STAT3-EphA7 axis contributes to the progression of esophageal squamous cell carcinoma.

BACKGROUND: Our previous study has revealed that EphA7 was upregulated in patient-derived esophageal squamous cell carcinoma (ESCC) xenografts with hyper-activated STAT3, but its mechanism was still unclear. MATERIALS AND METHODS: To assess the association between EphA7 and STAT3, western blotting, immunofluorescence, ChIP assay, and qRT-PCR were conducted. Truncated mutation and luciferase assay were performed to examine the promoter activity of EphA7. CCK-8 assay and colony formation were performed to assess the proliferation of ESCC. Cell-derived xenograft models were established to evaluate the effects of EphA7 on ESCC tumor growth. RNA-seq analyses were used to assess the effects of EphA7 on related signals. RESULTS: In this study, EphA7 was found upregulated in ESCC cell lines with high STAT3 activation, and immunofluorescence also showed that EphA7 was co-localized with phospho-STAT3 in ESCC cells. Interestingly, suppressing STAT3 activation by the STAT3 inhibitor Stattic markedly inhibited the protein expression of EphA7 in ESCC cells, in contrast, activation of STAT3 by IL-6 obviously upregulated the protein expression of EphA7. Moreover, the transcription of EphA7 was also mediated by the activation of STAT3 in ESCC cells, and the -2000∼-1500 region was identified as the key promoter of EphA7. Our results also indicated that EphA7 enhanced the cell proliferation of ESCC, and silence of EphA7 significantly suppressed ESCC tumor growth. Moreover, EphA7 silence markedly abolished STAT3 activation-derived cell proliferation of ESCC. Additionally, RNA-seq analyses indicated that several tumor-related signaling pathways were significantly changed after EphA7 downregulation in ESCC cells. CONCLUSION: Our results showed that the transcriptional expression of EphA7 was increased by activated STAT3, and the STAT3 signaling may act through EphA7 to promote the development of ESCC.

Dietary ginger polysaccharides (Gps) improve symptoms in hyperlipidemia rats via alterations in gut microbiota.

The aim of this research is to investigate lipid-lowering influence of dietary ginger (Zingier officinales Rocs) polysaccharides (GPS) on hyperlipidemia rats. Rat models with hyperlipidemia was established by high-fat food diet (HFD). Comparing to GP-negative model group, GPS attenuated several effects of HFD feeding, including the levels of blood lipid biochemistry, serum inflammatory markers (tumor necrosis factor TNF-a, interleukin IL-6), antioxidant capacity (superoxide dismutase SOD, glutathione peroxidase GSH-Px, total antioxidant capacity T-AOC, propylene dialdehyde MDA), uric acid and immune index. 16 S rDNA gene sequencing of fecal samples showed that GPS increased the growth of Akkermansia muciniphila and decreased the proportion of Firmicutes to Bacteroidetes; This changes in microbial community structure can help prevent diet-induced metabolic disease. These results suggest that GPs may act on the gut, changing the structure of the gut microbial community, thereby reducing intestinal and systemic inflammation, thus improved metabolic outcomes.

Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001).

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4-11.0) versus 8.0 months (95% CI, 6.6-9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1-27.3] vs. 15.7 months [13.0-20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.

Role of Quantitative Plaque Analysis and Fractional Flow Reserve Derived From Coronary Computed Tomography Angiography to Assess Plaque Progression.

PURPOSE: To explore the role of quantitative plaque analysis and fractional flow reserve (CT-FFR) derived from coronary computed angiography (CCTA) in evaluating plaque progression (PP). METHODS: A total of 248 consecutive patients who underwent serial CCTA examinations were enrolled. All patients' images were analyzed quantitatively by plaque analysis software. The quantitative analysis indexes included diameter stenosis (%DS), plaque length, plaque volume (PV), calcified PV, noncalcified PV, minimum lumen area (MLA), and remodeling index (RI). PP is defined as PAV (percentage atheroma volume) change rate >1%. CT-FFR analysis was performed using the cFFR software. RESULTS: A total of 76 patients (30.6%) and 172 patients (69.4%) were included in the PP group and non-PP group, respectively. Compared with the non-PP group, the PP group showed greater %DS, smaller MLA, larger PV and non-calcified PV, larger RI, and lower CT-FFR on baseline CCTA (all P <0.05). Logistic regression analysis showed that RI≥1.10 (odds ratio [OR]: 2.709, 95% CI: 1.447-5.072), and CT-FFR≤0.85 (OR: 5.079, 95% CI: 2.626-9.283) were independent predictors of PP. The model based on %DS, quantitative plaque features, and CT-FFR (area under the receiver-operating characteristics curve [AUC]=0.80, P <0.001) was significantly better than that based rarely on %DS (AUC=0.61, P =0.007) and that based on %DS and quantitative plaque characteristics (AUC=0.72, P <0.001). CONCLUSIONS: Quantitative plaque analysis and CT-FFR are helpful to identify PP. RI and CT-FFR are important predictors of PP. Compared with the prediction model only depending on %DS, plaque quantitative markers and CT-FFR can further improve the predictive performance of PP.

Effect of PCSK9 Monoclonal Antibody Versus Placebo/Ezetimibe on Atrial Fibrillation in Patients at High Cardiovascular Risk: A Meta-Analysis of 26 Randomized Controlled Trials.

BACKGROUND: Patients at high cardiovascular risk are closely associated with an increased risk of atrial fibrillation (AF). Whether proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9 mAbs) can attenuate AF progression remains unknown. METHODS: To compare PCSK9 mAbs with placebo or ezetimibe to explore the effect of PCSK9 mAbs therapy on the end-point of incidence of AF, we searched PubMed, Embase, and ClinicalTrials.gov for articles. We used Mantel-Haenszel risk ratio (RR) with corresponding 95% CI for the categorical data, including the incidence of AF and predefined other outcomes of interest. RESULTS: We included 21 articles consisting of 26 randomized controlled trials with a total of 95,635 participants. Quantitative synthesis revealed that PCSK9 mAbs significantly reduce the incidence of AF events (RR 0.84; 95% CI 0.72-0.98; p = 0.03), whereas no obvious differences were seen between the PCSK9 mAbs group and the ezetimibe group (RR 0.90; 95% CI 0.29-2.76; p = 0.85). PCSK9 mAbs also markedly decreased the incidence of cerebrovascular events (RR 0.75; 95% CI 0.66-0.85; p < 0.0001) and new-onset hypertension (RR 0.92; 95% CI 0.87-0.97; p = 0.003), but not the risk of cardiovascular death (RR 0.95; 95% CI 0.85-1.07; p = 0.40) and new-onset diabetes mellitus (RR 1.01; 95% CI 0.95-1.08; p = 0.67). CONCLUSIONS: Overall, the PCSK9 mAbs therapy reduced AF and presented certain cardiovascular benefits in patients at high cardiovascular risk. Further big-scale and long follow-up duration randomized controlled trials that compare PCSK9 mAbs with ezetimibe are required to evaluate the effect of PCSK9 mAbs versus ezetimibe on AF.

Efficacy and Safety of Finerenone for Prevention of Cardiovascular Events in Type 2 Diabetes Mellitus With Chronic Kidney Disease: A Meta-analysis of Randomized Controlled Trials.

ABSTRACT: Only a few meta-analyses evaluated the effect of finerenone on cardiovascular events in type 2 diabetes mellitus with chronic kidney disease. The main aim of this meta-analysis was to gain more reliable assessments of the efficacy and safety of finerenone for prevention of cardiovascular events in diabetic kidney disease. We searched for finerenone in the treatment of diabetic kidney disease from database (PubMed, Embase, and ClinicalTrials.gov ) until December 30, 2021. Relative risks (RRs) with 95% confidence intervals (CIs) calculated by the Mantel-Haenszel random-effects model were used as summary statistics for the categorical data. We included 4 studies that met the inclusion criteria with 13,943 participants. The finerenone group demonstrated a great benefit in reducing the incidence of major adverse cardiac events (RR: 0.88; 95% CI 0.80-0.96; P = 0.003), all-cause mortality (RR: 0.89; 95% CI 0.80-0.99; P = 0.04), myocardial infarction (RR: 0.79; 95% CI 0.67-0.92; P = 0.003), and new-onset hypertension (RR: 0.71; 95% CI 0.62-0.81; P < 0.00001). No difference was found in adverse events between the finerenone and placebo groups (RR: 1.00; 95% CI [0.98-1.01], P = 0.59), whereas a higher risk of hyperkalemia was observed in the finerenone group than in the placebo group (RR = 2.04, 95% CI 1.80-2.32; P < 0.00001). Besides, cerebrovascular events and new-onset atrial fibrillation did not increase in patients taking finerenone. Overall, finerenone treatment showed a great benefit of reducing the risk of major adverse cardiac events, all-cause mortality, myocardial infarction, and new-onset hypertension events in patients with type 2 diabetes mellitus and chronic kidney disease.

Isorhamnetin: A Novel Natural Product Beneficial for Cardiovascular Disease.

Cardiovascular disease (CVD) has become a severe threat to human beings with increasing morbidity and mortality. Isorhamnetin (Iso) shows multiple bioactivities, especially in the cardiovascular system. A literature retrieval strategy was conducted in databases of PubMed, GeenMedical, Sci-Hub, Web of Science, China National Knowledge Infrastructure (CNKI), and Baidu Scholar, with keywords defined as: "Isorhamnetin", "cardiovascular diseases", "pharmacological effects", "phytochemistry", "pharmacokinetics", "clinical application" and "toxicity". The language is restricted to Chinese and English, and publish date ranges from January, 2011 to September, 2021. So far, Iso has been isolated and identified from several natural medicines, including Hippophae rhamnoides L., Ginkgo biloba L. and Typha angustifolia L., etc. The effects of Iso on CVD are pharmacological, including anti-atherosclerosis, reducing blood fat, anti-inflammation, antioxidation, endothelial protection, antithrombosis, antiplatelet aggregation, myocardial protection, and anti-hypertension. Iso could inhibit the activities of CYPs in liver microsomes and suppress hepatocyte injury in vitro. However, no toxicity was observed in vivo. Taken together, Iso has a wide range of positive effects on CVD with safe and multiple pharmacological activities on the cardiovascular system and may be an ideal candidate drug for the prevention and treatment of CVD. Therefore, further studies, especially on its clinic use, need to be conducted. The present review summarizes the recent progress in phytochemistry, pharmacology, and mechanisms of action and provides a reference for future studies on Iso.

[Composition changes reveal relationship between color and enzymatic reaction of Magnoliae Officinalis Cortex during "sweating" process].

In this study, we employed Q Exactive to determine the main differential metabolites of Magnoliae Officinalis Cortex du-ring the "sweating" process. Further, we quantified the color parameters and determined the activities of polyphenol oxidase(PPO), peroxidase(POD), and tyrosinase of Magnoliae Officinalis Cortex during the "sweating" process. Gray correlation analysis was performed for the color, chemical composition, and enzyme activity to reveal the effect of enzymatic reaction on the color of Magnoliae Officinalis Cortex during the "sweating" process. Magnoliae Officinalis Cortex sweating in different manners showed similar metabolite changes. The primary metabolites that changed significantly included amino acids, nucleotides, and sugars, and the secondary metabolites with significant changes were phenols and phenylpropanoids. Despite the different sweating methods, eleven compounds were commonly up-regulated, including L-glutamic acid, acetylarginine, hypoxanthine, and xanthine; six compounds were commonly down-re-gulated, including L-arginine, L-aspartic acid, and phenylalanine. The brightness value(L~*), red-green value(a~*), and yellow-blue value(b~*) of Magnoliae Officinalis Cortex kept decreasing during the "sweating" process. The changes in the activities of PPO and POD during sweating were consistent with those in the color parameter values. The gray correlation analysis demonstrated that the main differential metabolites such as amino acids and phenols were closely related to the color parameters L~*, a~* and b~*; POD was correlated with amino acids and phenols; PPO had strong correlation with phenols. The results indicated that the color change of Magnoliae Officinalis Cortex during "sweating" was closely related to the reactions of enzymes dominated by PPO and POD. The study analyzed the correlations among the main differential metabolites, color parameters, and enzyme activities of Magnoliae Officinalis Cortex in the "sweating" process. It reveals the common law of material changes and ascertains the relationship between color changes and enzymatic reactions of Magnoliae Officinalis Cortex during "sweating". Therefore, this study provides a reference for studying the "sweating" mechanism of Magnoliae Officinalis Cortex and is of great significance to guarantee the quality of Magnoliae Officinalis Cortex.

Characterization of the complete chloroplast genome of Lonicera similis (Caprifoliaceae).

The complete chloroplast genome of Lonicera similis Hemsl. has been characterized by reference-based assembly using Illumina paired-end data. The circular complete cp genome is 155,463 bp in length, containing a large single copy (LSC) region of 89,282 bp, a small single copy (SSC) region of 18,661 bp, which are separated by a pair of inverted repeat (IR) regions of 23,760 bp. A total of 129 genes were predicted from the cp genome, including 83 protein-coding genes, 37 tRNA genes, and eight rRNA genes. Phylogenetic analysis reveals that L. similis is more closely related to Lonicera japonica Thunb. and Lonicera dasystyla Rehd. Our result will provide a reference for the phylogenetic relationship, plant identification and resource development and utilization of Lonicera species.

Development and validation of a deep learning model to screen hypokalemia from electrocardiogram in emergency patients.

BACKGROUND: A deep learning model (DLM) that enables non-invasive hypokalemia screening from an electrocardiogram (ECG) may improve the detection of this life-threatening condition. This study aimed to develop and evaluate the performance of a DLM for the detection of hypokalemia from the ECGs of emergency patients. METHODS: We used a total of 9908 ECG data from emergency patients who were admitted at the Second Affiliated Hospital of Nanchang University, Jiangxi, China, from September 2017 to October 2020. The DLM was trained using 12 ECG leads (lead I, II, III, aVR, aVL, aVF, and V1-6) to detect patients with serum potassium concentrations <3.5 mmol/L and was validated using retrospective data from the Jiangling branch of the Second Affiliated Hospital of Nanchang University. The blood draw was completed within 10 min before and after the ECG examination, and there was no new or ongoing infusion during this period. RESULTS: We used 6904 ECGs and 1726 ECGs as development and internal validation data sets, respectively. In addition, 1278 ECGs from the Jiangling branch of the Second Affiliated Hospital of Nanchang University were used as external validation data sets. Using 12 ECG leads (leads I, II, III, aVR, aVL, aVF, and V1-6), the area under the receiver operating characteristic curve (AUC) of the DLM was 0.80 (95% confidence interval [CI]: 0.77-0.82) for the internal validation data set. Using an optimal operating point yielded a sensitivity of 71.4% and a specificity of 77.1%. Using the same 12 ECG leads, the external validation data set resulted in an AUC for the DLM of 0.77 (95% CI: 0.75-0.79). Using an optimal operating point yielded a sensitivity of 70.0% and a specificity of 69.1%. CONCLUSIONS: In this study, using 12 ECG leads, a DLM detected hypokalemia in emergency patients with an AUC of 0.77 to 0.80. Artificial intelligence could be used to analyze an ECG to quickly screen for hypokalemia.

De-ubiquitination of p300 by USP12 Critically Enhances METTL3 Expression and Ang II-induced cardiac hypertrophy.

Stresses, such as neurohumoral activation, induced pathological cardiac hypertrophy is the main risk factor for heart failure. The ubiquitin-proteasome system (UPS) plays a key role in maintaining protein homeostasis and cardiac function. However, research on the role and mechanism of deubiquitinating enzymes (DUBs) in cardiac hypertrophy is limited. Here, we observe that the deubiquitinating enzyme ubiquitin-specific protease 12(USP12) is upregulated in Ang II-induced hypertrophic hearts and primary neonatal rat cardiomyocytes (NRCMs). Inhibition of USP12 ameliorate Ang II-induced myocardial hypertrophy, while overexpression of USP12 have the opposite effect. USP12 deficiency also significantly attenuate the phenotype of Ang II-induced cardiac hypertrophy in vivo. Moreover, we demonstrate that USP12 aggravate Ang II-induced cardiac hypertrophy by enhancing METTL3, a methyltransferase which catalyze N6-methyladenosine (m6A) modification on messenger RNA and acts as a harmful factor in pathological cardiac hypertrophy. Upregulation of METTL3 reverse the reduction of myocardial hypertrophy induced by USP12 silencing in NRCMs. In contrast, knockdown of METTL3 attenuate the aggravation of myocardial hypertrophy in USP12-overexpressing NRCMs. Furthermore, we discover that USP12 promote the expression of METTL3 via upregulating p300. Mechanistically, USP12 binds and stabilizes p300, thereby activating the transcription of its downstream gene METTL3. Finally, our data show that USP12 is partially dependent on the stabilization of p300 to activate METTL3 expression and promote myocardial hypertrophy. Taken together, our results demonstrate that USP12 acts as a pro-hypertrophic deubiquitinating enzyme via enhancing p300/METTL3 axis, indicating that targeting USP12 could be a potential treatment strategy for pathological cardiac hypertrophy.

A facile macroporous resin-based method for separation of yellow and orange Monascus pigments.

The yellow Monascus pigments (YMPs) named monascin and ankaflavin and the orange Monascus pigments (OMPs) named rubropunctatin and monascorubrin are two groups of bioactive components in a mixture state in the Monascus fermented products. In order to separate these two groups of bioactive pigments, a facile macroporous resin-based method was developed. The weak-polar resin CAD-40 was selected from the seven tested macroporous resins as it revealed better properties for the adsorption and desorption of the YMPs and OMPs. Then, CAD-40 resin was used for column-chromatographic separation. After eluted by 4 bed volumes of ethanol, the yellow group (monascin and ankaflavin) and the orange group (rubropunctatin and monascorubrin) were successfully separated and purified, with an increased content from 49.3% and 44.2% in the crude pigment extract to 85.2% and 83.0% in the final products, respectively. This method would be helpful for the large-scale separation and purification of Monascus pigment products with specific bioactivity.

[Comparative transcriptome and proteome profiling of chlorophyll metabolism pathway in four types of Magnolia officinalis].

Magnolia officinalis is a traditional Chinese medicine,with many years of cultivating process, M. officinalis leaves show more differentiation types due to the exchange of seeds from different provenances. "Da Ao"(DA), "Xiao Ao"(XA), "Chuan Hou"(CH),and "Liu Ye"(LY)are the main types of M. officinalis in Sichuan province of China,and there were obvious differences in growth rate,chemical composition,leaf shape and leaf colour. This study selected different types of M. officinalis leaves(DA,XA,LY and CH)from Sichuan to determine their chlorophyll content. Transcriptomic level sequencing of different types of M. officinalis leaf tissues was by high-throughput sequencing analysis and proteomics used an integrated approach involving TMT labelling and LC-MS/MS to quantify the dynamic changes of the whole proteome of M. officinalis. The results showed that CH had the lowest chlorophyll content while DA had the highest chlorophyll content. Furthermore,transcriptome and proteomics results showed that chlorophyll synthesis pathway in DA glutamine-tRNA reductase,urinary porphyrins decarboxylase(UROD),oxygen-dependent protoporphyrin(ODCO),the original-Ⅲ oxidase protoporphyrin oxidase(PPO),magnesium chelating enzyme subunit ChlD,protoporphyrin magnesium Ⅸ monomethyl ester [oxidative] cyclase(MPPMC)were significantly higher than CH,XA and LY,consistent in the results of determination of chlorophyll content(chlorophyll content was highest of 37.56 mg·g~(-1) FW). Some rate-limiting enzymes related to the chlorophyll synthesis,such as ODCO,PPO and MPPMC were tested by Parallel Reaction Monitoring(PRM),and the results showed that the rate-limiting enzyme content in DA was higher than that in other three types. Therefore,based on the differences in leaf color of four types of M. officinalis,the research conducted a preliminary study on the chlorophyll metabolism pathway in leaves of different types of M. officinalis,and explored relevant genes and proteins causing leaf color differences from the molecular level,so as to lay a foundation for studying the differences in growth and development of different types of M. officinalis.

[Research on network pharmacology of Mongolian medicine Cymbaria in treatment of type 2 diabetes].

The network pharmacology was used to explore the potential active ingredients and action mechanisms of Mongolian medicine Cymbaria in the treatment of type 2 diabetes. According to the literatures collected, Cymbaria component database was established to define important active ingredients and key targets for the anti-hyperglycemic effect to predict action mechanism by active ingredient screening and target prediction techniques. Molecular docking predicted binding activity of main active components with key targets in Cymbaria, then verified the action mechanism in vitro. The Cymbaria component database contained 177 chemical components, 90 chemical structures were confirmed, including 34 chemical components with effective targets. According to the prediction results from network pharmacology, 61 biological processes were significantly affected, such as fatty acid metabolism including PPARs signaling pathway, protein kinase activity and insulin signal pathway. Moreover, the key target proteins were Akt1 and TNFα and quercetin, luteolin and catalpol were the main active ingredients of Cymbaria. Molecular docking prediction showed that luteolin, quercetin and catalpol had a strong binding activity with Akt1; luteolin had strong binding activity but quercetin and catalpol had a certain binding activity with TNFα. Furthermore, catalpol showed hypoglycemic effects in vitro, which up-regulated p-Akt(Ser473)/Akt, PPARα and PPARδ levels and reduced FABP4 expression to regulate glycose and lipid metabolism for improving insulin sensitivity. The network pharmacology predicted that the hypoglycemic effect of Cymbaria was mainly related to anti-inflammatory and lipid regulation with a multi-component, multi-target manner. It provided a scientific view of hypoglycemic effect and action mechanism of Cymbaria for further study.

[Distal radius T-plate for 18 patients with vertical shear medial malleolus fractures].

OBJECTIVE: To explore clinical effects of distal radius T-plates in treating vertical shear medial malleolus fractures. METHODS: From March 2014 and March 2016, clinical data of 18 patients with vertical shear medial malleolus fractures were retrospectively analyzed, including 12 males and 6 females aged from 22 to 63 years old with an average of (41.3±5.2) years old; 6 patients were on the left side and 12 patients were on the right side; 5 patients combined with external malleolus fractures and 13 patients combined with external malleolus and posterior malleolus fractures. All patients were treated with distal radius T-plate fixation. Fracture healing time, loss of reduction, stability of internal fixation, occurrence of osteoarthritis were observed, postoperative AOFAS score at 12 months was used to evaluate clinical effects. RESULTS: All patients were followed up from 18 to 36 months with an average of (22.5±4.3) months. All incisions healed well at stageⅠ. Review of X-ray showed that ankle joints were got anatomically reset. All fractures healed well ranged from 12 to 18 weeks with an average of (13.4±2.4) weeks. After surgery, patients resumed normal walking from 12 to 17 weeks with an average of (14.5±1.3) weeks. No complications such as loss of reduction, loosening or rupture of internal fixation, nonunion of fracture, radiographic appearance of osteoarthritis occurred during following up. AOFAS scores was 92.4 ±6.7 at 12 months after operation, and 15 patients got excellent result, 3 moderate. CONCLUSION: Distal radius T-plates for treatment of vertical shear medial malleolus fractures have advantages of firm fixation, conforming to biomechanical requirements, better matching with plate anatomy, and less soft tissue stimulation. It could achieve early function exercise, obtain good recovery of function, and it is an ideal choice for the treatment of vertical shear medial malleolus fractures.

[Study on regulation of NLRP3/SOCS3-TLR4-NF-κB inflammatory pathway by wogonoside to improve hepatic insulin resistance].

This study was to investigate the hypoglycemic effect of wogonoside to improve hepatic insulin resistance( IR) and its relative anti-inflammatory mechanism. The stable IR-Hep G2 cell model was established by the combination of 1×10-9 mol·L-1 insulin and 3. 75×10-6 mol·L-1 dexamethasone for 48 hours. The changes of glucose consumption in IR-Hep G2 cells with different concentrations of wogonoside( 1,5,10,20,50 µmol·L-1) at different time points( 30,36,48,54 h) were detected by glucose oxidase assay to determine the optimal onset time. Glycogen content and cell viability were respectively detected by ketone method and CCK-8 method. Cryptothermal protein 3( NLRP3),suppressor of cytokine signaling 3( SOCS3),Toll-like receptor 4( TLR4),nuclear factor( NF-κB),interleukin( IL-1ß),IL-6,tumor necrosis factor( TNF-α) involving in the inflammatory signaling pathway,as well as leptin,Ob-R,p-IRS2/IRS2,p-PI3 K/PI3 K( p85),p-Akt/Akt and glucose transporter( GLUT1/2/4) involving in the insulin signaling pathway were detected in IR-HepG2 cells by Western blot. RESULTS: showed that 20 and 50 µmol·L-1 wogonoside significantly up-regulated the glucose consumption of IR-HepG2 cells( P<0. 001) as compared with IR model group,and the optimal onset time was 48 h.Wogonoside had no obvious effect on the cell viability of Hep G2 cells. Further studies showed that 20,50 µmol·L-1 wogonoside respectively increased the glycogen content of IR-HepG2 cells after 48 h treatment,especially in 50 µmol·L-1 group( P<0. 001). Compared with IR model group,wogonoside not only inhibited the protein expression of inflammatory nuclear transcriptional factors NLRP3,SOCS3,TLR4,NF-κB,but also decreased the expression of downstream inflammatory effect factors IL-1ß,IL-6 and TNF-α． In addition,wogonoside elevated Ob-R,p-IRS2/IRS2,p-PI3 K/PI3 K( p85),p-Akt/Akt and GLUT1/2/4 protein expression,whereas it suppressed leptin expression that was regulated by SOCS3. Wogonoside could promote glucose uptake and increase glycogen content to enhance insulin sensitivity in IR-Hep G2 cells. The hypoglycemic effect may be related to the intervention of NLRP3/SOCS3-TLR4-NF-κB inflammatory pathway and decrease of inflammatory factor expression.

Peripheral leukocyte count and risk of bleeding in patients with non-valvular atrial fibrillation taking dabigatran: a real-world study.

BACKGROUND: The association between peripheral leukocyte count and bleeding events in nonvalvular atrial fibrillation (NVAF) patients treated with dabigatran remains unclear. This study aimed to explore the association between leukocyte count and bleeding events after excluding other confounders in NVAF patients taking dabigatran. METHODS: A total of 851 NVAF patients treated with dabigatran (110 mg bid) were recruited from 12 centers in China from February 2015 to December 2017. Follow-up was completed by May 2018. The exposure and outcome variables were leukocyte count measured at baseline and the number of bleeding events within the subsequent 6 months. Multivariate Cox proportional hazards models were constructed to analyze independent associations, and a Cox proportional hazards regression with cubic spline functions and smooth curve fitting (penalized spline method) was used to address nonlinearity between leukocyte count and bleeding. The inflection point was calculated using a recursive algorithm, and then a two-piecewise Cox proportional hazards model for both sides of the inflection point was constructed. RESULTS: During 6-month follow-up, 87 participants occurred bleeding events. For every 1 × 10/L increase in leukocyte count, the risk of bleeding increased by 11% (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 0.99-1.25). The smooth curve showed nonlinear relationship between leukocyte count and bleeding events. The inflection point of the leukocyte count was 6.75 × 10/L. For leukocyte counts < 6.75 × 10/L, the HR (95% CI) was 0.88 (0.69-1.13), and for leukocyte counts ≥ 6.75 × 10/L, the HR (95% CI) was 1.28 (1.09-1.51). CONCLUSION: This study found a J-shaped association between baseline leukocyte count and risk of bleeding in NVAF patients treated with dabigatran. CLINICAL TRIAL REGISTRATION: NCT02414035, https://clinicaltrials.gov.

Treatment of chronic heart failure in the 21st century: A new era of biomedical engineering has come.

Chronic heart failure (CHF) is a challenging burden on public health. Therapeutic strategies for CHF have developed rapidly in the past decades from conventional medical therapy, which mainly includes administration of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists, to biomedical engineering methods, which include interventional engineering, such as percutaneous balloon mitral valvotomy, percutaneous coronary intervention, catheter ablation, biventricular pacing or cardiac resynchronization therapy (CRT) and CRT-defibrillator use, and implantable cardioverter defibrillator use; mechanical engineering, such as left ventricular assistant device use, internal artery balloon counterpulsation, cardiac support device use, and total artificial heart implantation; surgical engineering, such as coronary artery bypass graft, valve replacement or repair of rheumatic or congenital heart diseases, and heart transplantation (HT); regenerate engineering, which includes gene therapy, stem cell transplantation, and tissue engineering; and rehabilitating engineering, which includes exercise training, low-salt diet, nursing, psychological interventions, health education, and external counterpulsation/enhanced external counterpulsation in the outpatient department. These biomedical engineering therapies have greatly improved the symptoms of CHF and life expectancy. To date, pharmacotherapy, which is based on evidence-based medicine, large-scale, multi-center, randomized controlled clinical trials, is still a major treatment option for CHF; the current interventional and mechanical device engineering treatment for advanced CHF is not enough owing to its individual status. In place of HT or the use of a total artificial heart, stem cell technology and gene therapy in regenerate engineering for CHF are very promising. However, each therapy has its advantages and disadvantages, and it is currently possible to select better therapeutic strategies for patients with CHF according to cost-efficacy analyses of these therapies. Taken together, we think that a new era of biomedical engineering for CHF has begun.

[Compound traditional Chinese medicine in treatment of diabetes].

Diabetes is a chronic disorder of glucose metabolism characterized by elevated blood glucose levels. With the improvement in living standards and the changes in lifestyle,T2 DM incidence has a dramatic increase in the past decades,bringing a series of public health problems. In the research and development field of diabetic drugs,T1 DM drugs are mainly long-acting sustained-release insulin preparations,whereas T2 DM drugs mainly are based on single target. T2 DM drugs usually have a good anti-hyperglycemic effect,but with side effects for long-term administration. Therefore,the research and development of hypoglycemic drugs focus on formula drugs with multi-component,multi-target and multi-pathway effects. In the similar principle of action,traditional Chinese medicine formula has achieved a good efficacy in the treatment of diabetes,with mild anti-hyperglycemic effects and multiple-component synergistic effects in intervening the pathogenesis of diabetes,including additive effect,synergy effect and toxicity scattering effect. This article mainly reviews clinical trials and mechanisms of action of traditional Chinese medicine formula for the treatment of diabetes,so as to provide a reference to the rational and effective clinical application of traditional Chinese medicine formula in treating diabetes.

Procyanidin B2 protects against diet-induced obesity and non-alcoholic fatty liver disease via the modulation of the gut microbiota in rabbits.

BACKGROUND: Procyanidins have beneficial effects on metabolic syndrome and antimicrobial activity, but the mechanisms underlying these effects are unclear. AIM: To investigate the effects of procyanidin B2 (PB2) on non-alcoholic fatty liver disease and to explore the possible mechanism. METHODS: Thirty male New Zealand white rabbits were randomized into three groups. All of them were fed either a high-fat-cholesterol diet (HCD) or chow diet. HCD-fed rabbits were treated with vehicle or PB2 daily for 12 wk. Body weight and food intake were evaluated once a week. Serum biomarkers, such as total cholesterols, triglycerides, and aspartate transaminase, were detected. All rabbits were sacrificed and histological parameters of liver were assessed by hematoxylin and eosin-stained sections. Moreover, several lipogenic genes and gut microbiota (by 16S rRNA sequencing) were investigated to explore the possible mechanism. RESULTS: The HCD group had higher body weight, liver index, serum lipid profile, insulin resistance, serum glucose, and hepatic steatosis compared to the CHOW group. PB2 treatment prevented HCD-induced increases in body weight and hypertriglyceridemia in association with triglyceride accumulation in the liver. PB2 also ameliorated low-grade inflammation, which was reflected by serum lipopolysaccharides and improved insulin resistance. In rabbit liver, PB2 prevented the upregulation of steroid response element binding protein 1c and fatty acid synthase and the downregulation of carnitine palmitoyltransferase, compared to the HCD group. Moreover, HCD led to a decrease of Bacteroidetes in gut microbiota. PB2 significantly improved the proportions of Bacteroidetes at the phylum level and Akkermansia at the genus level. CONCLUSION: Our results indicate the possible mechanism of PB2 to improve HCD-induced features of metabolic syndrome and provide a new dietary supplement.