Novel Angiogenesis Role of GLP-1(32-36) to Rescue Diabetic Ischemic Lower Limbs via GLP-1R-Dependent Glycolysis in Mice.

BACKGROUND: Restoring the capacity of endothelial progenitor cells (EPCs) to promote angiogenesis is the major therapeutic strategy of diabetic peripheral artery disease. The aim of this study was to investigate the effects of GLP-1 (glucagon-like peptide 1; 32-36)-an end product of GLP-1-on angiogenesis of EPCs and T1DM (type 1 diabetes) mice, as well as its interaction with the classical GLP-1R (GLP-1 receptor) pathway and its effect on mitochondrial metabolism. METHODS: In in vivo experiments, we conducted streptozocin-induced type 1 diabetic mice as a murine model of unilateral hind limb ischemia to examine the therapeutic potential of GLP-1(32-36) on angiogenesis. We also generated Glp1r-/- mice to detect whether GLP-1R is required for angiogenic function of GLP-1(32-36). In in vitro experiments, EPCs isolated from the mouse bone marrow and human umbilical cord blood samples were used to detect GLP-1(32-36)-mediated angiogenic capability under high glucose treatment. RESULTS: We demonstrated that GLP-1(32-36) did not affect insulin secretion but could significantly rescue angiogenic function and blood perfusion in ischemic limb of streptozocin-induced T1DM mice, a function similar to its parental GLP-1. We also found that GLP-1(32-36) promotes angiogenesis in EPCs exposed to high glucose. Specifically, GLP-1(32-36) has a causal role in improving fragile mitochondrial function and metabolism via the GLP-1R-mediated pathway. We further demonstrated that GLP-1(32-36) rescued diabetic ischemic lower limbs by activating the GLP-1R-dependent eNOS (endothelial NO synthase)/cGMP/PKG (protein kinase G) pathway. CONCLUSIONS: Our study provides a novel mechanism with which GLP-1(32-36) acts in modulating metabolic reprogramming toward glycolytic flux in partnership with GLP-1R for improved angiogenesis in high glucose-exposed EPCs and T1DM murine models. We propose that GLP-1(32-36) could be used as a monotherapy or add-on therapy with existing treatments for peripheral artery disease. REGISTRATION: URL: www.ebi.ac.uk/metabolights/; Unique identifier: MTBLS9543.

Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in psoriasis: a systematic review and meta-analysis.

Psoriasis is a chronic, inflammatory skin disorder characterized by well-demarcated erythematous lesions with surface scaling. The disease is underpinned by a dysregulated immune response with a shift in the balance of neutrophils, lymphocytes and platelets. We sought to evaluate the novel systemic inflammatory markers, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), as psoriatic indicators. Pubmed, Web of Science and Scopus were systematically searched for relevant studies. Twenty-four studies consisting of a total of 2,275 psoriatic patients (1,301 males and 974 females) and 2,334 healthy controls (1,401 males and 933 females) were identified for inclusion in the quantitative analysis. The NLR and PLR were found to be significantly increased in psoriatic patients [standardized mean difference (SMD) = 0.68, 95% CI 0.56-0.80, p < 0.01, and SMD = 0.37, 95% CI 0.14-0.60, p < 0.01, respectively]. However, no association between the NLR and PLR with psoriasis severity was detected (p = 0.93, and p = 0.83, respectively). In conclusion, the NLR and PLR are simple and cost-effective markers of psoriatic presence, but their value as severity markers requires further study.

Neuroprotective effect of chrysophanol in Alzheimer disease via modulating the Ca2+/EGFR-PLCγ pathway.

Chrysophanol (CHR) is an anthraquinone compound found in rhubarb, and it possesses neuroprotective properties. The purpose of this study was to gain a better understanding of its role in Alzheimer's disease (AD). In vivo study, D-galactose combined with intracerebral injection of ß-protein 25-35(Aß25-35) were used to establish AD model rats. In vitro study, Aß25-35 was used to induce AD model cells. Our results indicated that CHR improves learning and memory in AD model rats and provides protection against neuronal damage in both AD model rats and cells. Additionally, we observed that CHR suppressed the protein expression of p-tau, EGFR, PLCγ, IP3R, and CAM, as well as the mRNA levels of tau, EGFR, PLCγ, IP3R, and CAM. Furthermore, we have confirmed that CHR inhibited the fluorescence expression of calcium ions (Ca2+). In conclusion, the CHR may exert neuroprotective effects in AD by reducing tau phosphorylation through the Ca2+/EGFR-PLCγ pathway.

Special electromyographic features in a child with paramyotonia congenita: A case report and review of literature.

BACKGROUND: Paramyotonia congenita (PMC) stands as a rare sodium channelopaty of skeletal muscle, initially identified by Eulenburg. The identification of PMC often relies on electromyography (EMG), a diagnostic technique. The child's needle EMG unveiled trains of myotonic discharges with notably giant amplitudes, alongside irregular wave trains of myotonic discharges. This distinctive observation had not surfaced in earlier studies. CASE SUMMARY: We report the case of a 3-year-old female child with PMC, who exhibited laryngeal stridor, muffled speech, myotonia from birth. Cold, exposure to cool water, crying, and physical activity exacerbated the myotonia, which was relieved in warmth, yet never normalized. Percussion myotonia was observable in bilateral biceps. Myotonia symptoms remained unchanged after potassium-rich food consumption like bananas. Hyperkalemic periodic paralysis was excluded. Cranial magnetic resonance imaging yielded normal results. Blood potassium remained within normal range, while creatine kinase showed slight elevation. Exome-wide genetic testing pinpointed a heterozygous mutation on chromosome SCN4A: c.3917G>A (p.G1306E). After a six-month mexiletine regimen, symptoms alleviated. CONCLUSION: In this case revealed the two types of myotonic discharges, and had not been documented in other studies. We underscore two distinctive features: Giant-amplitude potentials and irregular waves.

Synthesis and biological activity evaluation of phthalimide-donepezil hybrids / 药学学报

A series of phthalimide-donepezil (PTA-DPZ) hybrids (5a-e, 6a-l) were designed, synthesized and evaluated as selective inhibitors of acetylcholinesterase (AChE). The results showed that some hybrids had strong AChE inhibitory activity with half maximal inhibitory concentration (IC50) at nanomolar range, which was better than the control drugs galanthamine and tacrine, and equivalent to DPZ. Compound 6k exhibited the strongest inhibition to AChE with an IC50 value of 0.13 μmol·L-1. Kinetic and molecular modeling studies showed that 6k targeted both catalytic active site and peripheral anionic site of AChE. Moreover, some compounds could inhibit AChE-induced β-amyloid (Aβ) aggregation. In addition, absorption, distribution, metabolism and excretion prediction results showed 6k conforms to the Lipinski's rule of five and had high partition coefficient P value. These compounds, especially 6k, may be considered as a dual-functional lead compound for in-depth research.

[Huangdi Anxiao Capsules-containing serum protects cell model from cognitive dysfunction in diabetes via inhibiting NLRP3-mediated pyroptosis].

This study aims to investigate the effects and the molecular mechanism of Huangdi Anxiao Capsules(HDAX)-containing serum in protecting the rat adrenal pheochromocytoma(PC12) cells from diabetes-associated cognitive dysfunction induced by high glucose and whether the mechanism is related to the regulation of NOD-like receptor thermal protein domain associated protein 3(NLRP3)-mediated pyroptosis. The PC12 cell model of diabetes-associated cognitive dysfunction induced by high glucose was established and mcc950 was used to inhibit NLRP3. PC12 cells were randomized into control, model, HDAX-containing serum, mcc950, and HDAX-containing serum+mcc950 groups. Methyl thiazolyl tetrazolium(MTT) assay was employed to determine the viability, and Hoechst 33258/PI staining to detect pyroptosis of PC12 cells. Enzyme-linked immunosorbent assay(ELISA) was employed to measure the levels of interleukin-1 beta(IL-1ß) and IL-18. Western blot was employed to determine the protein levels of postsynaptic density protein 95(PSD-95), NLRP3, apoptosis-associated speck-like protein containing a CARD(ASC), gasdermin D(GSDMD), GSDMD-N, and cleaved cysteinyl aspartate specific proteinase-1(caspase-1), and RT-PCR to determine the mRNA levels of NLRP3, ASC, GSDMD, and caspase-1. The immunofluorescence assay was adopted to measure the levels and distribution of NLRP3 and GSDMD-N in PC12 cells. Compared with the control group, the model group showed decreased cell proliferation, increased PI positive rate, down-regulated protein level of PSD-95, up-regulated protein levels of NLRP3, ASC, GSDMD-N, GSDMD, and cleaved caspase-1, up-regulated mRNA levels of NLRP3, ASC, GSDMD, and caspase-1, and elevated levels of IL-1ß and IL-18. Compared with the model group, HDAX-containing serum, mcc950, and the combination of them improved cell survival rate and morphology, decreased the PI positive rate, down-regulated the protein levels of NLRP3, ASC, GSDMD-N, GSDMD, and cleaved caspase-1 and the mRNA levels of NLRP3, ASC, GSDMD, and caspase-1, and promoted the secretion of IL-1ß and IL-18. The findings demonstrated that HDAX-containing serum can inhibit the pyroptosis-mediated by NLRP3 and protect PC12 cells from the cognitive dysfunction induced by high glucose.

Systematic in vivo candidate evaluation uncovers therapeutic targets for LMNA dilated cardiomyopathy and risk of Lamin A toxicity.

BACKGROUND: Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease which ultimately results in heart failure (HF). Decades of research on DCM have revealed diverse aetiologies. Among them, familial DCM is the major form of DCM, with pathogenic variants in LMNA being the second most common form of autosomal dominant DCM. LMNA DCM is a multifactorial and complex disease with no specific treatment thus far. Many studies have demonstrated that perturbing candidates related to various dysregulated pathways ameliorate LMNA DCM. However, it is unknown whether these candidates could serve as potential therapeutic targets especially in long term efficacy. METHODS: We evaluated 14 potential candidates including Lmna gene products (Lamin A and Lamin C), key signaling pathways (Tgfß/Smad, mTor and Fgf/Mapk), calcium handling, proliferation regulators and modifiers of LINC complex function in a cardiac specific Lmna DCM model. Positive candidates for improved cardiac function were further assessed by survival analysis. Suppressive roles and mechanisms of these candidates in ameliorating Lmna DCM were dissected by comparing marker gene expression, Tgfß signaling pathway activation, fibrosis, inflammation, proliferation and DNA damage. Furthermore, transcriptome profiling compared the differences between Lamin A and Lamin C treatment. RESULTS: Cardiac function was restored by several positive candidates (Smad3, Yy1, Bmp7, Ctgf, aYAP1, Sun1, Lamin A, and Lamin C), which significantly correlated with suppression of HF/fibrosis marker expression and cardiac fibrosis in Lmna DCM. Lamin C or Sun1 shRNA administration achieved consistent, prolonged survival which highly correlated with reduced heart inflammation and DNA damage. Importantly, Lamin A treatment improved but could not reproduce long term survival, and Lamin A administration to healthy hearts itself induced DCM. Mechanistically, we identified this lapse as caused by a dose-dependent toxicity of Lamin A, which was independent from its maturation. CONCLUSIONS: In vivo candidate evaluation revealed that supplementation of Lamin C or knockdown of Sun1 significantly suppressed Lmna DCM and achieve prolonged survival. Conversely, Lamin A supplementation did not rescue long term survival and may impart detrimental cardiotoxicity risk. This study highlights a potential of advancing Lamin C and Sun1 as therapeutic targets for the treatment of LMNA DCM.

Phenotypic Switching of Vascular Smooth Muscle Cells in Atherosclerosis.

The medial layer of the arterial wall is composed mainly of vascular smooth muscle cells (VSMCs). Under physiological conditions, VSMCs assume a contractile phenotype, and their primary function is to regulate vascular tone. In contrast with terminally differentiated cells, VSMCs possess phenotypic plasticity, capable of transitioning into other cellular phenotypes in response to changes in the vascular environment. Recent research has shown that VSMC phenotypic switching participates in the pathogenesis of atherosclerosis, where the various types of dedifferentiated VSMCs accumulate in the atherosclerotic lesion and participate in the associated vascular remodeling by secreting extracellular matrix proteins and proteases. This review article discusses the 9 VSMC phenotypes that have been reported in atherosclerotic lesions and classifies them into differentiated VSMCs, intermediately dedifferentiated VSMCs, and dedifferentiated VSMCs. It also provides an overview of several methodologies that have been developed for studying VSMC phenotypic switching and discusses their respective advantages and limitations.

Lipidomics Profiling Reveals Serum Phospholipids Associated with Albuminuria in Early Type 2 Diabetic Kidney Disease.

Early screening and administration of DKD are beneficial for renal outcomes of type 2 diabetic patients. However, the current early diagnosis using the albuminuria/creatine ratio (ACR) contains limitations. This study aimed to compare serum lipidome variation between type 2 diabetes and early DKD patients with increased albuminuria through an untargeted lipidomics method to explore the potential lipid biomarkers for DKD identification. 92 type 2 diabetic patients were enrolled and divided into two groups: DM group (ACR < 3 mg/mmol, n = 49) and early DKD group (3 mg/mmol ≤ ACR < 30 mg/mmol, n = 43). Fasting serum was analyzed through an ultraperformance liquid mass spectrometry tandem chromatography system (LC-MS). Orthogonal partial least-squares discriminant analysis (OPLS-DA) and univariate and multivariate analysis were performed to filter differentially depressed lipids. Receiver operating characteristic (ROC) curves were used to estimate the diagnostic capability of potential lipid biomarkers. We found that serum phospholipids including phosphatidylserine (PS), sphingomyelin (SM), and phosphatidylcholine (PC) were significantly upregulated in the DKD group and were highly correlated with the ACR. In addition, a panel of two phospholipids including PS(27:0)-H and PS(30:2e)-H showed good performance to help clinical lipids in early DKD identification, which increased the area under the curve (AUC) from 0.568 to 0.954. The study exhibited the serum lipidome variation in early DKD patients, and the increased phospholipids might participate in the development of albuminuria. The panel of PS(27:0)-H and PS(30:2e)-H could be a potential biomarker for DKD diagnosis.

Comparison of micronutrients in adult enteral formulas widely used in clinical practice.

In recent decades, great progress in the area of enteral nutrition has provided a large variety and commercial availability of enteral formulas, usually produced by the nutrition divisions of several pharmaceutical or dairy manufacturers, with specific compositions for each type of disease or patient condition. Despite the widespread use of enteral formulas, both in hospitals and at home, studies performed on the micronutrient compositions of adult enteral formulas are few in China. The content of micronutrients in 31 commercially available adult enteral formulas in the Chinese market was compared with the Chinese dietary reference intakes (DRIs), the tolerable upper limits (UL), the limit requirements in Food Safety National Standards General Rules of Foods for Special Medical Purposes (GB 29922-2013), and the European Society for Clinical Nutrition and Metabolism (ESPEN) micronutrient guideline (2022). The micronutrient content was calculated by multiplying the value provided on the nutrition label for each product by the daily energy dose of 1500 and 1800 Kcal/day. The research results showed that most adult enteral formulas were generally suitable for patients on long-term total enteral nutrition support in the Chinese market, and foods for special medical purpose (FSMP) formulas were more suitable than enteral nutrition preparation (ENP) formulas. However, the vitamin D, vitamin K, and iron content in these formulas should be appropriately increased to the limit recommended by the ESPEN micronutrient guideline. The results could provide a basis for manufacturers to research and develop more suitable enteral formulas and help clinical dietitians administer more effective enteral nutrition support for patients on long-term total enteral nutrition in clinical practice, especially individualized treatment.

Investigating the Clinical Value of Novel Kidney Injury Inflammatory Biomarkers in Snakebite Victims.

OBJECTIVE: The expression of vascular endothelial growth factor-A (VEGF-A) in snakebite patients, its value in patient prognosis and the correlation of VEGF-A with renal function were analysed. METHODS: A total of 124 snakebite patients admitted from January 2019 to January 2021 were retrospectively analysed and included in the observation group, and 40 healthy individuals who underwent physical examination in the same hospital within the same period were included in the control group. The t-test was used in analysing differences between the serum VEGF-A levels of the observation and control groups and changes in VEGF-A and renal function indices before and after treatment in the observation group. The effects of treatment on each patient in the observation group were evaluated, and the patients were divided into improved and unimproved groups according to the post-treatment condition. The predictive value of VEGF-A and renal function indices in patients in the improved and unimproved groups and their efficacy for snakebite patients were analysed through receiver operating characteristic (ROC) analysis. Finally, correlation analysis was used in evaluating the correlation between VEGF-A and renal function indices. RESULTS: VEGF-A was significantly higher in patients in the observation group (339.66 ± 97.72 pg/mL) than in patients in the control group (52.41 ± 8.93 pg/mL; p < 0.001). VEGF-A and renal function indices in the serum of patients were significantly lower after treatment than those before treatment (p < 0.0001). According to efficacy, the patients were divided into improved group (n = 102) and unimproved group (n = 22). The pre-treatment VEGF-A levels were significantly lower in patients in the improved group (318.47 ± 90.80 pg/mL) than in patients in the unimproved group (437.88 ± 63.16 pg/mL; p < 0.001). ROC curve analysis revealed that the area under the curve for VEGF-A in predicting patient treatment efficacy was 0.886, and VEGF-A was positively correlated with blood urea nitrogen, creatinine and cystin C but negatively correlated with glomerular filtration rate (p < 0.001). CONCLUSIONS: VEGF-A was highly expressed in snakebite patients and can be used as an observational indicator for predicting the prognosis of snakebite patients.

ELABELA/APJ Axis Prevents Diabetic Glomerular Endothelial Injury by Regulating AMPK/NLRP3 Pathway.

ELABELA (ELA), a recently discovered peptide, is highly expressed in adult kidneys and the endothelium system. It has been identified as a novel endogenous ligand for the apelin receptor (APJ). This study aims to investigate the role of ELA in diabetic glomerular endothelial pyroptosis and its underlying mechanism. Initially, a significant decrease in ELA mRNA levels was observed in the renal cortex of db/db mice and high glucose-treated glomerular endothelial cells (GECs). It was also found that ELA deficiency in ELA+/- mice significantly accelerated diabetic glomerular injury, as shown by exacerbated glomerular morphological damage, increased serum creatine and blood urea nitrogen, and elevated 24-h urinary albumin excretion. In addition, in vivo overexpression of ELA prevented diabetic glomerular injury, reduced von Willebrand factor expression, restored endothelial marker CD31 expression, and attenuated the production of adhesive molecules such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Furthermore, in vitro studies confirmed that treatment with ELA inhibited GEC injury by regulating the NOD-like receptor protein 3 (NLRP3) inflammasome, as indicated by blocking NLRP3 inflammasome formation, decreasing cleaved Caspase-1 production, and inhibiting interleukin-1ß and interleukin-18 production. Moreover, in vitro experiments demonstrated that the protective effects of ELA in GECs during hyperglycemia were diminished by inhibiting adenosine monophosphate-activated protein kinase (AMPK) using Compound C or by APJ deficiency. Taken together, this study provides the first evidence that ELA treatment could prevent diabetic glomerular endothelial injury, which is partly mediated by the regulation of the AMPK/NLRP3 signaling pathway. Therefore, pharmacologically targeting ELA may serve as a novel therapeutic strategy for diabetic kidney disease.

LncRNA RP4-639F20.1 interacts with THRAP3 to attenuate atherosclerosis by regulating c-FOS in vascular smooth muscle cells proliferation and migration.

BACKGROUND AND AIMS: The aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) play an essential role in the pathogenesis of atherosclerosis (AS). Long noncoding RNAs (lncRNAs) have been reported as important regulators in a number of diseases. However, very little is known regarding the functional role of lncRNAs in governing proliferation and migration of VSMCs and AS development. METHODS: Both in vitro and in vivo assays were performed to investigate the role of lncRNA in the pathophysiology of AS. Our previous lncRNA arrays revealed that lncRNA RP4-639F20.1 was significantly decreased in atherosclerotic plaques. Lentivirus overexpressing RP4-639F20.1 and lncRNA RP4-639F20.1 silencing vectors (Si-lnc-RP4-639F20.1) were constructed and transfected in VSMCs. The in vitro functions of lncRNA were analyzed by CCK-8 assays, EdU assays, scratch wound assays, transwell assays, qRT-PCR and Western blot analyses. RNA fluorescence in situ hybridization, immunoprecipitation and mRNA microarrays were used to explore the underlying mechanism. Adeno-associated-virus-9 (AAV9) overexpressing RP4-639F20.1 was constructed and injected intravenously into ApoE-/- mice to explore the role of lncRNA in vivo. RESULTS: In vitro experiments showed that lncRNA RP4-639F20.1 interacted with THRAP3 and downregulated c-FOS expression. Both increase of lncRNA RP4-639F20.1 expression and knockdown of c-FOS inhibited the expression of MMP10 and VEGF-α in VSMCs and suppressed VSMCs proliferation and migration. In vivo experiments using ApoE-/- mice fed a high-fat diet demonstrated that lncRNA RP4-639F20.1 overexpression deterred atherosclerosis and decreased lipid levels in atherosclerotic lesions. Patients with coronary artery disease were found to have higher c-FOS levels than healthy individuals and c-FOS expression was positively correlated with the SYNTAX score of patients. CONCLUSIONS: Overall, these data indicated that lncRNA RP4-639F20.1/THRAP3/c-FOS pathway protects against the development of atherosclerosis by suppressing VSMCs proliferation and migration. LncRNA RP4-639F20.1 and c-FOS could represent potential therapeutic targets to ameliorate atherosclerosis-related diseases.

Investigating the Clinical Value of Novel Kidney Injury Inflammatory Biomarkers in Snakebite Victims

Objective: The expression of vascular endothelial growth factor-A (VEGF-A) in snakebite patients, its value in patient prognosis and the correlation of VEGF-A with renal function were analysed. Methods: A total of 124 snakebite patients admitted from January 2019 to January 2021 were retrospectively analysed and included in the observation group, and 40 healthy individuals who underwent physical examination in the same hospital within the same period were included in the control group. The t-test was used in analysing differences between the serum VEGF-A levels of the observation and control groups and changes in VEGF-A and renal function indices before and after treatment in the observation group. The effects of treatment on each patient in the observation group were evaluated, and the patients were divided into improved and unimproved groups according to the post-treatment condition. The predictive value of VEGF-A and renal function indices in patients in the improved and unimproved groups and their efficacy for snakebite patients were analysed through receiver operating characteristic (ROC) analysis. Finally, correlation analysis was used in evaluating the correlation between VEGF-A and renal function indices. Results: VEGF-A was significantly higher in patients in the observation group (339.66 ± 97.72 pg/mL) than in patients in the control group (52.41 ± 8.93 pg/mL; p < 0.001). VEGF-A and renal function indices in the serum of patients were significantly lower after treatment than those before treatment (p < 0.0001). According to efficacy, the patients were divided into improved group (n = 102) and unimproved group (n = 22). The pre-treatment VEGF-A levels were significantly lower in patients in the improved group (318.47 ± 90.80 pg/mL) than in patients in the unimproved group (437.88 ± 63.16 pg/mL; p < 0.001) (AU)

In-depth urinary and exosome proteome profiling analysis identifies novel biomarkers for diabetic kidney disease.

Diabetic kidney disease (DKD) is a major microvascular complication of type 2 diabetes mellitus (T2DM). Monitoring the early diagnostic period and disease progression plays a crucial role in treating DKD. In this study, to comprehensively elucidate the molecular characteristics of urinary proteins and urinary exosome proteins in type 2 DKD, we performed large-scale urinary proteomics (n=144) and urinary exosome proteomics (n=44) analyses on T2DM patients with albuminuria in varying degrees. The dynamics analysis of the urinary and exosome proteomes in our study provides a valuable resource for discovering potential urinary biomarkers in patients with DKD. A series of potential biomarkers, such as SERPINA1 and transferrin (TF), were detected and validated to be used for DKD diagnosis or disease monitoring. The results of our study comprehensively elucidated the changes in the urinary proteome and revealed several potential biomarkers reflecting the progression of DKD, which provide a reference for DKD biomarker screening.

Allele-Specific Epigenetic Regulation of FURIN Expression at a Coronary Artery Disease Susceptibility Locus.

Genome-wide association studies have revealed an association between the genetic variant rs17514846 in the FURIN gene and coronary artery disease. We investigated the mechanism through which rs17514846 modulates FURIN expression. An analysis of isogenic monocytic cell lines showed that the cells of the rs17514846 A/A genotype expressed higher levels of FURIN than cells of the C/C genotype. Pyrosequencing showed that the cytosine (in a CpG motif) at the rs17514846 position on the C allele was methylated. Treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine increased FURIN expression. An electrophoretic mobility super-shift assay with a probe corresponding to the DNA sequence at and around the rs17514846 position of the C allele detected DNA-protein complex bands that were altered by an anti-MeCP2 antibody. A chromatin immunoprecipitation assay with the anti-MeCP2 antibody showed an enrichment of the DNA sequence containing the rs17514846 site. siRNA-mediated knockdown of MeCP2 caused an increase in FURIN expression. Furthermore, MeCP2 knockdown increased monocyte migration and proliferation, and this effect was diminished by a FURIN inhibitor. The results of our study suggest that DNA methylation inhibits FURIN expression and that the coronary artery disease-predisposing variant rs17514846 modulates FURIN expression and monocyte migration via an allele-specific effect on DNA methylation.

Effect of probiotic supplementation on in-hospital mortality in patients with acute myocardial infarction: a study protocol for an open-label, randomized, controlled, superiority clinical trial.

BACKGROUND: Recent studies have demonstrated a correlation between intestinal flora and the severity of myocardial infarction as well as post-myocardial infarction repair. However, few studies have investigated whether probiotics reduce mortality and improve cardiovascular outcomes in patients with acute myocardial infarction. In this study, we will conduct a randomized controlled trial (RCT) to evaluate the effect of probiotics on in-hospital mortality and the incidence of major adverse cardiovascular events (MACE) in patients with acute myocardial infarction (AMI). METHODS: This is an open-label, randomized, controlled, superiority clinical trial involving 2594 adult patients who were diagnosed with acute myocardial infarction. Patients will be randomized to (1) receive bifidobacteria triple viable capsule (Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis) 840 mg, twice a day, plus standard treatment strategy during the hospital stay, for a maximum of 30 days, or (2) receive the standard treatment strategy and will not take the bifidobacterium triple live capsule. The primary outcome was in-hospital all-cause mortality. DISCUSSION: The purpose of this clinical trial is to determine whether probiotics can reduce in-hospital mortality and improve prognosis in patients with AMI, and the results will provide evidence for probiotics as a complementary treatment for AMI. TRIAL REGISTRATION: Chinese Clinical Trials Registry ChiCTR2000038797. Registered on 2 October 2020.

Probing Two Driven Double Quantum Dots Strongly Coupled to a Cavity.

We experimentally and theoretically study a driven hybrid circuit quantum electrodynamics (cQED) system beyond the dispersive coupling regime. Treating the cavity as part of the driven system, we develop a theory applicable to such strongly coupled and to multiqubit systems. The fringes measured for a single driven double quantum dot (DQD)-cavity setting and the enlarged splittings of the hybrid Floquet states in the presence of a second DQD are well reproduced with our model. This opens a path to study Floquet states of multiqubit systems with arbitrarily strong coupling and reveals a new perspective for understanding strongly driven hybrid systems.