MED1 Regulates BMP/TGF-ß in Endothelium: Implication for Pulmonary Hypertension.

BACKGROUND: Dysregulated BMP (bone morphogenetic protein) or TGF-ß (transforming growth factor beta) signaling pathways are imperative in idiopathic and familial pulmonary arterial hypertension (PAH) as well as experimental pulmonary hypertension (PH) in rodent models. MED1 (mediator complex subunit 1) is a key transcriptional co-activator and KLF4 (Krüppel-like factor 4) is a master transcription factor in endothelium. However, MED1 and KLF4 epigenetic and transcriptional regulations of the BMP/TGF-ß axes in pulmonary endothelium and their dysregulations leading to PAH remain elusive. We investigate the MED1/KLF4 co-regulation of the BMP/TGF-ß axes in endothelium by studying the epigenetic regulation of BMPR2 (BMP receptor type II), ETS-related gene (ERG), and TGFBR2 (TGF-ß receptor 2) and their involvement in the PH. METHODS: High-throughput screening involving data from RNA-seq, MED1 ChIP-seq, H3K27ac ChIP-seq, ATAC-seq, and high-throughput chromosome conformation capture together with in silico computations were used to explore the epigenetic and transcriptional regulation of BMPR2, ERG, and TGFBR2 by MED1 and KLF4. In vitro experiments with cultured pulmonary arterial endothelial cells (ECs) and bulk assays were used to validate results from these in silico analyses. Lung tissue from patients with idiopathic PAH, animals with experimental PH, and mice with endothelial ablation of MED1 (EC-MED1-/-) were used to study the PH-protective effect of MED1. RESULTS: Levels of MED1 were decreased in lung tissue or pulmonary arterial endothelial cells from idiopathic PAH patients and rodent PH models. Mechanistically, MED1 acted synergistically with KLF4 to transactivate BMPR2, ERG, and TGFBR2 via chromatin remodeling and enhancer-promoter interactions. EC-MED1-/- mice showed PH susceptibility. In contrast, MED1 overexpression mitigated the PH phenotype in rodents. CONCLUSIONS: A homeostatic regulation of BMPR2, ERG, and TGFBR2 in ECs by MED1 synergistic with KLF4 is essential for the normal function of the pulmonary endothelium. Dysregulation of MED1 and the resulting impairment of the BMP/TGF-ß signaling is implicated in the disease progression of PAH in humans and PH in rodent models.

ACDNet: Attention-guided Collaborative Decision Network for effective medication recommendation.

Medication recommendation using Electronic Health Records (EHR) is challenging due to complex medical data. Current approaches extract longitudinal information from patient EHR to personalize recommendations. However, existing models often lack sufficient patient representation and overlook the importance of considering the similarity between a patient's medication records and specific medicines. Therefore, an Attention-guided Collaborative Decision Network (ACDNet) for medication recommendation is proposed in this paper. Specifically, ACDNet utilizes attention mechanism and Transformer to effectively capture patient health conditions and medication records by modeling their historical visits at both global and local levels. ACDNet also employs a collaborative decision framework, utilizing the similarity between medication records and medicine representation to facilitate the recommendation process. The experimental results on two extensive medical datasets, MIMIC-III and MIMIC-IV, clearly demonstrate that ACDNet outperforms state-of-the-art models in terms of Jaccard, PR-AUC, and F1 score, reaffirming its superiority. Moreover, the ablation experiments provide solid evidence of the effectiveness of each module in ACDNet, validating their contribution to the overall performance. Furthermore, a detailed case study reinforces the effectiveness of ACDNet in medication recommendation based on EHR data, showcasing its practical value in real-world healthcare scenarios.

MDM2-Mediated Ubiquitination of Angiotensin-Converting Enzyme 2 Contributes to the Development of Pulmonary Arterial Hypertension.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) converts angiotensin II, a potent vasoconstrictor, to angiotensin-(1-7) and is also a membrane protein that enables coronavirus disease 2019 (COVID-19) infectivity. AMP-activated protein kinase (AMPK) phosphorylation of ACE2 enhances ACE2 stability. This mode of posttranslational modification of ACE2 in vascular endothelial cells is causative of a pulmonary hypertension (PH)-protective phenotype. The oncoprotein MDM2 (murine double minute 2) is an E3 ligase that ubiquitinates its substrates to cause their degradation. In this study, we investigated whether MDM2 is involved in the posttranslational modification of ACE2 through its ubiquitination of ACE2, and whether an AMPK and MDM2 crosstalk regulates the pathogenesis of PH. METHODS: Bioinformatic analyses were used to explore E3 ligase that ubiquitinates ACE2. Cultured endothelial cells, mouse models, and specimens from patients with idiopathic pulmonary arterial hypertension were used to investigate the crosstalk between AMPK and MDM2 in regulating ACE2 phosphorylation and ubiquitination in the context of PH. RESULTS: Levels of MDM2 were increased and those of ACE2 decreased in lung tissues or pulmonary arterial endothelial cells from patients with idiopathic pulmonary arterial hypertension and rodent models of experimental PH. MDM2 inhibition by JNJ-165 reversed the SU5416/hypoxia-induced PH in C57BL/6 mice. ACE2-S680L mice (dephosphorylation at S680) showed PH susceptibility, and ectopic expression of ACE2-S680L/K788R (deubiquitination at K788) reduced experimental PH. Moreover, ACE2-K788R overexpression in mice with endothelial cell-specific AMPKα2 knockout mitigated PH. CONCLUSIONS: Maladapted posttranslational modification (phosphorylation and ubiquitination) of ACE2 at Ser-680 and Lys-788 is involved in the pathogenesis of pulmonary arterial hypertension and experimental PH. Thus, a combined intervention of AMPK and MDM2 in the pulmonary endothelium might be therapeutically effective in PH treatment.

Characterization of Peptacetobacter hominis gen. nov., sp. nov., isolated from human faeces, and proposal for the reclassification of Clostridium hiranonis within the genus Peptacetobacter.

A novel, Gram-stain-positive, rod-shaped, non-motile, non-spore-forming, obligately anaerobic bacterium, designated strain ZHW00191T, was isolated from human faeces and characterized by using a polyphasic taxonomic approach. Growth occurred at 25-45 °C (optimum, 37-42 °C), at pH 5.5-10.0 (optimum, pH 6.5-7.0) and with 0-2 % (w/v) NaCl (optimum, 0 %). The end products of glucose fermentation were acetic acid, isobutyric acid and isovaleric acid and a small amount of propionic acid. The dominant cellular fatty acids (>10 %) of strain ZHW00191T were C16 : 0, C18 : 1 ω9с and C18 : 2ω6,9с. Its polar lipid profile comprised diphosphatidylglycerol, phosphatidylglycerol, three unidentified phospholipids and ten unidentified glycolipids. Respiratory quinones were not detected. The cell-wall peptidoglycan contained meso-2,6-diaminopimelic acid, and the whole-cell sugars were ribose and glucose. The genomic DNA G+C content was 32.8 mol%. Analysis of the 16S rRNA gene sequence indicated that ZHW00191T was most closely related to Clostridium hiranonis TO-931T (95.3 % similarity). Average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) analyses with closely related reference strains indicated that reassociation values were both well below the thresholds of 95-96% and 70 % for species delineation, respectively. Based on phenotypic, chemotaxonomic and genetic studies, a novel genus, Peptacetobacter gen. nov., is proposed. The novel isolate ZHW00191T (=JCM 33482T=GDMCC 1.1530T) is proposed as the type strain of the type species Peptacetobacter hominis gen. nov., sp. nov. of the proposed new genus. Furthermore, it is proposed that Clostridium hiranonis be transferred to this novel genus, as Peptacetobacter hiranonis comb. nov.

Correction to: Cardiac rupture complicating acute myocardial infarction: the clinical features from an observational study and animal experiment.

An amendment to this paper has been published and can be accessed via the original article.

Cardiac rupture complicating acute myocardial infarction: the clinical features from an observational study and animal experiment.

BACKGROUND: Cardiac rupture (CR) is a fatal complication of ST-elevation myocardial infarction (STEMI) with its incidence markedly declined in the recent decades. However, clinical features of CR patients now and the effect of reperfusion therapy to CR remain unclear. We investigated the clinical features of CR in STEMI patients and the effect of reperfusion therapy to CR in mice. METHODS: Two studies were conducted. In clinical study, data of 1456 STEMI patients admitted to the First Hospital, Xi'an Jiaotong University during 2015.12. ~ 2018.12. were analyzed. In experimental study, 83 male C57BL/6 mice were operated to induce MI. Of them, 39 mice were permanent MI (group-1), and remaining mice received reperfusion after 1 h ischemia (21 mice, group-2) or 4 h ischemia (23 mice, group-3). All operated mice were monitored up to day-10. Animals were inspected three times daily for the incidence of death and autopsy was done for all mice found died to determine the cause of death. RESULTS: CR was diagnosed in 40 patients: free-wall rupture in 17, ventricular septal rupture in 20, and combined locations in 3 cases. CR presented in 19 patients at admission and diagnosed in another 21 patients during 1 ~ 14 days post-STEMI, giving an in-hospital incidence of 1.4%. The mortality of CR patients was high during hospitalization accounting for 39% of total in-hospital death. By multivariate logistic regression analysis, older age, peak CK-MB and peak hs-CRP were independent predictors of CR post-STEMI. In mice with non-reperfused MI, 17 animals (43.6%) died of CR that occurred during 3-6 days post-MI. In MI mice received early or delayed reperfusion, all mice survived to the end of experiment except one mouse died of acute heart failure. CONCLUSION: CR remains as a major cause of in-hospital death in STEMI patients. CR patients are characterized of being elderly, having larger infarct and more server inflammation. Experimentally, reperfusion post-MI prevented CR.

Angiotensin II deteriorates advanced atherosclerosis by promoting MerTK cleavage and impairing efferocytosis through the AT1R/ROS/p38 MAPK/ADAM17 pathway.

Vulnerable plaques in advanced atherosclerosis have defective efferocytosis. The role of ANG II in the progression of atherosclerosis is not fully understood. Herein, we investigated the effects and the underlying mechanisms of ANG II on macrophage efferocytosis in advanced atherosclerosis. ANG II decreased the surface expression of Mer tyrosine kinase (MerTK) in macrophages through a disintegrin and metalloproteinase17 (ADAM17)-mediated shedding of the soluble form of MerTK (sMer) in the medium, which led to efferocytosis suppression. ANG II-activated ADAM17 required reactive oxygen species (ROS) and p38 MAPK phosphorylation. Selective angiotensin II type 1 receptor (AT1R) blocker losartan suppressed ROS production, and ROS scavenger N-acetyl-l-cysteine (NAC) prevented p38 MAPK phosphorylation. In addition, mutant MERTKΔ483-488 was resistant to ANG II-induced MerTK shedding and efferocytosis suppression. The advanced atherosclerosis model that is characterized by larger necrotic cores, and less collagen content was established by feeding apolipoprotein E knockout (ApoE-/-) mice with a high-fat diet for 16 wk. NAC and losartan oral administration prevented atherosclerotic lesion progression. Meanwhile, the inefficient efferocytosis represented by decreased macrophage-associated apoptotic cells and decreased MerTK+CD68+double-positive macrophages in advanced atherosclerosis were prevented by losartan and NAC. Additionally, the serum levels of sMer were increased and positively correlated with the upregulated levels of ANG II in acute coronary syndrome (ACS) patients. In conclusion, ANG II promotes MerTK shedding via AT1R/ROS/p38 MAPK/ADAM17 pathway in macrophages, which led to defective efferocytosis and atherosclerosis progression. Defining the molecular mechanisms of defective efferocytosis may provide a promising prognosis and therapy for ACS patients.

Association between elevated blood glucose level and non-valvular atrial fibrillation: a report from the Guangzhou heart study.

BACKGROUND: To estimate the prevalence of elevated blood glucose level (EBG, including type 2 diabetes mellitus and impaired fasting glucose), and its association with non-valvular atrial fibrillation (NVAF) in Guangzhou, China. METHODS: The population-based follow-up Guangzhou Heart Study collected baseline data from July 2015 to August 2017 among 12,013 permanent residents aged > 35 from 4 Guangzhou districts. Two streets (Dadong and Baiyun) in the Yuexiu District, and one street (Xiaoguwei) and two towns (Xinzao and Nancun) in the Panyu District were chosen as representative of urban and rural areas, respectively. Each participant completed a comprehensive questionnaire, and underwent physical examination, blood sample collection for laboratory testing, electrocardiography, and other evaluations. Multivariable logistic regression analyses were used to estimate the independent association between hyperglycemia and NVAF prevalence. RESULTS: The prevalence of EBG in overall study population was 29.9%. Compared with residents without EBG, the odds ratio (OR) for AF among residents with EBG was significantly higher (1.94, 95% confidence interval [CI]: 1.40-2.70, P <  0.001), even after multivariate adjustment for metabolic abnormalities (OR = 1.60, 95% CI: 1.14-2.25, P = 0.007), and driven by women (OR = 1.80, 95% CI: 1.12-2.91, P = 0.016). CONCLUSIONS: In Guangzhou, China, prevalence of EBG is high among residents aged > 35 years and associated with a multivariate adjusted increase in prevalence of NVAF overall and in women.

AMP-activated Protein Kinase Phosphorylation of Angiotensin-Converting Enzyme 2 in Endothelium Mitigates Pulmonary Hypertension.

RATIONALE: Endothelial dysfunction plays an integral role in pulmonary hypertension (PH). AMPK (AMP-activated protein kinase) and ACE2 (angiotensin-converting enzyme 2) are crucial in endothelial homeostasis. The mechanism by which AMPK regulates ACE2 in the pulmonary endothelium and its protective role in PH remain elusive. OBJECTIVES: We investigated the role of AMPK phosphorylation of ACE2 Ser680 in ACE2 stability and deciphered the functional consequences of this post-translational modification of ACE2 in endothelial homeostasis and PH. METHODS: Bioinformatics prediction, kinase assay, and antibody against phospho-ACE2 Ser680 (p-ACE2 S680) were used to investigate AMPK phosphorylation of ACE2 Ser680 in endothelial cells. Using CRISPR-Cas9 genomic editing, we created gain-of-function ACE2 S680D knock-in and loss-of-function ACE2 knockout (ACE2-/-) mouse lines to address the involvement of p-ACE2 S680 and ACE2 in PH. The AMPK-p-ACE2 S680 axis was also validated in lung tissue from humans with idiopathic pulmonary arterial hypertension. MEASUREMENTS AND MAIN RESULTS: Phosphorylation of ACE2 by AMPK enhanced the stability of ACE2, which increased Ang (angiotensin) 1-7 and endothelial nitric oxide synthase-derived NO bioavailability. ACE2 S680D knock-in mice were resistant to PH as compared with wild-type littermates. In contrast, ACE2-knockout mice exacerbated PH, a similar phenotype found in mice with endothelial cell-specific deletion of AMPKα2. Consistently, the concentrations of phosphorylated AMPK, p-ACE2 S680, and ACE2 were decreased in human lungs with idiopathic pulmonary arterial hypertension. CONCLUSIONS: Impaired phosphorylation of ACE2 Ser680 by AMPK in pulmonary endothelium leads to a labile ACE2 and hence is associated with the pathogenesis of PH. Thus, AMPK regulation of the vasoprotective ACE2 is a potential target for PH treatment.

[Analysis on academic characteristics and medication rules of traditional Chinese medical master Liu Zu-yi for treating insomnia].

To analyze the academic characteristics and medication rules of traditional Chinese medical master Liu Zu-yi for treating insomnia. Totally 178 cases of insomnia treated by Professor Liu were collected,and the treatment data were input into traditional Chinese medicine inheritance support system( TCMISS) by using data mining methods,such as essential information,frequency statistics of symptoms,syndrome type statistics,extraction of syndrome elements,frequency statistics of drugs; and four properties and five tastes of drugs,distribution of meridians,regularity of prescriptions,new prescription analysis were mined. It was found that the most commonly used drugs( over 100 times) were Albiziae Cortex,Longgu,Polygoni Multiflori Caulis,Ostreae Concha,Ziziphi Spinosae Semen,Crataegi Fructus; the commonly used couplet medicines were Longgu-Ostreae Concha,Ziziphi Spinosae Semen-Polygoni Multiflori Caulis,Ziziphi Spinosae Semen-Albiziae Cortex-Polygoni Multiflori Caulis; and seven new prescriptions in treating insomnia were explored,such as prescriptions containing Hordei Fructus Germinatus,Ziziphi Spinosae Semen,Galli Gigerii Endothelium Corneum,Rehmanniae Radix,Lilii Bulbus. Based on the introduction and discussion of Professor Liu's academic views and characteristics on insomnia treatment and the illustrative evidences added to the typical case list,this paper combines the academic characteristics,data support and typical medical records to verify each other,and objectively summarizes his academic experience for treating insomnia. Treatment shall focus on the primary cause of disease in three aspects; syndrome differentiation shall distinguish between excessive disease and deficient disease; therapy shall reinforce deficiency and reduce diarrhea,regulate the five internal organs,and emphasizes the heart and liver,particularly the liver; medication shall focus on the drugs for calming the mind and protecting the stomach and spleen,which are commonly combined with three types of traditional Chinese medicine with effect in introducing Yangqi( Pinelliae Rhizoma Praeparatum,Prunellae Spica,Polygoni Multiflori Caulis) and restraining Yangqi( Longgu,Ostreae Concha,Ziziphi Spinosae Semen); nursing care focuses on preserving the body and tranquilizing the mind by means of three methods for tranquilizing the mind and three methods for preserving the body.

Endogenous Hydrogen Sulfide Ameliorates NOX4 Induced Oxidative Stress in LPS-Stimulated Macrophages and Mice.

BACKGROUND/AIMS: Sepsis is a severe and complicated syndrome that is characterized by dysregulation of host inflammatory responses and organ failure. Cystathionine-γ-lyase (CSE)/ hydrogen sulfide (H2S) has potential anti-inflammatory activities in a variety of inflammatory diseases. NADPH oxidase 4 (Nox4), a member of the NADPH oxidases, is the major source of reactive oxygen species (ROS) and its expression is increased in sepsis, but its function in CSE-mediated anti-inflammatory activities remains unknown. METHODS: Macrophages were either transfected with CSE, Nox4 siRNA or transduced with lentiviral vector encoding CSE or Nox4, and then stimulated with lipopolysaccharide (LPS). The expression of inflammatory mediators and signaling pathway activation were measured by quantitative PCR (qPCR), ELISA, and immunoblotting. LPS-induced shock severity in WT, Nox4 knockdown and CSE knockout (CSE-/-) mice was assessed. RESULTS: Here we showed that CSE and Nox4 were upregulated in macrophage and mouse in response to LPS. After LPS stimulation, the inflammatory responses were significantly ameliorated by lentiviral Nox4 shRNA knockdown, but were exacerbated by lentiviral overexpressing Nox4. Furthermore, Nox4 mediated inflammation through PI3K/Akt and p-p38 mitogen-activated protein kinase signal pathway. Notably, CSE knockout served to amplify the inflammatory cascade by increasing Nox4-ROS signaling activation in septic mice and macrophage. Similarly, the enhanced production of inflammatory mediators by macrophages was reduced by CSE overexpression. CONCLUSION: Thus, we demonstrated that CSE/H2S attenuated LPS-induced sepsis against oxidative stress and inflammation damage probably largely through mediated Nox4 pathway.

The Role of Uric Acid in Hypertension of Adolescents, Prehypertension and Salt Sensitivity of Blood Pressure.

Uric acid is the end product of purine metabolism. Metabolic disorders of uric acid are associated with many disease states. Substantial evidence suggests the possible role of uric acid as a mediator of high blood pressure. Elevated uric acid is closely associated with new onset essential hypertension in adolescents and prehypertension; and urate-lowering agents can significantly improve these early stages of hypertension. Uric acid also influences salt sensitivity of blood pressure through two phases. Local renin-angiotensin-aldosterone system activation initiates renal damage, arteriolopathy, and endothelium dysfunction, which is followed by the dysregulation of sodium homeostasis, thereby leading to increased salt sensitivity. In this review we summarize the available evidence to contribute to a better understanding of the casual relationship between uric acid and early or intermediate stages of hypertension. We hope our review can contribute to the prevention of hypertension or provide new insights into a treatment that would slow the progression of hypertension.

Role of Kir2.1 in human monocyte-derived foam cell maturation.

The role of K(+) channels in macrophage immunomodulation has been well-established. However, it remains unclear whether K(+) channels are involved in the lipid uptake of macrophages. The expression and function of the inward rectifier potassium channel (Kir2.1, KCNJ2) in Human acute monocytic leukemia cell line (THP-1) cells and human monocytes derived macrophages (HMDMs) were investigated using RT-PCR and western blotting, and patch clamp technique. The expression of scavenger receptors in THP-1-derived macrophages was detected using western blotting. Expressions of Kir2.1 mRNA and protein in HMDMs were significantly decreased by 60% (P < 0.05) and 90% (P < 0.001) on macrophage maturation, but overexpressed by approximately 1.3 (P > 0.05) and 3.8 times (P = 0.001) after foam cell formation respectively. Concurrently, the Kir2.1 peak current density in HMDMs, mature macrophages and foam cells, measured at -150 mV, were -22.61 ± 2.1 pA/pF, -7.88 ± 0.60 pA/pF and -13.39 ± 0.80 pA/pF respectively (P < 0.05). In association with an up-regulation of Kir2.1 in foam cells, the SR-A protein level was significantly increased by over 1.5 times compared with macrophages (P < 0.05). THP-1 cells contained much less lipids upon Kir2.1 knockdown and cholesterol ester/total cholesterol ratio was 29.46 ± 2.01% (P < 0.05), and the SR-BI protein level was increased by over 6.2 times, compared to that of macrophages (P < 0.001). Kir2.1 may participate in macrophage maturation and differentiation, and play a key role in lipid uptake and foam cell formation through modulating the expression of scavenger receptors.

TLR4/MyD88/NF-κB signaling and PPAR-γ within the paraventricular nucleus are involved in the effects of telmisartan in hypertension.

Previous findings from our laboratory and others indicate that the main therapeutic effect of angiotensin II type 1 receptor (AT1-R) antagonists is to decrease blood pressure and exert anti-inflammatory effects in the cardiovascular system. In this study, we determined whether AT1-R antagonist telmisartan within the hypothalamic paraventricular nucleus (PVN) attenuates hypertension and hypothalamic inflammation via both the TLR4/MyD88/NF-κB signaling pathway and peroxisome proliferator-activated receptor-γ (PPAR-γ) in the PVN in hypertensive rats. Spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were treated for 4weeks through bilateral PVN infusion with the AT1-R antagonist telmisartan (TEL, 10µg/h), or losartan (LOS, 20µg/h), or the PPAR-γ antagonist GW9662 (GW, 100µg/h), or vehicle via osmotic minipump. Mean arterial pressure (MAP) was recorded by a tail-cuff occlusion method. PVN tissue and blood were collected for the measurement of AT1-R, PPAR-γ, pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6), inducible nitric oxide synthase (iNOS), TLR4, MyD88, nuclear factor-kappa B (NF-κB) activity and plasma norepinephrine (NE), respectively. Hypertensive rats exhibited significantly higher level of AT1-R and lower level of PPAR-γ in the PVN. PVN treatment with TEL attenuated MAP, improved cardiac hypertrophy, reduced TNF-α, IL-1ß, IL-6, iNOS levels, and plasma NE in SHR but not in WKY rats. These results were associated with reduced TLR4, MyD88 and NF-κB levels and increased PPAR-γ level in the PVN of hypertensive rats. Our findings suggest that TLR4/MyD88/NF-κB signaling and PPAR-γ within the PVN are involved in the beneficial effects of telmisartan in hypertension.

Plasma Renalase is Not Associated with Blood Pressure and Brachial-Ankle Pulse Wave Velocity in Chinese Adults With Normal Renal Function.

BACKGROUND/AIMS: This study aimed to investigate the association of renalase with blood pressure (BP) and brachial-ankle pulse wave velocity (baPWV) in order to better understand the role of renalase in the pathogenesis of hypertension and atherosclerosis. METHODS: A total of 344 subjects with normal kidney function were recruited from our previously established cohort in Shaanxi Province, China. They were divided into the normotensive (NT) and hypertensive (HT) groups or high baPWV and normal baPWV on the basis of BP levels or baPWV measured with an automatic waveform analyzer. Plasma renalase was determined through an enzyme-linked immunosorbent assay. RESULTS: Plasma renalase did not significantly differ between HT and NT groups (3.71 ± 0.69 µg/mL vs. 3.72 ± 0.73 µg/mL, P = 0.905) and between subjects with and without high baPWV (3.67 ± 0.66 µg/mL vs. 3.73 ± 0.74 µg/mL, P = 0.505). However, baPWV was significantly higher in the HT group than in the NT group (1460.4 ± 236.7 vs. 1240.7 ± 174.5 cm/s, P < 0.001). Plasma renalase was not correlated with BP levels and baPWV in the entire group. Linear and logistic regression analysis revealed that plasma renalase was not significantly associated with hypertension and high baPWV. CONCLUSION: Plasma renalase may not be associated with BP and baPWV in Chinese subjects with normal renal function.

New Thymoquinol Glycosides and Neuroprotective Dibenzocyclooctane Lignans from the Rattan Stems of Schisandra chinensis.

Three new lignans (1 - 3), together with four new thymoquinol glycosides (4 - 7), were isolated from 70%-EtOH extract of the rattan stems of Schisandra chinensis. The structures of 1 - 7 were elucidated by detailed spectroscopic analyses, and these new compounds were identified as pinobatol-9-O-ß-d-glucopyranoside (1), 1,2,13,14-tetramethoxydibenzocyclooctadiene 3,12-O-ß-d-diglucopyranoside (2), 3,7-dihydroxy-1,2,13,14-tetramethoxydibenzocyclooctadiene 12-O-ß-d-glucopyranoside (3), thymoquinol 2-O-ß-d-apiofuranosyl-(1→6)-ß-d-glucopyranoside (4), thymoquinol 2-O-α-d-arabinofuranosyl-(1→6)-ß-d-glucopyranoside (5), thymoquinol 5-O-ß-d-apiofuranosyl-(1→6)-ß-d-glucopyranoside (6), and thymoquinol 5-O-α-d-arabinofuranosyl-(1→6)-ß-d-glucopyranoside (7). The neuroprotective activity of 1 - 7 was evaluated on PC12 cells with neurotoxicity induced by amyloid-beta 1 - 42 (Aß1 - 42 ). Compounds 2 and 3 showed protecting activity against Aß-induced toxicity in PC12 cells.

High Salt Diet Affects Renal Sodium Excretion and ERRα Expression.

Kidneys regulate the balance of water and sodium and therefore are related to blood pressure. It is unclear whether estrogen-related receptor α (ERRα), an orphan nuclear receptor and transcription factor highly expressed in kidneys, affects the reabsorption of water and sodium. The aim of this study was to determine whether changes in the expressions of ERRα, Na⁺/K⁺-ATPase and epithelial sodium channel (ENaC) proteins affected the reabsorption of water and sodium in kidneys of Dahl salt-sensitive (DS) rats. SS.13BN rats, 98% homologous to the DS rats, were used as a normotensive control group. The 24 h urinary sodium excretion of the DS and SS.13BN rats increased after the 6-week high salt diet intervention, while sodium excretion was increased in DS rats with daidzein (agonist of ERRα) treatment. ERRα expression was decreased, while ß- and γ-ENaC mRNA expressions were increased upon high sodium diet treatment in the DS rats. In the chromatin immunoprecipitation (CHIP) assay, positive PCR signals were obtained in samples treated with anti-ERRα antibody. The transcriptional activity of ERRα was decreased upon high salt diet intervention. ERRα reduced the expressions of ß- and γ-ENaC by binding to the ENaC promoter, thereby increased Na+ reabsorption. Therefore, ERRα might be one of the factors causing salt-sensitive hypertension.

Endothelial cell-specific liver kinase B1 deletion causes endothelial dysfunction and hypertension in mice in vivo.

BACKGROUND: Liver kinase B1 (LKB1), a tumor suppressor, is a central regulator of cell polarity and energy homeostasis. The role of LKB1 in endothelial function in vivo has not been explored. METHODS AND RESULTS: Endothelium-specific LKB1 knockout (LKB1(endo-/-)) mice were generated by cross-breeding LKB1(flox/flox) mice with VE-Cadherin-Cre mice. LKB1(endo-/-) mice exhibited hypertension, cardiac hypertrophy, and impaired endothelium-dependent relaxation. LKB1(endo-/-) endothelial cells exhibited reduced endothelial nitric oxide synthase activity and AMP kinase (a downstream enzyme of LKB1) phosphorylation at Thr172 compared with wild-type (WT) cells. In addition, the levels of caveolin-1 were higher in the endothelial cells of LKB1(endo-/-) mice, and knockdown of caveolin-1 by siRNA normalized endothelial nitric oxide synthase activity. Human antigen R bound with the adenylate-uridylate-rich elements of caveolin-1 mRNA 3' untranslated region, resulting in the increased stability of caveolin-1, and genetic knockdown of human antigen R decreased the expression of caveolin-1 in LKB1-deficient endothelial cells. Finally, adenoviral overexpression of constitutively active AMP kinase, but not green fluorescent protein, decreased caveolin-1, lowered blood pressure, and improved endothelial function in LKB1(endo-/-) mice in vivo. CONCLUSIONS: Our findings indicate that endothelial LKB1 regulates endothelial nitric oxide synthase activity, endothelial function, and blood pressure by modulating AMP kinase-mediated caveolin-1 expression.

Curcumin retunes cholesterol transport homeostasis and inflammation response in M1 macrophage to prevent atherosclerosis.

Lipoprotein cholesterol metabolism dysfunction in the arterial wall is a major contributor to atherosclerosis, and excessive lipid intake and failed cholesterol homeostasis may accelerate the atherogenic process. Curcumin exerts multiple effects by alleviating inflammation, hyperlipidemia, and atherosclerosis; however, its role in cholesterol transport homeostasis and its underlying impact on inflammatory M1 macrophages are poorly understood. This work aimed to investigate the effect of curcumin on cholesterol transport, the inflammatory response and cell apoptosis in M1 macrophages. RAW264.7 macrophages (M0) were induced with LPS plus IFN-γ for 12 h to develop a M1 subtype and were then incubated with curcumin at different concentrations (6.25 and 12.5 µmol/L) in the presence or absence of oxLDL. Then, cholesterol influx/efflux and foam cell formation as well as inflammation and apoptosis were evaluated. It was found that curcumin increased cholesterol uptake measured by the Dil-oxLDL binding assay, and simultaneously increased cholesterol efflux carried out by Apo-A1 and HDL in M1 cells. Curcumin further reinforced ox-LDL-induced cholesterol esterification and foam cell formation as determined by Oil Red O and BODIPY staining. Moreover, curcumin dramatically reduced ox-LDL-induced cytokine production such as IL-1ß, IL-6 as well as TNF-α and M1 cell apoptosis. We also found that curcumin upregulated CD36 and ABCA1 in M1 macrophages. Curcumin increased PPARγ expression, which in turn promoted CD36 and ABCA1 expression. In conclusion, curcumin may increase the ability of M1 macrophages to handle harmful lipids, thus promoting lipid processing, disposal and removal, which may support cholesterol homeostasis and exert an anti-atherosclerotic effect.