CreERT2-SCF) specifically in endothelial cells (ECs) after tamoxifen treatment. These mice and a control group (wild-type VE-Cadherin CreERT2-WT) were subjected to hindlimb ischemia or aortic crush to evaluate perfusion/arteriogenesis and endothelial barrier permeability, respectively.
RESULTS
Our data confirmed the lower gene expression of c-Kit and SCF in the ECs of c-Kit and SCF mice, respectively. In addition, we confirmed the lower percentage of ECs positive for c-Kit in c-Kit mice. Further, we found that c-Kit and SCF mice had better limb perfusion and arteriogenesis compared to WT mice. We also demonstrated that c-Kit and SCF mice had a preserved endothelial barrier after aortic crush compared to WT.
CONCLUSIONS
Our data demonstrate the deleterious effects of endothelial SCF/c-Kit signaling on arteriogenesis and endothelial barrier integrity.
PubMed: 38927565
DOI: 10.3390/biomedicines12061358 -
Biology Jun 2024Eales' Disease is an idiopathic peripheral retinal vasculopathy first described by British ophthalmologist Henry Eales in 1880. Most prevalent in healthy young males,... (Review)
Review
Eales' Disease is an idiopathic peripheral retinal vasculopathy first described by British ophthalmologist Henry Eales in 1880. Most prevalent in healthy young males, Eales' Disease often presents with symptoms of sudden blurry or decreased vision and floaters. Although no clear, standardized stage of the disease exists, it progresses through three overlapping phases-peripheral periphlebitis, ischemic capillary ischemia, and retinal neovascularization. The etiology of Eales' Disease is unknown and appears to be multifactorial, but post-TB hypersensitivity to tuberculoprotein and DNA is the most potential cause in the etiology of Eales' Disease. With a thorough examination of the clinical presentation and diagnosis of Eales' Disease-incorporating the latest clinical findings related to the condition-the investigation for Eales' Disease extends to explore recent potential connections with other ocular conditions or possible cofactors, such as glaucoma, uncontrolled diabetes, drug abuse, or inherited medical conditions. Moreover, focusing on critical insights into the treatment of Eales' Disease across its various stages of progression, the overarching goal of the paper is to refine and suggest possible future diagnostic and therapeutic strategies. Widening our understanding of pathophysiology and utilizing various treatment options for individual patients holds immense potential for advancing ocular medicine and optimizing patient care for people with this disease with unknown pathophysiology.
PubMed: 38927340
DOI: 10.3390/biology13060460