MicroRNA-206 as a Potential Cholesterol-lowering Drug is Superior to Statins in Mice.

Hypercholesterolemia is frequently intertwined with hepatosteatosis, hypertriglyceridemia, and hyperglycemia. This study is designed to assess the therapeutic efficacy of miR-206 in contrast to statins in the context of managing hypercholesterolemia in mice. We previously showed that miR-206 is a potent inhibitor of de novo lipogenesis (DNL), cholesterol synthesis and gluconeogenesis in mice. Given that these processes occur within hepatocytes, we employed a mini-circle (MC) system to deliver miR-206 specifically to hepatocytes (designated as MC-miR-206). A single intravenous injection of MC-miR-206 maintained high levels of miR-206 in the liver for at least two weeks, thereby maintaining suppression of hepatic DNL, cholesterol synthesis and gluconeogenesis. MC-miR-206 significantly reduced DNA damage, endoplasmic reticulum and oxidative stress, and hepatic toxicity. Therapeutically, both MC-miR-206 and statins significantly reduced total serum cholesterol and triglycerides as well as LDL cholesterol and VLDL cholesterol in mice maintained on the normal chow and high-fat high-cholesterol diet. MC-miR-206 reduced liver weight, hepatic triglycerides and cholesterol and blood glucose, while statins slightly increased hepatic cholesterol and blood glucose and failed to affect levels of liver weight and hepatic triglycerides. Mechanistically, miR-206 alleviated hypercholesterolemia by inhibiting hepatic cholesterol synthesis, while statins increased HMGCR activity, hepatic cholesterol synthesis and fecal neutral steroid excretion. CONCLUSIONS: MiR-206 facilitates the regression of hypercholesterolemia, hypertriglyceridemia, hyperglycemia, and hepatosteatosis. MiR-206 outperforms statins by reducing hyperglycemia, hepatic cholesterol levels, and hepatic toxicity.

MicroRNA-206-3p suppresses hepatic lipogenesis and cholesterol synthesis while driving cholesterol efflux.

BACKGROUND AND AIMS: Hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia are interconnected metabolic disorders. This study is designed to characterize how microRNA-206-3p (miR-206) simultaneously prevents de novo lipogenesis (DNL), cholesterol synthesis, and VLDL production in hepatocytes while promoting cholesterol efflux in macrophages. APPROACH AND RESULTS: MiR-206 levels were reduced in hepatocytes and macrophages of mice subjected to a high-fat, high-cholesterol diet. A negative feedback between LXRα (liver X receptor alpha) and miR-206 is formed to maintain high LXRα and low miR-206 in hepatocytes. Systemic administration of miR-206 alleviated hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia in mice. A significant reduction in LDL cholesterol and VLDL cholesterol but unaltered HDL cholesterol was observed in miR-206-treated mice. Mirroring these findings, miR-206 reprogrammed the transcriptome of hepatocytes towards the inhibition of DNL, cholesterol synthesis, and assembly and secretion of VLDL. In macrophages, miR-206 activated the expression of genes regulating cholesterol efflux. Hepatocyte-specific expression of miR-206 reduced hepatic and circulating triglycerides and cholesterol, as well as VLDL production, while transplantation of macrophages bearing miR-206 facilitated cholesterol efflux. Mechanistically, miR-206 directly targeted Lxrα and Hmgcr in hepatocytes but facilitated expression of Lxrα in macrophages by targeting macrophage-specific tricho-rhino-phalangeal syndrome 1 (TRPS1), a transcription repressor of Lxrα . By targeting Hmgc r and Lxrα , miR-206 inhibited DNL, VLDL production, and cholesterol synthesis in hepatocytes, whereas it drove cholesterol efflux by activating the TRPS1-LXRα axis. CONCLUSIONS: MiR-206, through differentially modulating LXRα signaling in hepatocytes and macrophages, inhibits DNL, promotes cholesterol efflux, and concurrently hinders cholesterol synthesis and VLDL production. MiR-206 simulates the functions of lipid-lowering medications, statins, and LXRα agonists.

Seasonal variation and human impacts of the river biofilm bacterial communities in the Shiting River in southeastern China.

Bacterial communities in epilithic biofilm plays an important role in biogeochemistry processes in freshwater ecosystems. Nevertheless, our understanding of the geographical and seasonal variations of the composition of bacterial communities in the biofilm of gravels on river bed is still limited. Various anthropogenic activities also influence the biofilm bacteria in gravel rivers. By taking the Shiting River in the upper Yangtze River basin in Sichuan Province as an example, we studied the geographical and seasonal variations of epilithic bacteria and the impacts of weirs and other human activities (e.g., sewage pollution). The river has experienced severe degradation since the Ms 8.0 Wenchuan Earthquake, and weirs were constructed to prevent bed erosion. We collected epilithic biofilms samples at 17 sites along ~ 30 km river reach of the Shiting River in the autumn of 2021 and the summer of 2022, respectively. We applied 16S rRNA gene high-throughput sequencing technology and Functional Annotation of Prokaryotic Taxa (FAPROTAX) to analyze the seasonal and biogeographic patterns and potential functions of the biofilm bacterial communities. The results showed that epilithic bacteria from the two surveys exhibited variation in community composition, bacterial diversity and potential functions. The bacteria samples collected in the autumn have much higher alpha diversity and richness than those collected in the summer. Bacterial richness and diversity were lower downstream of the weirs than upstream. Low diversity was observed at a sampling site influenced by sewage inflow, which contains high level of nitrogen-related chemicals.

Machine learning prognosis model based on patient-reported outcomes for chronic heart failure patients after discharge.

BACKGROUND: Patient-reported outcomes (PROs) can be obtained outside hospitals and are of great significance for evaluation of patients with chronic heart failure (CHF). The aim of this study was to establish a prediction model using PROs for out-of-hospital patients. METHODS: CHF-PRO were collected in 941 patients with CHF from a prospective cohort. Primary endpoints were all-cause mortality, HF hospitalization, and major adverse cardiovascular events (MACEs). To establish prognosis models during the two years follow-up, six machine learning methods were used, including logistic regression, random forest classifier, extreme gradient boosting (XGBoost), light gradient boosting machine, naive bayes, and multilayer perceptron. Models were established in four steps, namely, using general information as predictors, using four domains of CHF-PRO, using both of them and adjusting the parameters. The discrimination and calibration were then estimated. Further analyze were performed for the best model. The top prediction variables were further assessed. The Shapley additive explanations (SHAP) method was used to explain black boxes of the models. Moreover, a self-made web-based risk calculator was established to facilitate the clinical application. RESULTS: CHF-PRO showed strong prediction value and improved the performance of the models. Among the approaches, XGBoost of the parameter adjustment model had the highest prediction performance with an area under the curve of 0.754 (95% CI: 0.737 to 0.761) for death, 0.718 (95% CI: 0.717 to 0.721) for HF rehospitalization and 0.670 (95% CI: 0.595 to 0.710) for MACEs. The four domains of CHF-PRO, especially the physical domain, showed the most significant impact on the prediction of outcomes. CONCLUSION: CHF-PRO showed strong prediction value in the models. The XGBoost models using variables based on CHF-PRO and the patient's general information provide prognostic assessment for patients with CHF. The self-made web-based risk calculator can be conveniently used to predict the prognosis for patients after discharge. CLINICAL TRIAL REGISTRATION: URL: http://www.chictr.org.cn/index.aspx ; Unique identifier: ChiCTR2100043337.

Up-regulated lncRNA SNHG9 mediates the pathogenesis of dilated cardiomyopathy via miR-326/EPHB3 axis.

Dilated cardiomyopathy (DCM) is a common cause of heart failure and also a major indication for heart transplantation. It has been reported that long non-coding RNAs (lncRNAs) are involved in the development of various cardiac diseases. However, the roles of lncRNAs in DCM are not fully understood. In this study, we uncovered that serum SNHG9 (small nucleolar RNA host gene 9, a lncRNA) serves as a biomarker for dilated cardiomyopathy. GEO datasets (GSE124405) were re-analyzed to identify the aberrant lncRNAs in the plasma sample of patients with heart failure. The receiver operating characteristic (ROC) curve was used to assess the expression alterations of the aberrant lncRNAs including SNHG9, XIST, PLCK2-AS1, KIF9-AS1, ARHGAP31-AS1, LINC00482, etc. Using the area under curve (AUC) of ROC, we found that serum SNHG9 exhibits considerable performance in distinguishing DCM from normal control and DCM stage-III from stage-I/II (New York Heart Association Class). Furthermore, we determined the serum SNHG9 expression level of the doxorubicin (Dox)-induced DCM mice model, and found that the upregulated SNHG9 is negatively associated with heart function. Besides, the deletion of SNHG9 by AAV-9 alleviated heart injury in the Dox-induced mice model. Taken together, the current results suggest that SNHG9 is a novel regulatory factor in dilated cardiomyopathy development.

Multiple Component Pharmacokinetics after Oral Administration of Gnaphalium affine Extract in Rats.

Gnaphalium affine is traditionally used to treat hyperuricemia and gout in China. Recently, the hypouricemic and renal protective effects of G. affine extract (GAD) have been deeply evaluated. However, little is known about the pharmacokinetics (PKs) of bioactive constituents in GAD. This study is aimed at investigating the individual and holistic pharmacokinetics of 10 bioactive components (including caffeic acid, caffeoylquinic acids, and flavonoids) in rats after single and multiple administrations of GAD. GAD is orally dosed to normal male rats at doses of 225, 450, or 900 mg/kg/day for 10 consecutive days and also orally administrated to uric acid nephropathy (UAN) rats at a dose of 900 mg/kg/day for 28 consecutive days. Integrated PKs of multiple components are calculated by area under the curve (AUC)-based weighting approach. All the components show a double-peak phenomenon in terms of their plasma concentration-time curves, suggesting that the components undergo enterohepatic circulation. The integrated AUC increases in a good dose-proportional manner with GAD dose. Compared with that in normal rats, the plasma exposure of caffeic acid and caffeoylquinic acids increases by 2.3- to 4.3-fold after 10-day chronic treatment of 900 mg/kg GAD in UAN rats. Modest drug accumulation is observed after 28-day chronic treatment.

Distal Transradial Access in Anatomical Snuffbox for Coronary Angiography and Intervention: An Updated Meta-Analysis.

OBJECTIVE: The previous meta-analysis has assessed that distal transradial access (dTRA) in anatomical snuffbox is safe and effective for coronary angiography and intervention and can reduce radial artery occlusion. However, since the publication of the previous meta-analysis, several observational studies have been added, so we performed an updated meta-analysis to include more eligible studies to compare distal transradial access in anatomical snuffbox with conventional transradial access (cTRA). METHOD: Pubmed, Embase, and Cochrane Library databases were searched for relevant studies from the literature published until 5 January 2021 to evaluate catheterization/puncture failure, hematoma, radial artery spasm, radial artery occlusion (RAO), access time, fluoroscopy time, radiation dose area product, total procedure time, and hemostatic device removal time. The pooled odds ratio (OR), weighted mean difference (WMD), and standardized mean difference (SMD) with 95% confidence interval (95% CI) were calculated for dichotomous and continuous variables, respectively. RESULTS: A total of 9,054 patients from 14 studies were included in the meta-analysis, and we found no significant difference in catheterization/puncture failure (OR = 1.94, 95CI [0.97, 3.86], P=0.06), hematoma (OR = 0.97, 95CI [0.55, 1.73], P=0.926), radial artery spasm (OR = 0.76, 95CI [0.43, 1.36], P=0.354), total procedure time (SMD = 0.23, 95CI [-0.21, 0.68], P=0.308), or radiation dose area product (WMD = 216.88 Gy/cm2, 95CI [-126.24, 560.00], P=0.215), but dTRA had a lower incidence of RAO (OR = 0.39, 95CI [0.23, 0.66], P < 0.001), shorter hemostatic device removal time (WMD = -66.62 min, 95CI [-76.68, -56.56], P < 0.001), longer access time (SMD = 0.32, 95CI [0.08, 0.56], P=0.008), and longer fluoroscopy time (SMD = 0.16, 95CI [-0.00, 0.33], P=0.05) than cTRA. CONCLUSION: Compared with the cTRA, the dTRA has a lower incidence of radial artery occlusion and shorter hemostatic device removal time, which is worthy of further evaluation in clinical practice.

MiR-26a-5p alleviates cardiac hypertrophy and dysfunction via targeting ADAM17.

Cardiac hypertrophy has been a high prevalence rate throughout the world. It has posed a big threat to public health due to limited therapeutic approaches. Previous studies showed that pathological cardiac hypertrophy was associated with autophagy, microRNAs (miRNA), and other signaling pathways, while the molecular mechanisms remain incompletely characterized. In this study, we used thoracic aortic constriction (TAC)-induced mice and angiotensin-II (Ang-II)-induced H9C2 cell line as cardiac hypertrophy model to investigate the role of miR-26a-5p in cardiac hypertrophy. We found that miR-26a-5p was downregulated in cardiac hypertrophy mice. Overexpression of miR-26a-5p by type 9 recombinant adeno-associated virus (rAAV9) reversed the heart hypertrophic manifestations. The phenotypes were also promoted by miR-26a-5p inhibitor in Ang-II-induced H9C2 cells. Through miRNA profile analysis and dual-luciferase reporter assay, ADAM17 was identified as a direct target of miR-26a-5p. Restored expression of ADAM17 disrupted the effect of miR-26a-5p on cardiac hypertrophy. To sum up, these results indicated that miR-26a-5p played an inhibitory role in cardiac hypertrophy and dysfunction via targeting ADAM17. The miR-26a-5p-ADAM17-cardiac hypertrophy axis provided special insight and a new molecular mechanism for a better understanding of cardiac hypertrophy disease, as well as the diagnostic and therapeutic practice.

Assessment of chronic disease self-management in patients with chronic heart failure based on the MCID of patient-reported outcomes by the multilevel model.

PURPOSE: The minimal clinically important difference (MCID) of a patient-reported outcome (PRO) represents the threshold value of the change in the score for that PRO. It is deemed to have an important implication in clinical management. This study was performed to evaluate the clinical significance of chronic disease self-management (CDSM) for patients with chronic heart failure based on the MCID of the chronic heart failure-PRO measure (CHF-PROM). METHODS: A multicenter, prospective cohort study of 555 patients with heart failure were enrolled from July 2018. Advice of CDSM was provided in written form at discharge to all patients. Information regarding CHF-PROM and CDSM were collected during follow-up. Multilevel models were applied to dynamically evaluate the effects of CDSM for CHF-PROM scores, as well as its physical and psychological domains. MCID changes of the PRO were introduced and compared with ß values of CDSM obtained from the multi-level models to further evaluate the clinical significance. The STROBE checklist is shown in Additional file 1. RESULTS: Scores for CHF-PROM improved significantly after discharge. The multilevel models showed that a regular schedule, avoidance of over-eating, a low-sodium diet and exercise increased scores on CHF-PROM. Compared with the MCID, avoidance of over-eating (12.39 vs. 9.75) and maintenance of a regular schedule often (10.98 vs. 9.75), and exercise almost every day (11.36 vs. 9.75) reached clinical significance for the overall summary. Avoidance of over-eating (5.88 vs. 4.79) and a regular schedule almost every day (4.96 vs. 4.79) reached clinical significance for the physical scores. Avoidance of over-eating half of the time (5.26 vs. 4.87) and a regular schedule almost every day (5.84 vs. 4.87) demonstrated clinical significance for the psychological scores. CONCLUSIONS: This study observed an association of avoidance of over-eating and maintenance of a regular schedule with the improvement of CHF-PROM. It provides further evidence for management of heart failure. TRIAL REGISTRATION: Current Prospective Trials NCT02878811; registered August 25, 2016; https://clinicaltrials.gov/ct2/show/NCT02878811?term=NCT02878811&draw=2&rank=1 .

Time-to-event prediction analysis of patients with chronic heart failure comorbid with atrial fibrillation: a LightGBM model.

BACKGROUND: Chronic heart failure (CHF) comorbid with atrial fibrillation (AF) is a serious threat to human health and has become a major clinical burden. This prospective cohort study was performed to design a risk stratification system based on the light gradient boosting machine (LightGBM) model to accurately predict the 1- to 3-year all-cause mortality of patients with CHF comorbid with AF. METHODS: Electronic medical records of hospitalized patients with CHF comorbid with AF from January 2014 to April 2019 were collected. The data set was randomly divided into a training set and test set at a 3:1 ratio. In the training set, the synthetic minority over-sampling technique (SMOTE) algorithm and fivefold cross validation were used for LightGBM model training, and the model performance was performed on the test set and compared using the logistic regression method. The survival rate was presented on a Kaplan-Meier curve and compared by a log-rank test, and the hazard ratio was calculated by a Cox proportional hazard model. RESULTS: Of the included 1796 patients, the 1-, 2-, and 3-year cumulative mortality rates were 7.74%, 10.63%, and 12.43%, respectively. Compared with the logistic regression model, the LightGBM model showed better predictive performance, the area under the receiver operating characteristic curve for 1-, 2-, and 3-year all-cause mortality was 0.718 (95%CI, 0.710-0.727), 0.744(95%CI, 0.737-0.751), and 0.757 (95%CI, 0.751-0.763), respectively. The net reclassification index was 0.062 (95%CI, 0.044-0.079), 0.154 (95%CI, 0.138-0.172), and 0.148 (95%CI, 0.133-0.164), respectively. The differences between the two models were statistically significant (P < 0.05). Patients in the high-risk group had a significantly higher hazard of death than those in the low-risk group (hazard ratios: 12.68, 13.13, 14.82, P < 0.05). CONCLUSION: Risk stratification based on the LightGBM model showed better discriminative ability than traditional model in predicting 1- to 3-year all-cause mortality of patients with CHF comorbid with AF. Individual patients' prognosis could also be obtained, and the subgroup of patients with a higher risk of mortality could be identified. It can help clinicians identify and manage high- and low-risk patients and carry out more targeted intervention measures to realize precision medicine and the optimal allocation of health care resources.

Visit-to-visit variability in blood pressure and the development of chronic kidney disease in treated general hypertensive patients.

BACKGROUND: Data on the association between visit-to-visit variability (VVV) in blood pressure (BP) and the risk of chronic kidney disease (CKD) in general treated hypertensive patients were limited. We aimed to evaluate the relation of VVV in BP with the development of CKD, and examine any possible effect modifiers in hypertensive patients without prior cardiovascular diseases (CVDs) or CKD. METHODS: This is a post hoc analysis of the Renal Sub-study of the China Stroke Primary Prevention Trial (CSPPT). A total of 10 051 hypertensives without CVD and CKD and with at least six visits of BP measurements from randomization to the 24-month visit were included. The main VVV in BP was expressed as standard deviation (SD). The primary outcome was the development of CKD, defined as a decrease in estimated glomerular filtration rate ≥30% and to a level of <60 mL/min/1.73 m2, or end-stage renal disease. RESULTS: The median treatment duration was 4.4 years. After multivariable adjustment, including baseline systolic blood pressure (SBP) and mean SBP during the first 2-year treatment period, there was a significantly positive relationship of SD of SBP with the risk of CKD development (per SD increment; odds ratio, 1.27; 95% confidence interval: 1.10-1.46). The results were similar for coefficient of variation (CV) of SBP. Results across various subgroups, including age, sex, SBP at baseline, treatment compliance, concomitant antihypertensive medications and mean SBP during the first 24-month treatment period, were consistent. CONCLUSIONS: SBP variability, irrespective of mean BP level, was significantly associated with the development of CKD in general treated hypertensive patients.

A nomogram based on a patient-reported outcomes measure: predicting the risk of readmission for patients with chronic heart failure.

BACKGROUND: Health-related quality of life, as evaluated by a patient-reported outcomes measure (PROM), is an important prognostic marker in patients with chronic heart failure. This study aimed to use PROM to establish an effective readmission nomogram for chronic heart failure. METHODS: Using a PROM as a measurement tool, we conducted a readmission nomogram for chronic heart failure on a prospective observational study comprising of 454 patients with chronic heart failure hospitalized between May 2017 to January 2020. A Concordance index and calibration curve were used to evaluate the discriminative ability and predictive accuracy of the nomogram. A bootstrap resampling method was used for internal validation of results. RESULTS: The median follow-up period in the study was 372 days. After a final COX regression analysis, the gender, income, health care, appetite-sleep, anxiety, depression, paranoia, support, and independence were identified and included in the nomogram. The nomogram showed moderate discrimination, with a concordance index of 0.737 (95% CI 0.673-0.800). The calibration curves for the probability of readmission for patients with chronic heart failure showed high consistency between the probability, as predicted, and the actual probability. CONCLUSIONS: This model offers a platform to assess the risk of readmission for different populations with CHF and can assist clinicians with personalized treatment recommendations.

Joint Sensor Selection and Power Allocation Algorithm for Multiple-Target Tracking of Unmanned Cluster based on Fuzzy Logic Reasoning.

The unmanned aerial vehicle (UAV) cluster is gradually attracting more attention, which takes advantage over a traditional single manned platform. Because the size of the UAV platform limits the transmitting power of its own radar, how to reduce the transmitting power while meeting the detection accuracy is necessary. Aim at multiple-target tracking (MTT), a joint radar node selection and power allocation algorithm for radar networks is proposed. The algorithm first uses fuzzy logic reasoning (FLR) to obtain the priority of targets to radars, and designs a radar clustering algorithm based on the priority to form several subradar networks. The radar clustering algorithm simplifies the problem of multiple-radar tracking multiple-target into several problems of multiple-radar tracking a single target, which avoids complex calculations caused by multiple variables in the objective function of joint radar node selection and power allocation model. Considering the uncertainty of the target RCS in practice, the chance-constraint programming (CCP) is used to balance power resource and tracking accuracy. Through the joint radar node selection and power allocation algorithm, the radar networks can use less power resource to achieve a given tracking performance, which is more suitable for working on drone platforms. Finally, the simulation proves the effectiveness of the algorithm.

Joint Adaptive Sampling Interval and Power Allocation for Maneuvering Target Tracking in a Multiple Opportunistic Array Radar System.

In this paper, a joint adaptive sampling interval and power allocation (JASIPA) scheme based on chance-constraint programming (CCP) is proposed for maneuvering target tracking (MTT) in a multiple opportunistic array radar (OAR) system. In order to conveniently predict the maneuvering target state of the next sampling instant, the best-fitting Gaussian (BFG) approximation is introduced and used to replace the multimodal prior target probability density function (PDF) at each time step. Since the mean and covariance of the BFG approximation can be computed by a recursive formula, we can utilize an existing Riccati-like recursion to accomplish effective resource allocation. The prior Cramér-Rao lower boundary (prior CRLB-like) is compared with the upper boundary of the desired tracking error range to determine the adaptive sampling interval, and the Bayesian CRLB-like (BCRLB-like) gives a criterion used for measuring power allocation. In addition, considering the randomness of target radar cross section (RCS), we adopt the CCP to package the deterministic resource management model, which minimizes the total transmitted power by effective resource allocation. Lastly, the stochastic simulation is embedded into a genetic algorithm (GA) to produce a hybrid intelligent optimization algorithm (HIOA) to solve the CCP optimization problem. Simulation results show that the global performance of the radar system can be improved effectively by the resource allocation scheme.

Trimethylamine-N-oxide (TMAO) increased aquaporin-2 expression in spontaneously hypertensive rats.

Recent evidence suggests that elevated plasma levels of Trimethylamine-N-oxide (TMAO) can prolong the duration of elevated blood pressure in rats. The purpose of this study was to investigate the plasma TMAO level in Spontaneously Hypertensive Rats (SHR) and to explore the possible relationship between TMAO and aquaporin-2 (AQP-2) in the formation of hypertension. Twelve-week-old, male Spontaneously Hypertensive rats (SHR, n = 40) and Wistar-Kyoto rats (WKY, n = 40) were accordingly grouped into SHR group and WKY group. Each group was divided randomly into four subgroups: Untreated group, TMAO group, TMAO+Tolvaptan (TMAO+TVP) group, and TVP group, respectively. Systolic blood pressure (SBP), plasma TMAO, plasma osmolality (POsm), plasma vasopressin (PAVP), and plasma AQP-2 (PAQP-2) concentration were measured, and the expression of AQP-2 in kidney medulla was detected by RT-PCR and Western blot. At 14 weeks, rats in SHR TMAO group were shown the increased plasma TMAO, POsm, PAVP, and PAQP-2 levels, while those rats in SHR TMAO+TVP group were shown the decreased plasma TMAO, POsm, and PAQP-2 levels, but an even higher PAVP (due to the blockage of TVP to V2 receptor). These findings indicate that an increase of plasma TMAO levels in SHR leads to a higher plasma osmotic pressure, triggers the regulation of the TMAO-AVP-AQP-2 axis in SHR, elicits the greater water reabsorption, and eventually leads to hypertension.

A new coumarin and a new norlignan from Ficus tsiangii.

Chemical investigation of the stem bark of Ficus tsiangii led to the isolation of a new coumarin ficuscoumarin (1) and a new norlignan ficuslignan (2) by chromatographic methods. Their structures were elucidated on the basis of spectroscopic analyses.

Three new triterpenoid saponins from Albizia julibrissin.

Three new triterpenoid saponins, julibrosides A5-A7 (1-3), together with five known saponins (4-8), were isolated from the stem bark of Albizia julibrissin. Their structures were elucidated on the basis of extensive spectroscopic data analysis of MS, 1D and 2D NMR, and chemical methods. Compounds 7 and 8 were isolated from the genus Albizia for the first time. The new compounds showed no cytotoxicity and anti-inflammatory activity.

CHF-PROM: validation of a patient-reported outcome measure for patients with chronic heart failure.

BACKGROUND: Due to a lack of an appropriate disease-specific patient-reported outcome (PRO) instrument for chronic heart failure including its social support and treatment aspects in China, this study was performed to develop a patient-reported outcome measure (PROM) for patients with chronic heart failure and evaluate its reliability, validity, and feasibility. METHODS: According to the standard PROM guidelines established by the Food and Drug Administration, an item pool was formed by reviewing a large amount of relevant literature and interviewing patients with chronic heart failure about their main symptoms. Thus, the primary scale was created after adjusting the items and language with the help of patients and experts in the field. Next, 155 patients from 8 hospitals in different districts were recruited for a pilot survey using questionnaires containing these items. The patients' responses were analyzed using the classical test theory and item response theory to select high-quality items and determine the subdomains of the scale. This was followed by a formal investigation in the same eight hospitals. In total, 360 patients and 100 healthy subjects were included to evaluate the reliability, validity, and feasibility of the items. Through this process, the final scale was established. RESULTS: The final scale comprised 12 subdomains with 57 items related to physical, psychological, social, and therapeutic areas. The data analysis results of the formal investigation showed that the PROM for chronic heart failure had good reliability, validity, and feasibility. Reliability was verified by Cronbach's alpha coefficient, which was 0.913 for the total scale, 0.903 for the physical domain, 0.941 for the psychological domain, 0.827 for the social domain, and 0.839 for the therapeutic domain. The construct validity results met the relative criteria of confirmatory factor analysis. Discriminant validity was represented by score comparisons of nine subdomains. The response rate and the effective rate of return of the CHF-PROM were 98.94% and 98.92%, respectively. CONCLUSIONS: The final scale coincides with the theoretical framework and better reflects the overall quality of life of patients with chronic heart failure. This scale can be used as a valid instrument to evaluate clinical treatment and clinical trials of chronic heart failure.

MicroRNA-223-5p and -3p Cooperatively Suppress Necroptosis in Ischemic/Reperfused Hearts.

Recent studies have shown that myocardial ischemia/reperfusion (I/R)-induced necrosis can be controlled by multiple genes. In this study, we observed that both strands (5p and 3p) of miR-223 were remarkably dysregulated in mouse hearts upon I/R. Precursor miR-223 (pre-miR-223) transgenic mouse hearts exhibited better recovery of contractile performance over reperfusion period and lesser degree of myocardial necrosis than wild type hearts upon ex vivo and in vivo myocardial ischemia. Conversely, pre-miR-223 knock-out (KO) mouse hearts displayed opposite effects. Furthermore, we found that the RIP1/RIP3/MLKL necroptotic pathway and inflammatory response were suppressed in transgenic hearts, whereas they were activated in pre-miR-223 KO hearts upon I/R compared with wild type controls. Accordingly, treatment of pre-miR-223 KO mice with necrostatin-1s, a potent necroptosis inhibitor, significantly decreased I/R-triggered cardiac necroptosis, infarction size, and dysfunction. Mechanistically, we identified two critical cell death receptors, TNFR1 and DR6, as direct targets of miR-223-5p, whereas miR-223-3p directly suppressed the expression of NLRP3 and IκB kinase α, two important mediators known to be involved in I/R-induced inflammation and cell necroptosis. Our findings indicate that miR-223-5p/-3p duplex works together and cooperatively inhibits I/R-induced cardiac necroptosis at multiple layers. Thus, pre-miR-223 may constitute a new therapeutic agent for the treatment of ischemic heart disease.

[Anti-tumor target identification and molecular mechanism study of total saponins from Albizia julibrissin].

Dried stem bark from Albizia julibrissin(AJ) is a common traditional Chinese herb with several therapy effects including insomnia, anxiety and anti-tumor. Recently, the anti-tumor effect and mechanism studies of AJ have drawn much attention; however, there are still some troubles in chemical composition separation, which leads to the difficulties in pharmacological research of AJ. In this study, we firstly confirmed the proliferation inhibitory effect of total saponins from AJ(TSAJ)on human hepatocarcinoma(HepG2) cells, and also tested the apoptosis induction effect of TSAJ. Then, we successfully captured the potential target proteins from HepG2 lysates by using TSAJ-modified solid beads, and identified the target proteins by LC-MS/MS. Finally, we confirmed 5 target proteins including Exportin-2, Beta-actin-like protein 2, Myosin-9, Protein transport protein Sec61 subunit beta,and Cytochrome c oxidase copper chaperone, which are responsible forcell apoptosis, proliferation, differentiation andmigration. In summary, our findings elucidate the potential anti-tumor mechanism of TSAJ from the direct target proteins, and provide a new insight for exploring the pharmacological mechanism of traditional Chinese medicine.