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Atherosclerosis represents the major cause of mortality worldwide and triggers higher risk of acute cardiovascular events. Pericytes‐endothelial cells (ECs) communication is orchestrated by ligand‐receptor interaction generating a microenvironment which results in intraplaque neovascularization, that is closely associated with atherosclerotic plaque instability. Notoginsenoside R1 (R1) exhibits anti‐atherosclerotic bioactivity, but its effect on angiogenesis in atherosclerotic plaque remains elusive. The aim of our study is to explore the therapeutic effect of R1 on vulnerable plaque and investigate its potential mechanism against intraplaque neovascularization. The impacts of R1 on plaque stability and intraplaque neovascularization were assessed in ApoE−/− mice induced by high‐fat diet. Pericytes‐ECs direct or non‐direct contact co‐cultured with VEGF‐A stimulation were used as the in vitro angiogenesis models. Overexpressing Ang1 in pericytes was performed to investigate the underlying mechanism. In vivo experiments, R1 treatment reversed atherosclerotic plaque vulnerability and decreased the presence of neovessels in ApoE−/− mice. Additionally, R1 reduced the expression of Ang1 in pericytes. In vitro experiments demonstrated that R1 suppressed pro‐angiogenic behavior of ECs induced by pericytes cultured with VEGF‐A. Mechanistic studies revealed that the anti‐angiogenic effect of R1 was dependent on the inhibition of Ang1 and Tie2 expression, as the effects were partially reversed after Ang1 overexpressing in pericytes. Our study demonstrated that R1 treatment inhibited intraplaque neovascularization by governing pericyte‐EC association via suppressing Ang1‐Tie2/PI3K‐AKT paracrine signaling pathway. R1 represents a novel therapeutic strategy for atherosclerotic vulnerable plaques in clinical application. [ABSTRACT FROM AUTHOR]

BACKGROUND: This study focused on circulating plasma protein profiles to identify mediators of hypertension-driven myocardial remodeling and heart failure. METHODS: A Mendelian randomization design was used to investigate the causal impact of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure on 82 cardiac magnetic resonance traits and heart failure risk. Mediation analyses were also conducted to identify potential plasma proteins mediating these effects. RESULTS: Genetically proxied higher SBP, DBP, and pulse pressure were causally associated with increased left ventricular myocardial mass and alterations in global myocardial wall thickness at end diastole. Elevated SBP and DBP were linked to increased regional myocardial radial strain of the left ventricle (basal anterior, mid, and apical walls), while higher SBP was associated with reduced circumferential strain in specific left ventricular segments (apical, mid-anteroseptal, mid-inferoseptal, and mid-inferolateral walls). Specific plasma proteins mediated the impact of blood pressure on cardiac remodeling, with FGF5 (fibroblast growth factor 5) contributing 2.96% (P =0.024) and 4.15% (P =0.046) to the total effect of SBP and DBP on myocardial wall thickness at end diastole in the apical anterior segment and leptin explaining 15.21% (P =0.042) and 23.24% (P =0.022) of the total effect of SBP and DBP on radial strain in the mid-anteroseptal segment. Additionally, FGF5 was the only mediator, explaining 4.19% (P =0.013) and 4.54% (P =0.032) of the total effect of SBP and DBP on heart failure susceptibility. CONCLUSIONS: This mediation Mendelian randomization study provides evidence supporting specific circulating plasma proteins as mediators of hypertension-driven cardiac remodeling and heart failure. [ABSTRACT FROM AUTHOR]

Hypertension is a progressive metabolic disease characterized by circadian regulation of lipid metabolism disorder. Identifying specific lipid components and maintaining circadian homeostasis of lipid metabolism might be a promising therapeutic strategy for hypertension. Isorhynchophylline (IRP) can regulate lipid metabolism; however, the underlying mechanism of IRP in improving lipid metabolism rhythm disorder is still unclear. The lipid circadian biomarkers and abnormal metabolic pathways intervened by IRP were investigated using diurnal lipidomic research methods. The 24‐h circadian changes in mRNA and protein expression levels of circadian genes, including Bmal1, Clock, Cry1, Cry2, Per1, and Per2, and lipid metabolism‐related factors (PPARα and LPL) were determined using RT‐PCR and western blot analyses, respectively. The underlying mechanisms were intensively investigated by inhibiting Bmal1. Molecular docking and drug affinity responsive target stability analyses were performed to assess the binding affinity of IRP and Bmal1. IRP treatment could effectively improve 24‐h blood pressure, ameliorate the lipid metabolic rhythm disorder, reverse the expression levels of circadian rhythm genes, and regulate lipid metabolism‐related genes (PPARα and LPL) by mediating Bmal1. This study highlighted the potential effects of IRP in maintaining the circadian homeostasis of lipid metabolism and the treatment of hypertension. [ABSTRACT FROM AUTHOR]

Atractylenolide‐III (AT‐III) is well known as its role in antioxidant and anti‐inflammatory. Present study was aimed to figure out its effects on osteoarthritis and potential mechanisms. Rat model, human osteoarthritis cartilage explants as well as rat/human chondrocyte cultures were prepared to test AT‐III's effects on osteoarthritis progression and chondrocyte senescence. Potential targeted molecules of AT‐III were predicted using network pharmacology and molecular docking, assessed by Western blotting and then verified with rescue experiments. AT‐III treatment alleviated osteoarthritis severity (shown by OARSI grading score and micro‐CT) and chondrocyte senescence (indexed by levels of SA‐β‐gal, P16, P53, MMP13, ROS and ratio of healthy/collapsed mitochondrial membrane potentials). Network pharmacology and molecular docking suggested that AT‐III might play role through NF‐κB pathway. Further experiments revealed that AT‐III reduced phosphorylation of IKKα/β, IκBα and P65 in NF‐κB pathway. As well as nuclear translocation of p65. Both in vivo and in vitro experiments indicated that AT‐III's effects on osteoarthritis and anti‐senescence were reversed by an NF‐κB agonist. AT‐III could alleviate osteoarthritis by inhibiting chondrocyte senescence through NF‐κB pathway, which indicated that AT‐III is a prospective drug for osteoarthritis treatment. [ABSTRACT FROM AUTHOR]

Radish seed (RS), the dried ripe seed of Raphanus sativus L., is widely used in traditional Chinese medicine (TCM) to reduce blood pressure. However, the molecular and pharmacological mechanisms underlying its therapeutic effects are still unclear. In this study, we analyzed the effects of RS in a rat model of prehypertension and assessed the mechanistic basis by integrating transcriptomics and metabolomics. RS administration significantly reduced blood pressure in prehypertensive male Wistar rats, negatively regulated endothelin-1, increased nitric oxide levels, and reduced the exfoliation of endothelium cells. In vitro vascular ring experiments further confirmed the effects of RS on vascular endothelial cells. Furthermore, we identified 65 differentially expressed genes (DEGs; P a d j < 0.05 and fold change (FC) > 2) and 52 metabolites (VIP > 1, P < 0.05 and FC ≥ 2 or ≤0.5) in the RS intervention group using RNA-seq and UPLC-MS/MS, respectively. A network of the DEGs and the metabolites was constructed,q which indicated that RS regulates purine metabolism, linoleic acid metabolism, arachidonic acid metabolism, circadian rhythm, and phosphatidylinositol signaling pathway, and its target genes are Pik3c2a, Hspa8, Dnaja1, Arntl, Ugt1a1, Dbp, Rasd1, and Aldh1a3. Thus, the antihypertensive effects of RS can be attributed to its ability to improve vascular endothelial dysfunction by targeting multiple genes and pathways. Our findings provide new insights into the pathological mechanisms underlying prehypertension, along with novel targets for the prevention and treatment of hypertension. [ABSTRACT FROM AUTHOR]

Two new three‐phase solvent systems combined with elution‐extrusion counter‐current chromatography mode were used to study the chemical constituents in Bidens pilosa Linn. var. radiata Sch. Bip. The first novel solvent system consisted of n‐hexane, acetonitrile, chloroform, and water in a ratio of 5:5:1:5, which was selected for elution‐extrusion counter‐current chromatography to separate the n‐hexane extraction part. A total of six constituents were obtained from this part in the up phase as the stationary phase and the middle phase as the mobile phase. The second novel solvent system, composed of n‐hexane‐butyl acetate‐acetonitrile‐water (3:1:4:3, v/v/v/v), was used for separating ethyl acetate extract of Bidens pilosa Linn. var. radiata Sch. Bip. Eight compounds were successfully isolated using elution‐extrusion counter‐current chromatography elution‐extrusion mode. Fourteen chemical constituents were identified as 2‐β‐D‐glucopyranosytoxy‐1‐hydroxy‐5(E)‐tridecene‐7,9,11‐triyne (Y1), 3‐β‐D‐glucopyranosyloxy ‐1‐hydroxy‐6(E)‐tetradecene‐8,10,12‐triyne (Y2), 1, 2‐dihydroxy‐5(E)‐tridecene‐7,9, 11‐triyne (Y3), isorhamnetin (Y4), kaempferol (Y5), icthyothereolacetate (Y6), quercetin‐3‐O‐β‐D‐ galactopyranosyl‐7‐O‐β‐D‐glucopyranoside (W1), quercetin 3‐O‐β‐L‐rhamnopyranoside (W2), neosperidin dihydrochalcone (W3), quercetin (W4), quercetagetin‐3,6,4' ‐trimethoxyl‐ 7‐O‐β‐D‐glucopyranoside (W5), taxifolin (W6), luteolin (W7), and apigenin (W8) by spectra of 1H‐NMR and 13C‐NMR data. Among them, compounds Y1, Y2, Y3, and Y6 belong to polyacetylene compounds, and the rest were flavonoids. In addition, counter‐current chromatography has been used to separate polyacetylene compounds for the first time. All compounds in this method were isolated from Bidens pilosa Linn. var. radiata Sch. Bip. for the first time. [ABSTRACT FROM AUTHOR]

Objectives. Yishenjiangyafang is a traditional Chinese medicine used to clinically treat hypertension. This study aimed to explore the effect of yishenjiangyafang on plasma metabolomics in senile spontaneously hypertensive rats (SHRs). Methods. Twelve 50-week-old SHR (6 males and 6 females) were randomly divided into two groups: a treatment group, in which rats were intragastrically administered with yishenjiangyafang (10.08 g kg−1·d−1), and a model group, in which all SHRs were administered the same volume of saline. Six age- and gender-matched Wistar–Kyoto (WKY) rats were used as the control group. Treatment was given for 6 days per week and lasted for 8 weeks. Systolic and diastolic blood pressures of the rats were measured with the noninvasive tail artery pressure measurement system. An ultraperformance liquid chromatography quadruple electrostatic field orbit (UPLC-Q-Exactive) was used to determine metabolite changes in the plasma of SHR rats before and after yishenjiangyafang treatment in the treatment group as well as in the model and control groups. Results. After yishenjiangyafang treatment, SHRs had significant lower blood pressure. Using UPLC-Q-Exactive, we identified 26 metabolic targets of yishenjiangyafang in aged SHRs and revealed that yishenjiangyafang targeted four major metabolic pathways, linoleic acid metabolism, glycerophospholipid metabolism, arginine and proline metabolism, and steroid hormone biosynthesis. Conclusion. Yishenjiangyafang decreases the blood pressure of SHRs at least in part through targeting of four major metabolic pathways. Our study illustrates mechanisms underlying the clinical application of yishenjiangyafang in the treatment of hypertensive patients. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) leads to deep changes in lipid metabolism and obvious dyslipidemia. The dysregulation of lipid metabolism in turn results in CKD progression and the complications of cardiovascular diseases. To obtain a profound insight into the associated dyslipidemia in CKD, we performed lipidomic analysis to measure lipid metabolites in the serum from a rat 5/6 nephrectomy (5/6 Nx) model of CKD as well as in the serum from CKD patients. HK-2 cells were also used to examine oxidative stress-induced sphingolipid changes. Totally 182 lipid species were identified in 5/6 Nx rats. We found glycerolipids, total free fatty acids, and sphingolipids levels were significantly upregulated in 5/6 Nx rats. The atypical sphingolipids, 1-deoxysphingolipids, were significantly altered in both CKD animals and human CKD patients. The levels of 1-deoxysphingolipids directly relevant to the level of oxidative stress in vivo and in vitro. These results demonstrate that 1-deoxysphingolipid levels are increased in CKD and this increase directly correlates with increased kidney oxidative stress. Image 1 • Sphingolipids were measured in blood in CKD patients and animal models • 1-deoxysphinganine and 1-deoxysphingosine increased in both CKD patients and animal models • The increase of 1-deoxysphingolipids is co-related with oxidative stress both in vivo and in vitro • 1-deoxysphingolipid levels are independent with sphingolipid de novo synthesis [ABSTRACT FROM AUTHOR]

Ginger, a widely used functional food and food additive, little is known about the effect of ginger juice, which is rich in many healthful agents, on healthy humans or on its relationship with gut microbiota composition variation. The aim of this study was to investigate the changes in the gut microbial communities that occur following the supplementation of fresh ginger-derived juice in healthy adults and its potential associations with function. A crossover intervention study in which 123 healthy subjects (63 men and 60 women) consumed fresh ginger juice from Zingiber officinale Rosc. or sterile 0.9% sodium chloride was conducted. 16S rRNA sequencing analyses were applied to characterize gut microbiota variation. We found that ginger juice intervention increased the species number of intestinal flora. A decreased relative abundance of the Prevotella-to-Bacteroides ratio and pro-inflammatory Ruminococcus_1 and Ruminococcus_2 while a tendency toward an increased Firmicutes-to-Bacteroidetes ratio, Proteobacteria and anti-inflammatory Faecalibacterium were found. When we did not consider gender, we found differences in bacterial diversity both in community evenness and in richness caused by ginger intervention. In fact, there were different changes in bacterial α-diversity induced by the ginger juice in men and women. We identified 19 bacterial genera with significant differences between the control group (women) and ginger group (women) and 15 significant differences between the control group (men) and ginger group (men) at the genus level. Our results showed that short-term intake of ginger juice had substantial effects on the composition and function of gut microbiota in healthy people. Moreover, our findings underscored the importance of analyzing both male and female individuals to investigate the effects of ginger on gut microbiota. Additional studies are necessary to confirm these findings. [ABSTRACT FROM AUTHOR]

Cardiometabolic diseases are characterized as a combination of multiple risk factors for cardiovascular disease (CVD) and metabolic diseases including diabetes mellitus and dyslipidemia. Cardiometabolic diseases are closely associated with cell glucose and lipid metabolism, inflammatory response and mitochondrial function. Farnesoid X Receptor (FXR), a metabolic nuclear receptor, are found to be activated by primary BAs such as chenodeoxycholic acid (CDCA), cholic acid (CA) and synthetic agonists such as obeticholic acid (OCA). FXR plays crucial roles in regulating cholesterol homeostasis, lipid metabolism, glucose metabolism, and intestinal microorganism. Recently, emerging evidence suggests that FXR agonists are functional for metabolic syndrome and cardiovascular diseases and are considered as a potential therapeutic agent. This review will discuss the pathological mechanism of cardiometabolic disease and reviews the potential mechanisms of FXR agonists in the treatment of cardiometabolic disease. [ABSTRACT FROM AUTHOR]

Uncaria rhynchophylla (Miq.) Miq. ex Havil is widely used in the treatment of hypertension. The Uncaria extract and its bioactives, rhynchophylline and isorhynchophylline, reduced the blood pressure and fatty content in liver cells. In the present study, the antihypertensive effects of Uncaria ethanol extract (UET), rhynchophylline (RT) and isorhynchophylline (IT) were investigated in spontaneously hypertensive rats (SHR) using UPLC-Q-Orbitrap/MS based lipidomics approach. Histological changes in the liver were evaluated. Cytolysis and fatty degeneration in the liver tissues were observed in the SHR group. Lipid species in WKY, SHR treated with UET, RT, and IT were plotted to obtain the Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) score plots. Fifty-six endogenous metabolites in the liver such as glycerides, glycerophospholipids, unsaturated fatty acids, and sphingomyelins were selected as potential hypertension associated biomarkers. In order to further explore the metabolite targets of UET for antihypertensive, student's t test and correlation analysis were performed to recognize the pattern recognition and to select the significant metabolites. Similar and prolonged reduction in blood pressure was observed in all SHR groups treated with UET, RT, and IT, while the metabolite profiles were perturbed slightly compared to that of the untreated SHR. Further analysis showed that only a few common components were observed in both RT and IT, which showed similar antihypertensive effect in spite of the distinct metabolic pathways. These results help in understanding the mechanisms of isomeric ingredients in exhibiting the antihypertensive effect but with different targets. [ABSTRACT FROM AUTHOR]

The occurrence of nonalcoholic fatty liver disease (NAFLD) is associated with major abnormalities of hepatic lipid metabolism. We propose that lipid abnormalities directly or indirectly contribute to NAFLD, especially fatty acid accumulation, arachidonic acid metabolic disturbance, and ceramide overload. The effects of lipid intake and accumulation on NAFLD and NAFLD treatment are explained with theoretical and experimental details. Overall, these findings provide further understanding of lipid metabolism in NAFLD and may lead to novel therapies. [ABSTRACT FROM AUTHOR]

The incidence of chronic kidney disease (CKD) is associated with major abnormalities in circulating lipoproteins and renal lipid metabolism. This article elaborates on the mechanisms of CKD and lipid uptake abnormalities. The viewpoint we supported is that lipid abnormalities directly cause CKD, resulting in forming a vicious cycle. On the theoretical and experiment fronts, this inference has been verified by elaborately elucidating the role of lipid intake and accumulation as well as their influences on CKD. Taken together, these findings suggest that further understanding of lipid metabolism in CKD may lead to novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Our previous studies have shown that Uncaria has an important role in lowering blood pressure, but its intervention mechanism has not been clarified completely in the metabolic level. Therefore, in this study, a combination method of HPLC-TOF/MS-based metabolomics and multivariate statistical analyses was employed to explore the mechanism and evaluate the antihypertensive effect of Uncaria. Serum samples were analyzed and identified by HPLC-TOF/MS, while the acquired data was further processed by partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares discriminant analysis (OPLS-DA) to discover the perturbed metabolites. A clear cluster among the different groups was obtained, and 7 significantly changed potential biomarkers were screened out. These biomarkers were mainly associated with lipid metabolism (dihydroceramide, ceramide, PC, LysoPC, and TXA2) and vitamin and amino acids metabolism (nicotinamide riboside, 5-HTP). The result indicated that Uncaria could decrease the blood pressure effectively, partially by regulating the above biomarkers and metabolic pathways. Analyzing and verifying the specific biomarkers, further understanding of the therapeutic mechanism and antihypertensive effect of Uncaria was acquired. Metabolomics provided a new insight into estimate of the therapeutic effect and dissection of the potential mechanisms of traditional Chinese medicine (TCM) in treating hypertension. [ABSTRACT FROM AUTHOR]