Trimethylamine-N-oxide aggravated the sympathetic excitation in D-galactose induced aging rats by down-regulating P2Y12 receptor in microglia.

This study aimed to determine whether trimethylamine N-oxide (TMAO) was involved in sympathetic activation in aging and the underlying mechanisms. Our hypothesis is TMAO reduces P2Y12 receptor (P2Y12R) and induces microglia-mediated inflammation in the paraventricular nucleus (PVN), then leading to sympathetic activation in aging. This study involved 18 young adults and 16 old adults. Aging rats were established by injecting D-galactose (D-gal, 200 mg/kg/d) subcutaneously for 12 weeks. TMAO (120 mg/kg/d) or 1% 3, 3-dimethyl-l-butanol (DMB) was administrated via drinking water for 12 weeks to investigate their effects on neuroinflammation and sympathetic activation in aging rats. Plasma TMAO, NE and IL-1ß levels were higher in old adults than in young adults. In addition, standard deviation of all normal to normal intervals (SDNN) and standard deviation of the average of normal to normal intervals (SDANN) were lower in old adults and negatively correlated with TMAO, indicating sympathetic activation in old adults, which is associated with an increase in TMAO levels. Treatment of rats with D-gal showed increased senescence-associated protein levels and microglia-mediated inflammation, as well as decreased P2Y12R protein levels in PVN. Plasma TMAO, NE and IL-1ß levels were increased, accompanied by enhanced renal sympathetic nerve activity (RSNA). While TMAO treatment exacerbated the above phenomenon, DMB mitigated it. These findings suggest that TMAO contributes to sympathetic hyperactivity in aging by downregulating P2Y12R in microglia and increasing inflammation in the PVN. These results may provide promising new target for the prevention and treatment of aging and aging-related diseases.

Decreased levels of hydrogen sulfide in the hypothalamic paraventricular nucleus contribute to sympathetic hyperactivity induced by cerebral infarction.

Paroxysmal sympathetic hyperactivity (PSH) is a common clinical feature secondary to ischemic stroke (IS), but its mechanism is poorly understood. We aimed to investigate the role of H2S in the pathogenesis of PSH. IS patients were divided into malignant (MCI) and non-malignant cerebral infarction (NMCI) group. IS in rats was induced by the right middle cerebral artery occlusion (MCAO). H2S donor (NaHS) or inhibitor (aminooxy-acetic acid, AOAA) were microinjected into the hypothalamic paraventricular nucleus (PVN). Compared with the NMCI group, patients in the MCI group showed PSH, including tachycardia, hypertension, and more plasma norepinephrine (NE) that was positively correlated with levels of creatine kinase, glutamate transaminase, and creatinine respectively. The 1-year survival rate of patients with high plasma NE levels was lower. The hypothalamus of rats with MCAO showed increased activity, especially in the PVN region. The levels of H2S in PVN of the rats with MCAO were reduced, while the blood pressure and renal sympathetic discharge were increased, which could be ameliorated by NaHS and exacerbated by AOAA. NaHS completely reduced the disulfide bond of NMDAR1 in PC12 cells. The inhibition of NMDAR by MK-801 microinjected in PVN of rats with MCAO also could lower blood pressure and renal sympathetic discharge. In conclusion, PSH may be associated with disease progression and survival in patients with IS. Decreased levels of H2S in PVN were involved in regulating sympathetic efferent activity after cerebral infarction. Our results might provide a new strategy and target for the prevention and treatment of PSH.

A specific inflammatory suppression fibroblast subpopulation characterized by MHCII expression in human dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a significant cause of heart failure that requires heart transplantation. Fibroblasts play a central role in the fibro-inflammatory microenvironment of DCM. However, their cellular heterogeneity and interaction with immune cells have not been well identified. An integrative analysis was conducted on single-cell RNA sequencing (ScRNA-Seq) data from human left ventricle tissues, which comprised 4 hearts from healthy donors and 6 hearts with DCM. The specific antigen-presenting fibroblast (apFB) was explored as a subtype of fibroblasts characterized by expressing MHCII genes, the existence of which was confirmed by immunofluorescence staining of 3 cardiac tissues from DCM patients with severe heart failure. apFB highly expressed the genes that response to IFN-γ, and it also have a high activity of the JAK-STAT pathway and the transcription factor RFX5. In addition, the analysis of intercellular communication between apFBs and CD4+T cells revealed that the anti-inflammatory ligand-receptor pairs TGFB-TGFR, CLEC2B-KLRB1, and CD46-JAG1 were upregulated in DCM. The apFB signature exhibited a positive correlation with immunosuppression and demonstrated diagnostic and prognostic value when evaluated using a bulk RNA dataset comprising 166 donors and 166 DCM samples. In conclusion, the present study identified a novel subpopulation of fibroblasts that specifically expresses MHCII-encoding genes. This specific apFBs can suppress the inflammation occurring in DCM. Our findings further elucidate the composition of the fibro-inflammatory microenvironment in DCM, and provide a novel therapeutic target.

Esketamine mitigates cognitive impairment following exposure to LPS by modulating the intestinal flora/subdiaphragmatic vagus nerve/spleen axis.

INTRODUCTION: Susceptibility to secondary infection often increases after primary infection. Secondary infections can lead to more severe inflammatory injuries; however, the underlying mechanisms are not yet fully elucidated. OBJECTIVE: To investigate whether esketamine treatment immediately after primary lipopolysaccharide (LPS) exposure could alleviate cognitive impairment caused by secondary infection. METHODS: Mice were injected intraperitoneally (IP) with LPS (5 mg/kg) 10 days apart. Esketamine (10, 15, or 30 mg/kg) was administered IP immediately after the primary LPS injection. Splenectomy or subdiaphragmatic vagotomy (SDV) was performed 7 days before secondary LPS exposure or broad-spectrum antibiotic administration. RESULTS: Splenomegaly was observed after the primary LPS injection on Days 3 and 10. Splenomegaly was attenuated by treatment with 30 mg/kg esketamine. Esketamine treatment prevented increased plasma proinflammatory cytokines levels and cognitive dysfunction induced by secondary LPS exposure. Mice that underwent splenectomy or SDV had lower proinflammatory cytokines levels, higher hippocampal brain-derived neurotrophic factor (BDNF) levels, and improved cognitive function 1 day after secondary infection, which was not further improved by esketamine. Fecal microbiota transplantation (FMT) from endotoxic mice treated with esketamine attenuated hippocampal BDNF downregulation and cognitive dysfunction only in pseudo germ-free (PGF) mice without splenectomy. FMT with fecal suspensions from esketamine-treated endotoxic mice abrogated splenomegaly only in PGF mice without SDV. Blocking BDNF signaling blocked esketamine's ameliorating effects on secondary LPS exposure-induced cognitive dysfunction. CONCLUSION: The intestinal flora/subdiaphragmatic vagus nerve/spleen axis-mediated hippocampal BDNF downregulation significantly affected secondary LPS-induced systemic inflammation and cognitive dysfunction. Esketamine preserves cognitive function via this mechanism.

Effect of Dispersing Solvents for an Ionomer on the Performance of Copper Catalyst Layers for CO2 Electrolysis to Multicarbon Products.

To explore the effects of solvent-ionomer interactions in catalyst inks on the structure and performance of Cu catalyst layers (CLs) for CO2 electrolysis, we used a "like for like" rationale to select acetone and methanol as dispersion solvents with a distinct affinity for the ionomer backbone or sulfonated ionic heads, respectively, of the perfluorinated sulfonic acid (PFSA) ionomer Aquivion. First, we characterized the morphology and wettability of Aquivion films drop-cast from acetone- and methanol-based inks on flat Cu foils and glassy carbons. On a flat surface, the ionomer films cast from the Aquivion and acetone mixture were more continuous and hydrophobic than films cast from methanol-based inks. Our study's second stage compared the performance of Cu nanoparticle CLs prepared with acetone and methanol on gas diffusion electrodes (GDEs) in a flow cell electrolyzer. The effects of the ionomer-solvent interaction led to a more uniform and flooding-tolerant GDE when acetone was the dispersion solvent (acetone-CL) than when we used methanol (methanol-CL). As a result, acetone-CL yielded a higher selectivity for CO2 electrolysis to C2+ products at high current density, up to 25% greater than methanol-CL at 500 mA cm-2. Ethylene was the primary product for both CLs, with a Faradaic efficiency for ethylene of 47.4 ± 4.0% on the acetone-CL and that of 37.6 ± 5.5% on the methanol-CL at a current density of 300 mA cm-2. We attribute the enhanced C2+ selectivity of the acetone-CL to this electrode's better resistance to electrolyte flooding, with zero seepage observed at tested current densities. Our findings reveal the critical role of solvent-ionomer interaction in determining the film structure and hydrophobicity, providing new insights into the CL design for enhanced multicarbon production in high current densities in CO2 electrolysis processes.

Non-invasive current collectors for improved current-density distribution during CO2 electrolysis on super-hydrophobic electrodes.

Electrochemical reduction of CO2 presents an attractive way to store renewable energy in chemical bonds in a potentially carbon-neutral way. However, the available electrolyzers suffer from intrinsic problems, like flooding and salt accumulation, that must be overcome to industrialize the technology. To mitigate flooding and salt precipitation issues, researchers have used super-hydrophobic electrodes based on either expanded polytetrafluoroethylene (ePTFE) gas-diffusion layers (GDL's), or carbon-based GDL's with added PTFE. While the PTFE backbone is highly resistant to flooding, the non-conductive nature of PTFE means that without additional current collection the catalyst layer itself is responsible for electron-dispersion, which penalizes system efficiency and stability. In this work, we present operando results that illustrate that the current distribution and electrical potential distribution is far from a uniform distribution in thin catalyst layers (~50 nm) deposited onto ePTFE GDL's. We then compare the effects of thicker catalyst layers (~500 nm) and a newly developed non-invasive current collector (NICC). The NICC can maintain more uniform current distributions with 10-fold thinner catalyst layers while improving stability towards ethylene (≥ 30%) by approximately two-fold.

Hydrogen sulfide ameliorates endothelial dysfunction in aging arteries by regulating ferroptosis.

Aging causes vascular endothelial dysfunction. We aimed to investigate the causes of vascular endothelial dysfunction during aging using plasma and renal arteries from patients who underwent nephrectomy and animal models. The results showed that the endogenous H2S-producing enzyme cystathione-γ-lyase (CSE) protein expression was downregulated in renal artery tissue, plasma H2S levels were reduced. Moreover, elevated lipid peroxidation and iron accumulation levels led to ferroptosis and endothelial diastolic function in the renal arteries was impaired in the elderly group. H2S enhanced the endogenous CSE expression in the elderly group, promoted endogenous H2S production, decreased lipid peroxide expression, and inhibited ferroptosis, which in turn improved vascular endothelial function in the elderly group. In animal models, we also observed the same results. In addition, we applied NaHS, Ferrostatin-1 (ferroptosis inhibitor) and erastin (ferroptosis inducer) to incubate renal arteries of SD rats. The results showed that NaHS enhanced ferroptosis related proteins expression, inhibited ferroptosis and improved vascular endothelial function. We demonstrated that endothelial dysfunction associated with aging is closely related to reduced endogenous H2S levels and ferroptosis in vascular endothelial cells. Notably, H2S reduced lipid peroxidation levels in vascular endothelial cells, inhibited ferroptosis in vascular endothelial cells, and improved endothelial dysfunction.

Inflammatory bowel disease and the associated risk of dry eye and ocular surface injury: a nationwide matched cohort study.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with lacrimal gland dysfunction and ocular inflammation. The objective of this research was to elucidate the temporal relationships between IBD, dry eye disease (DED), and corneal surface damage. METHODS: In a matched nationwide cohort study, we evaluated the risk of DED and corneal surface damage associated with IBD. Multivariable Cox proportional hazards regression analyses were implemented to estimate the risk of ocular complications. RESULTS: A total of 54,293 matched pairs were included for analyses. The median follow-up time was 8.3 years (interquartile range: 5.5 - 10.5). The period incidence of DED was 8.18 and 5.42 per 1000 person-years in the IBD and non-IBD groups, respectively. After adjusting for confounders, statistically significant associations were found between IBD and DED [adjusted hazard ratio (aHR): 1.43, 95% confidence interval (CI): 1.35 - 1.51, p < 0.0001], Sjögren's syndrome-related (aHR: 1.67, 95% CI:1.46 - 1.90, p < 0.0001) and non-Sjögren's syndrome-related subtypes (aHR: 1.38, 95% CI: 1.30 - 1.46, p < 0.0001). Furthermore, increased risks of corneal surface damage (aHR: 1.13, 95% CI: 1.03 - 1.24, p = 0.0094) among the patients with IBD were observed when compared with the controls. Other independent factors associated with corneal surface damage were age (aHR: 1.003), sex (male vs. female, aHR: 0.85), and monthly insurance premium (501-800 vs. 0-500 U.S. dollars, aHR: 1.45; ≥ 801 vs. 0-500 U.S. dollars, aHR: 1.32). CONCLUSIONS: Our results suggested that IBD was an independent risk factor for DED and ocular surface damage. Clinical strategies are needed to prevent visual impairment or losses in these susceptible patients.

Comparison and improvement of RNA extraction methods in Sargassum (Phaeophyta).

Sargassum (Sargassaceae) is widely distributed globally and plays an important role in regulating climate change, but the landscape of genomes and transcripts is less known. High-quality nucleic acids are the basis for molecular biology experiments such as high-throughput sequencing. Although extensive studies have documented methods of RNA extraction, these methods are not very applicable to Sargassum, which contains high levels of polysaccharides and polyphenols. To find a suitable method to improve the quality of RNA extracted, we compared and modified several popular RNA extraction methods and screened one practical method with three specific Sargassum spp. The results showed that three CTAB methods (denoted as Methods 1, 2, and 3) and the RNAprep Pure Plant Kit (denoted as Method 4) could, with slight modifications, effectively isolate RNA from Sargassum species, except for Method 4 used with S. fusiforme. By performing further screening, we determined Method 4 was the best choice for S. hemiphyllum and S. henslowianum, as revealed by RNA yields, RNA Integrity Number (RIN), extraction time, and unigene mapped ratio. For S. fusiforme, Methods 1, 2, and 3 showed no obvious differences among the yields, quality, or time to perform. In addition, one other method was tested, but we found the quality of the RNA extracted by TRIzol reagent methods (denoted as Method 5) performed the worst when compared with the above four methods. Therefore, our study provides four suitable methods for RNA extraction in Sargassum and is essential for future genetic exploration of Sargassum.

Hydralazine inhibits neuroinflammation and oxidative stress in APP/PS1 mice via TLR4/NF-κB and Nrf2 pathways.

Alzheimer's disease (AD) is a common chronic progressive neurodegenerative disorder, and curative treatment has not been developed. The objective of this study was to investigate the potential effects of hydralazine (Hyd, a hypertension treatment drug) on the development process of AD and its mechanisms. We treated 6-month-old male APP/PS1 mice with Hyd for 5 weeks, measured changes in behavior and pathological status, and analyzed differences in gene expression by RNA sequencing. The results demonstrated that Hyd improved cognitive deficits and decreased amyloid beta protein deposition in the cortex and hippocampus, while RNA sequencing analysis suggested that the regulation of neuroinflammation and energy metabolism might play pivotal roles for Hyd's beneficial effects. Therefore, we further investigated inflammatory response, redox state, and mitochondrial function, as well as the expression of toll-like receptor 4 (TLR4)/nuclear factor Kappa B (NF-κB)-dependent neuroinflammation gene and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant gene in AD mice. The results showed that Hyd reduced the damage of neuroinflammation and oxidative stress, improved mitochondrial dysfunction, downregulated pro-inflammation gene expression, and upregulated antioxidant gene expression. The results in lipopolysaccharide (LPS)-induced BV2 cell model demonstrated that Hyd suppressed pro-inflammatory response via TLR4/NF-κB signaling pathway. In addition, by silencing the Nrf2 gene expression, it was found that Hyd can reduce LPS-induced reactive oxygen species production by activating the Nrf2 signaling pathway. Therefore, administration of Hyd in the early stage of AD might be beneficial in delaying the pathological development of AD via inhibiting neuroinflammation and oxidative stress.

Ceruloplasmin is associated with the infiltration of immune cells and acts as a prognostic biomarker in patients suffering from glioma.

Glioma is regarded as a prevalent form of cancer that affects the Central Nervous System (CNS), with an aggressive growth pattern and a low clinical cure rate. Despite the advancement of the treatment strategy of surgical resection, chemoradiotherapy and immunotherapy in the last decade, the clinical outcome is still grim, which is ascribed to the low immunogenicity and tumor microenvironment (TME) of glioma. The multifunctional molecule, called ceruloplasmin (CP) is involved in iron metabolism. Its expression pattern, prognostic significance, and association with the immune cells in gliomas have not been thoroughly investigated. Studies using a variety of databases, including Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), and Gliovis, showed that the mRNA and protein expression levels of CP in patients suffering from glioma increased significantly with an increasing glioma grade. Kaplan-Meier (KM) curves and statistical tests highlighted a significant reduction in survival time of patients with elevated CP expression levels. According to Cox regression analysis, CP can be utilized as a stand-alone predictive biomarker in patients suffering from glioma. A significant association between CP expression and numerous immune-related pathways was found after analyzing the data using the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Tumor Immune Estimation Resource (TIMER) and CIBERSORT analyses indicated a substantial correlation between the CP expression and infiltration of immunocytes in the TME. Additionally, immune checkpoints and CP expression in gliomas showed a favorable correlation. According to these results, patients with glioma have better prognoses and levels of tumor immune cell infiltration when their CP expression is low. As a result, CP could be used as a probable therapeutic target for gliomas and potentially anticipate the effectiveness of immunotherapy.

Hydrogen sulfide ameliorates senescence in vascular endothelial cells through ameliorating inflammation and activating PPARδ/SGLT2/STAT3 signaling pathway.

Mounting evidence demonstrates that hydrogen sulfide (H 2S) promotes anti-inflammatory molecules and inhibits pro-inflammatory cytokines in endothelial cells (ECs). This study aims to investigate the favorable action of H 2S on endothelial function in senescence by inhibiting the production of inflammatory molecules. Senescent ECs exhibit a reduction in H 2S, endothelial nitric oxide synthase (eNOS) and peroxisome proliferator-activated receptor δ (PPARδ), coupled with increased inflammatory molecules, sodium glucose transporter type 2 (SGLT2) and phosphorylation of STAT3, which could be reversed by the administration of a slow but sustained release agent of H 2S, GYY4137. Decreased production of eNOS and upregulated p-STAT3 and SGLT2 levels in senescent ECs are reversed by replenishment of the SGLT2 inhibitor EMPA and the PPARδ agonist GW501516. The PPARδ antagonist GSK0660 attenuates eNOS expression and increases the production of p-STAT3 and SGLT2. However, supplementation with GYY4137 has no beneficial effect on GSK0660-treated ECs. GYY4137, GW501516 and EMPA preserve endothelial-dependent relaxation (EDR) in D-gal-treated aortae, while GSK0660 destroys aortic relaxation even with GYY4137 supplementation. In summary, senescent ECs manifest aggravated the expressions of the inflammatory molecules SGLT2 and p-STAT3 and decreased the productions of PPARδ, eNOS and CSE. H 2S ameliorates endothelial dysfunction through the anti-inflammatory effect of the PPARδ/SGLT2/p-STAT3 signaling pathway in senescent ECs and may be a potential therapeutic target for anti-ageing treatment.

Thriving psychological well-being in undergraduate nursing student: a grounded theory study with the life grid approach.

BACKGROUND: Psychological well-being (PWB) plays a vital role in successful adaptation to the Bachelor of Nursing journey and affects career development. However, there is little known about the functional and social processes associated with enhancing well-being specific to the subjective perspective of nursing students. AIM: To investigate how nursing students promote their psychological well-being to conceptualize thriving psychological well-being. METHOD: This qualitative study analyzed and reviewed a life grid and semi-structured in-depth interviews of 20 Chinese Nursing graduates by investigators and participants, following Charmaz's constructivist grounded theory. The constant comparative method was used to analyze data. This study took place between 2020 and 2022. RESULTS: All participants experienced fluctuations in psychological well-being. This study identified a new understanding of how nursing students enhance their psychological well-being. Thriving awareness was co-constructed as the core category and based on the relationship with a supportive environment, the thriving psychological well-being of nursing students is conceptualized. CONCLUSIONS: It is imperative to enhance the psychological counseling and support for nursing students during their clinical placements, during the period just entering university as well as after repeated outbreaks of COVID-19. Nursing educators and administrators could develop appropriate educational programs and interventions based on the theoretical model-Thriving psychological well-being.

The Evolution of Insulation Performance of Fiber-Reinforced Silica Aerogel after High-Temperature Treatment.

Fiber-reinforced silica aerogel blankets (FRABs) are an important high-temperature thermal insulation material for industry applications that have emerged in recent years. In order to better understand the performance evolution of FRABs at high temperatures, the effect of heat treatment at different temperatures on the performance of FRABs as well as their base material, hydrophobic silica aerogel powder and glass wool, was investigated. The property evolution of the hydrophobic silica aerogel powder showed two stages with an increase in thermal treatment temperatures. The skeleton structure of the aerogel remained unchanged, but the residual organic chemicals, such as hydrophobic groups, were decomposed when the heat treatment temperature was lower than 400 °C. Above 400 °C, the skeleton began to shrink with the increase in temperature, which led to an increase in thermal conductivity. The structure and room-temperature thermal conductivity of the glass wool blanket were less affected by a heat treatment temperature under 600 °C. Therefore, the performance degradation of FRABs at high temperatures is mainly due to the change in the aerogel powder. The insulation performance of the glass wool and FRAB at high temperatures was studied using a heating table which was designed to simulate working conditions. The energy savings of using FRABs instead of glass fiber were calculated and are discussed here.

Large but overlooked carbon differentiations inside China's provinces matters to mitigation strategies design: Evidence from county-level analysis.

In China, wide variations exist not only among different provinces, but also inside provinces. Therefore, intensive policy adjustments are essential for promoting carbon neutral in China, which calls for a clear understanding of carbon emission disparities in each individual province. Based on panel data of 2001 county-level administrative areas from 2004 to 2017, we use Theil index and spatial regression models to measure contributions and distributions of intra-provincial carbon inequality, as well as effects of intra-provincial economic inequality on intra-provincial carbon inequality, in order to design provincial specific strategies considering carbon differentiations inside each province. Our main contributions are studying China's carbon inequality from intra- instead of inter-provincial perspectives and exploring spatial connections of carbon inequality, which has not been fully discussed in previous studies. The empirical results indicate that intra- rather than inter- provincial carbon inequality contributes the majority of China's overall carbon inequality. Intra-provincial inequality shows high levels of regional clustering and decrease from west to east, although their differences are smaller in 2017 than 2004, mainly because carbon inequality levels experience large declines in some central and western provinces. Low carbon inequality levels in eastern provinces are mainly attributed to very negative correlation between development levels and carbon intensity. Intra-provincial economic development inequality plays nonnegligible roles in intra-provincial carbon inequality in all provinces, although they are not the major driving factors in some provinces. There also exist positive spatial spillover effects of intra-provincial economic inequality on intra-provincial carbon inequality. We provide specific policy suggestions on key areas of carbon emission reductions and demand degree of economic transitions for each individual province and also evaluate effects of "common prosperity" measures, which have been frequently discussed recently, on intra-provincial carbon distributions.

Reversal of the detrimental effects of social isolation on ischemic cerebral injury and stroke-associated pneumonia by inhibiting small intestinal γδ T-cell migration into the brain and lung.

Social isolation (ISO) is associated with an increased risk and poor outcomes of ischemic stroke. However, the roles and mechanisms of ISO in stroke-associated pneumonia (SAP) remain unclear. Adult male mice were single- or pair-housed with an ovariectomized female mouse and then subjected to transient middle cerebral artery occlusion. Isolated mice were treated with the natriuretic peptide receptor A antagonist A71915 or anti-gamma-delta (γδ) TCR monoclonal antibody, whereas pair-housed mice were treated with recombinant human atrial natriuretic peptide (rhANP). Subdiaphragmatic vagotomy (SDV) was performed 14 days before single- or pair-housed conditions. We found that ISO significantly worsened brain and lung injuries relative to pair housing, which was partially mediated by elevated interleukin (IL)-17A levels and the migration of small intestine-derived inflammatory γδ T-cells into the brain and lung. However, rhANP treatment or SDV could ameliorate ISO-exacerbated post-stroke brain and lung damage by reducing IL-17A levels and inhibiting the migration of inflammatory γδ T-cells into the brain and lung. Our results suggest that rhANP mitigated ISO-induced exacerbation of SAP and ischemic cerebral injury by inhibiting small intestine-derived γδ T-cell migration into the lung and brain, which could be mediated by the subdiaphragmatic vagus nerve.

Exercise protects vascular function by countering senescent cells in older adults.

Blood vessels are key conduits for the transport of blood and circulating factors. Abnormalities in blood vessels promote cardiovascular disease (CVD), which has become the most common disease as human lifespans extend. Aging itself is not pathogenic; however, the decline of physiological and biological function owing to aging has been linked to CVD. Although aging is a complex phenomenon that has not been comprehensively investigated, there is accumulating evidence that cellular senescence aggravates various pathological changes associated with aging. Emerging evidence shows that approaches that suppress or eliminate cellular senescence preserve vascular function in aging-related CVD. However, most pharmacological therapies for treating age-related CVD are inefficient. Therefore, effective approaches to treat CVD are urgently required. The benefits of exercise for the cardiovascular system have been well documented in basic research and clinical studies; however, the mechanisms and optimal frequency of exercise for promoting cardiovascular health remain unknown. Accordingly, in this review, we have discussed the changes in senescent endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) that occur in the progress of CVD and the roles of physical activity in CVD prevention and treatment.

Small-molecule BCL6 inhibitor protects chronic cardiac transplant rejection and inhibits T follicular helper cell expansion and humoral response.

Background: B cell lymphoma 6 (BCL6) is an important transcription factor of T follicular helper (Tfh) cells, which regulate the humoral response by supporting the maturation of germinal center B cells and plasma cells. The aim of this study is to investigate the expansion of T follicular helper cells and the effect of the BCL6 inhibitor FX1 in acute and chronic cardiac transplant rejection models. Methods: A mouse model of acute and chronic cardiac transplant rejection was established. Splenocytes were collected at different time points after transplantation for CXCR5+PD-1+ and CXCR5+BCL6+ Tfh cells detection by flow cytometry (FCM). Next, we treated the cardiac transplant with BCL6 inhibitor FX1 and the survival of grafts was recorded. The hematoxylin and eosin, Elastica van Gieson, and Masson staining of cardiac grafts was performed for the pathological analysis. Furthermore, the proportion and number of CD4+ T cells, effector CD4+ T cells (CD44+CD62L-), proliferating CD4+ T cells (Ki67+), and Tfh cells in the spleen were detected by FCM. The cells related to humoral response (plasma cells, germinal center B cells, IgG1+ B cells) and donor-specific antibody were also detected. Results: We found that the Tfh cells were significantly increased in the recipient mice on day 14 post transplantation. During the acute cardiac transplant rejection, even the BCL6 inhibitor FX1 did not prolong the survival or attenuate the immune response of cardiac graft, the expansion of Tfh cell expansion inhibit. During the chronic cardiac transplant rejection, FX1 prolonged survival of cardiac graft, and prevented occlusion and fibrosis of vascular in cardiac grafts. FX1 also decreased the proportion and number of splenic CD4+ T cells, effector CD4+ T cells, proliferating CD4+ T cells, and Tfh cells in mice with chronic rejection. Moreover, FX1 also inhibited the proportion and number of splenic plasma cells, germinal center B cells, IgG1+ B cells, and the donor-specific antibody in recipient mice. Conclusion: We found BCL6 inhibitor FX1 protects chronic cardiac transplant rejection and inhibits the expansion of Tfh cells and the humoral response, which suggest that BCL6 is a potential therapeutic target of the treatment for chronic cardiac transplant rejection.

Melatonin suppresses sympathetic vasomotor tone through enhancing GABAA receptor activity in the hypothalamus.

Introduction: Melatonin (5-methoxy-N-acetyl-tryptamine) is a circadian hormone synthesized and secreted by the pineal gland. In addition to regulating circadian rhythms of many physiological functions, melatonin is involved in regulating autonomic nervous function and blood pressure. Hypothalamus paraventricular nucleus (PVN), receiving melatonin projections from the superchiasmatic nucleus, is a critical brain region to regulate neuroendocrine and cardiovascular function. Here, we determined the synaptic mechanisms involved in the effect of melatonin on the sympathetic outflow and blood pressure. Methods and Results: Microinjection of melatonin into the PVN produced a depressor effect and decreased renal sympathetic nerve activity (RSNA). While microinjection of luzindole, a non-selective melatonin receptor antagonist, into the PVN did not change melatonin-induced sympathoinhibition, GABAA receptor antagonist bicuculline eliminated melatonin-induced sympathoinhibition. Furthermore, melatonin decreased firing rate of retrogradely labeled PVN neurons which project to the rostral ventrolateral medulla (RVLM), an effect was not altered by luzindole but eliminated by bicuculline. Melatonin significantly increased the amplitude of spontaneous and evoked GABAergic inhibitory synaptic currents, as well as GABA-induced currents. Conclusion: These data suggest that melatonin in the PVN suppresses sympathetic vasomotor tone through enhancing GABAA receptor activity. This study provides novel information for understanding the cellular mechanisms involved in the effect of melatonin on regulating blood pressure and sympathetic output.

Integrative identification of hub genes in development of atrial fibrillation related stroke.

BACKGROUND: As the most common arrhythmia, atrial fibrillation (AF) is associated with a significantly increased risk of stroke, which causes high disability and mortality. To date, the underlying mechanism of stroke occurring after AF remains unclear. Herein, we studied hub genes and regulatory pathways involved in AF and secondary stroke and aimed to reveal biomarkers and therapeutic targets of AF-related stroke. METHODS: The GSE79768 and GSE58294 datasets were used to analyze AF- and stroke-related differentially expressed genes (DEGs) to obtain a DEG1 dataset. Weighted correlation network analysis (WGCNA) was used to identify modules associated with AF-related stroke in GSE66724 (DEG2). DEG1 and DEG2 were merged, and hub genes were identified based on protein-protein interaction networks. Gene Ontology terms were used to analyze the enriched pathways. The GSE129409 and GSE70887 were applied to construct a circRNA-miRNA-mRNA network in AF-related stroke. Hub genes were verified in patients using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: We identified 3,132 DEGs in blood samples and 253 DEGs in left atrial specimens. Co-expressed hub genes of EIF4E3, ZNF595, ZNF700, MATR3, ACKR4, ANXA3, SEPSECS-AS1, and RNF166 were significantly associated with AF-related stroke. The hsa_circ_0018657/hsa-miR-198/EIF4E3 pathway was explored as the regulating axis in AF-related stroke. The qRT-PCR results were consistent with the bioinformatic analysis. CONCLUSIONS: Hub genes EIF4E3, ZNF595, ZNF700, MATR3, ACKR4, ANXA3, SEPSECS-AS1, and RNF166 have potential as novel biomarkers and therapeutic targets in AF-related stroke. The hsa_circ_0018657/hsa-miR-198/EIF4E3 axis could play an important role regulating the development of AF-related stroke.