Global Burden of Stroke Attributable to Low Physical Activity/High Body Mass Index Among People Aged 55 Years and Older.

BACKGROUND: This study aimed to quantify the global stroke burden attributable to low physical activity and high body mass index in adults aged ≥55 years using data from the Global Burden of Disease 2019 study. METHODS: We extracted data on stroke mortality, disability-adjusted life years, and risk factor exposure from the Global Burden of Disease 2019 study for people aged ≥55 years. We calculated the population-attributable fraction and absolute number of stroke cases and disability-adjusted life years attributable to low physical activity and high body mass index by location, age group, sex, and year. RESULTS: Globally, body mass index and physical inactivity-attributable stroke burden have declined modestly since 1990, but with diverging escalatory regional trajectories. Population growth and aging drive this rising burden. CONCLUSIONS: Multidimensional, context-specific strategies focused on modifiable lifestyle risks are imperative to address the modest declines and escalatory regional trajectories in body mass index and physical inactivity-attributable stroke burden.

Exosomal transfer of activated neutrophil-derived lncRNA CRNDE promotes proliferation and migration of airway smooth muscle cells in asthma.

Activated neutrophil-derived exosomes reportedly contribute to the proliferation of airway smooth muscle cells (ASMCs), thereby aggravating the airway wall remodeling during asthma; however, the specific mechanism remains unclear. Lipopolysaccharide (LPS)-EXO and si-CRNDE-EXO were extracted from the media of human neutrophils treated with LPS and LPS + si-CRNDE (a siRNA targets long non-coding RNA CRNDE), respectively. Human ASMCs were co-cultured with LPS-EXO or si-CRNDE-EXO, and cell viability, proliferation and migration were measured. The interplay of colorectal neoplasia differentially expressed (CRNDE), inhibitor of nuclear factor kappa B kinase subunit beta (IKKß) and nuclear receptor subfamily 2 group C member 2 (TAK1) was explored using RNA immunoprecipitation (RIP) and Co-IP assays. A mouse model of asthma was induced using ovalbumin. CRNDE was upregulated in LPS-EXO and successfully transferred from LPS-treated neutrophils to ASMCs through exosome. Mechanically, CRNDE loaded in LPS-EXO reinforced TAK1-mediated IKKß phosphorylation, thereby activating the nuclear factor kappa B (NF-κB) pathway. Functionally, silencing CRNDE in LPS-EXO, an IKKß inhibitor, and an NF-κB inhibitor all removed the upregulation of cell viability, proliferation and migration induced by LPS-EXO in ASMCs. In the end, the in vivo experiment demonstrated that CRNDE knockdown in neutrophils effectively reduced the thickness of bronchial smooth muscle in a mouse model for asthma. Activated neutrophils-derived CRNDE was transferred to ASMCs through exosomes and activated the NF-κB pathway by enhancing IKKß phosphorylation. The latter promoted the proliferation and migration of ASMCs and then contributed to airway remodeling in asthma.

Gut microbiota, circulating cytokines and dementia: a Mendelian randomization study.

BACKGROUND: Some studies have shown that gut microbiota may be associated with dementia. However, the causal effects between gut microbiota and different types of dementia and whether cytokines act as a mediator remain unclear. METHODS: Gut microbiota, cytokines, and five dementia types, including Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy body (DLB), vascular dementia (VD), and Parkinson's disease dementia (PDD) were identified from large-scale genome-wide association studies (GWAS) summary data. We used Mendelian randomization (MR) to investigate the causal relationships between gut microbiota, cytokines, and five types of dementia. Inverse variance weighting (IVW) was used as the main statistical method. In addition, we explored whether cytokines act as a mediating factor in the pathway from gut microbiota to dementia. RESULTS: There were 20 positive and 16 negative causal effects between genetic liability in the gut microbiota and dementia. Also, there were five positive and four negative causal effects between cytokines and dementias. Cytokines did not act as mediating factors. CONCLUSIONS: Gut microbiota and cytokines were causally associated with five types of dementia, and cytokines seemed not to be the mediating factors in the pathway from gut microbiota to dementia.

Construction of Cs2AgBiCl6/COF Heterojunction for Boosted Photocatalytic Thioester Oxidation.

Lead-free halide perovskites as a new kind of potential candidate for photocatalytic organic synthesis have attracted much attention recently. The rational heterojunction construction is regarded as an efficient strategy to delicately regulate their catalytic performances. Herein, a semi-conductive covalent organic framework (COF) nanosheet, C4N, is employed as the functional component to construct Cs2AgBiCl6/C4N (CABC/C4N) heterojunction. It is found that the C4N nanosheets with rich surface functional groups can serve as heterogeneous nucleation sites to manipulate the growth of CABC nanocrystals and afford close contact between each other, therefore facilitate the transfer and spatial separation of photogenerated charge carriers, as verified by in situ X-ray photoelectronic spectroscopy and Kelvin probe force microscopy. Moreover, the oxygen affinity of C4N endows the heterojunctions with outstanding aerobic reactivity, thus improving the photocatalytic performance largely. The optimal CABC/C4N heterojunction delivers a thioanisole conversion efficiency of 100% after 6 h, which is 2.2 and 7.7-fold of that of CABC and C4N. This work provides a new ideal for the design and application of lead-free perovskite heterojunction photocatalysts for organic reactions.

GraphTGI: an attention-based graph embedding model for predicting TF-target gene interactions.

MOTIVATION: Interaction between transcription factor (TF) and its target genes establishes the knowledge foundation for biological researches in transcriptional regulation, the number of which is, however, still limited by biological techniques. Existing computational methods relevant to the prediction of TF-target interactions are mostly proposed for predicting binding sites, rather than directly predicting the interactions. To this end, we propose here a graph attention-based autoencoder model to predict TF-target gene interactions using the information of the known TF-target gene interaction network combined with two sequential and chemical gene characters, considering that the unobserved interactions between transcription factors and target genes can be predicted by learning the pattern of the known ones. To the best of our knowledge, the proposed model is the first attempt to solve this problem by learning patterns from the known TF-target gene interaction network. RESULTS: In this paper, we formulate the prediction task of TF-target gene interactions as a link prediction problem on a complex knowledge graph and propose a deep learning model called GraphTGI, which is composed of a graph attention-based encoder and a bilinear decoder. We evaluated the prediction performance of the proposed method on a real dataset, and the experimental results show that the proposed model yields outstanding performance with an average AUC value of 0.8864 +/- 0.0057 in the 5-fold cross-validation. It is anticipated that the GraphTGI model can effectively and efficiently predict TF-target gene interactions on a large scale. AVAILABILITY: Python code and the datasets used in our studies are made available at https://github.com/YanghanWu/GraphTGI.

Spatiotemporal heterogeneity of LMOD1 expression summarizes two modes of cell communication in colorectal cancer.

Cellular communication (CC) influences tumor development by mediating intercellular junctions between cells. However, the role and underlying mechanisms of CC in malignant transformation remain unknown. Here, we investigated the spatiotemporal heterogeneity of CC molecular expression during malignant transformation. It was found that although both tight junctions (TJs) and gap junctions (GJs) were involved in maintaining the tumor microenvironment (TME), they exhibited opposite characteristics. Mechanistically, for epithelial cells (parenchymal component), the expression of TJ molecules consistently decreased during normal-cancer transformation and is a potential oncogenic factor. For fibroblasts (mesenchymal component), the expression of GJs consistently increased during normal-cancer transformation and is a potential oncogenic factor. In addition, the molecular profiles of TJs and GJs were used to stratify colorectal cancer (CRC) patients, where subtypes characterized by high GJ levels and low TJ levels exhibited enhanced mesenchymal signals. Importantly, we propose that leiomodin 1 (LMOD1) is biphasic, with features of both TJs and GJs. LMOD1 not only promotes the activation of cancer-associated fibroblasts (CAFs) but also inhibits the Epithelial-mesenchymal transition (EMT) program in cancer cells. In conclusion, these findings demonstrate the molecular heterogeneity of CC and provide new insights into further understanding of TME heterogeneity.

Bay41-4109-induced aberrant polymers of hepatitis b capsid proteins are removed via STUB1-promoted p62-mediated macroautophagy.

The hepatitis B virus (HBV) core protein (HBc) functions in multiple steps of the viral life cycle. Heteroaryldihydropyrimidine compounds (HAPs) such as Bay41-4109 are capsid protein allosteric modulators that accelerate HBc degradation and inhibit the virion secretion of HBV, specifically by misleading HBc assembly into aberrant non-capsid polymers. However, the subsequent cellular fates of these HAP-induced aberrant non-capsid polymers are not well understood. Here, we discovered that that the chaperone-binding E3 ubiquitin ligase protein STUB1 is required for the removal of Bay41-4109-induced aberrant non-capsid polymers from HepAD38 cells. Specifically, STUB1 recruits BAG3 to transport Bay41-4109-induced aberrant non-capsid polymers to the perinuclear region of cells, thereby initiating p62-mediated macroautophagy and lysosomal degradation. We also demonstrate that elevating the STUB1 level enhances the inhibitory effect of Bay41-4109 on the production of HBeAg and HBV virions in HepAD38 cells, in HBV-infected HepG2-NTCP cells, and in HBV transgenic mice. STUB1 overexpression also facilitates the inhibition of Bay41-4109 on the cccDNA formation in de novo infection of HBV. Understanding these molecular details paves the way for applying HAPs as a potentially curative regimen (or a component of a combination treatment) for eradicating HBV from hepatocytes of chronic infection patients.

Parallel evolution of morphological and genomic selfing syndromes accompany the breakdown of heterostyly.

Evolutionary transitions from outcrossing to selfing in flowering plants have convergent morphological and genomic signatures and can involve parallel evolution within related lineages. Adaptive evolution of morphological traits is often assumed to evolve faster than nonadaptive features of the genomic selfing syndrome. We investigated phenotypic and genomic changes associated with transitions from distyly to homostyly in the Primula oreodoxa complex. We determined whether the transition to selfing occurred more than once and investigated stages in the evolution of morphological and genomic selfing syndromes using 22 floral traits and both nuclear and plastid genomic data from 25 populations. Two independent transitions were detected representing an earlier and a more recently derived selfing lineage. The older lineage exhibited classic features of the morphological and genomic selfing syndrome. Although features of both selfing syndromes were less developed in the younger selfing lineage, they exhibited parallel development with the older selfing lineage. This finding contrasts with the prediction that some genomic changes should lag behind adaptive changes to morphological traits. Our findings highlight the value of comparative studies on the timing and extent of transitions from outcrossing to selfing between related lineages for investigating the tempo of morphological and molecular evolution.

Icariin rescues developmental BPA exposure induced spatial memory deficits in rats.

Bisphenol A (BPA) has been implicated in cognitive impairment. Icariin is the main active ingredient extracted from Epimedium Herb with protective function of nervous system. However, the potential therapeutic effects of Icariin on spatial memory deficits induced by developmental BPA exposure in Sprague-Dawley rats have not been investigated. This study investigated the therapeutic effect of Icariin (10 mg/kg/day, from postnatal day (PND) 21 to PND 60 by gavage) on spatial memory deficits in rat induced by developmental BPA exposure (1 mg/kg/day, from embryonic to PND 60), demonstrating that Icariin can markedly improve spatial memory in BPA-exposed rat. Furthermore, intra-gastric administration of Icariin could attenuate abnormal hippocampal cell dispersion and loss, improved the dendritic spine density and Nissl bodies. Moreover, Icariin reversed BPA induced reduction of frequency of miniature excitatory postsynaptic currents(mEPSC) and decrease of Vesicular glutamate transporter 1(VGlut1). Collectively, Icariin could effectively rescue BPA-induced spatial memory impairment in male rats by preventing cell loss and reduction of dendritic spines in the hippocampus. In addition, we also found that VGlut1 is a critical target in the repair of BPA-induced spatial memory by Icariin. Thus, Icariin may be a promising therapeutic agent to attenuate BPA-induced spatial memory deficits.

Global regulator IrrE on stress tolerance: a review.

Stress tolerance is a vital attribute for all living beings to cope with environmental adversities. IrrE (also named PprI) from Deinococcus radiodurans enhances resistance to extreme radiation stress by functioning as a global regulator, mediating the transcription of genes involved in deoxyribonucleic acid (DNA) damage response (DDR). The expression of IrrE augmented the resilience of various species to heat, radiation, oxidation, osmotic stresses and inhibitors, encompassing bacterial, fungal, plant, and mammalian cells. Moreover, IrrE was employed in a global regulator engineering strategy to broaden its applications in stress tolerance. The regulatory impacts of heterologously expressed IrrE have been investigated at the molecular and systems level, including the regulation of genes, proteins, modules, or pathways involved in DNA repair, detoxification proteins, protective molecules, native regulators and other aspects. In this review, we discuss the regulatory role and mechanism of IrrE in the antiradiation response of D. radiodurans. Furthermore, the applications and regulatory effects of heterologous expression of IrrE to enhance abiotic stress tolerance are summarized in particular.

Identification and mechanism of G protein-biased ligands for chemokine receptor CCR1.

Biased signaling of G protein-coupled receptors describes an ability of different ligands that preferentially activate an alternative downstream signaling pathway. In this work, we identified and characterized different N-terminal truncations of endogenous chemokine CCL15 as balanced or biased agonists targeting CCR1, and presented three cryogenic-electron microscopy structures of the CCR1-Gi complex in the ligand-free form or bound to different CCL15 truncations with a resolution of 2.6-2.9 Å, illustrating the structural basis of natural biased signaling that initiates an inflammation response. Complemented with pharmacological and computational studies, these structures revealed it was the conformational change of Tyr291 (Y2917.43) in CCR1 that triggered its polar network rearrangement in the orthosteric binding pocket and allosterically regulated the activation of ß-arrestin signaling. Our structure of CCL15-bound CCR1 also exhibited a critical site for ligand binding distinct from many other chemokine-receptor complexes, providing new insights into the mode of chemokine recognition.

Prokaryotic virus host prediction with graph contrastive augmentaion.

Prokaryotic viruses, also known as bacteriophages, play crucial roles in regulating microbial communities and have the potential for phage therapy applications. Accurate prediction of phage-host interactions is essential for understanding the dynamics of these viruses and their impacts on bacterial populations. Numerous computational methods have been developed to tackle this challenging task. However, most existing prediction models can be constrained due to the substantial number of unknown interactions in comparison to the constrained diversity of available training data. To solve the problem, we introduce a model for prokaryotic virus host prediction with graph contrastive augmentation (PHPGCA). Specifically, we construct a comprehensive heterogeneous graph by integrating virus-virus protein similarity and virus-host DNA sequence similarity information. As the backbone encoder for learning node representations in the virus-prokaryote graph, we employ LGCN, a state-of-the-art graph embedding technique. Additionally, we apply graph contrastive learning to augment the node representations without the need for additional labels. We further conducted two case studies aimed at predicting the host range of multi-species phages, helping to understand the phage ecology and evolution.

Knowledge graph embedding for profiling the interaction between transcription factors and their target genes.

Interactions between transcription factor and target gene form the main part of gene regulation network in human, which are still complicating factors in biological research. Specifically, for nearly half of those interactions recorded in established database, their interaction types are yet to be confirmed. Although several computational methods exist to predict gene interactions and their type, there is still no method available to predict them solely based on topology information. To this end, we proposed here a graph-based prediction model called KGE-TGI and trained in a multi-task learning manner on a knowledge graph that we specially constructed for this problem. The KGE-TGI model relies on topology information rather than being driven by gene expression data. In this paper, we formulate the task of predicting interaction types of transcript factor and target genes as a multi-label classification problem for link types on a heterogeneous graph, coupled with solving another link prediction problem that is inherently related. We constructed a ground truth dataset as benchmark and evaluated the proposed method on it. As a result of the 5-fold cross experiments, the proposed method achieved average AUC values of 0.9654 and 0.9339 in the tasks of link prediction and link type classification, respectively. In addition, the results of a series of comparison experiments also prove that the introduction of knowledge information significantly benefits to the prediction and that our methodology achieve state-of-the-art performance in this problem.

Electrochemical Trifluoromethylation/Bicyclization of N-Cyanamide Alkenes: Synthesis of Bicyclic Amidine Derivatives.

An anodically oxidizing trifluoromethylation cascade of N-cyanamide alkene bearing two electronically differentiated olefin moieties was reported, in which various N-unsaturated acyl cyanamide alkenes and CF3SO2Na acting as readily available starting materials furnished nonaromatic fused azaheterobicyclic compounds in a highly efficient and sustainable manner. The broad substrate scope, facile scalability, and sustainability enabled this electrochemical process to be an appealing complement for trifluoromethylated cyclic amidines.

GGC repeat expansion in NOTCH2NLC induces dysfunction in ribosome biogenesis and translation.

GGC repeat expansion in the 5' untranslated region (UTR) of NOTCH2NLC is associated with a broad spectrum of neurological disorders, especially neuronal intranuclear inclusion disease (NIID). Studies have found that GGC repeat expansion in NOTCH2NLC induces the formation of polyglycine (polyG)-containing protein, which is involved in the formation of neuronal intranuclear inclusions. However, the mechanism of neurotoxicity induced by NOTCH2NLC GGC repeats is unclear. Here, we used NIID patient-specific induced pluripotent stem cell (iPSC)-derived 3D cerebral organoids (3DCOs) and cellular models to investigate the pathophysiological mechanisms of NOTCH2NLC GGC repeat expansion. IPSC-derived 3DCOs and cellular models showed the deposition of polyG-containing intranuclear inclusions. The NOTCH2NLC GGC repeats could induce the upregulation of autophagic flux, enhance integrated stress response and activate EIF2α phosphorylation. Bulk RNA sequencing for iPSC-derived neurons and single-cell RNA sequencing (scRNA-seq) for iPSC-derived 3DCOs revealed that NOTCH2NLC GGC repeats may be associated with dysfunctions in ribosome biogenesis and translation. Moreover, NOTCH2NLC GGC repeats could induce the NPM1 nucleoplasm translocation, increase nucleolar stress, impair ribosome biogenesis and induce ribosomal RNA sequestration, suggesting dysfunction of membraneless organelles in the NIID cellular model. Dysfunctions in ribosome biogenesis and phosphorylated EIF2α and the resulting increase in the formation of G3BP1-positive stress granules may together lead to whole-cell translational inhibition, which may eventually cause cell death. Interestingly, scRNA-seq revealed that NOTCH2NLC GGC repeats may be associated with a significantly decreased proportion of immature neurons while 3DCOs were developing. Together, our results underscore the value of patient-specific iPSC-derived 3DCOs in investigating the mechanisms of polyG diseases, especially those caused by repeats in human-specific genes.

The Impacts of Nirmatrelvir-Ritonavir on Myocardial Injury and Long-Term Cardiovascular Outcomes in Hospitalized Patients with COVID-19 amid the Omicron Wave of the Pandemic.

PURPOSE: Even though nirmatrelvir-ritonavir can improve the short-term morbidity and mortality in COVID-19 patients, the effects of this treatment on long-term major adverse cardiovascular events (MACEs), especially myocardial injury, remains undetermined. METHODS: This prospective cohort study identified hospitalized adult patients with COVID-19 between April 19, 2022, and June 9, 2022, amid the omicron wave of the pandemic. Matched nirmatrelvir-ritonavir-treated and non-treated cohorts were formed using the propensity score matching method. The primary outcome of this study was the incidence of MACEs (cardiovascular death, myocardial infarction, stroke, new-onset heart failure or heart failure hospitalization or ventricular arrhythmia) from 30 days to 16 months after the diagnosis of COVID-19. RESULTS: Two 949-patient cohorts with balanced baseline characteristics were formed by propensity score matching. Patients with nirmatrelvir-ritonavir, compared to those untreated, had a lower level of troponin I peak as well as the incidence of troponin I elevation. During the follow-up period, 59 patients in the nirmatrelvir-ritonavir group and 86 patients in the control group developed MACEs (P = 0.020). Regarding specific constituents of MACEs, the differences are mainly reflected in new-onset heart failure or heart failure hospitalization. COVID-19 clinical severity and troponin I peak were the independent predictors, while nirmatrelvir-ritonavir was the independent protective factor for the occurrence of MACEs in this population. CONCLUSION: Nirmatrelvir-ritonavir was effective in reducing myocardial injury as well as long-term adverse cardiovascular outcomes among hospitalized patients with COVID-19 amid the omicron wave of the pandemic.

Effect of exposures to multiple metals on blood pressure and hypertension in the elderly: a community-based study.

A chronic disease, hypertension (HTN) is prevalent among the elderly. Exploring the factors that influence HTN and blood pressure (BP) changes is of great public health significance. However, mixed exposure to multiple serum metals has had less research on the effects on BP and HTN for the elderly. From April to August 2019, 2372 people participated in the community physical examination program for the elderly in Tongling City, Anhui Province. We measured BP and serum levels of 10 metals and collected basic demographic information. We analyzed the relationship between metal levels and changes in BP and HTN by the least absolute shrinkage and selection operator regression, Bayesian kernel machine regression model, and generalized linear model. In multiple models, lead (Pb) and cadmium (Cd) were still significantly associated with HTN occurrence after adjusting for potential confounders (Pb: ORquartile 4 VS quartile 1 = 1.20, 95% CI 1.01-1.43; Cd: ORquartile 4 VS quartile 1 = 1.37, 95% CI 1.16-1.62). In the male subgroup, results were similar to those of the general population. In the female group, Cd was positively correlated with HTN and systolic blood pressure, while Pb was not. According to this study, Pb and Cd were correlated with BP and HTN positively, and there was a certain joint effect. To some extent, our findings provide clues for the prevention of hypertension in the elderly.

Empagliflozin and liraglutide ameliorate HFpEF in mice via augmenting the Erbb4 signaling pathway.

Heart failure with preserved ejection fraction (HFpEF) is closely associated with metabolic derangement. Sodium glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) exert anti-HFpEF effects, but the underlying mechanisms remain unclear. In this study, we explored the anti-HFpEF effects of empagliflozin and liraglutide and the underlying molecular mechanisms in a mouse model of HFpEF. This model was established by high-fat diet (HFD) feeding plus Nω-nitro-L-arginine methyl ester (L-NAME) treatment. The mice were treated with empagliflozin (20 mg·kg-1·d-1, i.g.) or liraglutide (0.3 mg·kg-1·d-1, i.p.) or their combination for 4 weeks. At the end of the experimental protocol, cardiac function was measured using ultrasound, then mice were euthanized and heart, liver, and kidney tissues were collected. Nuclei were isolated from frozen mouse ventricular tissue for single-nucleus RNA-sequencing (snRNA-seq). We showed that administration of empagliflozin or liraglutide alone or in combination significantly improved diastolic function, ameliorated cardiomyocyte hypertrophy and cardiac fibrosis, as well as exercise tolerance but no synergism was observed in the combination group. Furthermore, empagliflozin and/or liraglutide lowered body weight, improved glucose metabolism, lowered blood pressure, and improved liver and kidney function. After the withdrawal of empagliflozin or liraglutide for 1 week, these beneficial effects tended to diminish. The snRNA-seq analysis revealed a subcluster of myocytes, in which Erbb4 expression was down-regulated under HFpEF conditions, and restored by empagliflozin or liraglutide. Pseudo-time trajectory analysis and cell-to-cell communication studies confirmed that the Erbb4 pathway was a prominent pathway essential for both drug actions. In the HFpEF mouse model, both empagliflozin and liraglutide reversed Erbb4 down-regulation. In rat h9c2 cells, we showed that palmitic acid- or high glucose-induced changes in PKCα and/or ERK1/2 phosphorylation at least in part through Erbb4. Collectively, the single-cell atlas reveals the anti-HFpEF mechanism of empagliflozin and liraglutide, suggesting that Erbb4 pathway represents a new therapeutic target for HFpEF. Effects and mechanisms of action of empagliflozin and liraglutide in HFpEF mice. HFpEF was induced with a high-fat diet and L-NAME for 15 weeks, and treatment with empagliflozin and liraglutide improved the HFpEF phenotype. Single nucleus RNA sequencing (snRNA-seq) was used to reveal the underlying mechanism of action of empagliflozin and liraglutide.

A novel mouse model of familial combined hyperlipidemia and atherosclerosis.

Within the context of residual cardiovascular risk in post-statin era, emerging evidence from epidemiologic and human genetic studies have demonstrated that triglyceride (TG)-rich lipoproteins and their remnants are causally related to cardiovascular risk. While, carriers of loss-of-function mutations of ApoC3 have low TG levels and are protected from cardiovascular disease (CVD). Of translational significance, siRNAs/antisense oligonucleotide (ASO) targeting ApoC3 is beneficial for patients with atherosclerotic CVD. Therefore, animal models of atherosclerosis with both hypercholesterolemia and hypertriglyceridemia are important for the discovery of novel therapeutic strategies targeting TG-lowering on top of traditional cholesterol-lowering. In this study, we constructed a novel mouse model of familial combined hyperlipidemia through inserting a human ApoC3 transgene (hApoC3-Tg) into C57BL/6 J mice and injecting a gain-of-function variant of adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-D377Y concurrently with high cholesterol diet (HCD) feeding for 16 weeks. In the last 10 weeks, hApoC3-Tg mice were orally treated with a combination of atorvastatin (10 mg·kg-1·d-1) and fenofibrate (100 mg·kg-1·d-1). HCD-treated hApoC3-Tg mice demonstrated elevated levels of serum TG, total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C). Oral administration of atorvastatin and fenofibrate significantly decreased the plaque sizes of en face aorta, aortic sinus and innominate artery accompanied by improved lipid profile and distribution. In summary, this novel mouse model is of considerable clinical relevance for evaluation of anti-atherosclerotic drugs by targeting both hypercholesterolemia and hypertriglyceridemia.

Urolithin A promotes atherosclerotic plaque stability by limiting inflammation and hypercholesteremia in Apolipoprotein E-deficient mice.

Urolithin A (UroA), a dietary phytochemical, is produced by gut bacteria from fruits rich in natural polyphenols ellagitannins (ETs). The efficiency of ETs metabolism to UroA in humans depends on gut microbiota. UroA has shown a variety of pharmacological activities. In this study we investigated the effects of UroA on atherosclerotic lesion development and stability. Apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model. Meanwhile the mice were administered UroA (50 mg·kg-1·d-1, i.g.). We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries, macrophage content in plaques, expression of endothelial adhesion molecules, intraplaque hemorrhage and size of necrotic core, while increased the expression of smooth muscle actin and the thickness of fibrous cap, implying features of plaque stabilization. The underlying mechanisms were elucidated using TNF-α-stimulated human endothelial cells. Pretreatment with UroA (10, 25, 50 µM) dose-dependently inhibited TNF-α-induced endothelial cell activation and monocyte adhesion. However, the anti-inflammatory effects of UroA in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) were independent of NF-κB p65 pathway. We conducted RNA-sequencing profiling analysis to identify the differential expression of genes (DEGs) associated with vascular function, inflammatory responses, cell adhesion and thrombosis in UroA-pretreated HUVECs. Human disease enrichment analysis revealed that the DEGs were significantly correlated with cardiovascular diseases. We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs. On the other hand, we found that UroA administration modulated the transcription and cleavage of lipogenic transcription factors SREBP1/2 in the liver to ameliorate cholesterol metabolism in ApoE-/- mice. This study provides an experimental basis for new dietary therapeutic option to prevent atherosclerosis.