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.

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.

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.

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.

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.

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.

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.

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 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 and cardiovascular disease: A cross-sectional study.

Background: Cardiovascular disease (CVD) poses a tremendous threat to global health, giving rise to exceedingly high morbidity and mortality among patients. A migraine is a common neurological disorder characterized by recurrent attacks of severe headache, while its cardiovascular burden remains unclear. Therefore, this study aims to investigate whether migraine is associated with CVD. Methods: The cross-sectional data of 5,692 subjects aged 20 or above was obtained from the National Health and Nutrition Examination Survey (NHANES) 1999-2004. To determine whether migraine is associated with CVD, weighted logistic regression models were used. In a subsequent subgroup analysis, several confounding factors were also explored to investigate the association between migraine and CVD. Results: In total, 5,692 subjects were enrolled in this study, with the prevalence of CVD being 13.3%. Participants with CVD tended to be older, male, non-Hispanic whites, more educated, former smokers, and alcohol drinkers, and had a higher waist circumference, less physical activity, a higher level of triglyceride and creatinine as well as a lower level of high-density lipoprotein cholesterol (HDL-C) and estimated glomerular filtration rate (eGFR) (all P < 0.05). Considering all potential confounders, migraine was associated with a higher risk of CVD [odds ratios (ORs) 2.77; 95% confidence intervals (CIs): 1.56-4.90]. Subgroup analysis showed a higher risk of CVD in females, those older than 60 years, with a lower body mass index (BMI) level (≤ 30 kg/m2), a higher level of eGFR (> 90 mL/min/1.73 m2), hypertension and hyperlipidemia and without diabetes. Conclusion: In summary, our study revealed a positive association between migraine with CVD in a nationally representative US adult population. Our findings highlighted that migraine should be considered an important risk factor for CVD.

Association between serum Klotho levels and the prevalence of diabetes among adults in the United States.

Background: Diabetes is a critical contributor to the pathogenesis of cardiovascular diseases. Klotho is an anti-aging protein with cardiovascular-renal protective effects. However, the relationship between serum Klotho levels and diabetes remains poorly understood. Objectives: This study aimed to investigate the relationship between serum Klotho levels and diabetes in US adults. Methods: We analyzed the cross-sectional data obtained from 13751 subjects aged 40-79 years in the National Health and Nutrition Examination Survey (NHANES) (2007-2016). Serum Klotho concentration was measured using an enzyme-linked immunosorbent assay (ELISA) and categorized into four quartiles (Q1-Q4). Multivariate logistic regression and restricted cubic spline (RCS) regression were conducted to explore the association between serum Klotho levels and the prevalence of diabetes. Results: As compared with quartile 1, serum Klotho levels in quartiles 2-4 yielded odds ratios (OR) (95% CI) of diabetes of 0.96 (0.80-1.15), 0.98 (0.82-1.18), and 1.25 (1.04-1.50), respectively, after covariate adjustment (P for trend = 0.018). The results implied an increased risk of diabetes. The RCS plot showed a U-shaped relationship linking serum Klotho levels with diabetes (P for nonlinearity = 0.003). Conclusions: In summary, a nonlinear and positive association was found between serum Klotho levels and the prevalence of diabetes. Further study is needed to verify the causality of this association and elucidate the underlying mechanisms.

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.

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.

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.

MicroRNA-210-5p alleviates cardiac fibrosis via targeting transforming growth factor-beta type I receptor in rats on high sodium chloride (NaCl)-based diet.

The present study was designed to explore whether high sodium chloride (NaCl)-based diet (HSD) caused cardiac fibrosis regardless of blood pressure in Sprague-Dawley (SD) rats, and to further determine the effects and the underlying mechanisms of microRNA (miR)-210-5p on HSD-induced cardiac fibrosis in rats or NaCl-induced cardiac fibroblast activation in neonatal rat cardiac fibroblasts (NRCFs). The SD rats received 8% HSD, and NRCFs were treated with NaCl. The levels of collagen I, alpha-smooth muscle actin (α-SMA) and transforming growth factor-beta 1 (TGF-ß1) were increased in the heart of hypertension (HTN), hypertension-prone (HP) and hypertension-resistant (HR) rats on HSD in vivo. NaCl increased the levels of collagen I, α-SMA and TGF-ß1 in NRCFs in vitro. The level of miR-210-5p was reduced in both NBD-induced rats' hearts and NaCl-treated NRCFs, which was consistent with the results of miR high-throughput sequencing in NRCFs. The HSD or NaCl-induced increases of collagen I, α-SMA and TGF-ß1 were inhibited by miR-210-5p agomiR in vitro and in vivo, respectively. miR-210-5p antagomiR could mimic the pathological effects of NaCl in NRCFS. Bioinformatics analysis and luciferase reporter assays demonstrated that TGF-ß type I receptor (TGFBR1) was a direct target gene of miR-210-5p. These results indicated that HSD resulted in cardiac fibrosis regardless of blood pressure. The upregulation of miR-210-5p could attenuate cardiac fibroblast activation in NRCFS via targeting TGFBR1. Thus, upregulating miR-210-5p might be a strategy for the treatment of cardiac fibrosis.

Identification of SSRI-evoked antidepressant sensory signals by decoding vagus nerve activity.

The vagus nerve relays mood-altering signals originating in the gut lumen to the brain. In mice, an intact vagus is required to mediate the behavioural effects of both intraluminally applied selective serotonin reuptake inhibitors and a strain of Lactobacillus with antidepressant-like activity. Similarly, the prodepressant effect of lipopolysaccharide is vagus nerve dependent. Single vagal fibres are broadly tuned to respond by excitation to both anti- and prodepressant agents, but it remains unclear how neural responses encode behaviour-specific information. Here we demonstrate using ex vivo experiments that for single vagal fibres within the mesenteric neurovascular bundle supplying the mouse small intestine, a unique neural firing pattern code is common to both chemical and bacterial vagus-dependent antidepressant luminal stimuli. This code is qualitatively and statistically discernible from that evoked by lipopolysaccharide, a non-vagus-dependent antidepressant or control non-antidepressant Lactobacillus strain and are not affected by sex status. We found that all vagus dependent antidepressants evoked a decrease in mean spike interval, increase in spike burst duration, decrease in gap duration between bursts and increase in intra-burst spike intervals. Our results offer a novel neuronal electrical perspective as one explanation for mechanisms of action of gut-derived vagal dependent antidepressants. We expect that our ex vivo individual vagal fibre recording model will improve the design and operation of new, extant electroceutical vagal stimulation devices currently used to treat major depression. Furthermore, use of this vagal antidepressant code should provide a valuable screening tool for novel potential oral antidepressant candidates in preclinical animal models.

Nitric Oxide Alleviated High Salt-Induced Cardiomyocyte Apoptosis and Autophagy Independent of Blood Pressure in Rats.

The present study aimed to explore whether high-salt diet (HSD) could cause cardiac damage independent of blood pressure, and whether nitric oxide (NO) could alleviate high-salt-induced cardiomyocyte apoptosis and autophagy in rats. The rats received 8% HSD in vivo. H9C2 cells or primary neonatal rat cardiomyocytes (NRCM) were treated with sodium chloride (NaCl) in vitro. The levels of cleaved-caspase 3/caspase 3, cleaved-caspase 8/caspase 8, Bax/Bcl2, LC3 II/LC3 I, Beclin-1 and autophagy related 7 (ATG7) were increased in the heart of HSD rats with hypertension (HTN), and in hypertension-prone (HP) and hypertension-resistant (HR) rats. Middle and high doses (50 and 100 mM) of NaCl increased the level of cleaved-caspase 3/caspase 3, cleaved-caspase 8/caspase 8, Bax/Bcl2, LC3 II/LC3 I, Beclin-1, and ATG7 in H9C2 cells and NRCM. The endothelial NO synthase (eNOS) level was increased, but p-eNOS level was reduced in the heart of HSD rats and H9C2 cells treated with 100 mM NaCl. The level of NO was reduced in the serum and heart of HSD rats. NO donor sodium nitroprusside (SNP) reversed the increases of cleaved-caspase 3/caspase 3, cleaved-caspase 8/caspase 8, Bax/Bcl2 induced by NaCl (100 mM) in H9C2 cells and NRCM. SNP treatment attenuated the increases of cleaved-caspase 3/caspase 3, Bax/Bcl2, LC3 II/LC3 I, Beclin-1, and ATG7 in the heart, but had no effect on the blood pressure of HSD rats with HR. These results demonstrated that HSD enhanced cardiac damage independently of blood pressure. Exogenous NO supplementarity could alleviate the high salt-induced apoptosis and autophagy in cardiomyocytes.

Squalamine Restores the Function of the Enteric Nervous System in Mouse Models of Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder thought to be caused by accumulation of α-synuclein (α-syn) within the brain, autonomic nerves, and the enteric nervous system (ENS). Involvement of the ENS in PD often precedes the onset of the classic motor signs of PD by many years at a time when severe constipation represents a major morbidity. Studies conducted in vitro and in vivo, have shown that squalamine, a zwitterionic amphipathic aminosterol, originally isolated from the liver of the dogfish shark, effectively displaces membrane-bound α-syn. OBJECTIVE: Here we explore the electrophysiological effect of squalamine on the gastrointestinal (GI) tract of mouse models of PD engineered to express the highly aggregating A53T human α-syn mutant. METHODS: GI motility and in vivo response to oral squalamine in PD model mice and controls were assessed using an in vitro tissue motility protocol and via fecal pellet output. Vagal afferent response to squalamine was measured using extracellular mesenteric nerve recordings from the jejunum. Whole cell patch clamp was performed to measure response to squalamine in the myenteric plexus. RESULTS: Squalamine effectively restores disordered colonic motility in vivo and within minutes of local application to the bowel. We show that topical squalamine exposure to intrinsic primary afferent neurons (IPANs) of the ENS rapidly restores excitability. CONCLUSION: These observations may help to explain how squalamine may promote gut propulsive activity through local effects on IPANs in the ENS, and further support its possible utility in the treatment of constipation in patients with PD.