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Abstract Background Sesterterpenoids are rare species among the terpenoids family. Ophiobolins are sesterterpenes with a 5-8-5 tricyclic skeleton. The oxidized ophiobolins exhibit significant cytotoxic activity and potential medicinal value. There is an urgent need for large amounts of ophiobolins supplication for drug development. The synthetic biology approach has been successfully employed in lots of terpene compound production and inspired us to develop a cell factory for ophiobolin biosynthesis. Results We developed a systematic metabolic engineering strategy to construct an ophiobolin biosynthesis chassis based on Saccharomyces cerevisiae. The whole-cell biotransformation methods were further combined with metabolic engineering to enhance the expression of key ophiobolin biosynthetic genes and improve the supply of precursors and cofactors. A high yield of 5.1 g/L of ophiobolin F was reached using ethanol and fatty acids as substrates. To accumulate oxidized ophiobolins, we optimized the sources and expression conditions for P450-CPR and alleviated the toxicity of bioactive compounds to cells through PDR engineering. We unexpectedly obtained a novel ophiobolin intermediate with potent cytotoxicity, 5-hydroxy-21-formyl-ophiobolin F, and the known bioactive compound ophiobolin U. Finally, we achieved the ophiobolin U titer of 128.9 mg/L. Conclusions We established efficient cell factories based on S. cerevisiae, enabling de novo biosynthesis of the ophiobolin skeleton ophiobolin F and oxidized ophiobolins derivatives. This work has filled the gap in the heterologous biosynthesis of sesterterpenoids in S. cerevisiae and provided valuable solutions for new drug development based on sesterterpenoids.

Background and objectiveStress hyperglycemia is common in critically ill patients and is associated with poor prognosis. Whether this association exists in pulmonary hypertension (PH) patients is unknown. The present cohort study investigated the association of stress hyperglycemia with 90-day all-cause mortality in intensive care unit (ICU) patients with PH.MethodsData of the study population were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. A new index, the ratio of admission glucose to HbA1c (GAR), was used to evaluate stress hyperglycemia. The study population was divided into groups according to GAR quartiles (Q1-Q4). The outcome of interest was all-cause mortality within 90 days, which was considered a short-term prognosis.ResultA total of 53,569 patients were screened. Ultimately, 414 PH patients were enrolled; 44.2% were male, and 23.2% were admitted to the cardiac ICU. As the GAR increased from Q2 to Q4, the groups had lower creatinine levels, longer ICU stays, and a higher proportion of renal disease. After adjusting for confounding factors such as demographics, vital signs, and comorbidities, an elevated GAR was associated with an increased risk of 90-day mortality.ConclusionStress hyperglycemia assessed by the GAR was associated with increased 90-day mortality in ICU patients with PH.

Abstract Background Abnormal glycemic variability is common in the intensive care unit (ICU) and is associated with increased in-hospital mortality and major adverse cardiovascular events, but little is known about whether adverse outcomes are partly mediated by ventricular arrhythmias (VA). We aimed to explore the association between glycemic variability and VA in the ICU and whether VA related to glycemic variability mediate the increased risk of in-hospital death. Methods We extracted all measurements of blood glucose during the ICU stay from The Medical Information Mart for Intensive Care IV (MIMIC-IV) database version 2.0. Glycemic variability was expressed by the coefficient of variation (CV), which was calculated by the ratio of standard deviation (SD) and average blood glucose values. The outcomes included the incidence of VA and in-hospital death. The KHB (Karlson, KB & Holm, A) is a method to analyze the mediation effect for nonlinear models, which was used to decompose the total effect of glycemic variability on in-hospital death into a direct and VA-mediated indirect effect. Results Finally, 17,756 ICU patients with a median age of 64 years were enrolled; 47.2% of them were male, 64.0% were white, and 17.8% were admitted to the cardiac ICU. The total incidence of VA and in-hospital death were 10.6% and 12.8%, respectively. In the adjusted logistic model, each unit increase in log-transformed CV was associated with a 21% increased risk of VA (OR 1.21, 95% CI: 1.11–1.31) and a 30% increased risk (OR 1.30, 95% CI: 1.20–1.41) of in-hospital death. A total of 3.85% of the effect of glycemic variability on in-hospital death was related to the increased risk of VA. Conclusion High glycemic variability was an independent risk factor for in-hospital death in ICU patients, and the effect was caused in part by an increased risk of VA.

Intermodular recognition in polyketide synthase (PKS) is a key prerequisite for catalysis and assembly-line engineering. Here, the authors present a specific domain interaction between modules and an evolution-oriented strategy for PKS engineering derived from the enoylreduction module of azalomycin F.

Abstract Aims There are limited data about the relationship between body mass index (BMI) and left ventricular ejection fraction (EF) in patients with heart failure (HF). The study aims to assess the correlation between BMI and left ventricular EF under HF conditions. Methods and results We derived the data from the Dryad Digital Repository for analysis, and the information of the original patients was obtained from the MIMIC‐III database by the data uploader. We performed smooth curve and two piecewise linear regression analyses to evaluate the association between BMI and EF in HF patients. A total of 962 participants were included in this study, with age of 73.7 ± 13.5 years, and 475 participants were male (49.4%). The results of the smooth curve supported a U‐shaped relationship between BMI and EF, and the inflection point was found to be a BMI of 23.3 kg/m2 in these HF patients. After adjusting for potential confounders, we found that EF decreased with increasing BMI up to the inflection point (β = −0.7, 95% CI −1.3 to −0.1, P = 0.028), whereas beyond the turning point, the relationship between EF and BMI showed a positive correlation (β = 0.2, 95% CI 0.1–0.3 P

It is important to improve the production of bioactive secondary products for drug development. The Escherichia coli—Streptomyces shuttle vector pSET152 and its derived vector pIB139 containing a strong constitutive promoter ermEp* are commonly used as integrative vectors in actinomycetes. Four new integrative vectors carrying the strong constitutive promoter kasOp*, hrdBp, SCO5768p, and SP44, respectively, were constructed and proven to be functional in different mangrove-derived Streptomyces host strains by using kanamycin resistance gene neo as a reporter. Some biosynthetic genes of elaiophylins, azalomycin Fs, and armeniaspirols were selected and inserted into these vectors to overexpress in their producers including Streptomyces sp. 219807, Streptomyces sp. 211726, and S. armeniacus DSM 43125, resulting in an approximately 1.1–1.4-fold enhancement of the antibiotic yields.

Objective: This study aims to search for structurally novel, natural bioactive products from mangrove-derived fungi. Methods: Compounds were isolated and purified by column chromatography on HP20 macroreticular resin, silica gel, Sephadex LH-20 gel, and high performance liquid chromatography. The structures of the isolates were analyzed using NMR and MS data, and the absolute configuration of 1 was determined by calculated ECD spectroscopic methods. The cytotoxicity of all the isolates was tested against HCT-116, HepG2, HEK 293t, and 5637 cancer cell lines using CCK-8 assay. Results: A new tetrahydroisoquinoline named peniciisoquinoline A (1) was obtained from Penicillium sp. DM27 along with five known compounds. Peniciisoquinoline A (1) was inactive against the four cancer cell lines. Conclusion: This study conducted chemical research on Penicillium sp. DM27 and tested the cytotoxic activity of the new alkaloid (1), which will assist in the further development and utilization of mangrove-derived fungi.

Abstract Background The influence of diabetes on the mortality and risk of implantable cardioverter defibrillator (ICD) therapies is still controversial, and a comprehensive assessment is lacking. We performed this systematic review and meta-analysis to address this controversy. Methods We systematically searched the PubMed, Embase, Web of Science and Cochrane Library databases to collect relevant literature. Fixed and random effects models were used to estimate the hazard ratio (HR) with 95% CIs. Results Thirty-six articles reporting on 162,780 ICD recipients were included in this analysis. Compared with nondiabetic ICD recipients, diabetic ICD recipients had higher all-cause mortality (HR = 1.45, 95% CI 1.36–1.55). The subgroup analysis showed that secondary prevention patients with diabetes may suffer a higher risk of all-cause mortality (HR = 1.89, 95% CI 1.56–2.28) (for subgroup analysis, P = 0.03). Cardiac mortality was also higher in ICD recipients with diabetes (HR = 1.68, 95% CI 1.35–2.08). However, diabetes had no significant effect on the risks of ICD therapies, including appropriate or inappropriate therapy, appropriate or inappropriate shock and appropriate anti-tachycardia pacing (ATP). Diabetes was associated with a decreased risk of inappropriate ATP (HR = 0.56, 95% CI 0.39–0.79). Conclusion Diabetes is associated with an increased risk of mortality in ICD recipients, especially in the secondary prevention patients, but does not significantly influence the risks of ICD therapies, indicating that the increased mortality of ICD recipients with diabetes may not be caused by arrhythmias. The survival benefits of ICD treatment in diabetes patients are limited.

IntroductionDimeric natural products are widespread in plants and microorganisms, which usually have complex structures and exhibit greater bioactivities than their corresponding monomers. In this study, we report five new dimeric tetrahydroxanthones, aculeaxanthones A−E (4−8), along with the homodimeric tetrahydroxanthone secalonic acid D (1), chrysoxanthones B and C (2 and 3), and 4−4’-secalonic acid D (9), from different fermentation batches of the title fungus.MethodsA part of the culture was added to a total of 60 flasks containing 300 ml each of number II fungus liquid medium and culture 4 weeks in a static state at 28˚C. The liquid phase (18 L) and mycelia was separated from the fungal culture by filtering. A crude extract was obtained from the mycelia by ultrasound using acetone. To obtain a dry extract (18 g), the liquid phase combined with the crude extract were further extracted by EtOAc and concentrated in vacuo. The MIC of anaerobic bacteria was examined by a broth microdilution assay. To obtain MICs for aerobic bacteria, the agar dilution streak method recommended in Clinical and Laboratory Standards Institute document (CLSI) M07-A10 was used. Compounds 1−9 was tested against the Bel-7402, A-549 and HCT-116 cell lines according to MTT assay.Results and DiscussionThe structures of these compounds were elucidated on the base of 1D and 2D NMR and HR-ESIMS data, and the absolute configurations of the new xanthones 4−8 were determined by conformational analysis and time-dependent density functional theory-electronic circular dichroism (TDDFT-ECD) calculations. Compounds 1–9 were tested for cytotoxicity against the Bel-7402, A549, and HCT-116 cancer cell lines. Of the dimeric tetrahydroxanthone derivatives, only compound 6 provided cytotoxicity effect against Bel-7402 cell line (IC50, 1.96 µM). Additionally, antimicrobial activity was evaluated for all dimeric tetrahydroxanthones, including four Gram-positive bacteria including Enterococcus faecium ATCC 19434, Bacillus subtilis 168, Staphylococcus aureus ATCC 25923 and MRSA USA300; four Gram-negative bacteria, including Helicobacter pylori 129, G27, as well as 26,695, and multi drug-resistant strain H. pylori 159, and one Mycobacterium M. smegmatis ATCC 607. However, only compound 1 performed activities against H. pylori G27, H. pylori 26695, H. pylori 129, H. pylori 159, S. aureus USA300, and B. subtilis 168 with MIC values of 4.0, 4.0, 2.0, 2.0, 2.0 and 1.0 μg/mL, respectively.

Two new sulfur-containing benzofurans, talarobenzofurans A and B (1 and 2), one new benzofuran talarobenzofuran C (3) and two new α-pyrones talaropyrones A and B (5 and 6), along with five known compounds eurothiocin A (4), nodulisporipyrone A (7), peniazaphilin B (8), ramulosin (9) and 6-hydroxyramulosin (10) were isolated and identified from the culture extract of the mangrove-derived fungus Talaromyces sp. WHUF0341 guided by OSMAC (one strain-many compounds) strategy. Their structures were established by extensive spectroscopic data analysis, the modified Mosher’s method and electronic circular dichroism (ECD) calculations. Structurally, compounds 1 and 2 possesed the unique thioester moiety derived from benzofuran and 2-hydroxy-3-mercaptopropionic acid, which was rarely-observed in natural products. The α-glucosidase inhibitory and antibacterial activities of the isolated compounds were evaluated. Compounds 3 and 4 exhibited inhibitory effects against α-glucosidase activity with IC50 values of 48.9 ± 2.16 and 8.8 ± 1.08 µM, respectively. The inhibitory type of 3 on α-glucosidase was determined as non-competitive-type inhibition with Ki value of 242.3 μM by using Lineweaver-Burk double reciprocal and Dixon single reciprocal plots. Meanwhile, the binding model of 3 and 4 with α-glucosidase was determined by molecular docking assay. The biosynthetic pathways of compounds 1−4 were also proposed. This study suggested that benzofurans 3 and 4 could be potential lead compounds for the hypoglycemic drugs.

BackgroundPrior investigation revealed that elevated serum total homocysteine (tHcy) are strongly correlated with atrial fibrillation (AF) recurrence. Herein, the goal of this study was to elucidate whether folic acid (FA) treatment reduced AF recurrence following radiofrequency catheter ablation (RFCA).MethodsTo conduct this retrospective research, we included consecutive H-type hypertensive AF patients, who were treated with first RFCA, between January 2010 and January 2022. We assessed the AF recurrence risk between patients who were taking 10 mg enalapril and 0.8 mg FA in a single-pill combination (enalapril–FA) daily and those who were taking a pill of 10 mg enalapril only. Outcomes were compared using the propensity-score matched analysis. Cox regression model was employed for the evaluation of AF recurrence events.ResultsOut of 2,714 patients, 645 patients receiving enalapril and 282 patients receiving enalapril-FA were included for analysis. Following propensity score matching, 239 patients remained in each group. These patients were followed-up for a median of 379 (137–596) days, and revealed that the enalapril-FA patients had drastically reduced AF recurrence, compared to the enalapril patients [adjusted hazard ratio (HR), 0.68; 95% confidence interval (CI), 0.48–0.97; P = 0.029]. Apart from this, no interactions were detected in the subgroup analysis.ConclusionIn H-type hypertensive AF patients who were treated with first RFCA, FA supplementation was correlated with a reduced AF recurrence risk.

Abstract Background Although the associations of antioxidant micronutrients, such as carotenoids and vitamins, with cardiovascular diseases (CVDs) have been studied extensively, blood concentrations of antioxidant micronutrients and heart rate variability (HRV), which has been proven to be an indicator of cardiac autonomic control, has not been reported. We aimed to explore whether blood concentrations of antioxidant micronutrients, including carotenoids and vitamins, are associated with elevated heart rate variability (HRV (beneficial change) in a cross-sectional analysis. Methods Data were obtained from the Midlife in the United States (MIDUS) study that includes a general adult population. A total of 1074 (aged 34–84) individuals were included. Multivariable analyses were performed to investigate the association between main blood carotenoids (total lutein, zeaxanthin, beta-cryptoxanthin, 13-cis-beta-carotene, alpha-carotene, all-trans-beta-carotene and total lycopene) and vitamins A (retinol) and E (gamma-tocopherol and alpha-tocopherol) and HRV after adjustments were made for lifestyle factors and age-related confounders. Results Pearson correlation analyses showed that the increased levels of carotenoids and vitamins were positively correlated with higher HRV (all P

α-Glucosidase (AGS) inhibitors have been regarded as an ideal target for the management of type 2 diabetes mellitus (T2DM) since they can maintain an acceptable blood glucose level by delaying the digestion of carbohydrates and diminishing the absorption of monosaccharides. In the process of our endeavor in mining AGS inhibitors from natural sources, the culture broth of two mangrove-derived actinomycetes Streptomyces sp. WHUA03267 and Streptomyces sp. WHUA03072 exhibited an apparent inhibitory activity against AGS. A subsequent chemical investigation into the two extracts furnished 28 secondary metabolites that were identified by spectroscopic methods as two previously undescribed linear polyketides 1–2, four benzenoid ansamycins 3–6, fourteen cyclodipeptides 7–18, one prenylated indole derivative 19, two fusicoccane-type diterpenoids 20–21, two hydroxamate siderophore 22–23, and five others 24–28. Among all of the isolates, 11 and 24 were obtained from actinomycetes for the first time, while 20–21 had never been reported to occur in a marine-derived microorganism previously. In the in vitro AGS inhibitory assay, compounds 3, 8, 9, 11, 14, 16, and 17 exhibited potent to moderate activity with IC50 values ranging from 35.76 ± 0.40 to 164.5 ± 15.5 μM, as compared with acarbose (IC50 = 422.3 ± 8.4 μM). The AGS inhibitory activity of 3, 9, 14, 16, and 17 was reported for the first time. In particular, autolytimycin (3) represented the first ansamycin derivative reported to possess the AGS inhibitory activity. Kinetics analysis and molecular docking were performed to determine the inhibition types and binding modes of these inhibitors, respectively. In the MTT assay, 3, 8, 9, 11, 14, 16, and 17 exhibited no apparent cytotoxicity to the human normal hepatocyte (LO2) cells, suggesting satisfactory safety of these AGS inhibitors.

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007.

Organic carbonates (OCs) are a class of compounds featured by a carbonyl flanked by two alkoxy/aryloxy groups. They exist in either linear or cyclic forms, of which the majority encountered in nature adopt a pentacyclic structure. However, the enzymatic basis for pentacyclic carbonate ring formation remains elusive. Here, we reported that a four-protein metabolon (AlmUII–UV) assembled by a small peptide protein (AlmUV) appends a reactive N-hydroxylcarbamoyl moiety to the decarboxylated aldgamycins followed by a non-enzymatic condensation to give the pentacyclic carbonate ring. Our results have documented an unprecedent mechanism for carbonate formation.

Abstract The human leukocyte antigen F-associated transcript 10 (FAT10) is a member of the small ubiquitin-like protein family that binds to its target proteins and subjects them to degradation by the ubiquitin–proteasome system (UPS). In the heart, FAT10 plays a cardioprotective role and affects predisposition to cardiac arrhythmias after myocardial ischemia (MI). However, whether and how FAT10 influences cardiac arrhythmias is unknown. We investigated the role of FAT10 in regulating the sodium channel Nav1.5, a major regulator of cardiac arrhythmias. Fat10 was conditionally deleted in cardiac myocytes using Myh6-Cre and Fat10 F/F mice (cFat10 −/− ). Compared with their wild-type littermates, cFat10 −/− mice showed prolonged RR, PR, and corrected QT (QTc) intervals, were more likely to develop ventricular arrhythmia, and had increased mortality after MI. Patch-clamp studies showed that the peak Na+ current was reduced, and the late Na+ current was significantly augmented, resulting in a decreased action potential amplitude and delayed depolarization. Immunoblot and immunofluorescence analyses showed that the expression of the membrane protein Nav1.5 was decreased. Coimmunoprecipitation experiments demonstrated that FAT10 stabilized Nav1.5 expression by antagonizing Nav1.5 ubiquitination and degradation. Specifically, FAT10 bound to the lysine residues in the C-terminal fragments of Nav1.5 and decreased the binding of Nav1.5 to the Nedd4-2 protein, a ubiquitin E3 ligase, preventing degradation of the Nav1.5 protein. Collectively, our findings showed that deletion of the Fat10 in cardiac myocytes led to increased cardiac arrhythmias and increased mortality after MI. Thus, FAT10 protects against ischemia-induced ventricular arrhythmia by binding to Nav1.5 and preventing its Neddylation and degradation by the UPS after MI.

Abstract Background Recent basic studies demonstrate that the lung is a primary organ of platelet biogenesis. However, whether the pathophysiological state of the lung affect the platelets is little known. We aim to investigate the incidence of thrombocytopenia in patients with pulmonary infection (PIN) and risk factors associated with pulmonary thrombocytopenia. Methods In total, 11,941 patients with pulmonary infection (PIN) were enrolled, and patients with other three infectious diseases were collected as controls. The incidence of thrombocytopenia was compared, and the risk factors associated with thrombocytopenia in PIN patients were investigated by multivariate analysis. To explore the mechanism of thrombocytopenia, hypoxic model was constructed. Blood platelet counts from the angular vein (PLTs), left ventricle (PLTpost) and right ventricle (PLTpre) were determined. Megakaryocytes identified by anti-CD41 antibody were detected through flow cytometry and immunofluorescence. Results The incidence of thrombocytopenia in PIN was higher than that in other three infectious diseases (9.8% vs. 6.4% ~ 5.0%, P

BackgroundHis bundle pacing (HBP) is a physiological pacing strategy, which aims to capture the His bundle-Purkinje system and synchronously activate the ventricles. Left bundle branch pacing (LBBP) is a newly discovered physiological pacing technique similar to HBP. We conducted this meta-analysis to compare the pacing parameters and clinical results between HBP and LBBP.MethodsWe systematically retrieved studies using the PubMed, Embase database, and Cochrane Library. Mean difference (MD) and relative risk (RR) with their 95% confidence intervals [CIs] were used to measure the outcomes. A random-effect model was used when studies were of high heterogeneity.ResultsA total of seven studies containing 867 individuals were included. Compared with HBP, LBBP was associated with higher implant success rates (RR: 1.12, 95% CI: 1.05–1.18; I2 = 60%, P = 0.0003), lower capture threshold at implantation (V/0.5 ms) (MD: 0.63, 95% CI: 0.35–0.90, I2 = 89%, P < 0.0001) and capture threshold at follow-up (V/0.5 ms) (MD: 0.76, 95% CI: 0.34–1.18, I2 = 93%, P = 0.0004), and larger sensed R wave amplitude (mV) at implantation (MD: 7.23, 95% CI: 5.29–9.16, P < 0.0001) and sensed R wave amplitude (mV) at follow-up (MD: 7.53, 95% CI: 6.85–8.22, P < 0.0001). In LBBP recipients, greater QRS wave complex reduction was found in the paced QRS duration at follow-up compared with HBP recipients at follow-up (MD: 6.12, 95% CI: 1.23–11.01, I2 = 0%, P = 0.01). No statistical differences were found in procedure duration, fluoroscopy time, native left ventricular ejection fractions (LVEF), LVEF improvement, native QRS duration, and QRS reduction from the native QRS duration vs. paced QRS duration at implantation.ConclusionCurrent evidence suggests that pacing characteristics are better in LBBP compared with HBP. Further prospective studies are needed to validate the clinical advantages of LBBP.

Abstract With the steadily increasing amount of leadless pacemaker implantations performed worldwide, it has called attention to the delivery difficulty in patients with severe large right heart. Nevertheless, limited studies have reported leadless pacemaker implantation in patients with tricuspid stenosis. Here, we report the successful implantation of leadless pacemaker in a 60‐year‐old female patient with giant right atrium and tricuspid valve stenosis. It is highlighted that leadless pacemaker should not be discouraged even if there are tricuspid valve stenosis and giant right atrium.

Background: Data on the existing evidence for the association between blood retinol and transient ischemic attack (TIA)/stroke risk are limited, and the results are inconclusive. This study aimed to further assess the associations between the blood retinol levels and the risk of TIA/stroke after controlling the lifestyle factors and age-related confounders.Methods: The cross-sectional data from 1,113 individuals (aged 34–84 years old) were obtained from the Midlife in the United States (MIDUS) study. The multivariable analyses were performed to investigate the association of blood retinol levels with ever and currently TIA/stroke.Results: There was an inverse association between the blood retinol levels and the risk of ever TIA or stroke (for per 1 μmol/L adjusted odds ration [OR]: 0.93; 95% CI: 0.89–0.97; for per 1-SD adjusted OR: 0.89; 95% CI: 0.83–0.96) and currently diagnosed TIA or stroke (for per 1 μmol/L adjusted OR: 0.91; 95% CI: 0.87–0.96; for per 1-SD adjusted OR: 0.84; 95% CI: 0.80–0.91) after controlling the lifestyle factors and age-related confounders. The significance of these associations was maintained after a sensitivity analysis and involving “ever chronic respiratory diseases” as a covariate. Moreover, the stratified analyses suggested that the inverse associations could be affected by overweight [body mass index (BMI) ≥ 28, kg/m2], hypertension, and diabetes.Conclusions: A significant inverse association between blood retinol and the risk of TIA or stroke was found. This inverse association did not change even after adjustment for many potential confounders. Moreover, the potential protective effect of retinol on TIA/stroke could be blunted by overweight [BMI ≥ 28, kg/m2], hypertension, and diabetes.

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disorder with high mortality. Multiple clinical diseases can induce PAH, but the underlying molecular mechanisms shared in PAHs associated with different diseases remain unclear. The aim of this study is to explore the key candidate genes and pathways in PAH associated with congenital heart disease (CHD-PAH), PAH associated with connective tissue disease (CTD-PAH), and idiopathic PAH (IPAH). We performed differential expression analysis based on a public microarray dataset GSE113439 and identified 1,442 differentially expressed genes, of which 80.3% were upregulated. Subsequently, both pathway enrichment analysis and protein–protein interaction network analysis revealed that the “Cell cycle” and “DNA damage” processes were significantly enriched in PAH. The expression of seven upregulated candidate genes (EIF2AK2, TOPBP1, CDC5L, DHX15, and CUL1–3) and three downregulated candidate genes (DLL4, EGFL7, and ACE) were validated by qRT-PCR. Furthermore, cell cycle-related genes Cul1 and Cul2 were identified in pulmonary arterial endothelial cells (PAECs) in vitro. The result revealed an increased expression of Cul2 in PAECs after hypoxic treatment. Silencing Cul2 could inhibit overproliferation and migration of PAECs in hypoxia. Taken together, according to bioinformatic analyses, our work revealed that “Cell cycle” and “DNA damage” process-related genes and pathways were significantly dysregulated expressed in PAHs associated with three different diseases. This commonality in molecular discovery might broaden the genetic perspective and understanding of PAH. Besides, silencing Cul2 showed a protective effect in PAECs in hypoxia. The results may provide new treatment targets in multiple diseases induced by PAH.

Abstract Background The relationship between serum vitamin D and atrial fibrillation (AF) or postoperative atrial fibrillation (POAF) in patients undergoing coronary artery bypass graft (CABG) is still debated. It is also unclear whether there is a dose-response relationship between circulating vitamin D and the risk of AF or POAF. Methods The Cochrane Library, PubMed, and Embase databases were searched for relevant studies. We used a “one-stage approach” with a restricted cubic spline model to summarize the dose-specific relationships between serum vitamin D and AF. Relative risk (RR) was used to measure the effects in this meta-analysis. Results In total, 13 studies were included with a total of 6519 cases of AF among 74,885 participants. Vitamin D deficiency ( 65 years) (RR = 0.68, 95% CI = 0.52–0.89) but not among young individuals (

Abstract. Background:. Deceleration capacity (DC) is a non-invasive marker for cardiac autonomic dysfunction; however, few studies have shown that the influence factors of cardiac autonomic dysfunction and the correlations between DC and stroke risk in paroxysmal atrial fibrillation (AF). We aimed to explore the influencing factors of abnormal DC and the relationships between DC and stroke risk in patients with paroxysmal AF. Methods:. The study included hospitalized paroxysmal AF patients with DC measurements derived from 24-h Holter electrocardiography recordings taken between August 2015 and June 2016. Multivariable regression analysis was performed to evaluate the associations between correlated variables and abnormal DC values. The relationship between DC and ischemic stroke risk scores in patients with paroxysmal AF was analyzed. Results:. We studied 259 hospitalized patients with paroxysmal AF (143 [55.2%] male, mean age 66.4 ± 12.0 years); 38 patients of them showed abnormal DC values. In the univariate analysis, age, hypertension, heart failure, and previous stroke/transient ischemic attack (TIA) were significantly associated with abnormal DC values. Among these factors, a history of previous stroke/TIA (odds ratio = 2.861, 95% confidence interval: 1.356–6.039) were independently associated with abnormal DC values in patients with paroxysmal AF. The abnormal DC group showed a higher stroke risk with the score of congestive heart failure, hypertension, age >75 years, diabetes mellitus, previous stroke and TIA (CHADS2) (2.25 ± 1.48 vs. 1.40 ± 1.34, t = −4.907, P = 0.001) and CHA2DS2-vascular disease, age 65–74 years and female category (VASc) (3.76 ± 1.95 vs. 2.71 ± 1.87, t = −4.847, P = 0.001) scores. Correlation analysis showed that DC was negatively correlated with CHADS2 scores (r = −0.290, P

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease and mitochondria plays a key role in the progression in HCM. Here, we analyzed the expression pattern of nuclear-encoded mitochondrial genes (NMGenes) in HCM and found that the expression of NMGenes was significantly changed. A total of 316 differentially expressed NMGenes (DE-NMGenes) were identified. Pathway enrichment analyses showed that energy metabolism-related pathways such as “pyruvate metabolism” and “fatty acid degradation” were dysregulated, which highlighted the importance of energy metabolism in HCM. Next, we constructed a protein-protein interaction network based on 316 DE-NMGenes and identified thirteen hubs. Then, a total of 17 TFs (transcription factors) were predicted to potentially regulate the expression of 316 DE-NMGenes according to iRegulon, among which 8 TFs were already found involved in pathological hypertrophy. The remaining TFs (like GATA1, GATA5, and NFYA) were good candidates for further experimental verification. Finally, a mouse model of transverse aortic constriction (TAC) was established to validate the genes and results showed that DDIT4, TKT, CLIC1, DDOST, and SNCA were all upregulated in TAC mice. The present study represents the first effort to evaluate the global expression pattern of NMGenes in HCM and provides innovative insight into the molecular mechanism of HCM.

Four new drimane sesquiterpenoids (1–4) and three known ones (5–7) were isolated from the fermentation broth of the mangrove-derived Aspergillus ustus 094102. Compound 5 was further resolved as four purified compounds 5a–5d. By means of extensive spectroscopic and ECD analysis as well as the chemical transformation, their structures were identified as (2R,3R,5S,9R,10S)-2,3,9,11-tetrahydroxydrim-7-en-6-one (ustusol F, 1), (2R,3R,5R,9S,10R)-2,3,11-trihydroxydrim-7-en-6-one (9-deoxyustusol F, 2), (3S,5R,9R,10R)-3,11,12-trihydroxydrim-7-en-6-one (ustusol G, 3), (5S,6R,9S,10S, 11R,2′E,4′E)-(11-dideoxy-11-hydroxystrobilactone A-6-yl)-5-carboxypenta-2,4-dienoate (ustusolate H, 4), ((5S,6R,9S,10S)-strobilactone A-6-yl) (2E,4E)-6,7-dihydroxyocta-2,4-dienoate (ustusolate I, 5), (2′E,4′E;6′,7′-erythro)-ustusolate I (5a) and (2′E,4′E;ent-6′,7′-erythro)-ustusolate I (5b), (2′E,4′E,6′R,7′R)-ustusolate I (5c) and (2′E,4′E,6′S,7′S)-ustusolate I (5d), (5S,6R,9S,10S,2′E,4′E)-(strobilactone A-6-yl)-5-carboxypenta-2,4-dienoate (ustusolate J, 6), and (2S,5S,9R,10S)-2,9,11-trihydroxydrim-7-en-6-one (ustusol B, 7), respectively. Compound 5 showed antiproliferation against the human tumor cells CAL-62 and MG-63 with the IC50 values of 16.3 and 10.1 µM, respectively.

Background To date, there is no cumulative evidence supporting the association of atrial fibrillation (AF) noninducibility after ablation and freedom from AF. We performed a systematic review and meta‐analysis to determine whether AF noninducibility by burst pacing after catheter ablation is associated with reduced AF recurrence. Methods and Results We searched PubMed, Embase, Web of Science, and Cochrane Library databases through July 2019 to identify studies that evaluated AF noninducibility versus inducibility by burst pacing after catheter ablation for freedom from AF. A fixed effects model was used to estimate relative risk (RR) with 95% CIs. Twelve prospective cohort studies with AF noninducibility (n=1612) and inducibility (n=1160) were included. Compared with AF inducibility, AF noninducibility by burst pacing after ablation was associated with a reduced risk of AF recurrence (RR, 0.68; 95% CI, 0.60–0.77). Subgroup analysis showed that different AF types (paroxysmal AF and nonparoxysmal AF), different follow‐up times (≤6, 6–12, and >12 months), and different degrees of burst pacing (mild, moderate, severe) had no significant impact on the RRs. However, different cut‐off times for AF inducibility had a significant impact on the RR (Pinteraction=0.009), and only the cut‐off time of 1 minute showed a significant correlation (RR, 0.54; 95% CI, 0.45–0.66). Conclusions AF noninducibility by burst pacing after catheter ablation is associated with reduced clinical recurrence of AF. Induction protocols with a different cut‐off time for AF inducibility have a significant impact on the correlation, and the AF ≥1 minute for AF inducibility is recommended.

Terpenoids are a large family of natural products with remarkable diverse biological functions, and have a wide range of applications as pharmaceuticals, flavors, pigments, and biofuels. Synthetic biology is presenting possibilities for sustainable and efficient production of high value-added terpenoids in engineered microbial cell factories, using Escherichia coli and Saccharomyces cerevisiae which are identified as well-known industrial workhorses. They also provide a promising alternative to produce non-native terpenes on account of available genetic tools in metabolic engineering and genome editing. In this review, we summarize the recent development in terpenoids production by synthetic biology approaches.

As antimicrobial resistance has been increasing, new antimicrobial agents are desperately needed. Azalomycin F, a natural polyhydroxy macrolide, presents remarkable antimicrobial activities. To investigate its pharmacokinetic characteristics in rats, the concentrations of azalomycin F contained in biological samples, in vitro, were determined using a validated high-performance liquid chromatography–ultraviolet (HPLC-UV) method, and, in vivo, samples were assayed by an ultra-high performance liquid chromatography–tandem mass spectrometric (UPLC–MS/MS) method. Based on these methods, the pharmacokinetics of azalomycin F were first investigated. Its plasma concentration-time courses and pharmacokinetic parameters in rats were obtained by a non-compartment model for oral (26.4 mg/kg) and intravenous (2.2 mg/kg) administrations. The results indicate that the oral absolute bioavailability of azalomycin F is very low (2.39 ± 1.28%). From combinational analyses of these pharmacokinetic parameters, and of the results of the in-vitro absorption and metabolism experiments, we conclude that azalomycin F is absorbed relatively slowly and with difficulty by the intestinal tract, and subsequently can be rapidly distributed into the tissues and/or intracellular f of rats. Azalomycin F is stable in plasma, whole blood, and the liver, and presents plasma protein binding ratios of more than 90%. Moreover, one of the major elimination routes of azalomycin F is its excretion through bile and feces. Together, the above indicate that azalomycin F is suitable for administration by intravenous injection when used for systemic diseases, while, by oral administration, it can be used in the treatment of diseases of the gastrointestinal tract.

There are few head-to-head trials directly comparing non-vitamin K antagonist oral anticoagulants (NOACs) against one other. A network meta-analysis (NMA) was performed to examine the indirect comparisons among NOACs in Asians with nonvalvular atrial fibrillation (NVAF). STATA 15.0 and ADDIS 1.16.8 softwares were used to perform the statistical analysis. Odds ratios with 95% credible intervals were applied to evaluate the end points. The probabilities of treatment rank were used to understand which interventions are more effective and safe, and the total rank probability was 1. In our NMA, the rank probabilities of apixaban in the case of stroke or systemic embolism, death from any cause, major bleeding, and intracranial hemorrhage (ICH) were 0.47, 0.49, 0.42, and 0.51, respectively. For cases of myocardial infarction, the rank probabilities of rivaroxaban were 0.40. This NMA indirectly compares the main efficacy and safety end points among NOACs in Asians with NVAF, and the rank probability analysis showed that apixaban likely performs best in cases of stroke or systemic embolism, death from any cause, and ICH; rivaroxaban may have the best performance for myocardial infarction.

Dilated cardiomyopathy (DCM) is increasingly indicated as a cause of cardioembolic syndrome, in particular, cardioembolic ischemia stroke. However, the potential risk factors for stroke among DCM patients remain under investigated. DCM patients hospitalized from June 2011 to June 2016 were included. The cases were defined as the group of DCM patients with stroke compared with those without stroke. Clinical characteristic data were collected and compared between the two groups including demographic data, complicated diseases, echocardiography index, and laboratory parameters and estimated glomerular filtration rate (eGFR). A multivariate logistic regression analysis model adjusted by sex and age was used to explore the related risk factors for stroke in DCM patients. A total of 779 hospitalized patients with DCM were included. Of these, 55 (7.1%) had experienced a stroke. Significantly lower eGFR levels (68.03 ± 26.22 vs 79.88 ± 24.25 mL/min/1.73 m 2 , P = .001) and larger left atrial diameters (45.32 ± 7.79 vs 43.25 ± 7.11 mm, P = .04) were found in the group of patients having DCM with stroke compared to those without stroke. When the eGFR was categorized as eGFR >60, 30

Background The efficacy of nifekalant in preexcited atrial fibrillation (AF) has not been assessed. Methods and Results The study populations consisted of patients with sustained preexcited AF (n=51), paroxysmal supraventricular tachycardia (n=201), and persistent AF (n=87). Effects of intravenous infusion of nifekalant were assessed on electrophysiological and clinical parameters. Nifekalant prolonged the shortest preexcited R‐R, the average preexcited R‐R, and the average R‐R intervals from 290±35 to 333±44 ms, 353±49 to 443±64 ms, and 356±53 to 467±75 ms, respectively, in patients with preexcited AF (all P

Antimicrobial resistance (AR) is recognized as one of the greatest threats to public health and in global concern. Consequently, the increased morbidity and mortality, which are associated with multidrug resistance bacteria, urgently require the discovery of novel and more efficient drugs. Conversely, cancer is a growing complex human disease that demands new drugs with no or fewer side effects. Most of the drugs currently used in the health care systems were of Streptomyces origin or their synthetic forms. Natural product researches from Streptomyces have been genuinely spectacular over the recent years from extreme environments. It is because of technical advances in isolation, fermentation, spectroscopy, and genomic studies which led to the efficient recovering of Streptomyces and their new chemical compounds with distinct activities. Expanding the use of the last line of antibiotics and demand for new drugs will continue to play an essential role for the potent Streptomyces from previously unexplored environmental sources. In this context, deep-sea, desert, cryo, and volcanic environments have proven to be a unique habitat of more extreme, and of their adaptation to extreme living, environments attribute to novel antibiotics. Extreme Streptomyces have been an excellent source of a new class of compounds which include alkaloids, angucycline, macrolide, and peptides. This review covers novel drug leads with antibacterial and cytotoxic activities isolated from deep-sea, desert, cryo, and volcanic environment Streptomyces from 2009 to 2019. The structure and chemical classes of the compounds, their relevant bioactivities, and the sources of organisms are presented.

The chemical investigation of the mangrove endophytic fungus Aspergillus sp. 085242 afforded eight isocoumarin derivatives 1–8 and one isoquinoline 9. Asperisocoumarins A and B (1 and 2) were new furoisocoumarins, and asperisocoumarins E and F (5 and 6) were new isocoumarins. Their structures were established by analysis of their spectroscopic data and the absolute configuration of compound 2 was unambiguously determined by X-ray structure analysis and ECD calculation. Moreover, the absolute configurations of compounds 3–5 were assigned by comparison of their ECD spectra with isocoumarins described in the literature. Asperisocoumarins C and D (3 and 4) were fully characterized spectroscopically and isolated from a natural source for the first time. Asperisocoumarins A–D (1–4) related to the class of furo[3,2-h]isocoumarins are rarely occurring in natural sources. Compounds 2, 5, and 6 showed moderate α-glucosidase inhibitory activity with IC50 of 87.8, 52.3, and 95.6 μM, respectively. In addition, compounds 1 and 3 exhibited weak radical scavenging activity with EC50 values of 125 and 138 μM, respectively.

Deep-sea fungi have become a new arsenal for the discovery of leading compounds. Here five new ophiobolins 1–5, together with six known analogues 6–11, obtained from a deep-sea derived fungus WHU0154. Their structures were determined by analyses of IR, HR-ESI-MS, and NMR spectra, along with experimental and calculated electronic circular dichroism (ECD) analysis. Pharmacological studies showed that compounds 4 and 6 exhibited obvious inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in murine macrophage RAW264.7 cells. Mechanical study revealed that compound 6 could inhibit the inducible nitric oxide synthase (iNOS) level in LPS-stimulated RAW264.7 cells. In addition, compounds 6, 9, and 10 could significantly inhibit the expression of cyclooxygenase 2 (COX 2) in LPS-induced RAW264.7 cells. Preliminary structure-activity relationship (SAR) analyses revealed that the aldehyde group at C-21 and the α, β-unsaturated ketone functionality at A ring in ophiobolins were vital for their anti-inflammatory effects. Together, the results demonstrated that ophiobolins, especially for compound 6, exhibited strong anti-inflammatory effects and shed light on the discovery of ophiobolins as new anti-inflammatory agents.

Five new compounds 15R-17,18-dehydroxantholipin (1), (3E,5E,7E)-3-methyldeca-3,5,7-triene-2,9-dione (2) and qinlactone A–C (3–5) were identified from mangrove Streptomyces qinglanensis 172205 with “genetic dereplication,” which deleted the highly expressed secondary metabolite-enterocin biosynthetic gene cluster. The chemical structures were established by spectroscopic methods, and the absolute configurations were determined by electronic circular dichroism (ECD). Compound 1 exhibited strong anti-microbial and antiproliferative bioactivities, while compounds 2–4 showed weak antiproliferative activities.

Background/Aims: MicroRNAs play regulatory role in cardiovascular disease. MicroRNA-223 (miR-223) was found to be expressed abundantly in myocardium. TNNI3K, a novel cardiac troponin I (cTnI)-interacting and cardiac hypertrophy related kinase, is computationally predicted as a potential target of miR-223. This study was designed to investigate the cellular and molecular effects of miR-223 on cardiomyoctye hypertrophy, focusing on the role of TNNI3K. Methods: Neonatal rat cardiomyocytes (CMs) were cultured, and CMs hypertrophy was induced by endothelin-1 (ET-1). In vivo cardiac hypertrophy was induced by transverse aorta constriction (TAC) in rats. Expression of miR-223 in CMs and myocardium was detected by real-time PCR (RT-PCR). MiR-223 and TNNI3K were overexpressed in CMs via chemically modifed sense RNA (miR-223 mimic) transfection or recombinant adenovirus infection, respectively. Cell size was measured by surface area calculation using fluorescence microscopy after anti-α-actinin staining. Expression of hypertrophy-related genes was detected by RT-PCR. The protein expression of TNNI3K and cTnI was determined by Western blots. Luciferase assay was employed to confirm the direct binding of miR-223 to the 3'UTR of TNNI3K mRNA. Intracellular calcium was measured by sensitive fluorescent indicator (Furo-2). Video-based edge detection system was employed to measure cardiomyocyte contractility. Results: MiR-223 was downregulated in ET-1 induced hypertrophic CMs and in hypertrophic myocardium compared with respective controls. MiR-223 overexpression in CMs alleviated ET-1 induced hypertrophy, evidenced by smaller cell surface area and downregulated ANP, α-actinin, Myh6 and Myh7 expression. Luciferase reporter gene assay showed that TNNI3K serves as a direct target gene of miR-223. In miR-223-overexpressed CMs, the protein expression of TNNI3K was significantly downregulated. MiR-223 overexpression also rescued the upregulated TNNI3K expression in hypertrophic CMs. Furthermore, cTnI phosphorylation was downregulated post miR-223 overexpression. Ad.rTNNI3K increased intracellular Ca2+ concentrations and cell shortening in CMs, while miR-223 overexpression significantly rescued these hypertrophic effects. Conclusion: By direct targeting TNNI3K, miR-223 could suppress CMs hypertrophy via downregulating cTnI phosphorylation, reducing intracellular Ca2+ and contractility of CMs. miR-223 / TNNI3K axis may thus be major players of CMs hypertrophy.

Ophiobolin O is a member of ophiobolin family, which has been proved to be a potent anti-tumor drug candidate for human breast cancer. However, the anti-tumor effect and the mechanism of ophiobolin O remain unclear. In this study, we further verified ophiobolin O-induced G1 phase arrest in human breast cancer MCF-7 cells, and found that ophiobolin O reduced the phosphorylation level of AKT and GSK3β, and induced down-regulation of cyclin D1. The inverse docking (INVDOCK) analysis indicated that ophiobolin O could bind to GSK3β, and GSK3β knockdown abolished cyclin D1 degradation and G1 phase arrest. Pre-treatment with phosphatase inhibitor sodium or thovanadate halted dephosphorylation of AKT and GSK3β, and blocked ophiobolin O-induced G1 phase arrest. These data suggest that ophiobolin O may induce G1 arrest in MCF-7 cells through interaction with AKT/GSK3β/cyclin D1 signaling. In vivo, ophiobolin O suppressed tumor growth and showed little toxicity in mouse xenograft models. Overall, these findings provide theoretical basis for the therapeutic use of ophiobolin O.

BackgroundIdiopathic ventricular tachycardia (VT) is a type of cardiac arrhythmia occurring in structurally normal hearts. The heritability of idiopathic VT remains to be clarified, and numerous genetic factors responsible for development of idiopathic VT are as yet unclear. Variations in FGF12 (fibroblast growth factor 12), which is expressed in the human ventricle and modulates the cardiac Na+ channel NaV1.5, may play an important role in the genetic pathogenesis of VT. Methods and ResultsWe tested the hypothesis that genetic variations in FGF12 are associated with VT in 2 independent Chinese cohorts and resequenced all the exons and exon–intron boundaries and the 5′ and 3′ untranslated regions of FGF12 in 320 unrelated participants with idiopathic VT. For population‐based case–control association studies, we chose 3 single‐nucleotide polymorphisms—rs1460922, rs4687326, and rs2686464—which included all the exons of FGF12. The results showed that the single‐nucleotide polymorphism rs1460922 in FGF12 was significantly associated with VT after adjusting for covariates of sex and age in 2 independent Chinese populations: adjusted P=0.015 (odds ratio: 1.54 [95% CI, 1.09–2.19]) in the discovery sample, adjusted P=0.018 (odds ratio: 1.64 [95% CI, 1.09–2.48]) in the replication sample, and adjusted P=2.52E‐04 (odds ratio: 1.59 [95% CI, 1.24–2.03]) in the combined sample. After resequencing all amino acid coding regions and untranslated regions of FGF12, 5 rare variations were identified. The result of western blotting revealed that a de novo functional variation, p.P211Q (1.84% of 163 patients with right ventricular outflow tract VT), could downregulate FGF12 expression significantly. ConclusionsIn this study, we observed that rs1460922 of FGF12 was significantly associated with VT and identified that a de novo variation of FGF12 may be an important genetic risk factor for the pathogenesis of VT.

Deep sea is a unique and extreme environment. It is a hot spot for hunting marine actinomycetes resources and secondary metabolites. The novel deep sea actinomycete species reported from 2006 to 2016 including 21 species under 13 genera with the maximum number from Microbacterium, followed by Dermacoccus, Streptomyces and Verrucosispora, and one novel species for the other 9 genera. Eight genera of actinomycetes were reported to produce secondary metabolites, among which Streptomyces is the richest producer. Most of the compounds produced by the deep sea actinomycetes presented antimicrobial and anti-cancer cell activities. Gene clusters related to biosynthesis of desotamide, heronamide, and lobophorin have been identified from the deep sea derived Streptomyces.

Early repolarization syndrome (ERS) may be a near-Mendelian or an oligogenic disease; however, no direct evidence has been provided to support this theory.We described a large Chinese family with nocturnal sudden cardiac death induced by ERS in most of the young male adults. One missense mutation (p.Q1916R) was found in the major subunit of the L-type calcium channel gene CACNA1C by the direct sequencing of candidate genes. A concomitant gain-of-function variant in the sodium channel gene SCN5A (p.R1193Q) was found to rescue the phenotype of the female CACNA1C-Q1916R mutation carriers, which led to the incomplete penetrance. The functional studies, via the exogenous expression approach, revealed that the CACNA1C-Q1916R mutation led to a decreasing L-type calcium current and the protein expression defect. The decreased calcium current produced by the mutant channel was improved by isoproterenol but exacerbated by testosterone. The effects of CACNA1C-Q1916R mutation and testosterone on cellular electrophysiology were further confirmed by the human ventricular action potential simulation.Our results demonstrated that the loss-of-function CACNA1C-Q1916R mutation contributed to ERS-related sudden cardiac death, and the phenotypic incomplete penetrance was modified by the SCN5A-R1193Q variant and sex. These findings suggest that phenotypes of ERS are modified by multiple genetic factors, which supports the theory that ERS may be an oligogenic disease.

This study aimed to describe the prevalence and risk factors of prehypertension and hypertension in Jiangxi Province, China. Individuals with prehypertension frequently progress into hypertension and are at high risk of developing cardiovascular disease and stroke.A cross-sectional survey of 15,296 participants (15 years or older) was conducted in Jiangxi Province, China, in 2013, using questionnaire forms and physical measurements.The prevalence of prehypertension and hypertension was 32.3% (39.2% in men and 27.6% in women) and 29.0% (30.1% in men and 28.2% in women), respectively. The awareness, treatment, and control rates among all hypertensive participants were 64.8%, 27.1%, and 12.6%, respectively. The prevalence of prehypertension in males declined with age, but the prevalence of hypertension increased in different genders. The prevalence of prehypertension and hypertension increased with increasing body mass index (BMI). The prevalence of prehypertension decreased, in parallel to an increase in the prevalence of hypertension, with increasing waist circumference (WC). A combination of WC and BMI was superior to individual indices in identifying hypertension. A multivariate logistic regression analysis indicated that increasing age, high BMI, high visceral adipose index, and high heart rate were risk factors for prehypertension and hypertension. The high body fat percentage was significantly associated with prehypertension. Living in an urban area, male sex, abdominal obesity, and menopause were correlated with hypertension.Prehypertension and hypertension are epidemic in southern China. Further studies are needed to explore an indicator that can represent the visceral fat accurately and has a close relationship with cardiovascular disease.

The purpose of this study is to assess the prevalence of overweight/obesity, abdominal obesity and obesity-related risk factors in southern China.A cross-sectional survey of 15,364 participants aged 15 years and older was conducted from November 2013 to August 2014 in Jiangxi Province, China, using questionnaire forms and physical measurements. The physical measurements included body height, weight, waist circumference (WC), body fat percentage (BFP) and visceral adipose index (VAI). Multivariate logistic regression analysis was performed to evaluate the risk factors for overweight/obesity and abdominal obesity.The prevalence of overweight was 25.8% (25.9% in males and 25.7% in females), while that of obesity was 7.9% (8.4% in males and 7.6% in females). The prevalence of abdominal obesity was 10.2% (8.6% in males and 11.3% in females). The prevalence of overweight/obesity was 37.1% in urban residents and 30.2% in rural residents, and this difference was significant (P < 0.001). Urban residents had a significantly higher prevalence of abdominal obesity than rural residents (11.6% vs 8.7%, P < 0.001). Among the participants with an underweight/normal body mass index (BMI), 1.3% still had abdominal obesity, 16.1% had a high BFP and 1.0% had a high VAI. Moreover, among obese participants, 9.7% had a low /normal WC, 0.8% had a normal BFP and 15.9% had a normal VAI. Meanwhile, the partial correlation analysis indicated that the correlation coefficients between VAI and BMI, VAI and WC, and BMI and WC were 0.700, 0.666, and 0.721, respectively. A multivariate logistic regression analysis indicated that being female and having a high BFP and a high VAI were significantly associated with an increased risk of overweight/obesity and abdominal obesity. In addition, living in an urban area and older age correlated with overweight/obesity.This study revealed that obesity and abdominal obesity, which differed by gender and age, are epidemic in southern China. Moreover, there was a very high, significant, positive correlation between WC, BMI and VAI. However, further studies are needed to explore which indicator of body fat could be used as the best marker to indirectly reflect cardiometabolic risk.

Mangroves are woody plants located in tropical and subtropical intertidal coastal regions. The mangrove ecosystem is becoming a hot spot for natural product discovery and bioactivity survey. Diverse mangrove actinomycetes as promising and productive sources are worth being explored and uncovered. At the time of writing, we report 73 novel compounds and 49 known compounds isolated from mangrove actinomycetes including alkaloids, benzene derivatives, cyclopentenone derivatives, dilactones, macrolides, 2-pyranones and sesquiterpenes. Attractive structures such as salinosporamides, xiamycins and novel indolocarbazoles are highlighted. Many exciting compounds have been proven as potential new antibiotics, antitumor and antiviral agents, anti-fibrotic agents and antioxidants. Furthermore, some of their biosynthetic pathways have also been revealed. This review is an attempt to consolidate and summarize the past and the latest studies on mangrove actinomycetes natural product discovery and to draw attention to their immense potential as novel and bioactive compounds for marine drugs discovery.

A new alkaloid, 2-(furan-2-yl)-6-(2S,3S,4-trihydroxybutyl)pyrazine (1), along with 12 known compounds, 2-(furan-2-yl)-5-(2S,3S,4-trihydroxybutyl)pyrazine (2), (S)-4-isobutyl-3-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbaldehyde (3), (S)-4-isopropyl-3-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbaldehyde (4), (4S)-4-(2-methylbutyl)-3-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbaldehyde (5), (S)-4-benzyl-3-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbaldehyde (6), flazin (7), perlolyrine (8), 1-hydroxy-β-carboline (9), lumichrome (10), 1H-indole-3-carboxaldehyde (11), 2-hydroxy-1-(1H-indol-3-yl)ethanone (12), and 5-(methoxymethyl)-1H-pyrrole-2-carbaldehyde (13), were isolated and identified from the fermentation broth of an endophytic actinomycetes, Jishengella endophytica 161111. The new structure 1 and the absolute configurations of 2–6 were determined by spectroscopic methods, J-based configuration analysis (JBCA) method, lactone sector rule, and electronic circular dichroism (ECD) calculations. Compounds 8–11 were active against the influenza A virus subtype H1N1 with IC50 and selectivity index (SI) values of 38.3(±1.2)/25.0(±3.6)/ 39.7(±5.6)/45.9(±2.1) μg/mL and 3.0/16.1/3.1/11.4, respectively. The IC50 and SI values of positive control, ribavirin, were 23.1(±1.7) μg/mL and 32.2, respectively. The results showed that compound 9 could be a promising new hit for anti-H1N1 drugs. The absolute configurations of 2–5, 13C nuclear magnetic resonance (NMR) data and the specific rotations of 3–6 were also reported here for the first time.

Multidrug-resistance is a major obstacle facing cancer chemotherapy. This paper demonstrates that novel compound Ophiobolin-O reverses MCF-7/ADR resistance to adriamycin (ADM). The IC50 of ADM treated MCF-7 cells was 2.02 ± 0.05 µM and 74.00 ± 0.18 µM treated MCF-7/ADR cells, about 37-fold, compared to the former. However, 0.1 µM Ophiobolin-O (less than 20% inhibition concentration) combined with ADM caused the decreased IC50 of ADM to 6.67 ± 0.98 µM, indicating it reversed ADM resistance of MCF-7/ADR cells (11-fold). Furthermore, Ophiobolin-O increased ADM-induced mitochondrial pathway apoptosis and G2/M phase arrest, which is partly due to the elevation level of ROS in MCF-7/ADR cells. As we described in this paper, the reversal effect of Ophiobolin-O may be due to the reduction of resistance-related protein P-Glycoprotein (P-gp, also known as MDR1) through inhibiting the activity of the multidrug resistance 1 (MDR1) gene promoter, which makes MCF-7/ADR cells more sensitive to ADM treatment. Assays in nude mice also showed that the combination of ADM and Ophiobolin-O significantly improved the effect of ADM.

Seven new azalomycin F analogs (1–7) were isolated from the broth of mangrove Streptomyces sp. 211726, and respectively identified as 25-malonyl demalonylazalomycin F5a monoester (1), 23-valine demalonylazalomycin F5a ester (2), 23-(6-methyl)heptanoic acid demalonylazalomycins F3a ester (3), F4a ester (4) and F5a ester (5), 23-(9-methyl)decanoic acid demalonylazalomycin F4a ester (6) and 23-(10-methyl)undecanoic acid demalony lazalomycin F4a ester (7). Their structures were established by their spectroscopic data and by comparing with those of azalomycins F3a, F4a and F5a. Biological assays exhibited that 1–7 showed broad-spectrum antimicrobial and anti HCT-116 activities.

The indolocarbazole (ICZ) alkaloids have attracted much attention due to their unique structures and potential therapeutic applications. A series of ICZs were recently isolated and identified from a marine-derived actinomycete strain, Streptomyces sanyensis FMA. To elucidate the biosynthetic machinery associated with ICZs production in S. sanyensis FMA, PCR using degenerate primers was carried out to clone the FAD-dependent monooxygenase gene fragment for ICZ ring formation, which was used as a probe to isolate the 34.6-kb DNA region containing the spc gene cluster. Sequence analysis revealed genes for ICZ ring formation (spcO, D, P, C), sugar unit formation (spcA, B, E, K, J, I), glycosylation (spcN, G), methylation (spcMA, MB), as well as regulation (spcR). Their involvement in ICZ biosynthesis was confirmed by gene inactivation and heterologous expression in Streptomyces coelicolor M1152. This work represents the first cloning and characterization of an ICZ gene cluster isolated from a marine-derived actinomycete strain and would be helpful for thoroughly understanding the biosynthetic mechanism of ICZ glycosides.

Background Several studies have investigated the impact of body mass index (BMI) on the prognosis of atrial fibrillation, but the results remain controversial. We sought to estimate the association of BMI with atrial fibrillation–related outcomes. Methods and Results We systematically searched the Cochrane Library, PubMed, and Elsevier databases for all studies reporting associations between BMI and atrial fibrillation–related outcomes. Relative risks (RRs) and 95% CIs were extracted and pooled. Nine studies with 49 364 participants were included. Underweight BMI was associated with an increased risk of stroke or systemic embolism (RR 1.67, 95% CI 1.12–2.49), all‐cause mortaliity (RR 2.61, 95% CI 2.21–3.09), and cardiovascular death (RR 2.49, 95% CI 1.38–4.50). Nevertheless, the pooled RRs of overweight and obese patients were lower than those of normal‐weight patients for stroke or systemic embolism (overweight: RR 0.91, 95% CI 0.80–1.04; obese: RR 0.84, 95% CI 0.72–0.98; grade 1 obesity: RR 0.89, 95% CI 0.71–1.11; grade 2 obesity: RR 0.64, 95% CI 0.45–0.91; grade 3 obesity: RR 0.82, 95% CI 0.54–1.25), all‐cause death (overweight: RR 0.78, 95% CI 0.62–0.96; obese: RR 0.84, 95% CI 0.64–1.10; grade 1 obesity: RR 0.64, 95% CI 0.57–0.73; grade 2 obesity: RR 0.70, 95% CI 0.47–1.03; grade 3 obesity: RR 0.72, 95% CI 0.59–0.88), and cardiovascular death (overweight: RR 0.79, 95% CI 0.58–1.08; obese: RR 0.99, 95% CI 0.79–1.24). Conclusions Underweight BMI is associated with an increased risk of stroke or systemic embolism, cardiovascular death, and all‐cause death in Asian patients with atrial fibrillation, whereas in all atrial fibrillation patients, overweight and obese BMI was not associated with increased risks of these outcomes.

A rapid method for characterization and online detection of surfactin isomers was developed based on HPLC-MSn (n = 1, 2, 3) analyses, and many surfactin isomers were detected and characterized from the bioactive fraction of the mangrove bacterium Bacillus sp. Inhibitory activities of surfactin isomers on the overproduction of nitric oxide and the release of TNF-a and IL-6 in LPS-induced macrophages were systematically investigated. It was revealed that the surfactin isomers showed strong inhibitory properties on the overproduction of nitric oxide and the release of IL-6 on LPS-induced murine macrophage cell RAW264.7 with IC50 values ranging from 1.0 to 7.0 mM. Structure-activity relationship (SAR) studies revealed that the existence of the free carboxyl group in the structure of surfactin isomers was crucial. These findings will be very helpful for the development of this novel kind of natural product as new anti-inflammatory agents.