Gender differences in the association between healthy eating index-2015 and hypertension in the US population: evidence from NHANES 1999-2018.

BACKGROUND: Diet has long been recognized as an important modifiable risk factor for hypertension. Herein, our research goal was to decipher the association of healthy eating index-2015 (HEI-2015) with hypertension, and to explore potential gender differences. METHODS: We collected the cross-sectional data of 42,391 participants of the National Health and Nutrition Examination Survey (NHANES) 1999-2018. The association of HEI-2015 with hypertension was estimated using weighted multivariate logistic regression, with restricted cubic spline (RCS) regression being adopted to examine the nonlinearity of this association in both genders, and the stability of the results were examined by sensitivity analysis. We also performed subgroup analysis to detect potential difference in the link between HEI-2015 and hypertension stratified by several confounding factors. RESULTS: After eliminating potential confounding bias, the adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for hypertension across higher HEI-2015 quartiles were 0.93 (0.85-1.03), 0.84 (0.77-0.93), and 0.78 (0.72-0.86) compared to the lowest quartile, respectively. HEI-2015 was nonlinearly and inversely associated with hypertension in all participants. The gender-specific RCS curves presented a U-shaped correlation in males, while showed a linear and inverse correlation in females. Besides, subgroup analyses showed a lower risk of hypertension in participants who were females, younger than 40 years, Whites, obese, and diabetic patients. CONCLUSIONS: We determined a nonlinear and inverse association between HEI-2015 and hypertension in the US general population, and revealed a remarkable gender difference when adhering to a HEI-2015 diet for preventing hypertension.

Association between dietary inflammatory index and Stroke in the US population: evidence from NHANES 1999-2018.

BACKGROUND: There is an increasing awareness that diet-related inflammation may have an impact on the stroke. Herein, our goal was to decipher the association of dietary inflammatory index (DII) with stroke in the US general population. METHODS: We collected the cross-sectional data of 44,019 participants of the National Health and Nutrition Examination Survey (NHANES) 1999-2018. The association of DII with stroke was estimated using weighted multivariate logistic regression, with its nonlinearity being examined by restricted cubic spline (RCS) regression. The least absolute shrinkage and selection operator (LASSO) regression was applied for identifying key stroke-related dietary factors, which was then included in the establishment of a risk prediction nomogram model, with the receiver operating characteristic (ROC) curve being built to evaluate its discriminatory power for stroke. RESULTS: After confounder adjustment, the adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for stroke across higher DII quartiles were 1.19 (0.94-1.54), 1.46 (1.16-1.84), and 1.87 (1.53-2.29) compared to the lowest quartile, respectively. The RCS curve showed a nonlinear and positive association between DII and stroke. The nomogram model based on key dietary factors identified by LASSO regression displayed a considerable predicative value for stroke, with an area under the curve (AUC) of 79.8% (78.2-80.1%). CONCLUSIONS: Our study determined a nonlinear and positive association between DII and stroke in the US general population. Given the intrinsic limitations of cross-sectional study design, it is necessary to conduct more research to ensure the causality of such association.

Nuclear import of Mas-related G protein-coupled receptor member D induces pathological cardiac remodeling.

Alamandine (Ala), a ligand of Mas-related G protein-coupled receptor, member D (MrgD), alleviates angiotensin II (AngII)-induced cardiac hypertrophy. However, the specific physiological and pathological role of MrgD is not yet elucidated. Here, we found that MrgD expression increased under various pathological conditions. Then, MrgD knockdown prevented AngII-induced cardiac hypertrophy and fibrosis via inactivating Gαi-mediacted downstream signaling pathways, including the phosphorylation of p38 (p-P38), while MrgD overexpression induced pathological cardiac remodeling. Next, Ala, like silencing MrgD, exerted its cardioprotective effects by inhibiting Ang II-induced nuclear import of MrgD. MrgD interacted with p-P38 and promoted its entry into the nucleus under Ang II stimulation. Our results indicated that Ala was a blocking ligand of MrgD that inhibited downstream signaling pathway, which unveiled the promising cardioprotective effect of silencing MrgD expression on alleviating cardiac remodeling. Video Abstract.

The emerging role of leptin in obesity-associated cardiac fibrosis: evidence and mechanism.

Cardiac fibrosis is a hallmark of various cardiovascular diseases, which is quite commonly found in obesity, and may contribute to the increased incidence of heart failure arrhythmias, and sudden cardiac death in obese populations. As an endogenous regulator of adiposity metabolism, body mass, and energy balance, obesity, characterized by increased circulating levels of the adipocyte-derived hormone leptin, is a critical contributor to the pathogenesis of cardiac fibrosis. Although there are some gaps in our knowledge linking leptin and cardiac fibrosis, this review will focus on the interplay between leptin and major effectors involved in the pathogenesis underlying cardiac fibrosis at both cellular and molecular levels based on the current reports. The profibrotic effect of leptin is predominantly mediated by activated cardiac fibroblasts but may also involve cardiomyocytes, endothelial cells, and immune cells. Moreover, a series of molecular signals with a known profibrotic property is closely involved in leptin-induced fibrotic events. A more comprehensive understanding of the underlying mechanisms through which leptin contributes to the pathogenesis of cardiac fibrosis may open up a new avenue for the rapid emergence of a novel therapy for preventing or even reversing obesity-associated cardiac fibrosis.

Association between migraine or severe headache and hypertension among US adults: A cross-sectional study.

BACKGROUND AND AIMS: Epidemiological evidence of the association between migraines, severe headaches, and hypertension is contradictory. Hypertension is a critical risk factor for cardiovascular diseases. Migraine is a common neurological disease and a major cause of disability worldwide. Therefore, we aimed to investigate the relationship between migraine, severe headaches, and hypertension among US adults. METHODS AND RESULTS: Cross-sectional data from 5716 subjects were obtained from the National Health and Nutrition Examination Survey between 1999 and 2004. Weighted logistic regression models investigated the association between migraines, severe headaches, and hypertension. In total, 5716 subjects were enrolled in the present study, of whom 1134 (19.8%) had migraine or severe headaches. Participants with migraine were predominantly younger females and had a higher body mass index (BMI), lower educational level, lower dietary intake of potassium and calcium, lower serum levels of total cholesterol (TC), creatinine, and hemoglobin, as well as a higher estimated glomerular filtration rate (eGFR) (all P < 0.05). After fully adjusting for potential confounders, migraine or severe headaches were positively associated with hypertension (OR 1.25, 95% CI: 1.03-1.53). CONCLUSION: Our study found a positive association between migraine, severe headaches, and hypertension. Further studies are needed to verify the causality of this association and elucidate the underlying mechanisms.

Non-Invasive Local Acoustic Therapy Ameliorates Diabetic Heart Fibrosis by Suppressing ACE-Mediated Oxidative Stress and Inflammation in Cardiac Fibroblasts.

PURPOSE: The extent of myocardial fibrosis is closely related to the prognosis of diabetic cardiomyopathy (DCM). Low-intensity pulsed ultrasound (LIPUS) has been reported to have multiple biological effects. However, the effect of LIPUS on diabetic heart fibrosis remains unclear. The present study aimed to investigate the effect of LIPUS on diabetic heart fibrosis and explore its underlying mechanisms. METHODS AND RESULTS: High glucose (HG) was applied to cultured neonatal rat cardiac fibroblasts (NRCFs) to mimic the in vivo hyperglycemia microenvironment. LIPUS (19.30 mW/cm2 to 77.20 mW/cm2) dose-dependently inhibited HG-induced fibrotic response in NRCFs. Also, LIPUS downregulated NADPH oxidase 4 (NOX4)-associated oxidative stress and nod-like receptor protein-3 (NLRP3) inflammasome activation in NRCFs. In vivo, diabetes in mice was induced with streptozotocin (STZ). Mice in the LIPUS group and STZ + LIPUS group were treated with LIPUS (77.20 mW/cm2) twice a week for 12 weeks and then euthanized at 12 weeks or 24 weeks post-diabetes. Treatment with LIPUS significantly ameliorated the progression of cardiac fibrosis (Masson staining 6.5 ± 2.3% vs. 2.8 ± 1.5%, P < 0.001) and dysfunction (E/A ratio 1.35 ± 0.14 vs. 1.59 ± 0.11, P < 0.05), as well as NOX4-associated oxidative stress (relative expression fold of NOX4 1.43 ± 0.12 vs. 1.07 ± 0.10, P < 0.01; relative DHE fluorescence 1.51 ± 0.13 vs. 1.28 ± 0.06, P < 0.05) and NLRP3 inflammasome activation (relative expression fold of NLRP3 1.57 ± 0.12 vs. 1.05 ± 0.16, P < 0.01), at 12 weeks post-diabetes. At 24 weeks post-diabetes, the heart function in diabetic mice treated with LIPUS was still significantly better than untreated diabetic mice (E/A ratio 1.08 ± 0.12 vs. 1.49 ± 0.14, P < 0.001). Further exploration revealed that LIPUS significantly attenuated the upregulated angiotensin-converting enzyme (ACE) and angiotensin II (AngII), in both HG-induced NRCFs and diabetic hearts (relative expression of ACE in myocardium 3.77 ± 0.55 vs. 1.07 ± 0.13, P < 0.001; AngII in myocardium 115.5 ± 21.77 ng/ml vs. 84.28 ± 9.03 ng/ml, P < 0.01). Captopril, an ACE inhibitor, inhibited NOX4-associated oxidative stress and NLRP3 inflammasome activation in both HG-induced NRCFs and diabetic hearts. CONCLUSION: Our results indicate that non-invasive local LIPUS therapy attenuated heart fibrosis and dysfunction in diabetic mice and the effect could be largely preserved at least 12 weeks after suspending LIPUS stimulation. LIPUS ameliorated diabetic heart fibrosis by inhibiting ACE-mediated NOX4-associated oxidative stress and NLRP3 inflammasome activation in cardiac fibroblasts. Our study may provide a novel therapeutic approach to hamper the progression of diabetic heart fibrosis.

Enantioselective synthesis of pyrano[2,3-c]pyrrole via an organocatalytic [4 + 2] cyclization reaction of dioxopyrrolidines and azlactones.

An enantioselective [4 + 2] cyclization reaction of dioxopyrrolidines and azlactones has been successfully developed through a squaramide catalysis strategy. This protocol provides an efficient and mild access to obtain pyrano[2,3-c]pyrrole scaffolds containing contiguous quaternary and tertiary stereogenic centers in excellent yields (up to 99%) with high levels of diastereo- and enantioselectivities (up to 99% ee). Two possible pathways were proposed to explain the observed stereoselectivity.

Synthesis, Biological Evaluation and Low-Toxic Formulation Development of Glycosylated Paclitaxel Prodrugs.

Paclitaxel (PTX) is a famous anti-cancer drug with poor aqueous solubility. In clinical practices, Cremophor EL (polyethoxylated castor oil), a toxic surfactant, is used for dissolution of PTX, which accounts for serious side effects. In the present study, a single glucose-conjugated PTX prodrug (SG-PTX) and a double glucose-conjugated PTX prodrug (DG-PTX) were synthesized with a glycosylated strategy via succinate linkers. Both of the two prodrugs presented significant solubility improvement and drug-like lipophilicities. Compared to DG-PTX, SG-PTX manifested more promising release of the parent drug in serum. A high percentage of PTX released from SG-PTX could be detected after enzymatic hydrolysis of ß-glucuronidase. Besides, both of the two prodrugs exhibited effective cytotoxicity against breast cancer cells and ovarian cancer cells, but presented reduced cytotoxicity against normal breast cells. Moreover, SG-PTX manifested impressive solubility in a low toxic formulation (without ethanol) with a different percentage of Cremophor EL. These results indicated that glycosylation is a promising strategy for PTX modification and SG-PTX may be a feasible and potential type of PTX prodrug. In addition, ethanol-free formulation with a low percentage of Cremophor EL might have the potential to develop a safer formulation for further studies of glycosylated PTX prodrugs.

Gut commensal microvesicles reproduce parent bacterial signals to host immune and enteric nervous systems.

Ingestion of a commensal bacteria, Lactobacillus rhamnosus JB-1, has potent immunoregulatory effects, and changes nerve-dependent colon migrating motor complexes (MMCs), enteric nerve function, and behavior. How these alterations occur is unknown. JB-1 microvesicles (MVs) are enriched for heat shock protein components such as chaperonin 60 heat-shock protein isolated from Escherichia coli (GroEL) and reproduce regulatory and neuronal effects in vitro and in vivo. Ingested labeled MVs were detected in murine Peyer's patch (PP) dendritic cells (DCs) within 18 h. After 3 d, PP and mesenteric lymph node DCs assumed a regulatory phenotype and increased functional regulatory CD4(+)25(+)Foxp3+ T cells. JB-1, MVs, and GroEL similarly induced phenotypic change in cocultured DCs via multiple pathways including C-type lectin receptors specific intercellular adhesion molecule-3 grabbing non-integrin-related 1 and Dectin-1, as well as TLR-2 and -9. JB-1 and MVs also decreased the amplitude of neuronally dependent MMCs in an ex vivo model of peristalsis. Gut epithelial, but not direct neuronal application of, MVs, replicated functional effects of JB-1 on in situ patch-clamped enteric neurons. GroEL and anti-TLR-2 were without effect in this system, suggesting the importance of epithelium neuron signaling and discrimination between pathways for bacteria-neuron and -immune communication. Together these results offer a mechanistic explanation of how Gram-positive commensals and probiotics may influence the host's immune and nervous systems.

The TRPV1 channel in rodents is a major target for antinociceptive effect of the probiotic Lactobacillus reuteri DSM 17938.

Certain probiotic bacteria have been shown to reduce distension-dependent gut pain, but the mechanisms involved remain obscure. Live luminal Lactobacillus reuteri (DSM 17938) and its conditioned medium dose dependently reduced jejunal spinal nerve firing evoked by distension or capsaicin, and 80% of this response was blocked by a specific TRPV1 channel antagonist or in TRPV1 knockout mice. The specificity of DSM action on TRPV1 was further confirmed by its inhibition of capsaicin-induced intracellular calcium increases in dorsal root ganglion neurons. Another lactobacillus with ability to reduce gut pain did not modify this response. Prior feeding of rats with DSM inhibited the bradycardia induced by painful gastric distension. These results offer a system for the screening of new and improved candidate bacteria that may be useful as novel therapeutic adjuncts in gut pain. Certain bacteria exert visceral antinociceptive activity, but the mechanisms involved are not determined. Lactobacillus reuteri DSM 17938 was examined since it may be antinociceptive in children. Since transient receptor potential vanilloid 1 (TRPV1) channel activity may mediate nociceptive signals, we hypothesized that TRPV1 current is inhibited by DSM. We tested this by examining the effect of DSM on the firing frequency of spinal nerve fibres in murine jejunal mesenteric nerve bundles following serosal application of capsaicin. We also measured the effects of DSM on capsaicin-evoked increase in intracellular Ca(2+) or ionic current in dorsal root ganglion (DRG) neurons. Furthermore, we tested the in vivo antinociceptive effects of oral DSM on gastric distension in rats. Live DSM reduced the response of capsaicin- and distension-evoked firing of spinal nerve action potentials (238 ± 27.5% vs. 129 ± 17%). DSM also reduced the capsaicin-evoked TRPV1 ionic current in DRG neuronal primary culture from 83 ± 11% to 41 ± 8% of the initial response to capsaicin only. Another lactobacillus (Lactobacillus rhamnosus JB-1) with known visceral anti-nociceptive activity did not have these effects. DSM also inhibited capsaicin-evoked Ca(2+) increase in DRG neurons; an increase in Ca(2+) fluorescence intensity ratio of 2.36 ± 0.31 evoked by capsaicin was reduced to 1.25 ± 0.04. DSM releasable products (conditioned medium) mimicked DSM inhibition of capsaicin-evoked excitability. The TRPV1 antagonist 6-iodonordihydrocapsaicin or the use of TRPV1 knock-out mice revealed that TRPV1 channels mediate about 80% of the inhibitory effect of DSM on mesenteric nerve response to high intensity gut distension. Finally, feeding with DSM inhibited perception in rats of painful gastric distension. Our results identify a specific target channel for a probiotic with potential therapeutic properties.

The gut-brain axis rewired: adding a functional vagal nicotinic "sensory synapse".

It is generally accepted that intestinal sensory vagal fibers are primary afferent, responding nonsynaptically to luminal stimuli. The gut also contains intrinsic primary afferent neurons (IPANs) that respond to luminal stimuli. A psychoactive Lactobacillus rhamnosus (JB-1) that affects brain function excites both vagal fibers and IPANs. We wondered whether, contrary to its primary afferent designation, the sensory vagus response to JB-1 might depend on IPAN to vagal fiber synaptic transmission. We recorded ex vivo single- and multiunit afferent action potentials from mesenteric nerves supplying mouse jejunal segments. Intramural synaptic blockade with Ca(2+) channel blockers reduced constitutive or JB-1-evoked vagal sensory discharge. Firing of 60% of spontaneously active units was reduced by synaptic blockade. Synaptic or nicotinic receptor blockade reduced firing in 60% of vagal sensory units that were stimulated by luminal JB-1. In control experiments, increasing or decreasing IPAN excitability, respectively increased or decreased nerve firing that was abolished by synaptic blockade or vagotomy. We conclude that >50% of vagal afferents function as interneurons for stimulation by JB-1, receiving input from an intramural functional "sensory synapse." This was supported by myenteric plexus nicotinic receptor immunohistochemistry. These data offer a novel therapeutic target to modify pathological gut-brain axis activity.-Perez-Burgos, A., Mao, Y.-K., Bienenstock, J., Kunze, W. A. The gut-brain axis rewired: adding a functional vagal nicotinic "sensory synapse."

Corrigendum: Nitric oxide alleviated high salt-induced cardiomyocyte apoptosis and autophagy independent of blood pressure in rats.

[This corrects the article DOI: 10.3389/fcell.2021.646575.].

Squalamine reverses age-associated changes of firing patterns of myenteric sensory neurons and vagal fibres.

Vagus nerve signaling is a key component of the gut-brain axis and regulates diverse physiological processes that decline with age. Gut to brain vagus firing patterns are regulated by myenteric intrinsic primary afferent neuron (IPAN) to vagus neurotransmission. It remains unclear how IPANs or the afferent vagus age functionally. Here we identified a distinct ageing code in gut to brain neurotransmission defined by consistent differences in firing rates, burst durations, interburst and intraburst firing intervals of IPANs and the vagus, when comparing young and aged neurons. The aminosterol squalamine changed aged neurons firing patterns to a young phenotype. In contrast to young neurons, sertraline failed to increase firing rates in the aged vagus whereas squalamine was effective. These results may have implications for improved treatments involving pharmacological and electrical stimulation of the vagus for age-related mood and other disorders. For example, oral squalamine might be substituted for or added to sertraline for the aged.

Psychoactive bacteria Lactobacillus rhamnosus (JB-1) elicits rapid frequency facilitation in vagal afferents.

Mounting evidence supports the influence of the gut microbiome on the local enteric nervous system and its effects on brain chemistry and relevant behavior. Vagal afferents are involved in some of these effects. We previously showed that ingestion of the probiotic bacterium Lactobacillus rhamnosus (JB-1) caused extensive neurochemical changes in the brain and behavior that were abrogated by prior vagotomy. Because information can be transmitted to the brain via primary afferents encoded as neuronal spike trains, our goal was to record those induced by JB-1 in vagal afferents in the mesenteric nerve bundle and thus determine the nature of the signals sent to the brain. Male Swiss Webster mice jejunal segments were cannulated ex vivo, and serosal and luminal compartments were perfused separately. Bacteria were added intraluminally. We found no evidence for translocation of labeled bacteria across the epithelium during the experiment. We recorded extracellular multi- and single-unit neuronal activity with glass suction pipettes. Within minutes of application, JB-1 increased the constitutive single- and multiunit firing rate of the mesenteric nerve bundle, but Lactobacillus salivarius (a negative control) or media alone were ineffective. JB-1 significantly augmented multiunit discharge responses to an intraluminal distension pressure of 31 hPa. Prior subdiaphragmatic vagotomy abolished all of the JB-1-evoked effects. This detailed exploration of the neuronal spike firing that encodes behavioral signaling to the brain may be useful to identify effective psychoactive bacteria and thereby offer an alternative new perspective in the field of psychiatry and comorbid conditions.

Trends in worldwide research on cardiac fibrosis over the period 1989-2022: a bibliometric study.

Background: Cardiac fibrosis is a hallmark of various end-stage cardiovascular diseases (CVDs) and a potent contributor to adverse cardiovascular events. During the past decades, extensive publications on this topic have emerged worldwide, while a bibliometric analysis of the current status and research trends is still lacking. Methods: We retrieved relevant 13,446 articles on cardiac fibrosis published between 1989 and 2022 from the Web of Science Core Collection (WoSCC). Bibliometrix was used for science mapping of the literature, while VOSviewer and CiteSpace were applied to visualize co-authorship, co-citation, co-occurrence, and bibliographic coupling networks. Results: We identified four major research trends: (1) pathophysiological mechanisms; (2) treatment strategies; (3) cardiac fibrosis and related CVDs; (4) early diagnostic methods. The most recent and important research themes such as left ventricular dysfunction, transgenic mice, and matrix metalloproteinase were generated by burst analysis of keywords. The reference with the most citations was a contemporary review summarizing the role of cardiac fibroblasts and fibrogenic molecules in promoting fibrogenesis following myocardial injury. The top 3 most influential countries were the United States, China, and Germany, while the most cited institution was Shanghai Jiao Tong University, followed by Nanjing Medical University and Capital Medical University. Conclusions: The number and impact of global publications on cardiac fibrosis has expanded rapidly over the past 30 years. These results are in favor of paving the way for future research on the pathogenesis, diagnosis, and treatment of cardiac fibrosis.

A 2-decade bibliometric analysis of epigenetics of cardiovascular disease: from past to present.

BACKGROUND: Cardiovascular disease (CVD) remains a major health killer worldwide, and the role of epigenetic regulation in CVD has been widely studied in recent decades. Herein, we perform a bibliometric study to decipher how research topics in this field have evolved during the past 2 decades. RESULTS: Publications on epigenetics in CVD produced during the period 2000-2022 were retrieved from the Web of Science Core Collection (WoSCC). We utilized Bibliometrix to build a science map of the publications and applied VOSviewer and CiteSpace to assess co-authorship, co-citation, co-occurrence, and bibliographic coupling. In total, 27,762 publications were included for bibliometric analysis. The yearly amount of publications experienced exponential growth. The top 3 most influential countries were China, the United States, and Germany, while the most cited institutions were Nanjing Medical University, Harbin Medical University, and Shanghai Jiao Tong University. Four major research trends were identified: (a) epigenetic mechanisms of CVD; (b) epigenetics-based therapies for CVD; (c) epigenetic profiles of specific CVDs; and (d) epigenetic biomarkers for CVD diagnosis/prediction. The latest and most important research topics, including "nlrp3 inflammasome", "myocardial injury", and "reperfusion injury", were determined by detecting citation bursts of co-occurring keywords. The most cited reference was a review of the current knowledge about how miRNAs recognize target genes and modulate their expression and function. CONCLUSIONS: The number and impact of global publications on epigenetics in CVD have expanded rapidly over time. Our findings may provide insights into the epigenetic basis of CVD pathogenesis, diagnosis, and treatment.

Association of Blood Heavy Metal Exposure with Atherosclerotic Cardiovascular Disease (ASCVD) Among White Adults: Evidence from NHANES 1999-2018.

Cardiovascular diseases (CVD) are main public health concerns highly prevalent in industrialized societies where human health is threatened by a series of environmental pollutants, particularly heavy metal contaminants. We aimed to find out if blood heavy metals are associated with the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) in a nationally representative sample of US adults. We analyzed the cross-sectional data on blood heavy metals of 3268 non-Hispanic white participants aged 40-79 years from the National Health and Nutrition Examination Survey (NHANES) 1999-2018. We introduced a risk estimation algorithm, namely the 2013 Pooled Cohort Equations (PCE), to assess the risk for ASCVD over a 10-year period. The 10-year risk for ASCVD was categorized as either reduced risk (< 7.5% risk) or elevated risk (≥ 7.5% risk). Blood lead, cadmium, and mercury were distributed into four quartiles. We used weighted multivariate logistic regression models and restricted cubic spline (RCS) regression to detect the association of blood heavy metal exposure with 10-year ASCVD risk. Following the adjustment of covariates, the adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for elevated 10-year ASCVD risk for participants from the highest quartiles were 4.50 (2.88-7.02), 2.59 (1.68-4.00), and 1.06 (0.66-1.71) for blood cadmium, lead, and mercury compared to the lowest quartiles, respectively. The RCS plot demonstrated that blood cadmium was linearly and positively associated with 10-year ASCVD risk (P for nonlinearity = 0.112). According to our findings, non-Hispanic whites aged 40-79 years had a greater 10-year ASCVD risk as their blood lead and cadmium levels increased. Consequently, when establishing approaches for ASCVD prevention, blood heavy metals should be considered.

The roles and mechanisms of epigenetic regulation in pathological myocardial remodeling.

Pathological myocardial remodeling was still one of the leading causes of death worldwide with an unmet therapeutic need. A growing number of researchers have addressed the role of epigenome changes in cardiovascular diseases, paving the way for the clinical application of novel cardiovascular-related epigenetic targets in the future. In this review, we summarized the emerged advances of epigenetic regulation, including DNA methylation, Histone posttranslational modification, Adenosine disodium triphosphate (ATP)-dependent chromatin remodeling, Non-coding RNA, and RNA modification, in pathological myocardial remodeling. Also, we provided an overview of the mechanisms that potentially involve the participation of these epigenetic regulation.

Ginkgolide A alleviates cardiac remodeling in mice with myocardial infarction via binding to matrix metalloproteinase-9 to attenuate inflammation.

Ginkgolides are terpenoids peculiar to Ginkgo biloba, which have protective properties against cardiac diseases. This study aims to explore whether ginkgolide A (GA) could improve cardiac dysfunction of MI mice, and whether it could alleviate cardiac remodeling via binding to matrix metalloproteinase-9 (MMP9) to attenuate inflammation. Cardiac remodeling in mice induced by left coronary artery ligation were used in the in vivo model, and angiotensin (Ang) II-induced cardiac fibroblasts (NRCFs) and cardiomyocytes (NRCMs) isolated from neonatal rats were used in in vitro fibrosis and hypertrophy models, respectively. Cardiac dysfunction and fibrosis in MI mice were alleviated by GA treatment. Upregulations of collagen I (Col I), collagen III (Col III) and fibronectin in NRCFs, and enhanced levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and beta-myosin heavy chain (ß-MHC) in NRCMs were inhibited by GA treatment. A total of 100 potential targets were found in 5 databases (TCMSP, BATMAN-TCM, PharmMapper, ETCM and SWISS Target). According to Protein Data Bank database GA could form hydrogen bonds between LYS65, GLU157, ASN17, ARG109, ARG106 of MMP9 protein, a target of GA. The regulatory role of GA in downregulating Col I, Col III, fibronectin in NRCFs, and enhancing levels of ANP, BNP and ß-MHC in NRCMs were reversed by MMP9 overexpression, so as the downregulation of IL-1ß, IL-6 and TNF-α in Ang II-induced NRCFs and NRCMs. GA could alleviate cardiac dysfunction and remodeling via binding to MMP9 to attenuate inflammation. Therefore, GA is a potential drug for cardiac remodeling therapy.

Alamandine alleviated heart failure and fibrosis in myocardial infarction mice.

Alamandine (Ala) is the newest identified peptide of the renin-angiotensin system and has protective effect on myocyte hypertrophy. However, it is still unclear whether Ala can alleviate heart failure (HF). The aim of this study was to explore the effects of Ala on HF and the related cardiac fibrosis, and to probe the mechanism. HF model was induced by myocardial infarction (MI) in mice. Four weeks after MI, Ala was administrated by intraperitoneal injection for two weeks. Ala injection significantly improved cardiac dysfunction of MI mice in vivo. The cardiac fibrosis and the related biomarkers were attenuated after Ala administration in HF mice in vivo. The increases of collagen I, alpha-smooth muscle actin and transforming growth factor-beta induced by oxygen-glucose deprivation (OGD) in neonatal rat cardiac fibroblasts (NRCFs) were inhibited by Ala treatment in vitro. The biomarkers of apoptosis were elevated in NRCFs induced by OGD, which were attenuated after treating with Ala in vitro. The enhancement of oxidative stress in the heart of MI mice or in the NRCFs treated with OGD was suppressed by treating with Ala in vivo and in vitro. These effects of Ala were reversed by tBHP, an exogenous inducer of oxidative stress in vitro. These results demonstrated that Ala could alleviate cardiac dysfunction and attenuate cardiac fibrosis via inhibition of oxidative stress.