Prognostic implications of machine learning-derived echocardiographic phenotypes in community hypertensive patients.

BACKGROUND: Echocardiogram is commonly used to evaluate cardiac remodeling in hypertension (HTN). However, study on echocardiographic phenotypes and their prognostic implications in HTN is limited. OBJECTIVE: We aimed to evaluate the prognostic implications echocardiographic phenotypes in community hypertensive patients. METHOD: A total of 1881 community hypertensive patients without overt cardiovascular disease and severe renal disease (mean age 62.8 years, women 57.9%) were included. Using Two-Step cluster analysis with four conventional echocardiographic variables, two clusters with distinct echocardiographic phenotypes were identified. RESULT: The Cluster 1 (namely "mild-remodeling" HTN; n = 1492) had low prevalence of enlarged left atrium (LA; 0.9%) and left ventricular hypertrophy (LVH; 16.2%) and better LV diastolic function. They were younger and more likely to be men and had lower comorbid burden. The Cluster 2 (namely "severe-remodeling" HTN; n = 389) had higher prevalence of enlarged LA (26.0%) and LVH (83.0%) and worse LV diastolic function. They were older and more likely to be women and had higher comorbid burden. After a median follow-up of 4.2 years, compared to the Cluster 1, the Cluster 2 had higher incidence of cardiovascular (4.1% vs 1.7%; P = .006) and all-cause (9.8% vs 4.8%; P < .001) death, with adjusted hazard ratio of 2.80 (95% CI 1.39-5.62; P = .004) and 2.04 (95% CI 1.32-3.14; P < .001) respectively. CONCLUSION: These findings indicate that the conventional echocardiographic variables-based algorithm could help identify asymptomatic community hypertensive patients at risk for cardiovascular and all-cause death. Further studies are needed to develop and validate phenotype-specific prevention and intervention strategies in HTN.

Repair of double aortic arch in patients with concomitant cardiac anomalies.

BACKGROUND: Double aortic arch (DAA) associated with other cardiac anomalies is uncommon. We review the outcomes of primary complete repair of DAA with concomitant cardiac anomalies in a single center. METHODS: From September 2005 through March 2014, 15 patients underwent primary complete repair of DAA with concomitant cardiac anomalies. The mean age was 53 months (range, two months to 19 years). RESULTS: All patients underwent primary complete correction through a median sternotomy. One patient died in hospital from severe pneumonia. The intubation time ranged from 20 to 68 h and the intensive care unit stay ranged from one day to five days. Postoperative complications were infrequent and included left vocal cord paralysis in one patient. A residual ventricular septal defect was found in one patient. During follow-up, all patients were in New York Heart Association Class I. CONCLUSIONS: Primary complete repair of DAA with concomitant cardiac anomalies is feasible and results in excellent long-term outcomes.

[Detection technologies of microRNA and their prospects for forensic applications].

MicroRNA (miRNA) belongs to a class of small, non-coding RNA molecules that contains 18-25 nucleotides and regulates gene expression at post-transcriptional level. Many miRNAs are highly conserved and display timing- and tissue-specific expression. With the advance of the miRNA detection technologies, miRNA has been introduced to forensic science as a potentially novel set of genetic markers of forensic body fluid identification, species identification and PMI estimation. In this article, the detection methodologies of miRNA are reviewed, and their potential applications in forensic practice and research future are also discussed.

Activation of the osteoblastic HIF-1α pathway partially alleviates the symptoms of STZ-induced type 1 diabetes mellitus via RegIIIγ.

The hypoxia-inducible factor-1α (HIF-1α) pathway coordinates skeletal bone homeostasis and endocrine functions. Activation of the HIF-1α pathway increases glucose uptake by osteoblasts, which reduces blood glucose levels. However, it is unclear whether activating the HIF-1α pathway in osteoblasts can help normalize glucose metabolism under diabetic conditions through its endocrine function. In addition to increasing bone mass and reducing blood glucose levels, activating the HIF-1α pathway by specifically knocking out Von Hippel‒Lindau (Vhl) in osteoblasts partially alleviated the symptoms of streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM), including increased glucose clearance in the diabetic state, protection of pancreatic ß cell from STZ-induced apoptosis, promotion of pancreatic ß cell proliferation, and stimulation of insulin secretion. Further screening of bone-derived factors revealed that islet regeneration-derived protein III gamma (RegIIIγ) is an osteoblast-derived hypoxia-sensing factor critical for protection against STZ-induced T1DM. In addition, we found that iminodiacetic acid deferoxamine (SF-DFO), a compound that mimics hypoxia and targets bone tissue, can alleviate symptoms of STZ-induced T1DM by activating the HIF-1α-RegIIIγ pathway in the skeleton. These data suggest that the osteoblastic HIF-1α-RegIIIγ pathway is a potential target for treating T1DM.

Effects of carvedilol treatment on cardiac cAMP response element binding protein expression and phosphorylation in acute coxsackievirus B3-induced myocarditis.

BACKGROUND: The role of ß-adrenergic stimulation on viral myocarditis has been investigated in animal models of viral myocarditis. Excess stimulation of ß-adrenergic receptors by catecholamines causes phosphorylation/activation of cAMP response element binding protein (CREB) by the cAMP signaling pathway. CREB as an important regulator of gene expression mediates the cardiovascular remodeling process and promotes anti-inflammatory immune responses. However, the CREB expression and phosphorylation have not been studied, and the effects of carvedilol (a nonselective ß-adrenoceptor antagonist) on the CREB has not been investigated in the setting of acute viral myocarditis. METHODS: This study was therefore designed to examine the effects of carvedilol on the transcriptional factor CREB in a murine model of acute viral myocarditis. In a coxsackievirus B3 murine myocarditis model (Balb/c), effects of carvedilol on plasma noradrenaline, heart rate and blood pressure, myocardial histopathological changes and fibrosis, cardiomyocyte apoptosis, cardiac CREB and phosphorylated CREB, cytokine levels, and viral RNA were studied. RESULTS: The expression and phosphorylation of CREB were decreased with concomitant increase of IL-6 and TNF-α in murine coxsackievirus-induced acute viral myocarditis. The levels of IL-6 and TNF-α were correlated with the expression of CREB or phosphorylated CREB. Carvedilol increased the cardiac CREB expression and phosphorylation and decreased the plasma catecholamine levels and the production of IL-6 and TNF-α with amelioration of acute viral myocarditis. CONCLUSION: These results show that CREB may be involved in the pathophysiology of viral myocarditis and carvedilol exerts some of its beneficial effects by increasing the CREB expression and phosphorylation.

The speed of information processing of 9- to 13-year-old intellectually gifted children.

In general, intellectually gifted children perform better than non-gifted children across many domains. The present validation study investigated the speed with which intellectually gifted children process information. 184 children, ages 9 to 13 years old (91 gifted, M age = 10.9 yr., SD = 1.8; 93 non-gifted children, M age = 11.0 yr., SD = 1.7) were tested individually on three information processing tasks: an inspection time task, a choice reaction time task, an abstract matching task. Intellectually gifted children outperformed their non-gifted peers on all three tasks obtaining shorter reaction time and doing so with greater accuracy. The findings supported the validity of the information processing speed in identifying intellectually gifted children.

Chinese version of the stressor scale for emergency nurse: A methodological study design.

AIM: The aim of this study was to modify and test the psychometric properties of the Chinese version of the stressor scale for emergency nurses. DESIGN: The methodological design was carried out in two phases: (a) form the Chinese version by Delphi method and (b) test the psychometric properties by cross-sectional survey. METHODS: The translated scale was administered to 420 nurses in Qingdao. Validity was assessed in terms of content validity, calibration correlation validity and construct validity using exploratory factor analysis and confirmatory factor analysis. Internal consistency was estimated using Cronbach α coefficients. RESULTS: The Chinese version of the SSEN retains 27 items, four common factors were extracted by exploratory factor analysis, and the factor cumulative variance contribution rate was 78.463%. The fitting indexes of the four-factor model of CFA were all in the acceptable range[χ2  = 711.30, df = 312, p < 0.001, χ2 /df = 2.280, CFI = 0.933, TLI = 0.924, IFI = 0.933, RMSEA = 0.079 (90% confidence interval = 0.071-0.086)].The item-level content validity index of the Chinese SSEN is 0.89 ~ 1.00; the scale-level content validity index is 0.98; the Cronbach α coefficient of the total table is 0.971 and the split-half reliability is 0.877. PATIENT OR PUBLIC CONTRIBUTION: The C-SSEN can be used to help nursing managers accurately formulate management measures to improve the stress coping ability of nurses in the ED, stabilize the nursing team and ensure nursing safety.

A cross-sectional study of clinical emergency department nurses' occupational stress, job involvement and team resilience.

INTRODUCTION: The occupational stress of clinical nurses has drawn increasing attention. It has been proven that occupational stress is related to job involvement, and job involvement affects team resilience. However, research on the relationship between emergency nurses' occupational stress, job involvement and team resilience is lacking. AIM: To explore relationships between occupational stress, job involvement, and team resilience among a sample of emergency nurses and determined significant influencing factors of occupational stress in emergency departments. METHODS: In four hospitals in Shandong, China, 187 emergency room nurses participated in a study. The Utrecht Work Engagement Scale, the Chinese version of the Stressors Scale for Emergency Nurses, and a scale for evaluating the team resilience of medical professionals were used to collect data. RESULTS: The overall occupational stress score of nurses working in the emergency departments in Shandong province was 81.07 ± 25.80. The results of Single-factor analysis demonstrated that the scores indicating the occupational stress for emergency nurses differed significantly with respect to age, education level, marital status, children, professional title, work experience and work shift (P < 0.05). Additionally, there is a negative correlation between job involvement and team resilience and occupational stress. Multiple linear regression results showed that the job involvement, team resilience and work shift were statistically significant influencing factors of the level of occupational stress (change R2 = 17.5 %, F = 5.386, P < 0.001). CONCLUSIONS: Stronger team resilience and more active job involvement resulted in lower occupational stress levels experienced by emergency nurses.

Idiopathic premature ventricular contractions and ventricular tachycardias originating from the vicinity of tricuspid annulus: results of radiofrequency catheter ablation in thirty-five patients.

BACKGROUND: In recent years, catheter ablation has increasingly been used for ablation of idiopathic premature ventricular complexes (PVCs) or ventricular tachycardias (IVTs). However, the mapping and catheter ablation of the arrhythmias originating from the vicinity of tricuspid annulus (TA) may not be fully understood. This study aimed to investigate electrophysiologic characteristics and effects of radiofrequency catheter ablation (RFCA) for patients with symptomatic PVCs and IVTs originating from the vicinity of TA. METHODS: Characteristics of body surface electrocardiogram (ECG) and electrophysiologic recordings were analyzed in 35 patients with symptomatic PVCs/ IVTs originating from the vicinity of TA. RFCA was performed using pace mapping and activation mapping. RESULTS: Among the 35 patients with PVCs/IVTs arising from the vicinity of TA, complete elimination of PVCs/IVTs could be achieved by RFCA in 32 patients (success rate 91.43%) during a median follow-up period of 21 months. PVCs/IVTs originating from the vicinity of TA had distinctive ECG characteristics that were useful for identifying the precise origin. An rS pattern was recorded in lead V1 in 93.1% of patients with PVCs/IVTs from the free wall of TA, vs 16.7% of patients with PVCs/IVTs from the septal TA, whereas a QS pattern in lead V1 occurred in 83.3% of patients with PVCs/IVTs from the septal TA vs 6.9% of patients with PVCs from the free wall of the TA. The precordial R wave transition occurred by lead V3 or earlier in all patients with PVCs/IVTs originating from the septal portion of the TA, as compared to transition beyond V3 in all patients with PVCs/IVTs from the free wall of the TA. CONCLUSIONS: RFCA is an effective curative therapy for symptomatic PVCs/IVTs originating from the vicinity of TA. There are specific characteristics in ECG and the ablation site could be located by ECG analysis.

Desferrioxamine alleviates UHMWPE particle-induced osteoclastic osteolysis by inhibiting caspase-1-dependent pyroptosis in osteocytes.

BACKGROUND: Cell death and inflammation are the two important triggers of wear particle-induced osteolysis. Particles, including cobalt-chromium-molybdenum and tricalcium phosphate, have been reported to induce pyroptosis in macrophages and osteocytes. Although macrophage pyroptosis facilitates osteoclastic bone resorption and osteolysis, whether osteocyte pyroptosis is involved in osteoclastic osteolysis still needs further investigation. Desferrioxamine (DFO), an FDA-approved medication and a powerful iron chelator, has been proven to reduce ultrahigh-molecular-weight polyethylene (UHMWPE) particle-induced osteolysis. However, whether DFO can ameliorate UHMWPE particle-induced osteolysis by decreasing pyroptosis in osteocytes is unknown. RESULTS: A mouse calvarial osteolysis model and the mouse osteocyte cell line MLO-Y4 was used, and we found that pyroptosis in osteocytes was significantly induced by UHMWPE particles. Furthermore, our findings uncovered a role of caspase-1-dependent pyroptosis in osteocytes in facilitating osteoclastic osteolysis induced by UHMWPE particles. In addition, we found that DFO could alleviate UHMWPE particle-induced pyroptosis in osteocytes in vivo and in vitro. CONCLUSIONS: We uncovered a role of caspase-1-dependent pyroptosis in osteocytes in facilitating osteoclastic osteolysis induced by UHMWPE particles. Furthermore, we found that DFO alleviated UHMWPE particle-induced osteoclastic osteolysis partly by inhibiting pyroptosis in osteocytes. Schematic of DFO reducing UHMWPE particle-induced osteolysis by inhibiting osteocytic pyroptosis. Wear particles, such as polymers, generated from prosthetic implant materials activate canonical inflammasomes and promote the cleavage and activation of caspase-1. This is followed by caspase-1-dependent IL-ß maturation and GSDMD cleavage. The N-terminal fragment of GSDMD binds to phospholipids on the cell membrane and forms holes in the membrane, resulting in the release of mature IL-ß and inflammatory intracellular contents. This further facilitates osteoclastic differentiation of BMMs, resulting in excessive bone resorption and ultimately leading to prosthetic osteolysis. DFO reduces UHMWPE particle-induced osteolysis by inhibiting osteocytic pyroptosis.

Premature ventricular contractions originating from the left ventricular septum: results of radiofrequency catheter ablation in twenty patients.

BACKGROUND: RFCA has been established as an effective and curative therapy for severely symptomatic PVC from the outflow tract in structurally normal hearts. However, it is unknown whether PVCs originating from the left ventricular septum, are effectively eliminated by RFCA. This study aimed to investigate electrophysiologic characteristics and effects of radiofrequency catheter ablation (RFCA) for patients with symptomatic premature ventricular contraction (PVC) originating from the left ventricular septum without including fascicular PVCs. METHODS: Characteristics of body surface electrocardiogram (ECG) and electrophysiologic recordings endocardiogram in a successful RFCA target were analyzed in 20 patients with symptomatic PVCs originating from the left ventricular septum. RFCA was performed using pace mapping and activation mapping. RESULTS: The QRS morphology of PVCs originating from the left ventricular septum is similar to that seen in fascicular tachycardia. Most of the PVCs originated from the left septum appears in the form of ventricular parasystole. The incidence of ventricular parasystole was 70%. Sustained ventricular tachycardia was not inducible by electrical stimulation and isoproterenol infusion in all 20 patients, ablation at the site recording the earliest Purkinje potential was not effective in all 20 patients, and Purkinje potentials were not identified at successful sites during point mapping. Sixteen patients were successful with RFCA using pace mapping and activation mapping, 3 failed, and 1 recurrent. CONCLUSION: Although the ECG characteristics of the PVCs arising from the left ventricular septum are similar to that seen in fascicular tachycardia, the electrophysiologic characteristics are different between the two types of PVCs. The distinguishing characteristic of the PVCs is that Purkinje potentials were not present at the site of successful ablation, suggesting a myocardial as opposed to fascicular substrate. RFCA is an effective curative therapy for symptomatic PVCs originating from the left ventricular septum (not from the left anterior and posterior fascicle).

Gene variations in autism spectrum disorder are associated with alteration of gut microbiota, metabolites and cytokines.

The genetic variations and dysbiosis of gut microbiota are associated with ASD. However, the role of the microbiota in the etiology of ASD in terms of host genetic susceptibility remains unclear. This study aims to systematically explore the interplay between host genetic variation and gut microbiota in ASD children. Whole-exon sequencing was applied to 26 ASD children and 26 matched controls to identify the single nucleotide variations (SNVs) in ASD. Our previous study revealed alteration in gut microbiota and disorder of metabolism activity in ASD for this cohort. Systematic bioinformatic analyses were further performed to identify associations between SNVs and gut microbiota, as well as their metabolites. The ASD SNVs were significantly enriched in genes associated with innate immune response, protein glycosylation process, and retrograde axonal transport. These SNVs were also correlated with the microbiome composition and a broad aspect of microbial functions, especially metabolism. Additionally, the abundance of metabolites involved in the metabolic network of neurotransmitters was inferred to be causally related to specific SNVs and microbes. Furthermore, our data suggested that the interaction of host genetics and gut microbes may play a crucial role in the immune and metabolism homeostasis of ASD. This study may provide valuable clues to investigate the interaction of host genetic variations and gut microbiota in the pathogenesis of ASD.

Minocycline ameliorates osteoporosis induced by ovariectomy (OVX) and iron accumulation via iron chelation, bone metabolism regulation and inhibition of oxidative stress.

OBJECTIVE: To investigate the effect and mechanism of minocycline on iron accumulation-related postmenopausal osteoporosis. METHODS: The present study established a rat model of ovariectomy (OVX), gave rats ferric ammonium citrate (FAC) and treated them with minocycline, then examined the severity of osteoporosis and iron metabolism in rats. To further explore the mechanism, osteoblasts were treated with FAC and minocycline, then their effects on cell viability, apoptosis, alkaline phosphatase (ALP) activity, bone metabolism proteins, iron metabolism proteins, and oxidative stress in osteoblasts were measured. RESULTS: In the animal study, OVX significantly decreased the serum estradiol level. Both OVX and FAC significantly increased the serum ferritin and tibial iron level, which was significantly decreased by minocycline (P < 0.05). Minocycline significantly increased the ratio of BV/TV, Tb.Th and Tb.N (P < 0.05), and the levels of BALP, BGP and CTX, but decreased the levels of TRAP and ratio of RANKL/OPG (P < 0.05 compared to OVX+FAC group). In the cell study, minocycline significantly decreased the cellular iron accumulation and induced cell death and apoptosis (P < 0.05). Minocycline significantly increased the ALP activity, the expression of Collagen I, Osteocalcin and OPG (P < 0.05). Minocycline significantly decreased the expression of Ferritin and hepcidin, and increased the expression of FPN) (P < 0.05). It also significantly decreased the cellular MD) and protein carbonyl level and RO) intensity, but increased the levels of SO) and GP) (P < 0.05). CONCLUSION: Minocycline ameliorated osteoporosis induced by OVX and iron accumulation. The mechanism may involve iron chelation, regulation of bone and iron metabolism, and inhibition of oxidative stress.

Acute Sleep-Wake Cycle Shift Results in Community Alteration of Human Gut Microbiome.

Disturbances of sleep and the underlying circadian rhythm are related to many human diseases, such as obesity, diabetes, cardiovascular disorders, and cognitive impairments. Dysbiosis of the gut microbiome has also been reported to be associated with the pathologies of these diseases. Therefore, we proposed that disturbed sleep may regulate gut microbiota homeostasis. In this study, we mimicked the sleep-wake cycle shift, one typical type of circadian rhythm disturbances in young people, in recruited subjects. We used 16S rRNA gene amplicon sequencing to define microbial taxa from their fecal samples. Although the relative abundances of the microbes were not significantly altered, the functional-profile analysis of gut microbiota revealed functions enriched during the sleep-wake cycle shift. In addition, the microbial networks were quite distinct among baseline, shift, and recovery stages. These results suggest that an acute sleep-wake cycle shift may exert a limited influence on the gut microbiome, mainly including the functional profiles of the microbes and the microbial relationships within the microbial community.IMPORTANCE Circadian rhythm misalignment due to social jet lag, shift work, early morning starts, and delayed bedtimes is becoming common in our modern society. Disturbances of sleep and the underlying circadian rhythms are related to multiple human diseases, such as obesity, diabetes, cardiovascular disorders, and cognitive impairments. Given the crucial role of microbiota in the same pathologies as are caused by sleep disturbance, how the gut microbiota is affected by sleep is of increasing interest. The results of this study indicate that the acute circadian rhythm disturbance caused by sleep-wake shifts affect the human gut microbiota, especially the functional profiles of gut microbes and interactions among them. Further experiments with a longer-time-scale intervention and larger sample size are needed to assess the effects of chronic circadian rhythm disruption on the gut microbiome and to guide possible microbial therapies for clinical intervention in the related diseases.

Alteration in gut microbiota is associated with dysregulation of cytokines and glucocorticoid therapy in systemic lupus erythematosus.

A growing corpus of evidence implicates the involvement of the commensal microbiota and immune cytokines in the initiation and progression of systemic lupus erythematosus (SLE). Glucocorticoids have been widely used in the treatment of SLE patients, however, glucocorticoid treatment carries a higher risk of other diseases. Using the 16S rRNA technique, we investigated the differences between the gut microbiota associated with the immune cytokines of SLE and relevant glucocorticoid treatment in a female cohort of 20 healthy control subjects (HC), 17 subjects with SLE (SLE-G), and 20 SLE patients having undergone glucocorticoid treatment (SLE+G). We observed that the diversity and structure of the microbial community in SLE+G patients were significantly changed compared to that of SLE-G patients, whereas the gut microbial community of the SLE+G group showed a similarity with the HC group, which implicate that the shift in the gut microbiome could represent a return to homeostasis. Furthermore, the up-regulations of immune cytokines in SLE-G were identified as closely related to gut dysbiosis, which indicates that the overrepresented genera in SLE patients may play roles in regulating expression level of these immune cytokines. This associated analysis of gut microbiota, glucocorticoid therapy, and immune factors might provide novel and insightful clues revealing the pathogenesis of SLE patients.

Altered gut microbial profile is associated with abnormal metabolism activity of Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a severe neurodevelopmental disorder. To enhance the understanding of the gut microbiota structure in ASD children at different ages as well as the relationship between gut microbiota and fecal metabolites, we first used the 16S rRNA sequencing to evaluate the gut microbial population in a cohort of 143 children aged 2-13 years old. We found that the α-diversity of ASD group showed no significant change with age, while the TD group showed increased α-diversity with age, which indicates that the compositional development of the gut microbiota in ASD varies at different ages in ways that are not consistent with TD group. Recent studies have shown that chronic constipation is one of the most commonly obvious gastrointestinal (GI) symptoms along with ASD core symptoms. To further investigate the potential interaction effects between ASD and GI symptoms, the 30 C-ASD and their aged-matched TD were picked out to perform metagenomics analysis. We observed that C-ASD group displayed decreased diversity, depletion of species of Sutterella, Prevotella, and Bacteroides as well as dysregulation of associated metabolism activities, which may involve in the pathogenesis of C-ASD. Consistent with metagenomic analysis, liquid chromatography-mass spectrometry (LC/MS) revealed some of the differential metabolites between C-ASD and TD group were involved in the metabolic network of neurotransmitters including serotonin, dopamine, histidine, and GABA. Furthermore, we found these differences in metabolites were associated with altered abundance of specific bacteria. The study suggested possible future modalities for ASD intervention through targeting the specific bacteria associated with neurotransmitter metabolism.

Anti-renal fibrosis effect of asperulosidic acid via TGF-ß1/smad2/smad3 and NF-κB signaling pathways in a rat model of unilateral ureteral obstruction.

BACKGROUND: Renal fibrosis is the most common pathway leading to end-stage renal disease. It is characterized by excess extracellular matrix (ECM) accumulation and renal tissue damage, subsequently leading to kidney failure. Asperulosidic acid (ASPA), a bioactive iridoid glycoside, exerts anti-tumor, anti-oxidant, and anti-inflammatory activities, but its effects on renal fibrosis induced by unilateral ureteral obstruction (UUO) have not yet been investigated. PURPOSE: This study aimed to investigate the protective effect of ASPA on renal fibrosis induced by UUO, and to explore its pharmacological mechanism. METHODS: Thirty-six Sprague-Dawley (SD) rats were randomly divided into six groups: sham group, UUO model group, three ASPA treatment groups (10, 20, and 40 mg/kg), and captopril group (20 mg/kg). Rats were administered vehicle, ASPA or captopril intraperitoneally once a day for 14 consecutive days. Urea nitrogen (BUN), uric acid (UA) and inflammatory factors in serum samples were evaluated on the 7th, 10th, and 14th day after renal fibrosis induction. In addition, the 12 h urine was collected to test the content of urinary protein (upro) on the 14th day. The obstructive renal tissues were collected for pathological analysis (hematoxylin and eosion (H&E) staining and Masson's Trichrome staining) and immunohistochemical analysis on the 14th day after renal fibrosis induction. The mRNA expression of related factors and the protein levels of smad2, smad3, and smad4 were measured in UUO-induced rats by real time PCR and Western blot, respectively. RESULTS: The levels of BUN, UA, and upro were elevated in UUO-induced rats, but ASPA treatment improved renal function by reducing the levels of BUN, UA, and upro. The protein levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6, as well as the mRNA levels of TNF-α, IL-1ß, IL-6, monocyte chemoattractant protein-1 (MCP-1) and interferon-γ (IFN-γ), were decreased after ASPA administration (10, 20 and 40 mg/kg) in a dose-dependent manner. The ASPA exerted an alleviation effect on the inflammatory response through inhibition of nuclear factor-kappa B (NF-κB) pathway. In addition, reductions in α-smooth muscle actin (α-SMA), collagen III, and fibronectin expression were observed after ASPA administration at doses of 20 and 40 mg/kg. Furthermore, the renal expression of transforming growth factor-ß1 (TGF-ß1), smad2, smad3, and smad4 was down-regulated by ASPA treatment at doses of 20 and 40 mg/kg. CONCLUSION: ASPA possessed protective effects on renal interstitial fibrosis in UUO-induced rats. These effects may be through inhibition of the activation of NF-κB and TGF-ß1/smad2/smad3 signaling pathways.

Drosophila Histone Demethylase KDM5 Regulates Social Behavior through Immune Control and Gut Microbiota Maintenance.

Loss-of-function mutations in the histone demethylases KDM5A, KDM5B, or KDM5C are found in intellectual disability (ID) and autism spectrum disorders (ASD) patients. Here, we use the model organism Drosophila melanogaster to delineate how KDM5 contributes to ID and ASD. We show that reducing KDM5 causes intestinal barrier dysfunction and changes in social behavior that correlates with compositional changes in the gut microbiota. Therapeutic alteration of the dysbiotic microbiota through antibiotic administration or feeding with a probiotic Lactobacillus strain partially rescues the behavioral, lifespan, and cellular phenotypes observed in kdm5-deficient flies. Mechanistically, KDM5 was found to transcriptionally regulate component genes of the immune deficiency (IMD) signaling pathway and subsequent maintenance of host-commensal bacteria homeostasis in a demethylase-dependent manner. Together, our study uses a genetic approach to dissect the role of KDM5 in the gut-microbiome-brain axis and suggests that modifying the gut microbiome may provide therapeutic benefits for ID and ASD patients.

Novel Regulatory Roles of Wnt1 in Infection-Associated Colorectal Cancer.

Salmonella infection is a major public health concern, and colonization in humans can be chronic and increases the risk of cancers. Wnt signaling is a key pathway for intestinal renewal and development, inflammation, and tumorigenesis. In the current study, we report a novel role of Wnt1 in infection and colon cancer using cell culture models, a Salmonella-colitis colon cancer model, and human samples. In contrast to the bacteria-induced increases in Wnt2 and Wnt11, Salmonella colonization significantly reduced the level of Wnt1 in intestinal epithelial cells in vivo and in vitro. The bacterial AvrA protein is known to activate the canonical Wnt pathway. Wnt1 expression level was downregulated by AvrA-expressing Salmonella but stabilized by AvrA-deficient Salmonella in the intestine of Salmonella-colitis mice. In a chronic Salmonella-infected cancer model, the Wnt1 protein level was decreased in the AvrA+ infected group. Thus, we further assessed the functional role of Wnt1 downregulation in the inflammatory response and colorectal cancer (CRC) progression. Moreover, downregulation of Wnt1 by the Crispr-Cas9 method affected cancer cell invasion and migration. Interestingly, we found that Wnt1 was downregulated in human CRC tissue, and Wnt1 downregulation may be correlated with cancer progression. Our study provides insights into mechanisms by which enteric bacteria regulate Wnt1 expression and potentially contribute to infection-associated colon cancer.

Comparison of effects of ivabradine versus carvedilol in murine model with the Coxsackievirus B3-induced viral myocarditis.

BACKGROUND: Elevated heart rate is associated with increased cardiovascular morbidity. The selective I(f) current inhibitor ivabradine reduces heart rate without affecting cardiac contractility, and has been shown to be cardioprotective in the failing heart. Ivabradine also exerts some of its beneficial effects by decreasing cardiac proinflammatory cytokines and inhibiting peroxidants and collagen accumulation in atherosclerosis or congestive heart failure. However, the effects of ivabradine in the setting of acute viral myocarditis and on the cytokines, oxidative stress and cardiomyocyte apoptosis have not been investigated. METHODOLOGY/PRINCIPAL FINDINGS: The study was designed to compare the effects of ivabradine and carvedilol in acute viral myocarditis. In a coxsackievirus B3 murine myocarditis model (Balb/c), effects of ivabradine and carvedilol (a nonselective ß-adrenoceptor antagonist) on myocardial histopathological changes, cardiac function, plasma noradrenaline, cytokine levels, cardiomyocyte apoptosis, malondialdehyde and superoxide dismutase contents were studied. Both ivabradine and carvedilol similarly and significantly reduced heart rate, attenuated myocardial lesions and improved the impairment of left ventricular function. In addition, ivabradine treatment as well as carvedilol treatment showed significant effects on altered myocardial cytokines with a decrease in the amount of plasma noradrenaline. The increased myocardial MCP-1, IL-6, and TNF-α. in the infected mice was significantly attenuated in the ivabradine treatment group. Only carvedilol had significant anti-oxidative and anti-apoptoic effects in coxsackievirus B3-infected mice. CONCLUSIONS/SIGNIFICANCE: These results show that the protective effects of heart rate reduction with ivabradine and carvedilol observed in the acute phase of coxsackievirus B3 murine myocarditis may be due not only to the heart rate reduction itself but also to the downregulation of inflammatory cytokines.