Saponins as therapeutic candidates for atherosclerosis.

Drug development for atherosclerosis, the underlying pathological state of ischemic cardiovascular diseases, has posed a longstanding challenge. Saponins, classified as steroid or triterpenoid glycosides, have shown promising therapeutic potential in the treatment of atherosclerosis. Through an exhaustive examination of scientific literature spanning from May 2013 to May 2023, we identified 82 references evaluating 37 types of saponins in terms of their prospective impacts on atherosclerosis. These studies suggest that saponins have the potential to ameliorate atherosclerosis by regulating lipid metabolism, inhibiting inflammation, suppressing apoptosis, reducing oxidative stress, and modulating smooth muscle cell proliferation and migration, as well as regulating gut microbiota, autophagy, endothelial senescence, and angiogenesis. Notably, ginsenosides exhibit significant potential and manifest essential pharmacological attributes, including lipid-lowering, anti-inflammatory, anti-apoptotic, and anti-oxidative stress effects. This review provides a comprehensive examination of the pharmacological attributes of saponins in atherosclerosis, with particular emphasis on their role in the regulation of lipid metabolism regulation and anti-inflammatory effects. Thus, saponins may warrant further investigation as a potential therapy for atherosclerosis. However, due to various reasons such as low oral bioavailability, the clinical application of saponins in the treatment of atherosclerosis still needs further exploration.

Molecular mechanisms of hepatotoxicity induced by compounds occurring in Evodiae Fructus.

Evodiae Fructus (EF) is a common herbal medicine with thousands of years of medicinal history in China, which has been demonstrated with many promising pharmacological effects on cancer, cardiovascular diseases and Alzheimer's disease. However, there have been increasing reports of hepatotoxicity associated with EF consumption. Unfortunately, in a long term, many implicit constituents of EF as well as their toxic mechanisms remain poorly understood. Recently, metabolic activation of hepatotoxic compounds of EF to generate reactive metabolites (RMs) has been implicated. Herein, we capture metabolic reactions relevant to hepatotoxicity of these compounds. Initially, catalyzed by the hepatic cytochrome P450 enzymes (CYP450s), the hepatotoxic compounds of EF are oxidized to generate RMs. Subsequently, the highly electrophilic RMs could react with nucleophilic groups contained in biomolecules, such as hepatic proteins, enzymes, and nucleic acids to form conjugates and/or adducts, leading to a sequence of toxicological consequences. In addition, currently proposed biological pathogenesis, including oxidative stress, mitochondrial damage and dysfunction, endoplasmic reticulum (ER) stress, hepatic metabolism disorder, and cell apoptosis are represented. In short, this review updates the knowledge on the pathways of metabolic activation of seven hepatotoxic compounds of EF and provides considerable insights into the relevance of proposed molecular hepatotoxicity mechanisms from a biochemical standpoint, for the purpose of providing a theoretical guideline for the rational application of EF in clinics.

A cross-sectional study exploring the relationship between the dietary inflammatory index and hyperlipidemia based on the National Health and Nutrition Examination Survey (2005-2018).

BACKGROUND: Hyperlipidemia is closely associated with dietary patterns and inflammation. However, the relationship between hyperlipidemia and the inflammatory potential of diets remains unexplored. The research was conducted to examine the relationship between hyperlipidemia and dietary inflammatory index (DII). METHODS: The data utilized in the research were acquired from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. The information on dietary intake was gathered by conducting 24-h dietary recall interviews. Restricted cubic spline (RCS) and Survey-weighted logistic regression were utilized to determine the association between DII and hyperlipidemia. Furthermore, stratification analysis was carried out. RESULTS: This study included 8982 individuals with and 3458 without hyperlipidemia. Participants with hyperlipidemia exhibited higher DII scores than those without hyperlipidemia. Following adjustment for gender, age, race, education level, marital status, poverty, drinking status, diabetes, hypertension, smoking status, body mass index (BMI), chronic kidney disease (CKD), cardiovascular disease (CVD), and hemoglobin (Hb), the association between the prevalence of hyperlipidemia and DII remained significant. The RCS data demonstrated that the hyperlipidemia prevalence did not exhibit an increase until the DII score was approximately 2.78. Stratification analysis revealed that the association between DII and hyperlipidemia persisted in all subgroups. CONCLUSIONS: DII was associated with hyperlipidemia, and the threshold DII score for the risk of hyperlipidemia was 2.78.

Therapeutic Role and Potential Mechanism of Resveratrol in Atherosclerosis: TLR4/NF-κB/HIF-1α.

Atherosclerosis, the main pathological basis of cardiovascular disease, is a chronic inflammatory disease that severely affects the quality of human life. Resveratrol (Res) is a natural polyphenol that is a major component of many herbs and foods. The present study analyzed resveratrol from the perspective of visualization and bibliometric analysis and found that resveratrol is closely related to the inflammatory response in cardiovascular diseases (associated with atherosclerosis). To explore the specific molecular mechanism of resveratrol, network pharmacology and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used, in which HIF-1α signaling may be a key pathway in the treatment of AS. Furthermore, we induced the polarization of macrophage RAW264.7 to M1 type to generate inflammatory response by the combination of lipopolysaccharide (LPS) (200 ng/mL) + interferon-γ (IFN-γ) (2.5 ng/mL). LPS and IFN-γ increased the inflammatory factor levels of IL-1ß, TNF-α, and IL-6 in RAW264.7, and the proportion of M1-type macrophages also increased, but the expression of inflammatory factors decreased after resveratrol administration, which confirmed the anti-inflammatory effect of resveratrol in AS. In addition, we found that resveratrol downregulated the protein expression of toll-like receptor 4 (TLR4)/NF-κB/hypoxia inducible factor-1 alpha (HIF-1α). In conclusion, resveratrol has a significant anti-inflammatory effect, alleviates HIF-1α-mediated angiogenesis, and prevents the progression of AS through the TLR4/NF-κB signaling pathway.

Jia-Wei-Kai-Xin-San Treatment Alleviated Mild Cognitive Impairment through Anti-Inflammatory and Antiapoptotic Mechanisms in SAMP8 Mice.

Background: Alleviating mild cognitive impairment (MCI) is crucial to delay the progression of Alzheimer's disease (AD). Jia-Wei-Kai-Xin-San (JWKXS) is applied for treating AD with MCI. However, the mechanism of JWKXS in the treatment of MCI is unclear. Thus, this study aimed to investigate the effect and mechanism of JWKXS in SAMP8 mice models of MCI. Methods: MCI models were established to examine learning and memory ability and explore the pathomechanisms in brain of SAMP8 mice at 4, 6, and 8 months. The mice were treated for 8 weeks and the effects of JWKXS on MCI were characterized through Morris water maze and HE/Nissl's/immunohistochemical staining. Its mechanism was predicted by the combination of UPLC-Q-TOF/MS and system pharmacology analysis, further verified with SAMP8 mice, BV2 microglial cells, and PC12 cells. Results: It was found that 4-month-old SAMP8 mice exhibited MCI. Two months of JWKXS treatment improved the learning and memory ability, alleviated the hippocampal tissue and neuron damage. Through network pharmacology, four key signaling pathways were found to be involved in treatment of MCI by JWKXS, including TLR4/NF-κB pathway, NLRP3 inflammasome activation, and intrinsic and extrinsic apoptosis. In vitro and in vivo experiments demonstrated that JWKXS attenuated neuroinflammation by inhibiting microglia activation, suppressing TLR4/NF-κB and NLRP3 inflammasome pathways, and blocking the extrinsic and intrinsic apoptotic pathways leading to neuronal apoptosis suppression in the hippocampus. Conclusion: JWKXS treatment improved the learning and memory ability and conferred neuroprotective effects against MCI by inducing anti-inflammation and antiapoptosis. Limitations. The small sample size and short duration of the intervention limit in-depth investigation of the mechanisms. Future Prospects. This provides a direction for further clarification of the anti-AD mechanism, and provides certain data support for the formulation to move toward clinical practice.

Therapeutic Candidates for Alzheimer's Disease: Saponins.

Drug development for Alzheimer's disease, the leading cause of dementia, has been a long-standing challenge. Saponins, which are steroid or triterpenoid glycosides with various pharmacological activities, have displayed therapeutic potential in treating Alzheimer's disease. In a comprehensive review of the literature from May 2007 to May 2023, we identified 63 references involving 40 different types of saponins that have been studied for their effects on Alzheimer's disease. These studies suggest that saponins have the potential to ameliorate Alzheimer's disease by reducing amyloid beta peptide deposition, inhibiting tau phosphorylation, modulating oxidative stress, reducing inflammation, and antiapoptosis. Most intriguingly, ginsenoside Rg1 and pseudoginsenoside-F11 possess these important pharmacological properties and show the best promise for the treatment of Alzheimer's disease. This review provides a summary and classification of common saponins that have been studied for their therapeutic potential in Alzheimer's disease, showcasing their underlying mechanisms. This highlights the promising potential of saponins for the treatment of Alzheimer's disease.

Impaired generation of mature neurons due to extended expression of Tlx by repressing Sox2 transcriptional activity.

As a master regulator of the dynamic process of adult neurogenesis, timely expression and regulation of the orphan nuclear receptor Tailless (Tlx) is essential. However, there is no study yet to directly investigate the essential role of precise spatiotemporal expressed Tlx. Here, we generated a conditional gain of Tlx expression transgenic mouse model, which allowed the extended Tlx expression in neural stem cells (NSCs) and their progeny by mating with a TlxCreERT2 mouse line. We demonstrate that extended expression of Tlx induced the impaired generation of mature neurons in adult subventricular zone and subgranular zone. Furthermore, we elucidated for the first time that this mutation decreased the endogenous expression of Sox2 by directly binding to its promoter. Restoration experiments further confirmed that Sox2 partially rescued these neuron maturation defects. Together, these findings not only highlight the importance of shutting-off Tlx on time in controlling NSC behavior, but also provide insights for further understanding adult neurogenesis and developing treatment strategies for neurological disorders.

Shengmai Yin formula exerts cardioprotective effects on rats with chronic heart failure via regulating Linoleic Acid metabolism.

The objective of this study was to investigate the protective effects of Shengmai Yin(SMY) on rats with chronic heart failure(CHF).Sprague-Dawley rats were used to establish a CHF animal model via ligation of the left anterior descending branch of the coronary artery and exhaustive swimming.Echocardiography, serum biochemical indicators and histopathology were used to evaluate the pharmacodynamics of SMY in CHF rats.UPLC-Q-TOF/MS analysis based on serum was performed to identify the potential metabolites in the pathological process of CHF. Metabolic pathway analysis was carried out to elucidate the metabolic network associated with SMY treatment of CHF.Moreover,quantitative real-time PCR (qRT-PCR), Western blotting (WB), and Enzyme-linked immunosorbent assay (ELISA) were used to measure the RNA and protein expression levels in related pathways. Results revealed that SMY significantly restored the cardiac function of CHF rats, reduced the serum biochemical indicators, and alleviated cardiac histological damage. Metabolomics analysis shows that the therapeutic effect of SMY for CHF involves 14 biomarkers and 8 metabolic pathways, especially linoleic acid pathway, to be influenced, which implied the potential mechanism of SMY in treating CHF. Two key indicators Lipoxygenase arachidonic acid 15 lipoxygenase (ALOX15) and Cytochrome P450 1A2(CYP1A2) of linoleic acid metabolism pathway were verified by RT-PCR, WB and ELISA. Verification result showed that compared with the model group, expression levels of ALOX15 and CYP1A2 in SMY group were lower. In conclusion, SMY has cardioprotective effect on chronic heart failure rats, and its mechanism may be related to linoleic acid metabolism pathway.

New Classification of Macrophages in Plaques: a Revolution.

PURPOSE: Macrophages play vital roles in the development of atherosclerosis in responding to lipid accumulation and inflammation. Macrophages were classified as inflammatory (M1) and alternatively activated (M2) macrophage types based on results of in vitro experiments. On the other hand, the composition of macrophages in vivo is more complex and remains unresolved. This review summarizes the transcriptional variations of macrophages in atherosclerosis plaques that were discovered by single-cell RNA sequencing (scRNA-seq) to better understand their contribution to atherosclerosis. RECENT FINDINGS: ScRNA-seq provides a more detailed transcriptional landscape of macrophages in atherosclerosis, which challenges the traditional view. By mining the data of GSE97310, we discovered the transcriptional variations of macrophages in LDLR-/- mice that were fed with high-fat diet (HFD) for 11 and 20 weeks. Cells were represented in a two-dimensional tSNE plane and clusters were identified and annotated via Seurat and SingleR respectively, which were R toolkits for single-cell genomics. The results showed that in healthy conditions, Trem2hi (high expression of triggering receptors expressed on myeloid cells 2)-positive, inflammatory, and resident-like macrophages make up 68%, 18%, and 6% of total macrophages respectively. When mice were fed with HFD for 11 weeks, Trem2hi, monocytes, and monocyte-derived dendritic cells take possession of 40%, 18%, and 17% of total macrophages respectively. After 20 weeks of HFD feeding, Trem2hi, inflammatory, and resident-like macrophages occupied 12%, 37%, and 35% of total macrophages respectively. The phenotypes of macrophages are very different from the previous studies. In general, Trem2hi macrophages are the most abundant population in healthy mice, while the proportion of monocytes increases after 11 weeks of HFD. Most importantly, inflammatory and resident-like macrophages make up 70% of the macrophage populations after 20 weeks of HFD. These strongly indicate that inflammatory and resident-like macrophages promote the progression of atherosclerosis plaques.

Bioactive equivalence of combinatorial components identified in screening of an herbal medicine.

PURPOSE: To identify bioactive equivalent combinatorial components (BECCs) in herbal medicines. The exact composition of effective components in herbal medicines is often elusive due to the lack of adequate screening methodology. Herein, we propose a hypothesis that BECCs accounting for the whole efficacy of original herbal medicines could be discovered from a complex mixture of constituents. METHODS: We developed a bioactive equivalence oriented feedback screening method and applied it to discover the BECCs from an herbal preparation Cardiotonic Pill (CP). The operations include chemical profiling of CP, followed by an iterative loop of determining, collecting and evaluating candidate BECCs. RESULTS: A combination of 18 compounds was identified as BECCs from CP, which accounts for 15.0% (w/w) of original CP. We have demonstrated that the BECCs were as effective as CP in cell models and in a rat model of myocardial infarction. CONCLUSIONS: This work answers the key question of which are real bioactive components for CP that have been used in clinic for many years, and provides a promising approach for discovering BECCs from herbal medicines. More importantly, the BECCs could be extended to improve quality control of herbal products and inspire an herbal medicines based discovery of combinatorial therapeutics.

Astrocyte modulation in cerebral ischemia-reperfusion injury: A promising therapeutic strategy.

Cerebral ischemia-reperfusion injury (CIRI) poses significant challenges for drug development due to its complex pathogenesis. Astrocyte involvement in CIRI pathogenesis has led to the development of novel astrocyte-targeting drug strategies. To comprehensively review the current literature, we conducted a thorough analysis from January 2012 to December 2023, identifying 82 drugs aimed at preventing and treating CIRI. These drugs target astrocytes to exert potential benefits in CIRI, and their primary actions include modulation of relevant signaling pathways to inhibit neuroinflammation and oxidative stress, reduce cerebral edema, restore blood-brain barrier integrity, suppress excitotoxicity, and regulate autophagy. Notably, active components from traditional Chinese medicines (TCM) such as Salvia miltiorrhiza, Ginkgo, and Ginseng exhibit these important pharmacological properties and show promise in the treatment of CIRI. This review highlights the potential of astrocyte-targeted drugs to ameliorate CIRI and categorizes them based on their mechanisms of action, underscoring their therapeutic potential in targeting astrocytes.

A rapid and simple HPLC-MS/MS method for the therapeutic drug monitoring of six special-grade antimicrobials in pediatric patients.

Meropenem, linezolid, fluconazole, voriconazole, posaconazole, and vancomycin are six important antimicrobials used for severe infections in critically ill patients listed in special-grade antimicrobials in China. The six antimicrobials' highly variable pharmacodynamics and pharmacokinetics in critically ill pediatric patients present significant challenges to clinicians in ensuring optimal therapeutic targets. Therefore, therapeutic drug monitoring of these antimicrobials in human plasma is necessary to obtain their plasma concentration. A rapid, simple, and sample-saving high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed, which could simultaneously determine all six antimicrobials. It required only 10 µL of plasma and a one-step protein precipitation process. Chromatographic separation was achieved on a reversed-phase column (C18, 30 × 2.1 mm, 2.6 µm) via gradient elution using water and acetonitrile containing 0.1 % formic acid as mobile phase. The injection volume was 2 µL, and the total run time was only 2.5 min. Detection was done using a Triple Quad™ 4500MD tandem mass spectrometer coupled with an electrospray ionization (ESI) source in positive mode. The calibration curves ranged from 0.5 to 64 µg/mL for meropenem and fluconazole, 0.2-25.6 µg/mL for linezolid and voriconazole, 0.1-12.8 µg/mL for posaconazole and 1-128 µg/mL for vancomycin, with the coefficients of correlation all greater than 0.996. Furthermore, the method was validated rigorously according to the European Medicines Agency (EMA) guidelines, demonstrating excellent accuracy (from 93.0 % to 110.6 %) and precision (from 2.0 % to 12.8 %). Moreover, its applicability to various matrices (including serum, hemolytic plasma, and hyperlipidemic plasma) was evaluated. Thus, this method was successfully applied to routine therapeutic drug monitoring for critically ill pediatric patients and other patients in need.

Sacubitril/valsartan ameliorates cardiac function and ventricular remodeling in CHF rats via the inhibition of the tryptophan/kynurenine metabolism and inflammation.

Sacubitril/valsartan has been highly recognized as a treatment for Chronic heart failure (CHF). Its potential cardioprotective benefits and mechanisms, however, remain to be explored. Metabolomics can be used to identify the metabolic characteristics and related markers, as well as the influence of drugs, thereby opening up the new mechanism for sacubitril/valsartan therapy in CHF disease. In this study, the ligation of left anterior descending and exhaustive swimming were used to induce a rat model of CHF after myocardial infarction. The efficacy was appraised with echocardiography, serum NT-proBNP, and histopathologica. UPLC-Q/TOF-MS combined with multivariate statistical analysis approach were used to analyze the effect of sacubitril/valsartan on CHF rats. RT-qPCR and western blot were performed to investigate the tryptophan/kynurenine metabolism pathway. Accordingly, the basal cardiac function were increased, while the serum NT-proBNP and collagen volume fraction decreased in CHF rats with sacubitril/valsartan. Sacubitril/valsartan regulated the expression of kynurenine et.al 8 metabolomic biomarkers in CHF rats serum, and it contributed to the cardioprotective effects through tryptophan metabolism pathway. In addition, the mRNA and protein expression of the indoleamine 2,3-dioxygenase (IDO) in the myocardial tissue of CHF rats, were down-regulated by sacubitril/valsartan, which was the same with the IL-1ß, IFN-γ, TNF-α, COX-2, and IL-6 mRNA expression, and IL-1ß, IFN-γ, and TNF-α expression in serum. In conclusion, sacubitril/valsartan can ameliorate cardiac function and ventricular remodeling in CHF rats, at least in part through inhibition of tryptophan/kynurenine metabolism.

The role of immune system in atherosclerosis: Molecular mechanisms, controversies, and future possibilities.

Numerous cardiovascular disorders have atherosclerosis as their pathological underpinning. Numerous studies have demonstrated that, with the aid of pattern recognition receptors, cytokines, and immunoglobulins, innate immunity, represented by monocytes/macrophages, and adaptive immunity, primarily T/B cells, play a critical role in controlling inflammation and abnormal lipid metabolism in atherosclerosis. Additionally, the finding of numerous complement components in atherosclerotic plaques suggests yet again how heavily the immune system controls atherosclerosis. Therefore, it is essential to have a thorough grasp of how the immune system contributes to atherosclerosis. The specific molecular mechanisms involved in the activation of immune cells and immune molecules in atherosclerosis, the controversy surrounding some immune cells in atherosclerosis, and the limitations of extrapolating from relevant animal models to humans were all carefully reviewed in this review from the three perspectives of innate immunity, adaptive immunity, and complement system. This could provide fresh possibilities for atherosclerosis research and treatment in the future.

Sodium Danshensu ameliorates cerebral ischemia/reperfusion injury by inhibiting CLIC4/NLRP3 inflammasome-mediated endothelial cell pyroptosis.

Endothelial pyroptosis promotes cerebral ischemia/reperfusion injury (CIRI). Sodium Danshensu (SDSS) has been shown to attenuate CIRI and have anti-inflammatory properties in endothelial cells. However, the mechanism and effect of SDSS on alleviating endothelial pyroptosis after CIRI remains poorly understood. Thus, we aimed to investigate the efficacy and mechanism of SDSS in reducing endothelial pyroptosis. It has been shown that SDSS administration inhibited NLRP3 inflammasome-mediated pyroptosis. As demonstrated by protein microarrays, molecular docking, CETSA and ITDRFCETSA , SDSS bound strongly to CLIC4. Furthermore, SDSS can decrease its expression and inhibit its translocation. Its effectiveness was lowered by CLIC4 overexpression but not by knockdown. Overall The beneficial effect of SDSS against CIRI in this study can be ascribed to blocking endothelial pyroptosis by binding to CLIC4 and then inhibiting chloride efflux-dependent NLRP3 inflammasome activation.

Research Advance of Chinese Medicine in Treating Atherosclerosis: Focus on Lipoprotein-Associated Phospholipase A2.

As a serious cardiovascular disease, atherosclerosis (AS) causes chronic inflammation and oxidative stress in the body and poses a threat to human health. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a member of the phospholipase A2 (PLA2) family, and its elevated levels have been shown to contribute to AS. Lp-PLA2 is closely related to a variety of lipoproteins, and its role in promoting inflammatory responses and oxidative stress in AS is mainly achieved by hydrolyzing oxidized phosphatidylcholine (oxPC) to produce lysophosphatidylcholine (lysoPC). Moreover, macrophage apoptosis within plaque is promoted by localized Lp-PLA2 which also promotes plaque instability. This paper reviews those researches of Chinese medicine in treating AS via reducing Lp-PLA2 levels to guide future experimental studies and clinical applications related to AS.

Tiaogan daozhuo formula attenuates atherosclerosis via activating AMPK -PPARγ-LXRα pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Tiaogan Daozhuo Formula (TGDZF) is a common formulation against atherosclerosis, however, there is limited understanding of its therapeutic mechanism. AIM OF THIS STUDY: To examine the effectiveness of TGDZF in the treatment of atherosclerosis and to explore its mechanisms. MATERIALS AND METHODS: In ApoE-/- mice, atherosclerosis was induced by a high-fat diet for 12 weeks and treated with TGDZF at different doses. The efficacy of TGDZF in alleviating atherosclerosis was evaluated by small animal ultrasound and histological methods. Lipid levels were measured by biochemical methods. The capacity of cholesterol efflux was tested with a cholesterol efflux assay in peritoneal macrophage, and the expression of AMPKα1, PPARγ, LXRα, and ABCA1 was examined at mRNA and protein levels. Meanwhile, RAW264.7-derived macrophages were induced into foam cells by ox-LDL, and different doses of TGDZF-conducting serum were administered. Similarly, we examined differences in intracellular lipid accumulation, cholesterol efflux rate, and AMPKα1, PPARγ, LXRα, and ABCA1 levels following drug intervention. Finally, changes in the downstream molecules were evaluated following the inhibition of AMPK by compound C or PPARγ silencing by small interfering RNA. RESULTS: TGDZF administration reduced aortic plaque area and lipid accumulation in aortic plaque and hepatocytes, and improved the serum lipid profiles of ApoE-/- mice. Further study revealed that its efficacy was accompanied by an increase in cholesterol efflux rate and the expression of PPARγ, LXRα, and ABCA1 mRNA and protein, as well as the promotion of AMPKα1 phosphorylation. Moreover, similar results were caused by the intervention of TGDZF-containing serum in vitro experiments. Inhibition of AMPK and PPARγ partially blocked the regulatory effect of TGDZF, respectively. CONCLUSIONS: TGDZF alleviated atherosclerosis and promoted cholesterol efflux from macrophages by activating the AMPK-PPARγ-LXRα-ABCA1 pathway.

Buyang Huanwu Decoction Alleviates Atherosclerosis by Regulating gut Microbiome and Metabolites in Apolipoprotein E-deficient Mice fed with High-fat Diet.

ABSTRACT: The traditional Chinese herbal prescription Buyang Huanwu decoction (BHD), effectively treats atherosclerosis. However, the mechanism of BHD in atherosclerosis remains unclear. We aimed to determine whether BHD could alleviate atherosclerosis by altering the microbiome-associated metabolic changes in atherosclerotic mice. An atherosclerotic model was established in apolipoprotein E-deficient mice fed high-fat diet, and BHD was administered through gavage for 12 weeks at 8.4 g/kg/d and 16.8 g/kg/d. The atherosclerotic plaque size, composition, serum lipid profile, and inflammatory cytokines, were assessed. Mechanistically, metabolomic and microbiota profiles were analyzed by liquid chromatography-mass spectrometry and 16S rRNA gene sequencing, respectively. Furthermore, intestinal microbiota and atherosclerosis-related metabolic parameters were correlated using Spearman analysis. Atherosclerotic mice treated with BHD exhibited reduced plaque area, aortic lumen occlusion, and lipid accumulation in the aortic root. Nine perturbed serum metabolites were significantly restored along with the relative abundance of microbiota at the family and genus levels but not at the phylum level. Gut microbiome improvement was strongly negatively correlated with improved metabolite levels. BHD treatment effectively slows the progression of atherosclerosis by regulating altered intestinal microbiota and perturbed metabolites.

LncRNA/CircRNA-miRNA-mRNA Axis in Atherosclerotic Inflammation: Research Progress.

Atherosclerosis is characterized by chronic inflammation of the arterial wall. However, the exact mechanism underlying atherosclerosis-related inflammation has not been fully elucidated. To gain insight into the mechanisms underlying the inflammatory process that leads to atherosclerosis, there is need to identify novel molecular markers. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-protein-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have gained prominence in recent years. LncRNAs/circRNAs act as competing endogenous RNAs (ceRNAs) that bind to miRNAs via microRNA response elements (MREs), thereby inhibiting the silencing of miRNA target mRNAs. Inflammatory mediators and inflammatory signaling pathways are closely regulated by ceRNA regulatory networks in atherosclerosis. In this review, we discuss the role of LncRNA/CircRNA-miRNA-mRNA axis in atherosclerotic inflammation and how it can be targeted for early clinical detection and treatment.