Background and Objectives: Atherosclerosis is a chronic inflammatory disease significantly contributing to cardiovascular morbidity and mortality. This study primarily aims to evaluate the role of baseline blood glucose levels and inflammatory markers in the histopathological features of atherosclerotic plaques in the carotid and femoro-popliteal arteries. Materials and Methods: In this retrospective, observational, and monocentric study, 165 patients diagnosed with infrainguinal peripheral arterial disease or carotid artery disease hospitalized in the Vascular Surgery Clinic, between January 2019 and December 2023, were included. From the electronic database of the hospital, we documented demographic data, cardiovascular comorbidities, including hypertension, atrial fibrillation, ischemic heart disease, and chronic heart failure, as well as chronic kidney disease, diabetes, and prevalent risk factors such as active smoking, dyslipidemia, and obesity. Additionally, we recorded the arterial site from which the atherosclerotic plaque was obtained, along with laboratory data obtained at the time of admission prior to the surgery. The patients were divided into "Carotid Artery" and "Femoro-Popliteal Axis" based on anatomical location. Results: A greater prevalence of male patients (p = 0.008) and dyslipidemia (p = 0.002) was found in the group with atherosclerotic plaques from the femoro-popliteal axis. Laboratory data also showed increased lymphocyte (p = 0.020) and PLT (p = 0.028) levels in this group. There was no significant difference in the types of atherosclerotic plaques between the two patient groups. However, those in the Carotid Artery group showed a higher rate of antiaggregant treatment and a reduced incidence of dual therapy (p < 0.001). The Spearman correlation analysis revealed a positive correlation between baseline glucose levels and NLR (r = 0.402, p < 0.001), MLR (r = 0.217, p = 0.005), PLR (r = 0.306, p < 0.001), and LGI (r = 0.693, p < 0.001). Furthermore, the predictive roles of glucose, NLR, MLR, and LGI were assessed through multivariate analysis. Consequently, elevated baseline values of the parameters above were associated with unstable atherosclerotic plaques, independent of demo-graphic data, standard cardiovascular risk factors, site of artery harvest, and chronic vascular treatments at the time of admission (for all p < 0.05). Conclusions: This study highlights the significant relationships between glucose levels and various inflammatory markers in patients with different histopathological diagnoses of atherosclerotic plaques. Additionally, elevated glycemic and systemic inflammation biomarkers were associated with unstable atherosclerotic plaque, independent of demographic data, comorbidities, cardiovascular risk factors, anatomical artery harvest, and vascular chronic medication at the time of admission.

Cerebral infarction (CI) is a prevalent and frequently occurring condition. However, the association between expansive remodeling in the carotid artery system and CI is still uncertain. This study aims to investigate the significance of the carotid artery system and aortic arch (AA) remodeling for the prevention and treatment of CI.

We collected data from 821 patients who underwent computed tomography angiography at our hospital, performed statistical analysis, and compared it with various clinical data.

We found that the diameters and detection rates of the common carotid artery (CCA), internal carotid artery (ICA), carotid bifurcation, and AA were significantly greater in the CI group than in the without CI group ( P <0.05). The number of carotid sinus plaque (CSP) and the length of aortic arch plaque (AAP) were considered to be 2 important factors in predicting CCA remodeling. Moreover, the thickness of AAP was considered to be an important factor in predicting AA remodeling.

Patients with CI exhibited a significant increase in the diameter of the carotid system and AA, which correlated with certain features of arterial plaque. Hence, early detection of arterial plaques, along with interventions to delay or potentially reverse expansive arterial remodeling, may be effective in preventing and treating CI.

This retrospective study aimed to investigate the association between carotid artery plaque characteristics evaluated by virtual histology intravascular ultrasound (VH-IVUS) and high-risk coronary plaques determined by coronary computed tomography angiography (CCTA) among patients (n = 72) who underwent carotid artery stenting (CAS). VH-IVUS examination was performed during CAS and CCTA examination before CAS. Logistic regression models were used to explore the association between carotid plaque characteristics and high-risk coronary plaque. Of 72 patients, 46 (63.9%) were diagnosed as having high-risk coronary plaques. The necrotic core (NC) area, NC percentage, dense calcium (DC) area, and symptomatic carotid artery stenosis were significantly associated with high-risk coronary plaques (all P < .05). Isolated upper-NC area, and upper-NC area combined with upper-DC area were associated with high-risk coronary plaques. Compared with the lower-NC area and lower-DC area groups, participants with upper-NC area and upper-NC area had 12.53 times higher odds ratio of having high-risk coronary plaques. This study showed that the NC area, NC percentage, DC area and symptomatic carotid artery stenosis were associated with high-risk coronary plaques. Participants with both upper-NC area and upper-DC area might have a higher risk of high-risk coronary plaques.

Abdominal aortic calcification (AAC), an indicator of systemic arteriosclerosis, is associated with short- and long-term outcomes in malignancies. We investigated the prognostic impact of AAC in patients who underwent hepatectomy for intrahepatic cholangiocarcinoma (IHCC).

The study cohort comprised 46 patients who underwent hepatectomy for IHCC between January 2008 and September 2020. The AAC volume measured by preoperative computed tomography was used to construct a model of the calcified segment from the renal artery to the common iliac artery bifurcation. We investigated the relationship between AAC and the long-term outcomes. The AAC volume cutoff value was calculated from a receiver-operating characteristic curve based on the three-year survival.

According to our cutoff AAC volume of 3,700 mm3, 11 patients (24%) had high AAC volumes. The high-AAC group was significantly older than the low-AAC group (73 vs. 62 years old, p < 0.01). A multivariate analysis of the cancer-specific survival showed that a high serum carbohydrate antigen 19-9 concentration (hazard ratio [HR] 5.57, p = 0.01), high AAC volume (HR 3.03, p = 0.04), and [high?] T3 or T4 levels (HR 9.05, p < 0.01) were independently associated with a poor prognosis.

AAC is a useful predictor of the oncological prognosis in patients undergoing hepatectomy for IHCC.

The genetic transcription profile and underlying molecular mechanisms of ischemic stroke (IS) remain elusive. To address this issue, four mRNA and one miRNA expression profile of rats with middle cerebral artery occlusion (MCAO) were acquired from the Gene Expression Omnibus (GEO) database. A total of 780 differentially expressed genes (DEGs) and 56 miRNAs (DEMs) were screened. Gene set and functional enrichment analysis revealed that a substantial number of immune-inflammation-related pathways were abnormally activated in IS. Through weighted gene co-expression network analysis, the turquoise module was identified as meaningful. By taking the intersection of the turquoise module genes, DEM-target genes, and all DEGs, 354 genes were subsequently obtained as key IS-related genes. Among them, six characteristic genes were identified using the least absolute shrinkage and selection operator. After validation with three external datasets, transforming growth factor beta 1 (Tgfb1) was selected as the hub gene. This finding was further confirmed by gene expression pattern analysis in both the MCAO model rats and clinical IS patients. Moreover, the expression of the hub genes exhibited a negative correlation with the modified Rankin scale score (P < 0.05). Collectively, these results expand our knowledge of the genetic profile and molecular mechanisms involved in IS and suggest that the Tgfb1 gene is a potential biomarker of this disease.

A global decline in male fertility has been reported, and climate change is considered a major cause of this. Climate change refers to long-term shifts in temperatures and weather patterns, and results from greenhouse gas emissions like carbon dioxide and methane that act as a blanket wrapped around the earth, trapping heat and elevating temperatures. Sad to say, the consequences of climatic variation are beyond the dramatic elevated temperature, they include cold stress, increased malnutrition, air pollution, cardiovascular diseases respiratory tract infections, cancer, sexually transmitted infections, mental stress, and heat waves. These negative effects of climate change impair male reproductive function through multiple pathways, like ROS-sensitive signaling, suppression of steroidogenic markers, and direct damage to testicular cells. The present study aimed to describe the impact of the consequences of climate change on male reproductive health with details of the various mechanisms involved. This will provide an in-depth understanding of the pathophysiological and molecular basis of the possible climatic variation-induced decline in male fertility, which will aid in the development of preventive measures to abate the negative effects of climate change on male reproductive function.

Atherosclerosis causes heart disease by forming plaques in arterial walls. IVUS imaging provides a high-resolution cross-sectional view of coronary arteries and plaque morphology. Healthcare professionals diagnose and quantify atherosclerosis physically or using VH-IVUS software. Since manual or VH-IVUS software-based diagnosis is time-consuming, automated plaque characterization tools are essential for accurate atherosclerosis detection and classification. Recently, deep learning (DL) and computer vision (CV) approaches are promising tools for automatically classifying plaques on IVUS images. With this motivation, this manuscript proposes an automated atherosclerotic plaque classification method using a hybrid Ant Lion Optimizer with Deep Learning (AAPC-HALODL) technique on IVUS images. The AAPC-HALODL technique uses the faster regional convolutional neural network (Faster RCNN)-based segmentation approach to identify diseased regions in the IVUS images. Next, the ShuffleNet-v2 model generates a useful set of feature vectors from the segmented IVUS images, and its hyperparameters can be optimally selected by using the HALO technique. Finally, an average ensemble classification process comprising a stacked autoencoder (SAE) and deep extreme learning machine (DELM) model can be utilized. The MICCAI Challenge 2011 dataset was used for AAPC-HALODL simulation analysis. A detailed comparative study showed that the AAPC-HALODL approach outperformed other DL models with a maximum accuracy of 98.33%, precision of 97.87%, sensitivity of 98.33%, and F score of 98.10%.

A growing body of research indicates the promising potential of vaccines in both preventing and treating atherosclerosis (AS). To gain a comprehensive understanding of the current research landscape and emerging trends in this field, this study conducted a bibliometric analysis of publications on AS vaccines using the Web of Science Core Collection (WoSCC) database, based on the "bibliometric" R package and VOSviewer software. From 1991 to 2024, a total of 462 publications were identified in the WoSCC. The United States appeared as the leading contributor in terms of both total publications and citations. The Vaccine journal exhibited the highest publications output. Nilsson J from the Lund University in Sweden was the author with the most published articles, total citations and Hirsch index (H-index). Keywords analysis and thematic maps analysis revealed the passive immunotherapy (AS protective antibodies vaccines) was a hot mature theme, the active immunotherapy (AS antigens vaccines) was an emerging and booming theme, while the efficacy and safety of AS vaccines was a niche and well-developed theme. These findings offered valuable insights into the AS vaccination and provided guidance for future research in this domain.

Chronic kidney disease (CKD) is a significant public health concern associated with a high prevalence of carotid plaques, which are indicators of atherosclerosis and predictors of adverse cardiovascular outcomes. Inflammation is a hallmark of CKD, contributing to both renal dysfunction and cardiovascular complications. This study aims to investigate the association between inflammatory markers-systemic inflammatory response index (SIRI), systemic immune-inflammation index (SII), aggregate inflammatory status index (AISI), monocyte to high-density lipoprotein cholesterol ratio (MHR), neutrophil to high-density lipoprotein cholesterol ratio (NHR), neutrophil to lymphocyte ratio (NLR), and monocyte to lymphocyte ratio (MLR)-and carotid plaques in CKD patients, and to explore the potential mediating role of estimated glomerular filtration rate (eGFR) in this relationship.

A cross-sectional analysis was conducted on patients admitted to the Division of Nephrology between January 2023 and June 2023. The primary endpoint was the presence of carotid plaques assessed using ultrasound imaging. Multivariable logistic regression models were used to examine the associations between inflammatory markers and carotid plaques, and trend tests were performed to evaluate the trending association of carotid plaques risk and inflammatory markers in tertiles. Restricted cubic spline (RCS) analysis was used to assess potential non-linear relationships, and subgroup analyses were conducted to examine consistency across different strata. Mediation analysis was performed to explore the role of eGFR.

Of the 609 participants, 387 were included in the final analysis after applying exclusion criteria. Elevated levels of LnSIRI (OR = 1.87, 95% CI = 1.25-2.80), LnSII (OR = 1.67, 95% CI = 1.09-2.56), LnAISI (OR = 1.70, 95% CI = 1.22-2.37), LnMHR (OR = 1.94, 95% CI = 1.15-3.26), LnNHR (OR = 1.82, 95% CI = 1.10-3.02), and LnMLR (OR = 2.26, 95% CI = 1.18-4.34) were significantly associated with the presence of carotid plaques. There were significant trends for increasing tertiles of SIRI, AISI, MHR and NHR. RCS analysis showed no significant non-linear associations. Subgroup analyses indicated similar associations across most strata. eGFR partially mediated these relationships, with proportions mediated ranging from 14.7 to 17.5%.

Inflammatory markers are significantly associated with carotid plaques in CKD patients, with eGFR playing a partial mediating role. These findings highlighted the importance of managing inflammation and maintaining renal function to mitigate the risk of atherosclerosis in CKD patients.

Not applicable.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Vital organs like the heart are affected by the occlusion of blood vessels due to atherosclerotic plaque formation. However, the role of infectious agents has always been an essential subject of investigation. This study investigated the presence of microorganisms, including nanobacteria, in atherosclerotic plaques removed from human carotid arteries by microbiological and metagenomic examination.

Atheroma plaque samples were obtained from 20 patients with carotid artery stenosis who had atherectomy by surgery or percutaneous intervention. Nanobacteria were grown by culturing homogenates of the atheroma plaques. Whole genome sequencing was done for samples. Because of the high percentage of Toxoplasma gondii (T. gondii) DNA, PCR investigation was applied to detect T. gondii DNA in the samples.

A molecular analysis of nanobacteria revealed them to be made of human proteins, supporting the theory that they are not living organisms. According to sequencing results, samples showed that more than 50 % of the metagenomic sequences belonged to Toxoplasma gondii. PCR investigation indicated that T. gondii DNA was positive in 8 (40 %) of 20 plaques.

Further evidence regarding the role of T. gondii in the etiology of plaque formation may help determine the strategy for prevention and treatment of infections in preventing atheroma plaque formation in the future.

Atherosclerosis, a complex inflammatory and metabolic disorder, is the underlying cause of several life-threatening cardiovascular diseases. Stress granules (SG) are biomolecular condensates composed of proteins and mRNA that form in response to stress. Recent studies suggest a potential link between SG and atherosclerosis development. However, there remain gaps in understanding SG role in atherosclerosis development. Here we provide a thorough analysis of the role of SG in atherosclerosis, covering cellular stresses stimulation, core components, and regulatory genes in SG formation. Furthermore, we explore atherosclerosis induced factors such as inflammation, low or oscillatory shear stress (OSS), and oxidative stress (OS) may impact SG formation and then the development of atherosclerotic lesions. We have assessed how changes in SG dynamics impact pro-atherogenic processes like endothelial dysfunction, lipid metabolism, and immune cell recruitment in atherosclerosis. In summary, this review emphasizes the complex interplay between SG and atherosclerosis that could open innovative directions for targeted therapeutic strategies in preventing or treating atherosclerotic cardiovascular diseases.

Metabolic dysfunction associated steatotic liver disease (MASLD) is associated with an increased risk of coronary artery disease. Computed Tomography Coronary Angiography (CTCA) can assess both the extent and the features of coronary plaques. We aimed to gather evidence about the prevalence and features of coronary plaques among MASLD patients.

PubMed, Scopus, and Google Scholar databases were searched for randomized controlled trials and adjusted observational studies assessing the prevalence and features of coronary plaques by means of CTCA in MASLD patients as compared with a control group. The prevalence of coronary stenosis (defined as >30% and >50% diameter of stenosis), of increasing coronary artery calcium (CAC) score and of high-risk features (namely low-attenuation plaques, napkin ring sign, spotty calcification and positive remodelling) in MASLD patients were the endpoints of interest.

Twenty-four observational studies were included. MASLD was associated with an increased prevalence of critical coronary stenosis compared with controls (odds ratio [OR] 1.54, 95%CI 1.23-1.93). Increased values of CAC score were observed in MASLD patients (OR 1.35, 95%CI 1.02-1.78 and OR 2.26, 95%CI 1.57-3.23 for CAC score 0-100 and >100, respectively). An increased risk of 'high-risk' coronary plaques was observed in MASLD patients (OR 2.13, 95%CI 1.42-3.19). As high-risk features plaques, a higher prevalence of positive remodelling and spotty calcification characterize MASLD patients (OR 2.92, 95%CI 1.79-4.77 and OR 2.96, 95%CI 1.22-7.20).

Patients with MASLD are at increased risk of developing critical coronary stenosis and coronary plaques characterized by high-risk features as detected by CTCA.

In 2024, over 775 million cases of COVID-19 were recorded, including approximately 7 million deaths, indicating its widespread and dangerous nature. The disease is caused by the SARS-CoV-2 virus, which can manifest a wide spectrum of symptoms, from mild infection to respiratory failure and even death. Neurological symptoms, such as headaches, confusion, and impaired consciousness, have also been reported in some COVID-19 patients. These observations suggest the potential of SARS-CoV-2 to invade the central nervous system and induce neuroinflammation during infection. This review specifically explores the relationship between SARS-CoV-2 infection and selected neurological diseases such as multiple sclerosis (MS), ischemic stroke (IS), and Alzheimer's disease (AD). It has been observed that the SARS-CoV-2 virus increases the production of cytokines whose action can cause the destruction of the myelin sheaths of nerve cells. Subsequently, the body may synthesize autoantibodies that attack nerve cells, resulting in damage to the brain's anatomical elements, potentially contributing to the onset of multiple sclerosis. Additionally, SARS-CoV-2 exacerbates inflammation, worsening the clinical condition in individuals already suffering from MS. Moreover, the secretion of pro-inflammatory cytokines may lead to an escalation in blood clot formation, which can result in thrombosis, obstructing blood flow to the brain and precipitating an ischemic stroke. AD is characterized by intense inflammation and heightened oxidative stress, both of which are exacerbated during SARS-CoV-2 infection. It has been observed that the SARS-CoV-2 demonstrates enhanced cell entry in the presence of both the ACE2 receptor, which is already elevated in AD and the ApoE ε4 allele. Consequently, the condition worsens and progresses more rapidly, increasing the mortality rate among AD patients. The above information underscores the numerous connections between SARS-CoV-2 infection and neurological diseases.

Atherosclerosis, a multifaceted and persistent inflammatory condition, significantly contributes to the progression of cardiocerebrovascular disorders, such as myocardial infarctions and cerebrovascular accidents. It involves the accumulation of cholesterol, fatty deposits, calcium and cellular debris in the walls of arteries, leading to the formation of plaques. Our aim is to investigate the potential of sinomenine to counteract atherosclerosis in mice lacking Apolipoprotein E (ApoE-/-) Mice. We employed the high-fat diet-induced method to induce atherosclerosis in ApoE-/- mice, and the mice were treated with sinomenine (5, 10, and 15 mg/kg) and simvastatin (0.5 mg/kg) for 12 weeks. Body weight, water intake, and food intake were assessed. Lipid parameters, oxidative stress, inflammatory cytokines, and mRNA levels were estimated. Sinomenine treatment remarkably (P < 0.001) suppressed body weight, along with food and water intake. Sinomenine altered the levels of total cholesterol (TC), high-density lipoprotein (HDL), triglyceride (TG), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL), which were modulated in the atherosclerosis group. Sinomenine treatment also altered the levels of oxidative stress parameters such as glutathione peroxidase (GPx), catalase (CAT), malonaldehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH). In addition, it modulated cardiac parameters like C-reactive protein (CRP), endothelin-1 (ET-1), thromboxane B2 (TXB2), nitric oxide (NO), cardiac troponin I (cTnI), lactate dehydrogenase (LDH), and creatinine kinase isoenzymes (CK-MB). Inflammatory cytokines interleukin (IL)-1α, IL-1β, TNF-α, IL-6, and IL-10 were also affected. Sinomenine further suppressed the mRNA expression of IL-6, IL-17, IL-10, tumor necrosis factor-α (TNF-α), Il-1β, monocyte chemoattractant protein-1 (MCP-1), MCP-2, MCP-3, transforming Growth Factor-1β (TGF-1β), vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1). The results suggest that sinomenine remarkably suppressed the development of atherosclerosis in the early stage.

Chimeric antigen receptor (CAR) T cell therapy holds enormous potential for the treatment of hematologic malignancies. Despite its benefits, it is still used as a second line of therapy, mainly because of its severe side effects and patient unresponsiveness. Numerous researchers worldwide have attempted to identify effective predictive biomarkers for early prediction of treatment outcomes and adverse effects in CAR T cell therapy, albeit so far only with limited success. This review provides a comprehensive overview of the current state of predictive biomarkers. Although existing predictive metrics correlate to some extent with treatment outcomes, they fail to encapsulate the complexity of the immune system dynamics. The aim of this review is to identify six major groups of predictive biomarkers and propose their use in developing improved and efficient prediction models. These groups include changes in mitochondrial dynamics, endothelial activation, central nervous system impairment, immune system markers, extracellular vesicles, and the inhibitory tumor microenvironment. A comprehensive understanding of the multiple factors that influence therapeutic efficacy has the potential to significantly improve the course of CAR T cell therapy and patient care, thereby making this advanced immunotherapy more appealing and the course of therapy more convenient and favorable for patients.

Large-artery atherosclerosis (LAA) is a leading cause of cerebrovascular disease. However, LAA diagnosis is costly and needs professional identification. Many metabolites have been identified as biomarkers of specific traits. However, there are inconsistent findings regarding suitable biomarkers for the prediction of LAA. In this study, we propose a new method integrates multiple machine learning algorithms and feature selection method to handle multidimensional data. Among the six machine learning models, logistic regression (LR) model exhibited the best prediction performance. The value of area under the receiver operating characteristic curve (AUC) was 0.92 when 62 features were incorporated in the external validation set for the LR model. In this model, LAA could be well predicted by clinical risk factors including body mass index, smoking, and medications for controlling diabetes, hypertension, and hyperlipidemia as well as metabolites involved in aminoacyl-tRNA biosynthesis and lipid metabolism. In addition, we found that 27 features were present among the five adopted models that could provide good results. If these 27 features were used in the LR model, an AUC value of 0.93 could be achieved. Our study has demonstrated the effectiveness of combining machine learning algorithms with recursive feature elimination and cross-validation methods for biomarker identification. Moreover, we have shown that using shared features can yield more reliable correlations than either model, which can be valuable for future identification of LAA.

Atherosclerosis is an underlying pathology of many vascular diseases as a result of cellular, structural and molecular dysfunctions within the sub-endothelial space. This review deals with the events involved in the formation, growth and remodeling of plaque, including the cell recruitment, cell polarization, and cell fat droplets. It also describes cross talking between endothelial cells, macrophages, and vascular smooth muscle cells, as well as the cellular pathways involved in plaque development in the plaque microenvironment. Finally, it describes the plaque structural components and the role of factors involved in the rupture and erosion of plaques in the vessel. Video Abstract.

Besides plaque enhancement grade, the incremental value of enhancement-related high-resolution MRI features in defining culprit plaques needs further evaluation. This study was focused on assessing whether plaque enhancement features contribute to culprit plaque identification and further risk stratification.

We retrospectively studied patients who experienced an acute ischaemic stroke and transient ischaemic attack due to intracranial atherosclerosis from 2016 to 2022. The enhancement features included enhancement grade, enhanced length, and enhancement quadrant. Associations between plaque enhancement features and culprit plaques, as well as diagnostic value, were investigated using logistic regression and receiver operating characteristic analyses.

Overall, 287 plaques were identified, of which 231 (80.5%) and 56 (19.5%) were classified as culprit and non-culprit plaques, respectively. Comparison of the pre- and post-enhancement images revealed enhanced length longer than the plaque length in 46.32% of the culprit plaques. Multivariate logistic regression showed that enhanced length longer than plaque length (OR 6.77; 95% CI 2.47-18.51) and grade II enhancement (OR 7.00; 95% CI 1.69-28.93) were independently associated with culprit plaques. The area under the curve value for the combination of stenosis and plaque enhancement grade for the diagnosis of culprit plaques was 0.787, which increased significantly to 0.825 on the addition of enhanced length longer than the plaque length (p = 0.026 for DeLong's test).

Enhanced length longer than the plaque length and grade II enhancement were independently associated with culprit plaques. The combination of the enhanced plaque features resulted in better culprit plaque identification.

Cardiovascular diseases (CVDs) are a set of heart and blood vessel disorders that include coronary heart disease (CHD), rheumatic heart disease, and other conditions. Traditional Chinese Medicine (TCM) has definite effects on CVDs due to its multitarget and multicomponent properties, which are gradually gaining national attention. Tanshinones, the major active chemical compounds extracted from Salvia miltiorrhiza, exhibit beneficial improvement on multiple diseases, especially CVDs. At the level of biological activities, they play significant roles, including anti-inflammation, anti-oxidation, anti-apoptosis and anti-necroptosis, anti-hypertrophy, vasodilation, angiogenesis, combat against proliferation and migration of smooth muscle cells (SMCs), as well as anti-myocardial fibrosis and ventricular remodeling, which are all effective strategies in preventing and treating CVDs. Additionally, at the cellular level, Tanshinones produce marked effects on cardiomyocytes, macrophages, endothelia, SMCs, and fibroblasts in myocardia. In this review, we have summarized a brief overview of the chemical structures and pharmacological effects of Tanshinones as a CVD treatment to expound on different pharmacological properties in various cell types in myocardia.

Predicting the prognosis of transient ischaemic attack (TIA) is difficult for many frontline clinicians. The purpose of this study was to determine whether subsequent stroke in TIA patients can be predicted via red blood cell distribution width (RDW).

A total of 360 consecutive patients with new-onset TIA in our stroke centre, were enrolled over the period studied. The patients were divided into three groups: 103 TIA patients, 206 ischaemic stroke (IS) patients and 51 patients with haemorrhagic stroke (HS) within 7 days after TIA. Complete blood count, biochemical parameters and brain imaging were performed on all patients.

The mean RDW values of patients with IS and HS after TIA were significantly higher than patients with TIA (13.35 ± 1.59 vs 12.84 ± 1.19, 13.32 ± 1.08 vs 12.84 ± 1.19, respectively, all p ≤ .001). In a multivariate model, RDW was independently associated with stroke after TIA (IS: odds ratio (OR) = 2.52, 95% confidence interval (CI) = 1.46-3.35, p = .002; HS: OR = 1.511, 95% CI = 1.101-2.074, p = .011). Compared to ABCD² scores, the diagnostic power of RDW in the differentiation of patients with IS after TIA was better (area under curve (AUC): 0.731 vs 0.613, p = .015). When an RDW cut-off value of 13.95% was accepted for differentiating patients with IS from TIA, the sensitivity and specificity were 73.7% and 74.3%, respectively. However, the AUC for the ability of the RDW to predict HS was 0.653 (95% CI = 0.589-0.716; p < .001).

The early determination of RDW is a promising, rapid, easy and inexpensive biomarker to predict the subsequent stroke in TIA patients, especially for IS. KEY MESSAGESThe most important result of our study is to show that (1) the higher RDW, the earlier the stroke onset and (2) RDW ≥13.95% has a 2.52-fold risk of ischaemic stroke in TIA patients, and RDW ≥12.85% has a 1.51-fold risk of haemorrhagic stroke.As an economic and accessible hematological marker, baseline RDW may serve as a useful biomarker for risk stratification in TIA patients.

Nowadays, emerging data demonstrate that the toll-like receptor (TLR) signaling pathway plays an important role in the progression of inflammatory atherosclerosis. Indeed, dysregulated TLR signaling pathway could be a cornerstone of inflammation and atherosclerosis, which contributes to the development of cardiovascular diseases. It is interesting to note that this pathway is heavily controlled by several mechanisms, such as epigenetic factors in which the role of non-coding RNAs (ncRNAs), particularly microRNAs and long noncoding RNAs as well as circular RNAs in the pathogenesis of atherosclerosis has been well studied. Recent years have seen a significant surge in the amount of research exploring the interplay between ncRNAs and TLR signaling pathway downstream targets in the development of atherosclerosis; however, there is still considerable room for improvement in this field. The current study was designed to review underlying mechanisms of TLR signaling pathway and ncRNA interactions to shed light on therapeutic implications in patients with atherosclerosis.

Acute ischaemic stroke (AIS) is a highly heterogeneous disorder and warrants further investigation to stratify patients with different outcomes and treatment responses. Using a large-scale stroke registry cohort, we applied data-driven approach to identify novel phenotypes based on multiple biomarkers.

In a nationwide, prospective, 201-hospital registry study taking place in China between August 01, 2015 and March 31, 2018, the patients with AIS who were over 18 years of age and admitted to the hospital within 7 days from symptom onset were included. 92 biomarkers were included in the analysis. In the derivation cohort (n=9539), an unsupervised Gaussian mixture model was applied to categorize patients into distinct phenotypes. A classifier was developed using the most important biomarkers and was applied to categorize patients into their corresponding phenotypes in an validation cohort (n=2496). The differences in biological features, clinical outcomes, and treatment response were compared across the phenotypes.

We identified four phenotypes with distinct characteristics in 9288 patients with non-cardioembolic ischaemic stroke. Phenotype 1 was associated with abnormal glucose and lipid metabolism. Phenotype 2 was characterized by inflammation and abnormal renal function. Phenotype 3 had the least laboratory abnormalities and small infarct lesions. Phenotype 4 was characterized by disturbance in homocysteine metabolism. Findings were replicated in the validation cohort. In comparison with phenotype 3, the risk of stroke recurrence (adjusted hazard ratio [aHR] 2.02, 95% confidence intervals [CI] 1.04-3.94), and mortality (aHR 18.14, 95%CI 6.62-49.71) at 3-month post-stroke were highest in phenotype 2, followed by phenotype 4 and phenotype 1, after adjustment for age, gender, smoking, drinking, history of stroke, hypertension, diabetes mellitus, dyslipidemia, and coronary heart disease. The Monte Carlo simulation showed that the patients with phenotype 2 could benefit from high-intensity statin therapy.

A data-driven approach could aid in the identification of patients at a higher risk of adverse clinical outcomes following non-cardioembolic ischaemic stroke. These phenotypes, based on different pathophysiology, can suggest individualized treatment plans.

Beijing Natural Science Foundation (grant number Z200016), Beijing Municipal Committee of Science and Technology (grant number Z201100005620010), National Natural Science Foundation of China (grant number 82101360, 92046016, 82171270), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (grant number 2019-I2M-5-029).

DANSK RESUMÉ (DANISH SUMMARY): Aldersrelateret makuladegeneration (AMD) er den hyppigste årsag til uopretteligt synstab og blindhed i højindkomstlande. Det er en progredierende nethindesygdom som gradvist fører til ødelaeggelse af de celler som er ansvarlige for vores centralsyn. De tidlige stadier er ofte asymptomatiske, imens senstadie AMD, som opdeles i to former, neovaskulaer AMD (nAMD) og geografisk atrofi (GA), begge udviser gradvist synstab, dog generelt med forskellig hastighed. Tidlig AMD er karakteriseret ved tilstedevaerelsen af druser og pigmentforandringer i nethinden mens nAMD og GA udviser henholdsvis karnydannelse i og atrofi af nethinden. AEtiologien er multifaktoriel og udover alder omfatter patogenesen miljø- og genetiske risikofaktorer. Forskning har specielt fokuseret på lokale forandringer i øjet hvor man har fundet at inflammation spiller en betydelig rolle for udviklingen af sygdommen, men flere studier tyder også på at systemiske forandringer og specielt systemisk inflammation spiller en vaesentlig rolle i patogenesen. De Philadelphia-negative myeloproliferative neoplasier (MPNs) er en gruppe af haematologiske kraeftsygdomme med en erhvervet genetisk defekt i den tidlige pluripotente stamcelle som medfører en overproduktion af en eller flere af blodets modne celler. Sygdommene er fundet at udvikle sig i et biologisk kontinuum fra tidligt cancerstadie, essentiel trombocytose (ET) over polycytaemi vera (PV) og endelig til det sene myelofibrose stadie (PMF). Symptomer hos disse patienter skyldes isaer den aendrede sammensaetning af blodet, hyperviskositet, kompromitteret mikrocirkulation og nedsat vaevsgennemblødning. Den øgede morbiditet og mortalitet beror i høj grad på tromboembolier, blødninger og leukemisk transformation. En raekke mutationer som driver MPN sygdommene er identificeret, bl.a. JAK2V617F-mutationen som medfører en deregulering JAK/STAT signalvejen, der bl.a. har betydning for cellers vaekst og overlevelse. Et tidligere stort registerstudie har vist at patienter med MPNs har en øget risiko for neovaskulaer AMD og et pilotstudie har vist øget forekomst af intermediaer AMD. Dette ønsker vi at undersøge naermere i et større studie i dette Ph.d.- projekt. Flere studier har også vist at kronisk inflammation spiller en vigtig rolle for både initiering og udvikling af den maligne celleklon hos MPNs og herfra er en "Human Inflammationsmodel" blevet udviklet. Siden er MPN sygdommene blevet anvendt som "model sygdomme" for en tilsvarende inflammationsmodel for udvikling af Alzheimers sygdom. I dette Ph.d.-projekt vil vi tilsvarende forsøge at undersøge systemisk inflammation i forhold til forekomst af druser. Det vil vi gøre ved at sammenligne systemiske immunologiske markører som tidligere er undersøgt hos patienter med AMD og sammenligne med MPN. Specielt er vi interesseret i systemiske immunologiske forskelle på patienter med MPN og druser (MPNd) og MPN med normale nethinder (MPNn). Denne afhandling består af to overordnede studier. I Studie I, undersøgte vi forekomsten af retinale forandringer associeret med AMD hos 200 patienter med MPN (artikel I). Studie II, omhandlede immunologiske ligheder ved AMD og MPN, og var opdelt i yderligere tre delstudier hvor vi undersøgte hhv. systemiske markører for inflammation, aldring og angiogenese (artikel II, III og IV). Vi undersøgte markørerne i fire typer af patienter: nAMD, intermediaer AMD (iAMD), MPNd og MPNn. Undersøgelsen af forskelle mellem MPNd og MPNn, vil gøre det muligt at identificere forandringer i immunsystemet som kunne vaere relevante for AMD-patogenesen. Vi vil endvidere sammenholde resultaterne for patienter med MPN med patienter som har iAMD og nAMD. I studie I (Artikel I) fandt vi at patienter med MPN har en signifikant højere praevalens af store druser og AMD tidligere i livet sammenlignet med estimater fra tre store befolkningsundersøgelser. Vi fandt også at forekomst af druser var associeret med højere neutrofil-lymfocyt ratio, hvilket indikerer et højere niveau af kronisk inflammation i patienterne med druser sammenlignet med dem uden druser. I studie II (Artikel II, III og IV) fandt vi flere immunologiske forskelle mellem patienter med MPNd og MPNn. Da vi undersøgte markører for inflammation, fandt vi en højere grad af systemisk inflammation i MPNd end MPNn. Dette blev vist ved en højere inflammationsscore (udregnet på baggrund af niveauer af pro-inflammatoriske markører), en højere neutrofil-lymfocyt ratio, samt indikationer på et dereguleret komplementsystem. Ved undersøgelse af aldringsmarkører fandt vi tegn på accelereret immunaldring hos MPNd i forhold til MPNn, hvilket kommer til udtryk ved en større procentdel af "effector memory T celler". Endelig fandt vi en vaesentlig lavere ekspression af CXCR3 på T celler og monocytter hos patienter med nAMD sammenlignet med iAMD, MPNd og MPNn. Dette er i overensstemmelse med tidligere studier hvor CXCR3 ekspression er fundet lavere end hos raske kontroller. Derudover fandt vi en faldende CXCR3 ekspression på monocytter over det biologiske MPN-kontinuum. Disse studier indikerer en involvering af CXCR3 i både nAMD og PMF, begge sygdomsstadier som er karakteriseret ved angiogenese og fibrose. Ud fra resultaterne af denne afhandling kan vi konkludere at forekomsten af druser og AMD hos MPN er øget i forhold til baggrundsbefolkningen. Endvidere viser vores resultater at systemisk inflammation muligvis spiller en vaesentlig større rolle i udviklingen af AMD end tidligere antaget. Vi foreslår derfor en AMD-model (Figur 18) hvor inflammation kan initiere og accelerere den normale aldersafhaengige akkumulation af affaldsstoffer i nethinden, som senere udvikler sig til druser, medførende øget lokal inflammation og med tiden tidlig og intermediaer AMD. Dette resulterer i den øgede risiko for udvikling til de invaliderende senstadier af AMD. ENGLISH SUMMARY: Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss and blindness in high-income countries. It is a progressive retinal disease leading to damage of the cells responsible for central vision. The early stages of the disease are often asymptomatic, while late-stage AMD, which is divided into two entities, neovascular AMD and geographic atrophy (GA), both show vision loss, though generally with different progression rates. Drusen and pigmentary abnormalities in the retina characterise early AMD, while nAMD and GA show angiogenesis in and atrophy of the retina, respectively. The aetiology is multifactorial and, in addition to ageing, which is the most significant risk factor for developing AMD, environmental- and genetic risk factors are implicated in the pathogenesis. Research has focused on local changes in the eye where inflammation has been found to play an essential role, but studies also point to systemic alterations and especially systemic inflammation to be involved in the pathogenesis. The Philadelphia-negative myeloproliferative neoplasms (MPN) are a group of haematological cancers with an acquired genetic defect of the pluripotent haematopoietic stem cell, characterised by excess haematopoiesis of the myeloid cell lineage. The diseases have been found to evolve in a biological continuum from early cancer state, essential thrombocythemia, over polycythaemia vera (PV), to the advanced myelofibrosis stage (PMF). The symptoms in these patients are often a result of the changes in the blood composition, hyperviscosity, microvascular disturbances, and reduced tissue perfusion. The major causes of morbidity and mortality are thromboembolic- and haemorrhagic events, and leukemic transformation. A group of mutations that drive the MPNs has been identified, e.g., the JAK2V617F mutation, which results in deregulation of the JAK/STAT signal transduction pathway important, for instance, in cell differentiation and survival. A previous large register study has shown that patients with MPNs have an increased risk of neovascular AMD, and a pilot study has shown an increased prevalence of intermediate AMD. We wish to study this further in a larger scale study. Several studies have also shown that systemic inflammation plays an essential role in both the initiation and progression of the malignant cell clone in MPNs. From this knowledge, a "Human inflammation model" has been developed. Since then, the MPNs has been used as model diseases for a similar inflammation model for the development of Alzheimer's disease. In this PhD project, we would like to investigate systemic inflammation in relation to drusen presence. We will do this by comparing systemic immunological markers previously investigated in patients with AMD and compare with MPN. We are primarily interested in systemic immunological differences between patients with MPN and drusen (MPNd) and MPN with normal retinas (MPNn). This thesis consists of two main studies. Study I investigated the prevalence of retinal changes associated with AMD and the prevalence of different AMD stages in 200 patients with MPN (paper I). Study II examined immunological similarities between AMD and MPNs. This study was divided into three substudies exploring systemic markers of inflammation, ageing and angiogenesis, respectively. This was done in four types of patients: nAMD, intermediate AMD (iAMD), MPNd and MPNn. Investigating, differences between MPNd and MPNn, will make it possible to identify changes in the immune system, relevant for AMD pathogenesis. Additionally, we will compare patients with MPNs with patients with iAMD and nAMD. In study I (Paper I), we found that patients with MPNs have a significantly higher prevalence of large drusen and consequently AMD from an earlier age compared to the estimates from three large population-based studies. We also found that drusen prevalence was associated with a higher neutrophil-to-lymphocyte ratio indicating a higher level of chronic low-grade inflammation in patients with drusen compared to those without drusen. In study II (papers II, III and IV), we found immunological differences between patients with MPNd and MPNn. When we investigated markers of inflammation, we found a higher level of systemic inflammation in MPNd than MPNn. This was indicated by a higher inflammation score (based on levels of pro-inflammatory markers), a higher neutrophil-to-lymphocyte ratio, and indications of a deregulated complement system. When examining markers of ageing, we found signs of accelerated immune ageing in MPNd compared to MPNn, shown by more senescent effector memory T cells. Finally, when exploring a marker of angiogenesis, we found a lower CXCR3 expression on monocytes and T cells in nAMD compared to iAMD, MPNd and MPNn, in line with previous studies of nAMD compared to healthy controls. Further, we found decreasing CXCR3 expression over the MPN biological continuum. These studies indicate CXCR3 involvement in both nAMD and PMF, two disease stages characterised by angiogenesis and fibrosis. From the results of this PhD project, we can conclude that the prevalence of drusen and AMD is increased in patients with MPN compared to the general population. Further, our results show that systemic inflammation may play a far more essential role in AMD pathogenesis than previously anticipated. We, therefore, propose an AMD model (Figure 18) where inflammation can initiate and accelerate the normal age-dependent accumulation of debris in the retina, which later evolve into drusen, resulting in increased local inflammation, and over time early- and intermediate AMD. This results in the increased risk of developing the late debilitating stages of AMD.

Rosmarinic acid (RA) and tanshinone IIA (TA) which are effective components in Salvia miltiorrhiza show anti-inflammatory potential against atherosclerosis. Based on polysulfated propylene-polyethylene glycol (PPS-PEG), RA was grafted onto this polymer via amide bonds to form a micelle carrier for TA encapsulation: PPS-PEG-RA@TA. A potent inhibitory effect on lipopolysaccharide (LPS) -induced proliferation of endothelial cells with significant intracellular uptake was observed with this system. This could have been the result of release of TA in a reactive oxygen species (ROS) environment and stronger antioxidant effect of RA. The synergistic effect was optimized when the combination was used in a molar ratio of 1:1. Mechanistic studies showed that, compared with PPS-PEG-RA and TA+RA, PPS-PEG-RA@TA micelles could more effectively regulate the nuclear factor-kappa B (NF-κB) pathway to reduce expression of vascular cell adhesion molecule-1 (VCAM-1), inhibit the inflammatory cascade and reduce endothelial-cell injury. One month after intravenous injection of PPS-PEG-RA@TA micelles, the plaque area in murine aortic vessels was reduced significantly, and serious toxic side-effects were not observed in vivo, along with excellent biocompatibility. In summary, PPS-PEG-RA@TA micelles could achieve synergistic treatment of atherosclerosis.

The main therapeutic strategies for coronary artery disease (CAD) are mainly based on the correction of abnormal cholesterol levels; however, residual risks remain. The newly proven gut microbial metabolite trimethylamine N-oxide (TMAO) linked with CAD has broadened our horizons. In this study, we determined the role of proline/serine-rich coiled-coil protein 1 (PSRC1) in TMAO-driven atherosclerosis.

We first analyzed the levels of TMAO and PSRC1 in patients with or without atherosclerosis with a target LDL-C < 1.8 mmol/L. Plasma TMAO levels were increased and negatively associated with decreased PSRC1 in peripheral blood mononuclear cells. Animals and in vitro studies showed that TMAO inhibited macrophage PSRC1 expression due to DNA hypermethylation of CpG islands. ApoE^-/- mice fed a choline-supplemented diet exhibited reduced PSRC1 expression accompanied by increased atherosclerotic lesions and plasma TMAO levels. We further deleted PSRC1 in apoE^-/- mice and PSRC1 deficiency significantly accelerated choline-induced atherogenesis, characterized by increased macrophage infiltration, foam cell formation and M1 macrophage polarization. Mechanistically, we overexpressed and knocked out PSRC1 in cultured macrophages to explore the mechanisms underlying TMAO-induced cholesterol accumulation and inflammation. PSRC1 deletion impaired reverse cholesterol transport and enhanced cholesterol uptake and inflammation, while PSRC1 overexpression rescued the proatherogenic phenotype observed in TMAO-stimulated macrophages, which was partially attributed to sulfotransferase 2B1b (SULT2B1b) inhibition.

Herein, clinical data provide evidence that TMAO may participate in the development of CAD beyond well-controlled LDL-C levels. Our work also suggests that PSRC1 is a negative regulator mediating the unfavorable effects of TMAO-containing diets. Therefore, PSRC1 overexpression and reduced choline consumption may further alleviate atherosclerosis.

It remains unclear if principal components of the local cerebral stroke immune response can be reliably and reproducibly observed in patients with acute large-vessel-occlusion (LVO) stroke. We prospectively studied a large independent cohort of n = 318 consecutive LVO stroke patients undergoing mechanical thrombectomy during which cerebral blood samples from within the occluded anterior circulation and systemic control samples from the ipsilateral cervical internal carotid artery were obtained. An extensive protocol was applied to homogenize the patient cohort and to standardize the procedural steps of endovascular sample collection, sample processing, and laboratory analyses. N = 58 patients met all inclusion criteria. (1) Mean total leukocyte counts were significantly higher within the occluded ischemic cerebral vasculature (I) vs. intraindividual systemic controls (S): +9.6%, I: 8114/µL ± 529 vs. S: 7406/µL ± 468, p = 0.0125. (2) This increase was driven by neutrophils: +12.1%, I: 7197/µL ± 510 vs. S: 6420/µL ± 438, p = 0.0022. Leukocyte influx was associated with (3) reduced retrograde collateral flow (R2 = 0.09696, p = 0.0373) and (4) greater infarct extent (R2 = 0.08382, p = 0.032). Despite LVO, leukocytes invade the occluded territory via retrograde collateral pathways early during ischemia, likely compromising cerebral hemodynamics and tissue integrity. This inflammatory response can be reliably observed in human stroke by harvesting immune cells from the occluded cerebral vascular compartment.

Carotid artery atherosclerosis, the result of a multitude of vascular risk factors, is a promising marker for use in risk stratification. Recent evidence suggests that carotid artery atherosclerosis affects cognitive function and is an independent risk factor for the development of cognitive impairment. Both atherosclerosis and cognitive impairment develop over a prolonged period (years), and due to the aging population, markers to identify persons at risk are needed. Carotid artery atherosclerosis can easily be visualized using non-invasive ultrasound, potentially enabling early and intensified risk factor management to preserve cognitive function or delay further decline. However, the burden of atherosclerosis and temporal exposure required to pose a risk of cognitive impairment is unclear. This mini-review aims to explore the available evidence on the association between carotid atherosclerosis and cognition, and furthermore identify the remaining gaps in knowledge.

Vessel wall magnetic resonance imaging can improve the evaluation of intracranial atherosclerotic disease. However, pathological validation is needed to improve vessel wall magnetic resonance imaging techniques. Human pathology samples are not practical for such analysis, so an animal model is therefore needed.

Watanabe heritable hyperlipidemic rabbits and apolipoprotein E knockout rabbits were evaluated against New Zealand white wild-type rabbits. Evaluation of intracranial arteries was performed with vessel wall magnetic resonance imaging and pathological analysis, rating the presence and severity of disease in each segment. Two-tailed t-tests were performed to compare disease occurrence and severity prevalence among rabbit subtypes. Sensitivity and specificity were calculated to assess the diagnostic accuracy of vessel wall magnetic resonance imaging.

Seventeen rabbits (five Watanabe heritable hyperlipidemic, four apolipoprotein E knockout and eight New Zealand white) were analysed for a total of 51 artery segments. Eleven segments (five Watanabe heritable hyperlipidemic and six apolipoprotein E knockout) demonstrated intracranial atherosclerotic disease on pathology. Disease model animals had lesions more frequently than New Zealand white animals (P<0.001). The sensitivity and specificity of vessel wall magnetic resonance imaging for the detection of intracranial atherosclerotic disease were 68.8% and 95.2%, respectively. When excluding mild cases to assess vessel wall magnetic resonance imaging accuracy for detecting moderate to severe intracranial atherosclerotic disease lesions, sensitivity improved to 100% with unchanged specificity.

Intracranial atherosclerotic disease can be reliably produced and detected using 3T vessel wall magnetic resonance imaging-compatible Watanabe heritable hyperlipidemic and ApoE rabbit models. Further analysis is needed to characterize better the development and progression of the disease to correlate tissue-validated animal findings with those in human vessel wall magnetic resonance imaging studies.

The severe acute respiratory syndrome coronavirus 2 or coronavirus disease 2019 (COVID-19) pandemic has raised concerns about the correlation with this viral illness and increased risk of stroke. Although it is too early in the pandemic to know the strength of the association between COVID-19 and stroke, it is an opportune time to review the relationship between acute viral illnesses and stroke. Here, we summarize pathophysiological principles and available literature to guide understanding of how viruses may contribute to ischemic stroke. After a review of inflammatory mechanisms, we summarize relevant pathophysiological principles of vasculopathy, hypercoagulability, and hemodynamic instability. We will end by discussing mechanisms by which several well-known viruses may cause stroke in an effort to inform our understanding of the relationship between COVID-19 and stroke.

Inflammation is a key contributor to atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine/chemokine secretion. DJ1, an anti-oxidant protein, has shown to paradoxically protect against chronic and acute inflammation. However, the role of DJ1 in atherosclerosis remains elusive. To assess the role of Dj1 in atherogenesis, we generated whole-body Dj1-deficient atherosclerosis-prone Apoe null mice (Dj1^-/-Apoe^-/-). After 21 weeks of atherogenic diet, Dj1^-/- Apoe^-/-mice were protected against atherosclerosis with significantly reduced plaque macrophage content. To assess whether haematopoietic or parenchymal Dj1 contributed to atheroprotection in Dj1-deficient mice, we performed bone-marrow (BM) transplantation and show that Dj1-deficient BM contributed to their attenuation in atherosclerosis. To assess cell-autonomous role of macrophage Dj1 in atheroprotection, BM-derived macrophages from Dj1-deficient mice and Dj1-silenced macrophages were assessed in response to oxidized low-density lipoprotein (oxLDL). In both cases, there was an enhanced anti-inflammatory response which may have contributed to atheroprotection in Dj1-deficient mice. There was also an increased trend of plasma DJ-1 levels from individuals with ischemic heart disease compared to those without. Our findings indicate an atheropromoting role of Dj1 and suggests that targeting Dj1 may provide a novel therapeutic avenue for atherosclerosis treatment or prevention.

Host defense peptides (HDPs) comprise a heterogeneous group of evolutionarily conserved and biologically active small molecules that are produced by different organisms. HDPs are widely researched because they often have multiple biological activities, for example antimicrobial, immunomodulatory and anticancer activity. In this context, in this review we focus on cryptic HDPs, molecules derived specifically from proteolytic processing of endogenous precursor proteins. Here, we explore the biological activity of such molecules and we further discuss the development of optimized sequences based on these natural cryptic HDPs. In addition, we present clinical-phase studies of cryptic HDPs (natural or optimized), and point out the possible applicability of these molecules in medicinal chemistry.

Since the first report by Perry et al. (1955), most studies affirmed the hypertensive effects of cadmium (Cd) in humans. Nonetheless, conclusions between studies remain inconsistent.

The aim of this study was to reevaluate the evidence for a potential relationship between Cd exposure and altered blood pressure and/or hypertension, focusing on studies published between January 2010 and March 2020.

We reviewed all observational studies from database searches (PubMed and SCOPUS) on Cd exposure and blood pressure or hypertension. We extracted information from studies that provided sufficient data on population characteristics, smoking status, exposure, outcomes, and design.

Thirty-eight studies met our inclusion criteria; of those, twenty-nine were cross sectional, three case control, five cohort and one interventional study. Blood or urinary Cd levels were the most commonly used biomarkers.

A positive association between blood Cd levels and blood pressure and/or hypertension was identified in numerous studies at different settings. Limited number of representative population-based studies of never-smokers was observed, which may have confounded our conclusions. The association between urinary Cd and blood pressure and/or hypertension remains uncertain due to conflicting results, including inverse relationships with lack of strong mechanistic support. We point to the urgent need for additional longitudinal studies to confirm our findings.

To better understand how lipoproteins interact and enter endothelium and participate in cellular processes, we investigated preferential lipid partitioning of triglyceride rich lipoproteins (TGRL), chylomicrons (CM), low density lipoproteins (LDL), very low density lipoproteins (VLDL) and their lipolysis products using supported phospholipid raft membrane (SPRM) patterns. We prepared SPRM patterns with Texas red labeled phospholipid patterns and Marina blue labeled raft patterns and added Atto-520 labeled lipoproteins (TGRL, CM, VLDL, LDL) and their lipolysis products in separate experiments and characterized these interactions using fluorescence microscopy. We observed that VLDL and LDL preferentially interacted with raft patterns. In contrast the TGRL and lipolysed products of TGRL interacted with both the patterns, slightly elevated preference for raft patterns and CM and its lipolysis products showed greater affinity to phospholipid patterns. The clear preference of VLDL and LDL for raft patterns suggests that these lipoproteins associate with cholesterol and sphingomyelin rich lipid micro-domains during their early interactions with endothelial cells, leading to atherosclerosis.

Previous studies indicate that the levels of d-dimer and blood lipids at admission affect the prognosis of patients with acute ischemic stroke (AIS), however, whether there is a dose-response effect of d-dimer on prognosis, or a combined effect of d-dimer with blood lipids on prognosis, remains unclear.

In this prospective cohort study, 1485 AIS patients were recruited. All participants received medical care within 24 h from the onset of stroke, the level of d-dimer and related indices were measured at admission. Then, National Institutes of Health Stroke Scale (NIHSS) scores were obtained at the time of admission and discharge. Afterwards, 3-, 6- and 12- month follow-up was conducted to obtain Modified Rankin Scale (mRS) scores after discharge.

A high level of d-dimer at admission was associated with clinical outcome of AIS, after adjusting other relevant factors, with an OR (95%CI) of 2.934(1.914-4.500), 3.052(1.912-4.872), 3.306(1.873-5.835) and 2.828(1.447-5.527) at discharge, at 3-, 6-, and 12-month follow-up respectively, a dose-response effect was observed during follow-up (p = 0.00001). When d-dimer was combined with total cholesterol (TC), after adjusting other relevant factors, OR (95%CI) was 2.799 (1.708-4.587), 2.473 (1.475-4.147), 2.381 (1.333-4.255), and 2.619 (1.320-5.193), at each follow-up period respectively. When combined with low-density lipoprotein (LDL), OR (95%CI) was 3.105 (1.729-5.577), 3.280 (1.762-6.104), 2.744 (1.344-5.604), and 4.400 (1.883-10.282), respectively.

D-dimer levels at admission may predict the prognosis of AIS patients in a dose-response pattern. Moreover, d-dimer combined with TC or LDL predict prognosis of AIS.