Plaque Formation Research Articles

Molecular Imaging of Fibroblast Activation in Rabbit Atherosclerotic Plaques: a Preclinical PET/CT Study.

Atherosclerosis remains the pathological basis of myocardial infarction and ischemic stroke. Early and accurate identification of plauqes is crucial to improve clinical outcomes of atherosclerosis patients. Our study aims to evaluate the potential value of fibroblast activation protein inhibitor (FAPI)-04 PET/CT in identifying plaques via a preclinical rabbit model of atherosclerosis. New Zealand white rabbits were fed high-fat diet (HFD), and randomly divided into the model group injured by the balloon, and the sham group only with incisions. Ultrasound was performed to detect plaques, and FAPI-avid was determined through Al18F-NOTA-FAPI-04 PET/CT. Mean standardized uptake values (SUVmean) in lesions were compared, and biodistribution of Al18F-NOTA-FAPI-04 and target-to-background ratios (TBRs) were calculated. Histological staining was performed to display arterial plaques, and autoradiography (ARG) was employed to measure the in vitro intensity of Al18F-NOTA-FAPI-04. At last, the correlation among FAP levels, plaque area, SUVmean values and fibrous cap thickness was assessed. The rabbit carotid and abdominal atherosclerosis model was established. Al18F-NOTA-FAPI-04 showed a higher uptake in carotid plaques (SUVmean 1.32 ± 0.11) and abdominal plaques (SUVmean 0.73 ± 0.13) compared to corresponding controls (SUVmean 1.07 ± 0.06; 0.46 ± 0.03) (P < 0.05). Biodistribution analysis of Al18F-NOTA-FAPI-04 revealed that the bigger plaques were delineated with higher TBRs. Pathological staining showed the formation of arterial plaques, and ARG staining exhibited a higher intensity of Al18F-NOTA-FAPI-04 in the bigger plaques. Lastly, plaque area was found to be positively correlated to FAP expression and SUVmean, while FAP expression was negatively correlated to fibrous cap thickness of plaques. We successfully achieve molecular imaging of fibroblast activation in atherosclerotic lesions of rabbits, suggesting Al18F-NOTA-FAPI-04 PET/CT may be a potentially valuable tool to identify plaques.

Asprosin aggravates atherosclerosis via regulating the phenotype transformation of vascular smooth muscle cells

Phenotype transformation of vascular smooth muscle cells (VSMCs) plays an important role in the development of atherosclerosis. Asprosin is a newly discovered adipokine, which is critical in regulating metabolism. However, the relationship between asprosin and phenotype transformation of VSMCs in atherosclerosis remains unclear. The aim of this study is to investigate whether asprosin affects the progression of atherosclerosis by inducing phenotype transformation of VSMCs. We established an atherosclerosis model in ApoE−/− mice and administered asprosin recombinant protein and asprosin antibody to mice. Knocking down asprosin was also as an intervention. Interestingly, we found a correlation between asprosin levels and atherosclerosis. Asprosin promoted plaque formation and phenotype transformation of VSMCs. While, AspKD or asprosin antibody reduced the plaque lesion and suppressed vascular stiffness in ApoE−/− mice. Mechanistically, asprosin induced phenotype transformation of MOVAs by binding to GPR54, leading to Gαq/11 recruitment and activation of the PLC-PKC-ERK1/2-STAT3 signaling pathway. Si GPR54 or GPR54 antagonist partially inhibited the action of asprosin in MOVAs. Mutant GPR54-(267, 307) residue cancelled the binding of asprosin and GPR54. In summary, this study confirmed asprosin activated GPR54/Gαq/11-dependent ERK1/2-STAT3 signaling pathway, thereby promoting VSMCs phenotype transformation and aggravating atherosclerosis, thus providing a new target for the treatment of atherosclerosis.

Immunoproteasomal Inhibition With ONX-0914 Attenuates Atherosclerosis and Reduces White Adipose Tissue Mass and Metabolic Syndrome in Mice.

Atherosclerosis is the major underlying pathology of cardiovascular disease and is driven by dyslipidemia and inflammation. Inhibition of the immunoproteasome, a proteasome variant that is predominantly expressed by immune cells and plays an important role in antigen presentation, has been shown to have immunosuppressive effects. We assessed the effect of ONX-0914, an inhibitor of the immunoproteasomal catalytic subunits LMP7 (proteasome subunit β5i/large multifunctional peptidase 7) and LMP2 (proteasome subunit β1i/large multifunctional peptidase 2), on atherosclerosis and metabolism in LDLr-/- and APOE*3-Leiden.CETP mice. ONX-0914 treatment significantly reduced atherosclerosis, reduced dendritic cell and macrophage levels and their activation, as well as the levels of antigen-experienced T cells during early plaque formation, and Th1 cells in advanced atherosclerosis in young and aged mice in various immune compartments. Additionally, ONX-0914 treatment led to a strong reduction in white adipose tissue mass and adipocyte progenitors, which coincided with neutrophil and macrophage accumulation in white adipose tissue. ONX-0914 reduced intestinal triglyceride uptake and gastric emptying, likely contributing to the reduction in white adipose tissue mass, as ONX-0914 did not increase energy expenditure or reduce total food intake. Concomitant with the reduction in white adipose tissue mass upon ONX-0914 treatment, we observed improvements in markers of metabolic syndrome, including lowered plasma triglyceride levels, insulin levels, and fasting blood glucose. We propose that immunoproteasomal inhibition reduces 3 major causes underlying cardiovascular disease, dyslipidemia, metabolic syndrome, and inflammation and is a new target in drug development for atherosclerosis treatment.

Coronary atherosclerotic plaque regression strategies.

Atherosclerosis poses a significant and widespread problem at the population level. Consequently, there is a pressing need to develop effective methods to reduce the risk associated with this condition, which holds a prominent position in cardiology research. The primary manifestation of atherosclerosis involves plaque formation on the walls of coronary arteries. These plaques not only disrupt blood flow but also raise the likelihood of thrombosis and subsequent cardiovascular events. Unfortunately, atherosclerosis itself is usually asymptomatic, resulting in challenges with diagnosis and a delayed initiation of treatment. Hence, strategies focusing on the regression of existing plaques within blood vessels play a crucial role. The present review encompasses comprehensive data on the regression of coronary atherosclerotic plaques, examining both the underlying mechanisms and a range of regression strategies, encompassing lifestyle modifications to medical interventions.

A novel rabbit model of atherosclerotic vulnerable plaque established by cryofluid-induced endothelial injury

Acute thrombosis secondary to atherosclerotic plaque rupture is the main cause of acute cardiac and cerebral ischemia. An animal model of unstable atherosclerotic plaques is highly important for investigating the mechanism of plaque rupture and thrombosis. However, current animal models involve complex operations, are costly, and have plaque morphologies that are different from those of humans. We aimed to establish a simple animal model of vulnerable plaques similar to those of humans. Rabbits were randomly divided into three groups. Group A was given a normal formula diet for 13 weeks. Group C underwent surgery on the intima of the right carotid artery with – 80 °C cryofluid-induced injury after 1 week of a high-fat diet and further feeding a 12-week high-fat diet. Group B underwent the same procedure as Group C but without the – 80 °C cryofluid. Serum lipid levels were detected via ELISA. The plaque morphology, stability and degree of stenosis were evaluated through hematoxylin–eosin (HE) staining, Masson trichrome staining, Elastica van Gieson staining (EVG), and oil red O staining. Macrophages and inflammatory factors in the plaques were assessed via immunohistochemical analysis. The serum low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and total cholesterol (TC) levels in groups B and C were significantly greater than those in group A. No plaque formation was observed in group A. The plaques in group B were very small. In group C, obvious plaques were observed in the blood vessels, and the plaques exhibited a thin fibrous cap, a large lipid core, and partially visible neovascularization, which is consistent with the characteristics of vulnerable plaques. In the plaques of group C, a large number of macrophages were present, and matrix metalloproteinase 9 (MMP-9) and lectin-like oxidized LDL receptor 1 (LOX-1) were abundantly expressed. We successfully established a rabbit model of vulnerable carotid plaque similar to that of humans through the combination of cryofluid-induced endothelial injury and a high-fat diet, which is feasible and cost effective.

A Review: The Significance of Toll-Like Receptors 2 and 4, and NF-κB Signaling in Endothelial Cells during Atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory vascular disease that begins with endothelial activation followed by a series of inflammatory responses, plaque formation, and finally rupture. An early event in endothelial dysfunction is activation of the nuclear factor-κB (NF-κB) signaling axis. Toll-like receptors (TLRs) in endothelial cells (ECs) play an essential role in recognizing pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and lifestyle-associated molecular patterns (LAMPs). Activation of the canonical NF-κB pathway stimulates the expression of cytokines, chemokines, and an array of additional genes which activate and amplify AS-associated inflammatory responses. In this review, we discuss the involvement of TLR2/4 and NF-κB signaling in ECs during AS initiation, as well as regulation of the inflammatory response during AS by noncoding RNAs, especially microRNA (miRNA) and circular RNA (circRNA).

Exosomal long non-coding RNA AU020206 alleviates macrophage pyroptosis in atherosclerosis by suppressing CEBPB-mediated NLRP3 transcription

Recent studies have suggested exosomes (EXO) as potential therapeutic tools for cardiovascular diseases, including atherosclerosis (AS). This study investigates the function of bone marrow stem cell (BMSC)-derived exosomes (EXO) on macrophage pyroptosis in AS and explores the associated mechanism. BMSC-EXO were isolated from healthy mice and identified. RAW264.7 cells (mouse macrophages) were exposed to oxLDL to simulate an AS condition. BMSC-EXO treatment enhanced viability and reduced lactate dehydrogenase release of macrophages. An animal model of AS was established using ApoE−/− mice. BMSC-EXO treatment suppressed plaque formation as well as macrophage and lipid infiltration in mouse aortic tissues. Moreover, BMSC-EXO decreased concentrations of pyroptosis-related markers interleukin (IL)-1β, IL-18, cleaved-caspase-1 and gasdermin D in vitro and in vivo. Long non-coding RNA AU020206 was carried by the BMSC-EXO, and it bound to CCAAT enhancer binding protein beta (CEBPB) to block CEBPB-mediated transcriptional activation of NLR family pyrin domain containing 3 (NLRP3). Functional assays revealed that silencing of AU020206 aggravated macrophage pyroptosis and exacerbated AS symptoms in mice. These exacerbations were blocked upon CEBPB silencing but then restored after NLRP3 overexpression. In conclusion, this study demonstrates that AU020206 delivered by BMSC-EXO alleviates macrophage pyroptosis in AS by blocking CEBPB-mediated transcriptional activation of NLRP3.

NEAT1 regulates VSMC differentiation and calcification in as long noncoding RNA NEAT1 enhances phenotypic and osteogenic switching of vascular smooth muscle cells in atherosclerosis via scaffolding EZH2.

Atherosclerosis (AS) is a significant contributor to cardio-cerebrovascular ischemia diseases, resulting in high mortality rates worldwide. During AS, vascular smooth muscle cells (VSMCs) play a crucial role in plaque formation by undergoing phenotypic and osteogenic switching. Long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has previously been identified as a nuclear regulator that promotes tumorigenesis and metastasis, but its role in regulating VSMCs in AS remains unclear. Our study aimed to investigate the biological functions and specific mechanisms of NEAT1 in regulating VSMCs in AS. We found that NEAT1 was upregulated in the aortas of AS mouse models and dedifferentiated primary VSMCs. Silencing NEAT1 in vitro attenuated the proliferation, migration, and osteogenic differentiation of VSMCs, while NEAT1 overexpression had the opposite effect. Furthermore, NEAT1 promoted VSMC osteogenic differentiation and vascular calcification in both in vivo and in vitro vascular calcification models. We also discovered that NEAT1 directly activates enhancer of zeste homolog 2 (EZH2), an epigenetic enzyme that suppresses the expression of senescence- and antimigration-related genes, by translocating it into the nucleus. CUT&Tag assay revealed that NEAT1 guides EZH2 to the promoters of senescence-related genes (P16, P21, and TIMP3), methylating local histones to reduce their transcription. Our findings suggest that NEAT1 functions in AS by modulating the epigenetic function of EZH2, which enhances the proliferation, migration, and osteogenic differentiation of VSMCs. This study provides new insights into the molecular mechanisms underlying the pathogenesis of AS and highlights the potential of NEAT1 as a therapeutic target of AS.NEW & NOTEWORTHY Our study demonstrates that the upregulation of long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) promotes proliferation and migration during phenotypic switching of vascular smooth muscle cells in atherosclerosis. We also provide in vivo and in vitro evidence that NEAT1 accelerates vascular calcification. Our findings identified the direct interaction between enhancer of zeste homolog 2 (EZH2) and NEAT1 during atherosclerosis. NEAT1 is necessary for EZH2 to translocate from the cytoplasm to the nucleus, where EZH2 epigenetically inhibits the expression of genes related to senescence and antimigration.

R20 (S)-protopanaxatriol improves atherosclerosis by inhibiting low-density lipoprotein receptor degradation in ApoE KO mice.

Atherosclerosis (AS) is a chronic progressive disease caused by various factors and causes various cerebrovascular and cardiovascular diseases (CVDs). Reducing the plasma levels of low-density lipoprotein-cholesterol (LDL-C) is the primary goal in preventing and treating AS. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) plays a crucial role in regulating LDL-C metabolism. Panax notoginseng has potent lipid-reducing effects and protects against CVDs, and its saponins induce vascular dilatation, inhibit thrombus formation, and are used in treating CVDs. However, the anti-AS effect of the secondary metabolite, 20(S) protopanaxatriol (20(S)-PPT), remains unclear. In this study, the anti-AS effect and molecular mechanism of 20(S)-PPT were investigated in vivo and in vitro by western blotting, real time-polymerase chain reaction (RT-PCR), Enzyme-linked Immunosorbent Assay (ELISA), immunofluorescence staining, and other assays. The in vitro experiments revealed that 20(S)-PPT reduced the levels of PCSK9 in the supernatant of HepG2 cells, upregulated low density lipoprotein receptor (LDLR) protein levels, promoted LDL uptake by HepG2 cells, and reduced PCSK9 mRNA transcription by upregulating the levels of FoxO3 protein and mRNA and decreasing the levels of HNF1α and SREBP2 protein and mRNA. The in vivo experiments revealed that 20(S)-PPT upregulated aortic αSMA expression, increased the stability of atherosclerotic plaques, and reduced aortic plaque formation induced by a high-cholesterol fed in ApoE-/- mice (HCF group). Additionally, 20(S)PPT reduced the aortic expression of CD68, reduced inflammation in the aortic root, and alleviated the hepatic lesions in the HCF group. The study revealed that 20(S)-PPT inhibited LDLR degradation via PCSK9 to alleviate AS.

Comparison of the Safety Effects of Antiplatelets on the Kidneys in Patients with Vascular Disease

Aims: Most vascular disorders fall under the category of inflammatory diseases because they gradually harm blood vessels, disrupting the normal flow of blood to and from vital organs. The purpose of this research was to determine the potential dangers to kidney health associated with acetylsalicylic acid and clopidogrel treatment in patients with vascular diseases. Methodology: A cross-sectional research design was employed in the study, as well as retrospective data collection methods on medical records, and purposive sampling-based data sampling methodologies. Results: The study's findings indicated that there was no significant correlation between the use of antiplatelets and the risk of developing kidney disorders. It is rather, a patient's lifestyle, use of medications that increase the risk of renal GFR, and co-occurring diseases that may impair blood flow in the renal afferen can all increase their risk of developing a renal disorder with p-value &lt;0.05. Nevertheless, the prolonged use of medication also plays a significant role in kidney function. The study's results indicate that renal problems are not attributed to the usage of antiplatelet drugs such as clopidogrel and acetylsalicylic acid. Scientific Novelty: Several using antiplatelet for indicated cardiovascular disease such us, atherosclerosis, plaque formation, endothelial dysfunction, and blockage or damage to the vascular endotelial matrix are all symptoms of vascular disease, a progressive inflammatory illness, it's frequently associated with the risk of kidney disorders. The use of antiplatelet will enlarge the afferent blood vessels. Conclusion: Instead, factors such as a patient's lifestyle, the severity of their condition, and their medical history could have a more significant impact on the likelihood of developing kidney dysfunction.

QUINQUAUD’S DISEASE IN THE SPECTRUM OF CONCOMITANT DERMATOLOGIC PATHOLOGY

Cicatrical alopecia is one of the acute issues of modern dermatology due to a permanent cosmetic defect in the form of bald areas with non-recoverable loss of hair follicles. Interrelation of cicatrical alopecia with other dermatoses and somatic diseases is also topical. The article presents a clinical case of development of Quinquaud’s disease of the scalp combined with parapsoriasis lichenoides and multiple seborrheic keratosis on the top of already administered targeted therapy in connection with previously removed skin melanoma. Among the features of this pathology, we noted: appearance of rashes after a past oncological disease, erythema diffusely spreading throughout the entire scalp, multiple follicular pustules and rapid formation of cicatricial atrophy, severe itching and soreness, resistance to the ongoing therapy, as well as multiple rashes on the skin of body and extremities in the form of lichenoid papules and plaques. For differential diagnostics, multifocal biopsic examination of the skin was carried out, which showed presence of histologic signs of three dermatoses, which make up a spectrum of the concomitant pathology in the patient. Taking into account the important role of staphylococcal infection in the pathogenesis of Quinquaud’s disease and parapsoriasis lichenoides, we can assume similar pathogenetic mechanisms for the development of these diseases in the patient, associated with disorders of cutaneous microbiome. It is possible that a history of the oncological pathology and targeted therapy could lead to a decrease in resistance and suppression of the immune system, which was also a factor contributing to the development of concomitant dermatoses. Appearance of multiple eruptive seborrheic keratomas on skin of the body and extremities may be an indicator of a paraneoplastic process and require oncological screening. Understanding the causes and common factors of formation of dermatoses comorbid with cicatricial alopecia is extremely important for a dermatologist, because it allows performing early diagnostics in a timely manner, assigning treatment and preventing development of the permanent cosmetic defect leading to a decrease in the quality of life.

QUINQUAUD’S DISEASE IN THE SPECTRUM OF CONCOMITANT DERMATOLOGIC PATHOLOGY

Cicatrical alopecia is one of the acute issues of modern dermatology due to a permanent cosmetic defect in the form of bald areas with non-recoverable loss of hair follicles. Interrelation of cicatrical alopecia with other dermatoses and somatic diseases is also topical. The article presents a clinical case of development of Quinquaud’s disease of the scalp combined with parapsoriasis lichenoides and multiple seborrheic keratosis on the top of already administered targeted therapy in connection with previously removed skin melanoma. Among the features of this pathology, we noted: appearance of rashes after a past oncological disease, erythema diffusely spreading throughout the entire scalp, multiple follicular pustules and rapid formation of cicatricial atrophy, severe itching and soreness, resistance to the ongoing therapy, as well as multiple rashes on the skin of body and extremities in the form of lichenoid papules and plaques. For differential diagnostics, multifocal biopsic examination of the skin was carried out, which showed presence of histologic signs of three dermatoses, which make up a spectrum of the concomitant pathology in the patient. Taking into account the important role of staphylococcal infection in the pathogenesis of Quinquaud’s disease and parapsoriasis lichenoides, we can assume similar pathogenetic mechanisms for the development of these diseases in the patient, associated with disorders of cutaneous microbiome. It is possible that a history of the oncological pathology and targeted therapy could lead to a decrease in resistance and suppression of the immune system, which was also a factor contributing to the development of concomitant dermatoses. Appearance of multiple eruptive seborrheic keratomas on skin of the body and extremities may be an indicator of a paraneoplastic process and require oncological screening. Understanding the causes and common factors of formation of dermatoses comorbid with cicatricial alopecia is extremely important for a dermatologist, because it allows performing early diagnostics in a timely manner, assigning treatment and preventing development of the permanent cosmetic defect leading to a decrease in the quality of life.

Identification of Critical Genes Differentiating Stable and Unstable Atherosclerotic Plaques: A Bioinformatic and Computational Analysis.

Identification of biomarkers to distinguish between stable and unstable plaque formation would be very useful to predict plaque vulnerability. We downloaded microarray profiles of gene set enrichment (GSE) accession numbers including GSE71226 and GSE20680 (group A: containing healthy vs stable plaque samples) and GSE62646 and GSE34822 (group B: containing stable vs unstable plaque samples) from Gene expression omnibus (GEO) database. Differentially expressed genes were compared in both data sets of each group. Ten and 12 key genes were screened in groups A and B, respectively. Gene Ontology (GO) enrichment was applied by the plugin "BiNGO" (Biological networks gene ontology tool) of the Cytoscape. The key genes were mostly enriched in the biological process of positive regulation of the cellular process. The protein-protein interaction and co-expression network were analyzed by the STRING (search tool for the retrieval of interacting genes/proteins) and GeneMANIA (gene multiple association network integration algorithm) plugin of Cytoscape, respectively, which showed that Epidermal growth factor (EGF), Heparin-binding EGF like growth factor (HBEGF), and Matrix metalloproteinase 9 (MMP9) were at the core of the network. Further validation of key genes using two datasets showed that Phosphodiesterase 5A (PDE5A) and Protein S (PROS1) were decreased in unstable plaques, while Suppressor of cytokine signaling (SOCS3), HBEGF, and Leukocyte immunoglobulin-like receptor B4 (LILRB4) were increased. The present study used several datasets to identify key genes associated with stable and unstable atherosclerotic plaque.

Divergent Associations of Slow-Wave Sleep versus Rapid Eye Movement Sleep with Plasma Amyloid-Beta.

Recent evidence shows that during slow-wave sleep (SWS), the brain is cleared from potentially toxic metabolites, such as the amyloid-beta protein. Poor sleep or elevated cortisol levels can worsen amyloid-beta clearance, potentially leading to the formation of amyloid plaques, a neuropathological hallmark of Alzheimer disease. Here, we explored how nocturnal neural and endocrine activity affects amyloid-beta fluctuations in the peripheral blood. We acquired simultaneous polysomnography and all-night blood sampling in 60 healthy volunteers aged 20-68 years. Nocturnal plasma concentrations of amyloid-beta-40, amyloid-beta-42, cortisol, and growth hormone were assessed every 20 minutes. Amyloid-beta fluctuations were modeled with sleep stages, (non)oscillatory power, and hormones as predictors while controlling for age and participant-specific random effects. Amyloid-beta-40 and amyloid-beta-42 levels correlated positively with growth hormone concentrations, SWS proportion, and slow-wave (0.3-4Hz) oscillatory and high-band (30-48Hz) nonoscillatory power, but negatively with cortisol concentrations and rapid eye movement sleep (REM) proportion measured 40-100 minutes previously (all t values > |3|, p values < 0.003). Older participants showed higher amyloid-beta-40 levels. Slow-wave oscillations are associated with higher plasma amyloid-beta levels, whereas REM sleep is related to decreased amyloid-beta plasma levels, possibly representing changes in central amyloid-beta production or clearance. Strong associations between cortisol, growth hormone, and amyloid-beta presumably reflect the sleep-regulating role of the corresponding releasing hormones. A positive association between age and amyloid-beta-40 may indicate that peripheral clearance becomes less efficient with age. ANN NEUROL 2024;96:46-60.

A Multi-Faceted Analysis Showing CRNDE Transcripts and a Recently Confirmed Micropeptide as Important Players in Ovarian Carcinogenesis.

CRNDE is considered an oncogene expressed as long non-coding RNA. Our previous paper is the only one reporting CRNDE as a micropeptide-coding gene. The amino acid sequence of this micropeptide (CRNDEP) has recently been confirmed by other researchers. This study aimed at providing a mass spectrometry (MS)-based validation of the CRNDEP sequence and an investigation of how the differential expression of CRNDE(P) influences the metabolism and chemoresistance of ovarian cancer (OvCa) cells. We also assessed cellular localization changes of CRNDEP, looked for its protein partners, and bioinformatically evaluated its RNA-binding capacities. Herein, we detected most of the CRNDEP sequence by MS. Moreover, our results corroborated the oncogenic role of CRNDE, portraying it as the gene impacting carcinogenesis at the stages of DNA transcription and replication, affecting the RNA metabolism, and stimulating the cell cycle progression and proliferation, with CRNDEP being detected in the centrosomes of dividing cells. We also showed that CRNDEP is located in nucleoli and revealed interactions of this micropeptide with p54, an RNA helicase. Additionally, we proved that high CRNDE(P) expression increases the resistance of OvCa cells to treatment with microtubule-targeted cytostatics. Furthermore, altered CRNDE(P) expression affected the activity of the microtubular cytoskeleton and the formation of focal adhesion plaques. Finally, according to our in silico analyses, CRNDEP is likely capable of RNA binding. All these results contribute to a better understanding of the CRNDE(P) role in OvCa biology, which may potentially improve the screening, diagnosis, and treatment of this disease.

ASYMPTOTIC STABILITY FOR A FREE BOUNDARY MODEL OF AN ATHEROSCLEROTIC PLAQUE FORMATION IN THE PRESENCE OF REVERSE CHOLESTEROL TRANSPORT WITH HOLLING TYPE-III FUNCTIONAL RESPONSE

Atherosclerosis, as a chronic inflammatory disease, has been a threat to human health. How to diagnose and prevent this disease has long been the focus of medical and biomathematics study. In this paper, we investigate a free boundary model of an atherosclerotic plaque formation in the presence of reverse cholesterol transport, which includes low-density lipoprotein, high-density lipoprotein, endothelial stimulating cytokines, pro-inflammatory and anti-inflammatory macrophages, as well as foam cells. For this model, we use the Holling type-III response function instead of the usual Holling type-II to describe the change of the concentration of each substance. We first introduce the auxiliary function [Formula: see text] to prove the existence and uniqueness of small radially symmetric stationary plaque for appropriate [Formula: see text] and [Formula: see text] by using the contraction mapping principle and maximum principle, and then establish a condition to ensure their asymptotic stability behavior by expanding the corresponding steady-state solution.

Engineering Nanoplatforms for Theranostics of Atherosclerotic Plaques.

Atherosclerotic plaque formation is considered the primary pathological mechanism underlying atherosclerotic cardiovascular diseases, leading to severe cardiovascular events such as stroke, acute coronary syndromes, and even sudden cardiac death. Early detection and timely intervention of plaques are challenging due to the lack of typical symptoms in the initial stages. Therefore, precise early detection and intervention play a crucial role in risk stratification of atherosclerotic plaques and achieving favorable post-interventional outcomes. The continuously advancing nanoplatforms have demonstrated numerous advantages including high signal-to-noise ratio, enhanced bioavailability, and specific targeting capabilities for imaging agents and therapeutic drugs, enabling effective visualization and management of atherosclerotic plaques. Motivated by these superior properties, various noninvasive imaging modalities for early recognition of plaques in the preliminary stage of atherosclerosis are comprehensively summarized. Additionally, several therapeutic strategies are proposed to enhance the efficacy of treating atherosclerotic plaques. Finally, existing challenges and promising prospects for accelerating clinical translation of nanoplatform-based molecular imaging and therapy for atherosclerotic plaques are discussed. In conclusion, this review provides an insightful perspective on the diagnosis and therapy of atherosclerotic plaques.

Pre-clinical evaluation of 99mTc-labeled chalcone derivative for amyloid-β imaging post-head trauma.

Aβ42 plaque formation is one of the preliminary pathologic events that occur post traumatic brain injury (TBI) which is also among the most noteworthy hallmarks of AD. Their pre symptomatic detection is therefore vital for better disease management. Chalcone-picolinic acid chelator derivative, 6-({[(6-carboxypyridin-2-yl)methyl](2-{4-[(2E)-3-[4-(dimethyl amino)phenyl]prop-2-enoyl]phenoxy}ethyl)amino}methyl)pyridine-2-carboxylic acid, Py-chal was synthesized to selectively identify amyloid plaques formed post head trauma using SPECT imaging by stable complexation to 99mTc with > 97% efficiency without compromising amyloid specificity. The binding potential of the Py-chal ligand to amyloid plaques remained high as confirmed by in vitro binding assay and photophysical spectra. Further, the Py-chal complex stained amyloid aggregates in the brain sections of rmTBI mice model. In vivo scintigraphy in TBI mice model displayed high uptake followed by high retention while the healthy rabbits displayed higher brain uptake followed by a rapid washout attributed to absence of amyloid plaques. Higher uptake in brain of TBI model was also confirmed by ex vivo biodistribution analysis wherein brain uptake of 3.38 ± 0.2% ID/g at 2min p.i. was observed for TBI mice model. This was followed by prolonged retention and more than twofold higher activity as compared to sham mice brain. This preliminary data suggests the specificity of the radiotracer for amyloid detection post head trauma and applicability of 99mTc labeled Py-chal complex for TBI-induced β-amyloid SPECT imaging.

The Role of Macrophage Dynamics in Atherosclerosis Analyzed Using a Petri Net-Based Model

Atherosclerosis, a chronic inflammatory and oxidative stress-mediated disease impacting the arterial system, stands as a primary cause of morbidity and mortality worldwide. The complexity of this disease, driven by numerous factors, requires a thorough investigation of its underlying mechanisms. In our study, we explore the complex interplay between cholesterol homeostasis, macrophage dynamics, and atherosclerosis development using a Petri net-based model anchored in credible, peer-reviewed biological and medical research. Our findings underscore the significant role of macrophage colony-stimulating factor (M-CSF) inhibition in reducing atherosclerotic plaque formation by modulating inflammatory responses and lipid accumulation. Furthermore, our model highlights the therapeutic potential of targeting the C-X-C motif ligand 12 (CXCL12)/ C-X-C motif chemokine receptor type 4 (CXCR4) pathway to hinder hematopoietic stem and progenitor cells’ (HSPCs’) mobilization and plaque development. Based on the results obtained, which are in agreement with current studies, additional strategies are also proposed, such as decreasing M1 macrophage polarization for therapeutic gains, opening the door to future research and novel treatment approaches.

Geniposide ameliorates atherosclerosis by restoring lipophagy via suppressing PARP1/PI3K/AKT signaling pathway

BackgroundAtherosclerosis (AS) is the leading cause of global death, which manifests as arterial lipid stack and plaque formation. Geniposide is an iridoid glycoside extract from Gardenia jasminoides J.Ellis that ameliorates AS by mediating autophagy. However, how Geniposide regulates autophagy and treats AS remains unclear. PurposeTo evaluate the efficacy and mechanism of Geniposide in treating AS.Study design and methods: Geniposide was administered to high-fat diet-fed ApoE−/− mice and oxidized low-density lipoprotein-incubated primary vascular smooth muscle cells (VSMCs). AS was evaluated with arterial lipid stack, plaque progression, and collagen loss in the artery. Foam cell formation was detected by lipid accumulation, inflammation, apoptosis, and the expression of foam cell markers. The mechanism of Geniposide in treating AS was assessed using network pharmacology. Lipophagy was measured by lysosomal activity, expression of lipophagy markers, and the co-localization of lipids and lipophagy markers. The effects of lipophagy were blocked using Chloroquine. The role of PARP1 was assessed by Olaparib (a PARP1 inhibitor) intervention and PARP1 overexpression. ResultsIn vivo, Geniposide reversed high-fat diet-induced hyperlipidemia, plaque progression, and inflammation. In vitro, Geniposide inhibited VSMC-derived foam cell formation by suppressing lipid stack, apoptosis, and the expressions of foam cell markers. Network pharmacological analysis and in vitro validation suggested that Geniposide treated AS by enhancing lipophagy via suppressing the PI3K/AKT signaling pathway. The benefits of Geniposide in alleviating AS were offset by Chloroquine in vivo and in vitro. Inhibiting PARP1 using Olaparib promoted lipophagy and alleviated AS progression, while PARP1 overexpression exacerbated foam cell formation and lipophagy blockage. The above effects of PARP1 were weakened by PI3K inhibitor LY294002. PARP1 also inhibited the combination of the ABCG1 and PLIN1. ConclusionGeniposide alleviated AS by restoring PARP1/PI3K/AKT signaling pathway-suppressed lipophagy. This study is the first to present the lipophagy-inducing effect of Geniposide and the binding of ABCG1 and PLIN1 inhibited by PARP1.