Association between dietary live microbe intake and Life's Essential 8 in US adults: a cross-sectional study of NHANES 2005-2018.

Background: Assessing the impact of dietary live microbe intake on health outcomes has gained increasing interest. This study aimed to elucidate the relationship between dietary live microbe intake and Life's Essential 8 (LE8) scores, a metric for cardiovascular health (CVH), in the U.S. adult population. Methods: We analyzed data from 10,531 adult participants of the National Health and Nutrition Examination Survey (NHANES) spanning 2005-2018. Participants were stratified into low, medium, and high intake groups of dietary live microbe based on Marco's classification system. We employed weighted logistic and linear regression analyses, along with subgroup, interaction effect, and sensitivity analyses. Additionally, Restricted Cubic Splines (RCS) were used to explore the dose-response relationship between food intake and CVH in different groups. Results: Compared to the low live microbe intake group, the medium and high live microbe intake groups had significantly higher LE8, with ß coefficients of 2.75 (95% CI: 3.89-5.65) and 3.89 (95% CI: 6.05-8.11) respectively. Additionally, moderate and high groups significantly reduced the risk of high cardiovascular health risk, defined as an LE8 score below 50, with odds ratios (OR) of 0.73 and 0.65 respectively. Subgroup analysis and sensitivity analysis proved the stability of the results. In the low intake group, food intake shows a linear negative correlation with LE8, whereas in the high intake group, it exhibits a linear positive correlation. In contrast, in the moderate live microbe intake group, the relationship between food intake and LE8 presents a distinct inverted "U" shape. Conclusion: This study highlights the potential benefits of medium to high dietary intake of live microbe in improving LE8 scores and CVH in adults. These findings advocate for the inclusion of live microbes in dietary recommendations, suggesting their key role in CVH enhancement.

Effects of Banxia Baizhu Tianma Decoction in alleviating atherosclerosis based on the regulation of perivascular adipose.

ETHNOPHARMACOLOGICAL RELEVANCE: The occurrence and development of atherosclerosis, a common chronic inflammatory vascular disease, are closely related to cardiovascular and cerebrovascular diseases. Banxia Baizhu Tianma Decoction (BBTD) is a representative traditional Chinese medicine formula that resolves phlegm, disperses wind, invigorates the spleen and eliminates dampness and is also a commonly used clinical medication for treating vascular diseases. AIM OF THE STUDY: To explore the pharmacological mechanisms of BBTD in alleviating atherosclerosis, the present study was carried out by conducting an integrative analysis of aortic and perivascular adipose tissue (PVAT) proteomics and metabolomics. MATERIALS AND METHODS: Eight-week-old ApoE-/- mice were randomly divided into the BBTD group and the model group, and nine age-matched C57BL/6J (C57) mice were used as the control group (n = 9). The C57 mice were fed a standard diet, while the ApoE-/- mice were fed a high-fat, high-cholesterol diet for 12 weeks. Mice in the BBTD group were transgastrically administered BBTD at a dose of 17.8 g/kg/day for 8 weeks, while the model group and control group mice received an equivalent volume of saline by gavage. Histomorphology of the aortas and PVAT was assessed by HE staining, oil red O staining, Masson staining, and α-SMA and CD68 immunohistochemical methods. An integrative analysis of aortic proteomics, PVAT proteomics and PVAT metabolomics was conducted to study the pharmacological mechanisms of BBTD. RESULTS: Compared to the model group, mice treated with BBTD had thicker fibrous caps, increased collagen content, less erosion of smooth muscle cells and infiltration of macrophages, as well as a relatively low inflammatory response level, suggesting that BBTD treatment reduced plaque vulnerability. Omics analysis suggested that BBTD treatment demonstrated anti-atherosclerotic effects and increased plaque stability in the aorta by activating the TGF-beta pathway. Simultaneously, BBTD inhibited PVAT inflammation levels (decreased the levels of MCP and IL-6). Proteomics and metabolomics of PVAT suggested that the targets of BBTD included upregulation of the α-linolenic acid metabolic pathway and downregulation of multiple inflammatory pathways, such as the NF-kappa B signalling pathway, primary immunodeficiency and Th17 cell differentiation in PVAT. CONCLUSIONS: BBTD reduces the vulnerability of atherosclerotic plaques and inhibits the inflammatory phenotype of perivascular adipose tissue.

Novel Ag-modified vanadate nanosheets for determination of small organic molecules with laser desorption ionization mass spectrometry.

Laser desorption ionization mass spectrometry (LDI-MS) aroused intensive concerns for the merits of label-free and high-throughput analysis. Here, we designed a silver nanoparticles (AgNP)-modified indium vanadate nanosheets with doping samarium (AgNP@InVO4:Sm) nanosheets. The developed AgNP@InVO4:Sm nanosheets (AIVON) were synthesized based on the microemulsion-mediated solvothermal method and ultraviolet-assisted in situ formation of AgNP, then for the first time applied as a matrix in LDI-MS analysis. With the advantages including enhanced MS signal, little matrix-related background, high reproducibility, and good salt tolerance, AIVON exhibited much better prospect than non-modified indium vanadate nanosheets with doping samarium (IVON) and traditional organic matrix, thus allowing sensitive MS detection for a wide range of low-molecular-weight (LMW) molecules. Moreover, by coupling with headspace sampling thin-film microextraction (TFME), a kind of representative pollutant chlorophenols were identified and quantified via AIVON-assisted LDI-MS in environmental and biological samples. Volatile LMW pollutants could be preconcentrated after TFME, hence a sensitive and rapid assay with negligible sample matrix effect was realized by using AIVON-assisted LDI-MS. It is anticipated that this novel nano-matrix AIVON and the proposed TFME coupling detection strategy were of competitive merits for LDI-MS analysis in the fields of environment, biomedicine, and agriculture.

Bibliometric analysis of residual cardiovascular risk: trends and frontiers.

BACKGROUND: The presence of residual cardiovascular risk is an important cause of cardiovascular events. Despite the significant advances in our understanding of residual cardiovascular risk, a comprehensive analysis through bibliometrics has not been performed to date. Our objective is to conduct bibliometric studies to analyze and visualize the current research hotspots and trends related to residual cardiovascular risk. This will aid in understanding the future directions of both basic and clinical research in this area. METHODS: The literature was obtained from the Web of Science Core Collection database. The literature search date was September 28, 2022. Bibliometric indicators were analyzed using CiteSpace, VOSviewer, Bibliometrix (an R package), and Microsoft Excel. RESULT: A total of 1167 papers were included, and the number of publications is increasing rapidly in recent years. The United States and Harvard Medical School are the leading country and institution, respectively, in the study of residual cardiovascular risk. Ridker PM and Boden WE are outstanding investigators in this field. According to our research results, the New England Journal of Medicine is the most influential journal in the field of residual cardiovascular risk, whereas Atherosclerosis boasts the highest number of publications on this topic. Analysis of keywords and landmark literature identified current research hotspots including complications of residual cardiovascular risk, risk factors, and pharmacological prevention strategies. CONCLUSION: In recent times, global attention toward residual cardiovascular risk has significantly increased. Current research is focused on comprehensive lipid-lowering, residual inflammation risk, and dual-pathway inhibition strategies. Future efforts should emphasize strengthening international communication and cooperation to promote the comprehensive evaluation and management of residual cardiovascular risk.

Quercetin Attenuates Atherosclerosis via Modulating Apelin Signaling Pathway Based on Plasma Metabolomics.

OBJECTIVE: To interpret the pharmacology of quercetin in treatment of atherosclerosis (AS). METHODS: Fourteen apolipoprotein E-deficient (ApoE-/-) mice were divided into 2 groups by a random number table: an AS model (ApoE-/-) group and a quercetin treatment group (7 in each). Seven age-matched C57 mice were used as controls (n=7). Quercetin [20 mg/(kg·d)] was administered to the quercetin group intragastrically for 8 weeks for pharmacodynamic evaluation. Besides morphological observation, the distribution of CD11b, F4/80, sirtuin 1 (Sirt1) and P21 was assayed by immunohistochemistry and immunofluorescence to evaluate macrophage infiltration and tissue senescence. Ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MSC/MS) was performed to study the pharmacology of quercetin against AS. Then, simultaneous administration of an apelin receptor antagonist (ML221) with quercetin was conducted to verify the possible targets of quercetin. Key proteins in apelin signaling pathway, such as angiotensin domain type 1 receptor-associated proteins (APJ), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), tissue plasminogen activator (TPA), uncoupling protein 1 (UCP1) and angiotensin II receptor 1 (AT1R), were assayed by Western blot. RESULTS: Quercetin administration decreased lipid deposition in arterial lumen and improved the morphology of ApoE-/- aortas in vivo. Quercetin decreased the densities of CD11b, F4/80 and P21 in the aorta and increased the level of serum apelin and the densities of APJ and Sirt1 in the aorta in ApoE-/- mice (all P<0.05). Plasma metabolite profiling identified 118 differential metabolites and showed that quercetin affected mainly glycerophospholipids and fatty acyls. Bioinformatics analysis suggested that the apelin signaling pathway was one of the main pathways. Quercetin treatment increased the protein expressions of APJ, AMPK, PGC-1α, TPA and UCP1, while decreased the AT1R level (all P<0.05). After the apelin pathway was blocked by ML221, the effect of quercetin was abated significantly, confirming that quercetin attenuated AS by modulating the apelin signaling pathway (all P<0.05). CONCLUSION: Quercetin alleviated AS lesions by up-regulation the apelin signaling pathway.

The Latest Research Advances of Danggui Buxue Tang as an Effective Prescription for Various Diseases: A Comprehensive Review.

Danggui Buxue Tang (DBT) is composed of Astragali Radix and Angelicae Sinensis Radix in a weight ratio of 5:1. The recipe of the decoction is simple, and DBT has been widely used in the treatment of blood deficiency syndrome for more than 800 years in China. Studies on its chemical constituents show that saponins, flavonoids, volatile oils, organic acids, and polysaccharides are the main components of DBT. Many techniques such as third-generation sequencing, PCR-denaturing gradient gel electrophoresis, and HPLC-MS have been used for the quality control of DBT. DBT has a wide range of biological activities, including blood enhancement, antagonizing diabetic nephropathy, cardiovascular protection, immunity stimulation, estrogen-like effect, and antifibrosis, among others. In this paper, we summarize the recent research advances of DBT in terms of its components, pharmacological activities, and possible mechanisms of action as well as provide suggestions for further research.

Astragalus membranaceus and Salvia miltiorrhiza Ameliorate Hypertensive Renal Damage through lncRNA-mRNA Coexpression Network.

lncRNAs and mRNA are closely associated with hypertensive renal damage, and Astragalus membranaceus and Salvia miltiorrhiza (AS) have a therapeutic effect; however, the mechanism of AS to ameliorate hypertensive renal damage through the co-expression network of lncRNA-mRNA was unclear. In this study, we investigated the role of AS regulated the coexpression network of lncRNA-mRNA in improving hypertensive renal damage. Sixteen 24-week old spontaneous hypertensive rats (SHRs) were randomly divided into model group (M) and drug intervention group (AS, 5.9 g/kg), 8 Wistar Kyoto rats (WKY) of the same age as normal group (N). The treatment of rats was 4 weeks. Detecting the change of blood pressure, renal pathology and renal function related indicators, and lncRNA and mRNA sequencing and joint analysis was performed on the kidney. AS reduced blood pressure; decreased urine NAG, urine mALB, serum CysC, and IL-6; and improved renal pathology compared with group M. Simultaneously, AS reversed the disordered expression of 178 differential expression (DE) mRNAs and 237 DE-lncRNAs in SHRs, and their joint analysis showed that 13 DE-mRNAs and 32 DE-lncRNAs were coexpressed. Further analysis of 13 coexpressed DE-mRNAs showed negative regulation of blood pressure and fatty acid beta-oxidation was highly enriched in GO pathways, PPAR signaling pathway was highly enriched in KEGG pathways, and the verification related to these pathways was also highly consistent with the sequence. AS can alleviate hypertensive renal damage through the coexpression network of lncRNA-mRNA, of which coexpressed 13 DE-mRNAs and 32 DE-lncRNAs were the important targets, and the pathway negative regulation of blood pressure, fatty acid beta-oxidation, and PPAR signaling pathway play a major regulatory role.

Indicators for Evaluating High-Quality Agricultural Development: Empirical Study from Yangtze River Economic Belt, China.

Agriculture is the foundation of the national economy, and achieving high-quality agricultural development is an important support for strong economic development in the post-pandemic era. Based on the new development philosophy of the Chinese government, this study constructs an evaluation framework of "innovation-coordination-green-openness-sharing" for high-quality agricultural development, and quantitatively assesses the level of high-quality agricultural development in China's Yangtze River Economic Belt with a systematic integration model, and explores the spatial evolution characteristics and obstacles of the level of high-quality agricultural development in Yangtze River Economic Belt. It reveals that the level of high-quality agricultural development in the Yangtze River Economic Belt shows a fluctuating upward trend in general, but there is variability among regions. The green dimension has the fastest development rate, followed by innovation and sharing. In terms of spatial characteristics, it gradually shows a pattern dominated by high levels and shows the characteristics of agglomeration, but the spatial correlation is not high. In terms of obstacle factors, openness and coordination are the main obstacle factors. Considering the different agricultural development models, it is suggested that international cooperation, new agricultural cooperation, and differentiated policies can be considered to promote high-quality agricultural development. This study provides a more complete evaluation framework for government policy-making authorities to measure the level of regional agricultural development and help regional agriculture achieve sustainable development at a higher quality level.

Conflict or Coordination? Spatiotemporal Coupling of Urban Population-Land Spatial Patterns and Ecological Efficiency.

The coordinated relationship between urban population-land spatial patterns (UPLSPs) and ecological efficiency (EE) is conducive not only to the rational utilization of resources and environment and the sustainable development of society, but also to the provision of a living environment that benefits public health. Identifying the coupling relationship of urban development and EE can provide critical information for urban planning. Previous studies have mainly focused on the coupling relationship between urban population and land, urbanization, and ecological development, while ignoring that between UPLSPs and EE. This study integrates several models to construct a novel framework for coupling UPLSPs and EE. Taking Hubei Province as the research area, we calculate the UPLSPs, EE, and their coupling coordination degree for 12 cities from 2000 to 2019. The paper offers several conclusions. (1) the urban population-land spatial matching degree increased, but the overall matching level was not high; the average value of EE showed an "N"-shaped change trajectory, and its overall level was low, with small changes and obvious regional differences. (2) The average value of the coupling coordination degree between UPLSPs and EE was a slow upward trend, with a radial distribution high in the middle and low in the periphery. There was conflict between the spatial patterns and EE, and the former restricted the development of the latter. (3) There were strong correlations between coordination degree and various indicators of UPLSPs and EE. While we should revitalize the stock of construction land and optimize the upgrading of the industrial structure, we also must coordinate human and land resources and the ecological environment, and narrow regional development differences. This study provides a new framework for urban environmental assessment and urban planning decision-making.

Study on the Mechanism of Bu-Shen-He-Mai Granules in Improving Renal Damage of Ageing Spontaneously Hypertensive Rats by Regulating Th17 Cell/Tregs Balance.

Methods: Blood pressure and urine biochemical indices were recorded. Renal blood flow was evaluated by renal ultrasonography. Transmission electron microscopy (TEM) and HE staining were used to assess kidney and spleen morphology. Renal fibrosis was assessed using Masson staining. Serum levels of IL-6, IL-10, and IL-17A were measured using ELISAs. The density of RORγ and Foxp3 in the spleen was observed by immunofluorescence staining. The levels of Th17 cells and Tregs in blood were detected via flow cytometry. Transcriptome sequencing was performed to screen the targets of BSHM granules in hypertensive kidneys. Results: BSHM granules decreased SBP by 21.2 mm·Hg and DBP by 8.8 mm·Hg in ageing SHRs (P < 0.05), decreased the levels of urine mALB, ß2-Mg, and NAG (P < 0.01), and improved renal blood flow and arteriosclerosis. BSHM granules increased IL-10 expression (P < 0.05) while decreasing IL-6 (P < 0.01) and IL-17A (P < 0.05) levels. BSHM granules improved Foxp3 density and the number of Tregs (P < 0.01) and reduced RORγt density and the number of Th17 cells (P < 0.01). Transcriptome sequencing identified 747 differentially expressed (DE) mRNAs in kidneys after BSHM treatment. GO analysis suggested that BSHM granules act through immunoregulation. Conclusions: BSHM granules attenuated hypertensive renal damage in ageing SHRs, by significantly increasing Tregs and decreasing Th17 cells.

Heavy Metals in the Mainstream Water of the Yangtze River Downstream: Distribution, Sources and Health Risk Assessment.

Since the mainstream of the Yangtze River lower reach is an important drinking water source for residents alongside it, it is essential to investigate the concentration, distribution characteristics and health risks of heavy metals in the water. In this study, a total of 110 water samples were collected on both the left and right banks from the upstream to the downstream. Principal component analysis (PCA) was used to determine the sources of heavy metals. Their non-carcinogenic and carcinogenic risks were studied with health risk assessment models, and uncertainties were determined through Monte Carlo simulation. Results showed that concentrations of all heavy metals were significantly lower than the relevant authoritative standards in the studied area. From the upstream to the downstream, Ni, Cu and Cr had similar concentration distribution rules and mainly originated from human industrial activities. Pb, Cd and Zn had a fluctuating but increasing trend, which was mainly due to the primary geochemistry, traffic pollution and agricultural activities. The maximum As concentration appeared in the upstream mainly because of the carbonatite weathering or mine tail water discharge. Concentrations of Zn, As, Cd and Pb on the left bank were higher than those on the right bank, while concentrations of Cu, Ni and Cr on the right bank were higher than those on the left bank. The non-carcinogenic risk index (HI) was less than 1 (except of L11), and HI on the left bank was higher than that on the right bank. The carcinogenic risk (CR) was generally larger than 1.0 × 10-4, CR on the right bank overall was higher than that on the left bank, and the health risk of kids was greater than that of adults. Furthermore, Monte Carlo simulation results and the actual calculated values were basically the same.

Naringin protects human nucleus pulposus cells against TNF-α-induced inflammation, oxidative stress, and loss of cellular homeostasis by enhancing autophagic flux via AMPK/SIRT1 activation.

Activation of the proinflammatory-associated cytokine, tumor necrosis factor-α (TNF-α), in nucleus pulposus (NP) cells is essential for the pathogenesis of intervertebral disc degeneration (IDD). Restoring autophagic flux has been shown to effectively protect against IDD and is a potential target for treatment. The goal of this study was to explore particular autophagic signalings responsible for the protective effects of naringin, a known autophagy activator, on human NP cells. The results showed that significantly increased autophagic flux was observed in NP cells treated with naringin, with pronounced decreases in the inflammatory response and oxidative stress, which rescued the disturbed cellular homeostasis induced by TNF-α activation. Autophagic flux inhibition was detectable in NP cells cotreated with 3-methyladenine (3-MA, an autophagy inhibitor), partially offsetting naringin-induced beneficial effects. Naringin promoted the expressions of autophagy-associated markers via SIRT1 (silent information regulator-1) activation by AMPK (AMP-activated protein kinase) phosphorylation. Either AMPK inhibition by BML-275 or SIRT1 silencing partially counteracted naringin-induced autophagic flux enhancement. These findings indicate that naringin boosts autophagic flux through SIRT1 upregulation via AMPK activation, thus protecting NP cells against inflammatory response, oxidative stress, and impaired cellular homeostasis. Naringin can be a promising inducer of restoration autophagic flux restoration for IDD.

Proteomics reveals the role of Eucommia ulmoides-Tribulus terrestris in the central regulation of antihypertension by improving the hypothalamus in spontaneously hypertensive rats.

BACKGROUND: In this study, the combination of Eucommia ulmoides-Tribulus terrestris (EU-TT) was used to intervene in aging spontaneously hypertensive rats (SHRs). Quantitative proteomics sequencing was performed to screen the targets of EU-TT, so as to provide data support for the clinical application of EU-TT. METHODS: Eighteen-month-old SHRs were administered EU-TT (5.53 g/kg/day) intragastrically for 8 weeks. Blood pressure was recorded to evaluate the efficacy of EU-TT in vivo. Transmission electron microscopy (TEM) and hematoxylin-eosin (HE) staining were used to assess the morphology of the hypothalamus. The label free proteomics assay was performed to screen the targets of EU-TT in hypertensive hypothalami. ERK, JNK, and p38 were chosen for Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR) and Western blot. RESULTS: After 8 weeks of treatment, EU-TT effectively decreased systolic blood pressure (SBP) by 19.2 mmHg and diastolic blood pressure (DBP) by 8.6 mmHg (P<0.05), and improved the hypothalamus morphology of aging SHRs. Label free proteomics identified 248 differentially expressed (DE) proteins (157 were upregulated and 91 were downregulated) in the hypothalamus after EU-TT treatment. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that EU-TT regulated the MAPK signal transduction pathway, which was also confirmed by RT-qPCR and Western blot. CONCLUSIONS: EU-TT steadily decreased the SBP and DBP of aging SHRs, and improved the morphology of the hypothalamus, which was pharmacologically related to the MAPK signaling pathway. KEYWORDS: Aging spontaneously hypertensive rats (SHRs); Eucommia ulmoides-Tribulus terrestris (EU-TT); hypothalamus; label free proteomics; MAPK signaling pathway.

Astragali Radix-Coptis Rhizoma Herb Pair Attenuates Atherosclerosis in ApoE-/- Mice by Regulating the M1/M2 and Th1/Th2 Immune Balance and Activating the STAT6 Signaling Pathway.

OBJECTIVE: Immune imbalance and the inflammatory response are associated with atherosclerosis (AS) progression. Astragali Radix and Coptis Rhizoma (ARCR) are an ancient and classic herb pair that is used in herbal medicines for the treatment of coronary heart disease. We focused on the effects and mechanisms of the ARCR herb pair attenuation of atherosclerosis in apolipoprotein E knockout (ApoE-/-) mice. METHODS: ApoE-/- mice were fed a high-fat diet for 12 weeks to establish a model of AS. The ApoE-/- mice were randomly divided into a model group, simvastatin group (Simva), Astragali Radix group (AR), Coptis Rhizoma group (CR), Astragali Radix-Coptis Rhizoma group (ARCR), and Astragali Radix-Coptis Rhizoma + signal transducer and activator of transcription factor 6 (STAT6) inhibitor (AS1517499) group (ARCR + AS1517499). C57BL/6 mice were used as controls. Each group was administered the corresponding drugs, and mice in the model and control groups were given the same volume of normal saline once daily for 6 weeks. The body weights of the mice were observed regularly. The effect of the ARCR herb pair on lipid content in peripheral blood was evaluated using blood lipid tests. The levels of serum matrix metalloproteinase-9 (MMP-9), interleukins-12 (IL-12), IL-10, interferon-γ (IFN-γ), and IL-4 were determined to assess inflammation. Oil Red O staining, Sirius Red staining, and immunohistochemistry were used to observe changes in plaque stability. Western blotting was used to assay M1/M2 macrophages, Th1/Th2 cells, and STAT6 signaling pathway protein expression. Flow cytometry and immunofluorescence were used to detect M1/M2 macrophages and Th1/Th2 cells and reflect the immune imbalance. RESULTS: The ARCR herb pair significantly reduced blood lipids levels and plaque vulnerability and regulated the levels of inflammatory factors and the number of M1/M2 macrophages and Th1/Th2 cells in ApoE-/- AS mice. It also decreased iNOS and T-bet protein levels and increased the Arg-1 and GATA-3 protein levels. The ARCR herb pair also increased STAT6 phosphorylation. A STAT6 inhibitor attenuated the regulation of M1/M2 and Th1/Th2 markers induced by the ARCR herb pair. CONCLUSION: The ARCR herb pair regulates blood lipid metabolism and attenuates atherosclerosis via regulation of M1/M2 and Th1/Th2 immune balance, which is achieved partially by increasing STAT6 phosphorylation. Our study provides new evidence for the possible use of ARCR herb pair in the prevention and treatment of AS.

Calycosin Alleviates Doxorubicin-Induced Cardiotoxicity and Pyroptosis by Inhibiting NLRP3 Inflammasome Activation.

Calycosin (CAL) is the main active component present in Astragalus and reportedly possesses diverse pharmacological properties. However, the cardioprotective effect and underlying mechanism of CAL against doxorubicin- (DOX-) induced cardiotoxicity need to be comprehensively examined. Herein, we aimed to investigate whether the cardioprotective effects of CAL are related to its antipyroptotic effect. A cardiatoxicity model was established by stimulating H9c2 cells and C57BL/6J mice using DOX. In vitro, CAL increased H9c2 cell viability and decreased DOX-induced pyroptosis via NLRP3, caspase-1, and gasdermin D signaling pathways in a dose-dependent manner. In vivo, CAL-DOX cotreatment effectively suppressed DOX-induced cytotoxicity as well as inflammatory and cardiomyocyte pyroptosis via the same molecular mechanism. Next, we used nigericin (Nig) and NLRP3 forced overexpression to determine whether CAL imparts antipyroptotic effects by inhibiting the NLRP3 inflammasome in vitro. Furthermore, CAL suppressed DOX-induced mitochondrial oxidative stress injury in H9c2 cells by decreasing the generation of reactive oxygen species and increasing mitochondrial membrane potential and adenosine triphosphate. Likewise, CAL attenuated the DOX-induced increase in malondialdehyde content and decreased superoxide dismutase and glutathione peroxidase activities in H9c2 cells. In vivo, CAL afforded a protective effect against DOX-induced cardiac injury by improving myocardial function, inhibiting brain natriuretic peptide, and improving the changes of the histological morphology of DOX-treated mice. Collectively, our findings confirmed that CAL alleviates DOX-induced cardiotoxicity and pyroptosis by inhibiting NLRP3 inflammasome activation in vivo and in vitro.

Deciphering the Protein, Modular Connections and Precision Medicine for Heart Failure With Preserved Ejection Fraction and Hypertension Based on TMT Quantitative Proteomics and Molecular Docking.

Background: Exploring the potential biological relationships between heart failure with preserved ejection fraction (HFpEF) and concomitant diseases has been the focus of many studies for the establishment of personalized therapies. Hypertension (HTN) is the most common concomitant disease in HFpEF patients, but the functional connections between HFpEF and HTN are still not fully understood and effective treatment strategies are still lacking. Methods: In this study, tandem mass tag (TMT) quantitative proteomics was used to identify disease-related proteins and construct disease-related networks. Furthermore, functional enrichment analysis of overlapping network modules was used to determine the functional similarities between HFpEF and HTN. Molecular docking and module analyses were combined to identify therapeutic targets for HFpEF and HTN. Results: Seven common differentially expressed proteins (co-DEPs) and eight overlapping modules were identified in HFpEF and HTN. The common biological processes between HFpEF and HTN were mainly related to energy metabolism. Myocardial contraction, energy metabolism, apoptosis, oxidative stress, immune response, and cardiac hypertrophy were all closely associated with HFpEF and HTN. Epinephrine, sulfadimethoxine, chloroform, and prednisolone acetate were best matched with the co-DEPs by molecular docking analyses. Conclusion: Myocardial contraction, energy metabolism, apoptosis, oxidative stress, immune response, and cardiac hypertrophy were the main functional connections between HFpEF and HTN. Epinephrine, sulfadimethoxine, chloroform, and prednisolone acetate could potentially be effective for the treatment of HTN and HFpEF.

Quercetin Attenuates Cardiac Hypertrophy by Inhibiting Mitochondrial Dysfunction Through SIRT3/PARP-1 Pathway.

Cardiac hypertrophy is an important characteristic in the development of hypertensive heart disease. Mitochondrial dysfunction plays an important role in the pathology of cardiac hypertrophy. Recent studies have shown that sirtuin 3 (SIRT3)/poly (ADP-ribose) polymerase-1 (PARP-1) pathway modulation inhibits cardiac hypertrophy. Quercetin, a natural flavonol agent, has been reported to attenuate cardiac hypertrophy. However, the molecular mechanism is not completely elucidated. In this study, we aimed to explore the mechanism underlying the protective effect of quercetin on cardiac hypertrophy. Spontaneously hypertensive rats (SHRs) were treated with quercetin (20 mg/kg/d) for 8 weeks to evaluate the effects of quercetin on blood pressure and cardiac hypertrophy. Additionally, the mitochondrial protective effect of quercetin was assessed in H9c2 cells treated with Ang II. SHRs displayed aggravated cardiac hypertrophy and fibrosis, which were attenuated by quercetin treatment. Quercetin also improved cardiac function, reduced mitochondrial superoxide and protected mitochondrial structure in vivo. In vitro, Ang II increased the mRNA level of hypertrophic markers including atrial natriuretic factor (ANF) and ß-myosin heavy chain (ß-MHC), whereas quercetin ameliorated this hypertrophic response. Moreover, quercetin prevented mitochondrial function against Ang II induction. Importantly, mitochondrial protection and PARP-1 inhibition by quercetin were partly abolished after SIRT3 knockdown. Our results suggested that quercetin protected mitochondrial function by modulating SIRT3/PARP-1 pathway, contributing to the inhibition of cardiac hypertrophy.

Identification of lncRNA-mRNA regulatory network associated with isolated systolic hypertension and atherosclerotic cerebral infarction.

BACKGROUND: Increasingly, evidence has shown that long non-coding RNAs (lncRNAs) play an important role in isolated systolic hypertension (ISH). However, a systematic lncRNA-messenger RNA (mRNA) regulatory network is still absent in isolated systolic hypertension and atherosclerotic cerebral infarction patients (ISH & ACI). This research aimed to establish a lncRNA-mRNA co-expression network in patients with ISH & ACI, to probe into the potential functions of lncRNA in such patients. METHODS: Expression profiles of lncRNA and mRNAs were collected and compared, from 8 patients with ISH and 8 patients with ISH & ACI by RNA-seq data. Differentially expressed lncRNAs and mRNAs were screened out via high-throughput sequencing in the plasma of ISH/ACI patients and control ISH patients. Then, a lncRNA-mRNA interaction network was built using the Pearson correlation coefficient by Cytoscape software. The expression levels of the hub genes and lncRNAs were verified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in another 10 ISH/ACI patients and 10 control patients. This study was approved by the responsible institutional review board (IRB) and informed consent was provided by participants. RESULTS: A total of 2,768 differentially expressed lncRNAs and 747 differentially expressed mRNAs were identified. We identified two hub genes (CD226 and PARVB) and 11 lncRNAs in the lncRNA-mRNA interaction network. The results of qRT-PCR and cell assay verified that lncRNAs ENST00000590604 and CD226 are highly expressed in patients of ISH & ACI. Further, CD226 was associated with vascular endothelial cells growth and stability through the platelet activation and focal adhesion pathway. CONCLUSIONS: We established a novel mRNA-lncRNA interaction network. The lncRNAs ENST00000590604 and CD226 might be the potential biomarkers of ISH & ACI.

MCC950 attenuates doxorubicin-induced myocardial injury in vivo and in vitro by inhibiting NLRP3-mediated pyroptosis.

MCC950, an NLRP3 inflammasome inhibitor, displays multiple pharmacological properties. However, the protective potential and underlying mechanism of MCC950 against doxorubicin (DOX)-induced myocardial injury has not been well investigated yet. Herein, DOX-induced myocardial injury in mice and in H9c2 myocardial cells was investigated, and the protective effects and underlying mechanism of MCC950 were fully explored. The results showed that MCC950 co-treatment significantly improved myocardial function, inhibited inflammatory and myocardial fibrosis, and attenuated cardiomyocyte pyroptosis in DOX-treated mice. Mechanismly, MCC950 had the potential to inhibit DOX-induced the cleavage of NLRP3, ASC, Caspase-1, IL-18, IL-1ß and GSDMD in vivo. Moreover, MCC950 co-treatment in vivo suppressed DOX-induced cytotoxicity as well as inflammatory and cardiomyocyte pyroptosis through the same molecular mechanism. Taken together, our findings validated that MCC950, an NLRP3 inflammasome inhibitor, has the potential to attenuate doxorubicin-induced myocardial injury in vivo and in vitro by inhibiting NLRP3-mediated pyroptosis.