Search

Shikonin Attenuates Acetaminophen-Induced Hepatotoxicity by Upregulation of Nrf2 through Akt/GSK3 Signaling. (D) L-02 cells were pretreated with lithium chloride (20 mM) for 4 h, followed by treatment with SHK for 4 h, and GSK3 protein and phosphorylated GSK3 levels were evaluated via Western blotting. (C) L-02 cells were pretreated with LY294002 (20 M) for 1 h followed by treatment with SHK for 4 h, and GSK3 protein and phosphorylated GSK3 levels were evaluated via Western blotting. [Extracted from the article]

Background: Postoperative atrial fibrillation (POAF) is the most common complication after cardiothoracic surgery or cardiac intervention. Colchicine is an anti-inflammatory agent that was associated with improved cardiovascular outcomes. However, its effect on POAF prevention was inconsistent across studies. Therefore, the aim of this meta-analysis was to evaluate the efficacy of colchicine in prevention of POAF.Methods: We searched PubMed, Embase, ClinicalTrials.gov, Cochrane Library database and Google Scholar for randomized controlled trials (RCTs), using terms "atrial fibrillation" and "colchicine". The primary end point was the occurrence of clinically diagnosed atrial fibrillation. The relative risk (RR) and 95% confidence interval (CI) were evaluated. Estimates were pooled using DerSimonian-Laird random-effects model. We also performed subgroup analyses based on the duration and dose of colchicine treatment.Results: A total of 9 RCTs were included in this meta-analysis, enrolling a total of 2031 patients. Colchicine significantly reduces the incidence of POAF (RR 0.62; 95% CI, 0.52-0.74, P < 0.001, I2 = 0%). Subgroup analyses indicated that the protective effect of colchicine on POAF was slightly stronger in the long-duration group (RR 0.60; 95% CI, 0.48-0.75, P < 0.001, I2 = 0%) than in the short-duration group (RR 0.65; 95% CI, 0.49-0.86, P < 0.001, I2 = 0%).Conclusion: Colchicine is effective in preventing the occurrence of POAF. The efficacy of colchicine can be slightly increased over treatment duration, with no obvious adverse reactions. [ABSTRACT FROM AUTHOR]

Background: Physicians' depression can damage their physical and mental health and can also lead to prescribing errors and reduced quality of health care. Emergency physicians are a potentially high-risk community, but there have been no large-sample studies on the prevalence and predictors of depression among this population. Methods: A nationally representative cross-sectional survey of 15,243 emergency physicians was conducted in 31 provinces across China between July and September 2019. Multivariable logistic regression analysis was performed to identify predictors of depression. Results: A total of 35.59% of emergency physicians suffered from depression. Emergency physicians who were male (OR=0.91) and older [>37 and ≤43 (OR=0.83) or >43 (OR=0.71)], had high (OR=0.63) or middle (OR=0.70) level income, and participated in physical inactivity (OR=0.85) were not more likely to suffer depression. Meanwhile, those who were unmarried (OR=1.13) and smokers (OR=1.12) had higher education levels [Bachelor's degree (OR=1.57) or Master's degree or higher (OR=1.82)], long work tenure [>6 and ≤11 (OR=1.15) or >11;11 (OR=1.19)], poorer health status [fair (OR=1.67) or poor (OR=3.79)] and sleep quality [fair (OR=2.23) or poor (OR=4.94)], a history of hypertension (OR=1.13) and coronary heart disease (OR=1.57) and experienced shift work (OR=1.91) and violence (OR=4.94)]. Conclusion: Nearly one third of emergency physicians in China suffered from depression. Targeted measures should be taken to reduce the prevalence of depression to avoid a decline in health care quality and adversely impact the supply of emergency medical services. [ABSTRACT FROM AUTHOR]

Background: Data on the efficacy and safety of nonvitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients with cancer are limited. Therefore, we conducted a meta-analysis to compare the efficacy and safety between NOACs and warfarin in this population. Methods: A comprehensive search of the PubMed, Embase, and Cochrane databases for articles published through July 2020 was performed. An evaluation of each study was conducted, and data were extracted. Pooled odds ratio (OR) estimates and 95% CIs were calculated. Results: Eight studies (3 randomized controlled trials (RCTs) and 5 retrospective cohort studies) involving a total of 24,665 patients were included. Among the RCTs, there were no significant differences in the rates of stroke or systemic embolism (OR=0.69; 95% CI, 0.45–1.06; P=0.09), venous thromboembolism (OR=0.91; 95% CI, 0.33–2.52; P=0.86), myocardial infarction (OR=0.74; 95% CI, 0.44–1.23; P=0.24), major bleeding (OR=0.81; 95% CI, 0.61–1.06; P=0.12), or major or nonmajor clinically relevant bleeding (OR= 0.98; 95% CI, 0.82–1.19; P=0.86) between the NOAC and warfarin groups. Among the observational studies, patients who used NOACs had a significantly lower risk than those who used warfarin. The prevalence rates of ischemic stroke (OR=0.51; 95% CI, 0.28–0.92; P=0.02), VTE (OR=0.50; 95% CI, 0.41–0.60; P<0.00001), major bleeding (OR=0.28; 95% CI, 0.14–0.55; P=0.0002), and intracranial or gastrointestinal bleeding (OR=0.59; 95% CI, 0.37–0.92; P=0.02) were significantly reduced in the NOAC group. Conclusion: Our meta-analysis confirms that NOACs are as safe and effective as warfarin and can be applied in the real world; this data can serve as a reference for clinical doctors for formulating treatment strategies. [ABSTRACT FROM AUTHOR]

Background and Purpose: The free fatty acid receptor 1 (FFAR1) plays an important role in glucose-stimulated insulin secretion making it an attractive anti-diabetic target. This study characterizes the pharmacological profile of HWL-088 (2-(2-fluoro-4-((2'-methyl-[1,1'- biphenyl]-3-yl)methoxy)phenoxy)acetic acid), a novel highly potent FFAR1 agonist in vitro and in vivo. Moreover, we investigated the long-term effects of HWL-088 alone and in combination with metformin in diabetic mice.Experimental Approach: In vitro effects of HWL-088 on FFAR1 and PPARα/γ/δ were studied in cell-based assays. Glucose-dependent insulinotropic effects were evaluated in MIN6 cell line and in rats. Long-term effects on glucose and lipid metabolism were investigated in ob/ob mice.Key Results: HWL-088 is a highly potent FFAR1 agonist (EC50 = 18.9 nM) with moderate PPARδ activity (EC50 = 570.9 nM) and promotes glucose-dependent insulin secretion in vitro and in vivo. Long-term administration of HWL-088 exhibited better glucose control and plasma lipid profiles than those of another FFAR1 agonist, TAK-875, and synergistic improvements were observed when combined with metformin. Moreover, HWL-088 and combination therapy improved β-cell function by up-regulation of pancreas duodenum homeobox-1, reduced fat accumulation in adipose tissue and alleviated fatty liver in ob/ob mice. The effect of HWL-088 involves a reduction in hepatic lipogenesis and oxidative stress, increased lipoprotein lipolysis, glucose uptake, mitochondrial function and fatty acid β-oxidation.Conclusion and Implications: These data indicate that long-term treatment with HWL-088, a highly potent FFAR1 agonist, improves glucose and lipid metabolism and may be useful for the treatment of diabetes mellitus by mono-therapy or combination with metformin. [ABSTRACT FROM AUTHOR]

Abstract The free fatty acid receptor 1 (FFA1 or GPR40) and peroxisome proliferator-activated receptor δ (PPARδ) have attracted a lot of attention due to their role in promoting insulin secretion and sensibility, respectively, which are two major features of diabetes. Therefore, the dual FFA1/PPARδ agonists would increase insulin secretion and sensibility by FFA1 and PPARδ activation. In this study, we hybrid FFA1 agonist AM-4668 with PPARδ agonist GW501516, leading to the identification of orally bioavailable dual agonist 32 , which revealed high selectivity over other PPARs. Moreover, compound 32 exhibited good pharmacokinetic profiles with high plasma concentration, sustained half-life and low clearance in vivo. During the hypoglycemic test, a dual agonist 32 enhanced the tolerance of ob/ob mice for glucose loading in a dose-dependent manner. Our results suggest that dual FFA1/PPARδ agonist could be a valuable therapy for type 2 diabetes. Graphical abstract Aiming to develop potent dual FFA1/PPARδ agonists, we have hybrid the FFA1 agonist AM-4668 with PPARδ agonist GW501516 based on their structural similarity, exemplified by the orally bioavailable dual FFA1/PPARδ agonist 32. Image 1 Highlights • A therapeutic strategy that simultaneous targets insulin secretion and resistance. • The first-in-class dual FFA1/PPARδ agonist was identified by the hybrid strategy. • Compound 32 revealed high activity on FFA1/PPARδ and high selectivity over other PPARs. • Compound 32 revealed excellent pharmacokinetic profiles. • Compound 32 suppressed the excursion of glucose levels in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

The free fatty acid receptor 1 (FFA1) enhances the glucose-stimulated insulin secretion without the risk of hypoglycemia. However, most of FFA1 agonists have a common biphenyl moiety, leading to a relative deprivation in structure types. Herein, we describe the exploration of non-biphenyl scaffold based on the co-crystal structure of FFA1 to increase additional interactions with the lateral residues, which led to the identification of lead compounds 3 and 9 . In induced-fit docking study, compound 3 forms an edge-on interaction with Trp150 by slightly rotating the indole ring of Trp150, and compound 9 has additional hydrogen bond and δ-π interactions with Leu135, which demonstrated the feasibility of our design strategy. Moreover, lead compounds 3 and 9 revealed improved polar surface area compared to GW9508, and have considerable hypoglycemic effects in mice. This structure-based study might inspire us to design more promising FFA1 agonists by increasing additional interactions with the residues outside of binding pocket. [ABSTRACT FROM AUTHOR]

Identifying the factors dominating ecosystem water flux is a critical step for predicting evapotranspiration (ET). Here, the fuzzy rough set with binary shuffled frog leaping (BSFL-FRSA) was used to identify both individual factors and multi-factor combinations that dominate the half-hourly ET variation at evergreen needleleaf forests (ENFs) sites across three different climatic zones in the North America. Among 21factors, air temperature (TA), atmospheric CO 2 concentration (CCO 2 ), soil temperature (TS), soil water content (SWC) and net radiation (NETRAD) were evaluated as dominant single factors, contributed to the ET variation averaged for all ENF sites by 48%, 36%, 32%, 18% and 13%, respectively. While the importance order would vary with climatic zones, and TA was assessed as the most influential factor at a single climatic zone level, counting a contribution rate of 54.7%, 49.9%, and 38.6% in the subarctic, warm summer continental, and Mediterranean climatic zones, respectively. In view of impacts of each multi-factors combination on ET, both TA and CCO 2 made a contribution of 71% across three climate zones; the combination of TA, CCO 2 and NETRAD was evaluated the most dominant at Mediterranean and subarctic ENF sites, and the combination of TA, CCO 2 and TS at warm summer continental sites. Our results suggest that temperature was most critical for ET variation at the warm summer continental ENF. [ABSTRACT FROM AUTHOR]

Colchicine significantly reduces the incidence of POAF (RR 0.62; 95% CI, 0.52-0.74, I P i < 0.001, I SP 2 sp = 0%). Correction: A meta-analysis of colchicine in prevention of atrial fibrillation following cardiothoracic surgery or cardiac intervention Colchicine significantly reduces the incidence of POAF (RR 0.62; 95% CI, 0.52-0.74, I P i < 0.001, I SP 2 sp = 0%). [Extracted from the article]

The spatial variability, driving forces, and uncertainties of the net ecosystem exchange (NEE) of carbon between the temperate forests and the atmosphere remain elusive. Here, we proposed a fuzzy rough set algorithm with binary shuffled frog leaping (BSFL-FRSA) to identify main driving variables and define the contribution rate of main drivers to NEE. As a case study, we applied the approach to nine deciduous forest eddy covariance flux sites in the northeastern United States. The results show that the BSFL-FRSA effectively retained most information using just a few variables, and it performed better than the GA-FRSA (fuzzy rough set with genetic algorithm). Temperature, radiation, and soil water content were identified as the most influential variables (impact in descending order) to NEE across all sites. Soil temperature was the most important variable explained 59.6% of the NEE variance. Soil temperature and net radiation together, explained 72.7% of the NEE variance, was the most important two variables among all possible two-variable combinations. The most influential three variables on NEE among all possible three-variable combinations were soil temperature, net radiation, and soil water content or relative humidity (explained 81.1% of the NEE variance). The variance attribution approach presented here is generic and can be applied to other studies; the dominant influence of soil temperature begs for accurate characterization of soil temperature dynamics in time and space particularly in the global warming context. [ABSTRACT FROM AUTHOR]

Abstract: Separation and collection of environmental nanoparticles (ENPs) in natural systems are of paramount importance in research on their nature and physicochemical properties for understanding their associated properties of adsorbing or binding to organic and trace metal contaminants. However, efficient separation and collection of ENPs in nature system remain obscure. This study aimed to use an automated ultrafiltration device (AUD) to demonstrate efficient collection of ENPs from highly weathered red soils. Synchrotron and conventional X-ray diffraction (XRD) with oriented and random powder specimens were employed to identify the composition of clay minerals with various particle-size fractions (PSFs, <2000, 450–2000, 100–450, and 1–100nm). The AUD was used successfully to overcome the problem of efficiently collecting ENPs in large quantities in red soils. This study showed that the major clay minerals in the <2000 and 450–2000nm size fractions were illite, kaolinite, and minor constituents of goethite and hematite by synchrotron and conventional XRD analyses. Illite and kaolinite were confirmed to be presented in the 1–100nm size fraction by conventional XRD analysis with oriented specimens. From synchrotron random powder XRD analysis, illite, kaolinite, goethite, and hematite nanoparticles were present. Synchrotron XRD patterns and transmission electron microscopy (TEM) images provided unequivocal evidence of goethite and hematite existence in the 1–100nm size fraction. The AUD has the characteristics of automation, easy operation, and high efficiency in the separation of nanoparticles and would, thus, facilitate future research and developments in environmental nanoscience, nanotechnology and their impacts on the ecosystem. [Copyright &y& Elsevier]

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with a disappointing prognosis. The aim of this study was to investigate the anticancer effect of sesamin and the underlying mechanism. The MTT assay was used to detect the proliferation of NSCLC cells. The cell cycle and apoptosis were analyzed by flow cytometry. The protein levels of Akt, p-Akt (Ser473), p53, cyclin D1, CDK2, MDM2, p-MDM2 (Ser166) were detected by western blotting. The expression of p-Akt (Ser473), p53 and Ki67 in vivo was analyzed by IHC. Histopathologic analyses of major organs (heart, liver, spleen, lung and kidney) were performed by H&E staining. The results show that sesamin suppressed cell proliferation and induced apoptosis of NSCLC cells (A549 and H1792) in a dose-dependent manner. Treatment with sesamin caused cell cycle arrest at G1 phase and inhibited cyclin D1 and CDK2 expression. In addition, sesamin inhibited Akt activity and upregulated p53 expression both in vivo and in vitro. When Akt and p53 were suppressed by LY294002 and PFTα, respectively, sesamin exerted no additional effects. The in vivo results mostly matched the in vitro findings. Specifically, sesamin exerted little damage to major organs. Taken together, this study demonstrates that sesamin suppresses NSCLC cell proliferation by induction of G1 phase cell cycle arrest and apoptosis via Akt/p53 pathway. Therefore, sesamin may be a promising adjuvant treatment for NSCLC therapy. Unlabelled Image • Sesamin suppresses NSCLC cell proliferation and viability. • Sesamin induces G1 phase cell cycle arrest and apoptosis via Akt/p53 pathway. • Sesamin inhibits NSCLC growth in vivo without damage to major organs. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) overdose-induced acute liver damage is mostly due to overwhelmingly increased oxidative stress. Nuclear factor-erythroid 2-related factor2 (Nrf2) plays an important role in alleviating APAP hepatic toxicity. Shikonin (SHK) enhances Nrf2 in multiple lines of normal cells. Nevertheless, whether SHK protects against APAP-induced liver toxicity remains undefined. This study found SHK defended APAP-induced liver toxicity, as well as reversed the levels of serum alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO) activity, and reactive oxygen species (ROS), while it enhanced the liver glutathione (GSH) level in APAP-treated mice. SHK rescued the cell viability and GSH depletion, but neutralized oxidative stress in APAP-treated human normal liver L-02 cells. Mechanically, SHK increased Nrf2 expression in the exposure of APAP at the protein level but not at the mRNA level. Inhibition of Nrf2 blocked the SHK effect in APAP-treated hepatocytes. Furthermore, SHK improved Nrf2 stability through stimulating PI3K/Akt pathway, thus inhibiting GSK-3β. In vivo studies confirmed the close correlation of liver protection of SHK against APAP and Akt/GSK-3β/Nrf2 pathway. In conclusion, this study reveals that SHK prevents APAP hepatotoxicity by upregulation of Nrf2 via PI3K/Akt/GSK-3β pathway. Therefore, SHK may be a promising candidate against APAP-induced liver injury. [ABSTRACT FROM AUTHOR]

Objective. Since early diagnosis is very important for treating gastric cancer (GC), we aimed to detect serum small proline-rich protein2A (SPRR2A) to verify its diagnostic value for GC patients. Methods. Serum samples were collected from 200 patients with GC, 100 patients with gastritis, 40 patients with rectal cancer (RC), 50 patients with colon cancer (CC), and 100 healthy controls. An enzyme-linked immunosorbent assay (ELISA) detection kit was applied to measure serum SPRR2A concentration. The correlations between serum SPRR2A and carcinoembryonic antigen (CEA), clinical pathological parameters of GC, and receiver operating characteristic (ROC) curve were also analyzed. Results. The median serum SPRR2A concentration in GC patients was significantly higher than those in healthy controls and gastritis or colorectal cancer patients (P < 0.001). Serum SPRR2A concentration at a cut-off value of 80.7 pg/ml yielded an AUC of 0.851, with 75.7% sensitivity and 74.5% specificity for discriminating GC patients from healthy people. The AUC for the serum SPRR2A concentration combined with the CEA concentration was 0.876, with 79.7% sensitivity and 78.7% specificity. Similarly, serum SPRR2A discriminated GC patients from gastritis patients with an AUC of 0.820, with 90.5% sensitivity and 61.7% specificity. The AUC for the serum SPRR2A concentration combined with the CEA concentration was 0.848, with 87.8% sensitivity and 68.1% specificity. The serum SPRR2A levels in GC patients were associated with lymph node metastasis and the tumor-node-metastasis (TNM) stage (P < 0.05). There was an obvious difference in serum SPRR2A expression between GC patients before and after surgery (P < 0.0001). Conclusion. These results suggest that serum SPRR2A can be used as an effective marker for GC. [ABSTRACT FROM AUTHOR]

Background and Purpose: Non‐small‐cell lung cancer (NSCLC) accounts for up to 80–85% of all lung cancers and has a disappointing prognosis. Flavonoids exert anticancer properties, mostly involving stimulation of ROS production without significant toxicity to normal cells. This study was aimed to delineate the effect of diosmetin, a natural flavonoid, on NSCLC cells and its ability to enhance the antitumour activity of paclitaxel. Experimental Approach NSCLC cells, normal cell lines HLF‐1 and BEAS‐2B, and immunodeficient mice were chosen as models to study the effects of diosmetin. Changes in cell viability, apoptosis, and ROS were analysed by MTT assay, flow cytometry assay, and fluorescent probe DCFH‐DA. Expression of proteins and mRNA was determined by Western blotting and real‐time RT‐PCR. Growth of xenografted tumours was measured. Spleens and other vital organs were analysed with histological and immunohistochemical techniques. Key Results: Diosmetin induced selective apoptotic death in NSCLC cells but spared normal cells, via ROS accumulation. Diosmetin induced ROS production in NSCLC cells probably via reducing Nrf2 stability through disruption of the PI3K/Akt/GSK‐3β pathway. The in vitro and in vivo xenograft studies showed that combined treatment of diosmetin and paclitaxel synergistically suppressed NSCLC cells. Histological analysis of vital organs showed no obvious toxicity of diosmetin, which matched our in vitro findings. Conclusions and Implications: Diosmetin selectively induced apoptosis and enhanced the efficacy of paclitaxel in NSCLC cells via ROS accumulation through disruption of the PI3K/Akt/GSK‐3β/Nrf2 pathway. Therefore, diosmetin may be a promising candidate for adjuvant treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Objective To investigate the differential protein expression before and after menopause in women with nonalcoholic fatty liver disease (NAFLD) and to explore novel markers for menopausal NAFLD. Methods Eight serum samples collected from pre- or post-menopausal women with NAFLD were analysed by iTRAQ 2D-LC-MS/MS. Two protein candidates were selected and verified by enzyme-linked immunosorbent assay (ELISA) in serum samples collected from a one hundred and fifty-three female population subsequently, including 51 in post-menopausal status with NAFLD, 41 in pre-menopausal with NAFLD, 19 healthy individuals in post-menopausal status and 42 healthy pre-menopausal women. Results A total of one hundred and sixty-seven proteins exhibiting significant changes were characterized, among which sixty-five were up-regulated and one hundred and two were down-regulated. Of those altered proteins, the expression of serum retinol binding protein 4 (RBP4) and galectin-3 binding protein (LGALS3BP) was obviously increased in the post-menopausal patient group compared to the other. ELISA validations for the two proteins were consistent with the proteomic profiling. Conclusions Serum RBP4 and LGAL3BP were up-regulated after menopause under NAFLD conditions, which suggested the two proteins may be potential markers as NAFLD in postmenopausal population. [ABSTRACT FROM AUTHOR]

Background: Distinctive exosomal contents could be useful for cancer diagnosis and prognosis. However, little is known about whether serum exosomal heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) mRNA is a satisfactory biomarker for hepatocellular carcinoma (HCC). Methods: Two hundred and ninety-one participants divided into four age- and gender-matched groups, including a HCC group (n=88), a liver cirrhosis (LC) group (n=67), a chronic hepatitis B (CHB) group (n=68) and a healthy control group (n=68), were enrolled. Serum exosomal hnRNPH1 mRNA and GAPDH mRNA were measured using TaqMan real-time PCR, and the relative expression levels were calculated. Receiver operating characteristic (ROC) curves were constructed to evaluate the effectiveness of hnRNPH1 mRNA alone and in combination with α-fetoprotein (AFP) in the diagnosis of HCC. The correlation between hnRNPH1 mRNA levels and clinicopathological characteristics and overall survival (OS) in HCC was determined. Results: The serum exosomal hnRNPH1 mRNA levels in HCC patients were remarkably higher than in the other groups (p<0.05). The hnRNPH1 mRNA discriminated HCC from CHB with an area under the ROC curve (AUC) of 0.865, with sensitivity of 85.2% and specificity of 76.5% at cut-off value of 0.670. The AUC for hnRNPH1 mRNA in combination with AFP was further improved. The exosomal hnRNPH1 mRNA levels in HCC patients were associated with the Child-Pugh classification, portal vein tumor emboli, lymph node metastasis, TNM stage and OS (p<0.05). Conclusions: These findings suggested that serum exosomal hnRNPH1 mRNA could be an effective marker for HCC in high HBV prevalence areas. [ABSTRACT FROM AUTHOR]

This study sought to evaluate the diagnostic value of the methylation of multiple gene promoters in serum in hepatitis B virus- (HBV-) related hepatocellular carcinoma (HCC). A total of 343 participants were enrolled, including 98 patients with HCC, 75 patients with liver cirrhosis (LC), 90 patients with chronic hepatitis B (CHB), and 80 healthy individuals. RASSF1A, APC, BVES, TIMP3, GSTP1, and HOXA9 were selected as the candidate genes. The MethyLight method was used to assay promoter methylation statuses. The diagnostic performances of markers were assessed by constructing receiver operating characteristic (ROC) curves. The prevalences of methylation for RASSF1A, APC, BVES, HOXA9, GSTP1, and TIMP3 were 52.04%, 36.73%, 29.59%, 20.41%, 17.35%, and 11.22%, respectively. APC methylation completely overlapped with RASSF1A methylation. The area under the curve (AUC) for RASSF1A methylation (0.718) was better than the corresponding AUC for AFP (0.609) in distinguishing HCC from CHB. When RASSF1A, BVES, HOXA9, and AFP were combined, the AUC was 0.852 (95% CI = 0.796–0.908, P=0.028), and the sensitivity and specificity were 83.7% and 78.9%, respectively. In conclusion, an assay that combines methylation of the RASSF1A, BVES, and HOXA9 gene promoters in serum and AFP could significantly improve HBV-related HCC diagnoses. [ABSTRACT FROM AUTHOR]

Background: Extensive patellar tendon ossification is very uncommon and requires surgical intervention when ossification significantly affects knee function. While various approaches and grafts are available for reconstructing ruptured patellar tendons, there is a paucity of literature regarding the management of joint ankylosis due to severely ossified patellar tendons. Case Presentation: This is a case involving an extensively ossified patellar tendon after patellar and tibial tuberosity fracture fixation. Reconstruction of the patellar tendon was performed using ipsilateral semitendinosus and gracilis autografts. At the latest follow‐up of 12 months, the patient achieved knee flexion up to 120° with a slight extension lag and resumed daily activities. Conclusions: Autograft hamstring reconstruction of the patellar tendon is suitable for extensive heterotopic ossification of the patellar tendon, resulting in significant improvement in postoperative knee function. Similar patients may be referred for this reconstruction technique. [ABSTRACT FROM AUTHOR]

Myocardial injury induced by sepsis is the most common cause of death. Topiroxostat has been found to have organ protective effects, but its role in septic shock-related cardiomyocyte damage is still unclear and needs further study. An endotoxemic shock model in rats was constructed. After topiroxostat treatment, hemodynamic parameters, myocardial injury marker enzymes, oxidative stress, myocardial injury, and apoptosis were measured by polyphysiograph, enzyme-linked immunosorbent assay, hematoxylin and eosin staining, TUNEL staining, and western blot. During in vitro experiments, the effect of topiroxostat on cell vitality, oxidative stress, inflammatory factors, apoptosis-related markers, phosphorylated-p65 (p-p65) and p65 expressions were measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and western blot. Topiroxostat improved myocardial dysfunction and superoxide dismutase activity while suppressing levels of creatine kinase, lactate dehydrogenase and malondialdehyde in serum of endotoxemic shock rats. Additionally, topiroxostat augmented dry-wet weight ratios of the hearts in rats. Meanwhile, topiroxostat was proved to alleviate interstitial edema and apoptosis in myocardial tissues of endotoxemic shock rats. During in vitro experiments, topiroxostat pretreatment elevated lipopolysaccharide (LPS)-induced H9c2 cell vitality, and alleviated oxidative stress and inflammation. Moreover, topiroxostat pretreatment downregulated apoptosis-related markers, p-p65, and p-p65/p65 levels in LPS-induced H9c2 cells. Topiroxostat attenuated LPS-induced myocardial injury via repressing apoptosis and oxidative stress. [ABSTRACT FROM AUTHOR]

In this study, TiC/TiAl composite coatings are prepared on TC4 substrate via laser cladding. The effect of TiC content (5, 10, 15, and 20 vol%) on the microstructure, microhardness, and wear characteristics of the coatings are investigated. The results show that the physical phases in all four coatings are mainly TiAl, Ti 3 Al, TiC, and Ti 2 AlC. The amount of rod-shaped Ti 2 AlC increases and the TiC dendrite orientation is weakened and significantly refined with decreasing TiC content. The hardness of the four coatings is 1.8–2.4 times that of the substrate, with the 15 vol% coating being the hardest (799 HV 1.0). The wear rate of the 5 vol% coating is the lowest, 1.6 times lower than that of the substrate. This is mainly attributed to the heterogeneous structure of the coating composed of Ti-Al substrate, hard TiC particles, and self-lubricating Ti 2 AlC phase. The surface energy of the 5 vol% coating is the lowest, resulting in a very slight material migration from the wear surface, and the wear mechanism is micro-cutting. [ABSTRACT FROM AUTHOR]

Background and Purpose: Non-small-cell lung cancer (NSCLC) accounts for up to 80-85% of all lung cancers and has a disappointing prognosis. Flavonoids exert anticancer properties, mostly involving stimulation of ROS production without significant toxicity to normal cells. This study was aimed to delineate the effect of diosmetin, a natural flavonoid, on NSCLC cells and its ability to enhance the antitumour activity of paclitaxel.Experimental Approach: NSCLC cells, normal cell lines HLF-1 and BEAS-2B, and immunodeficient mice were chosen as models to study the effects of diosmetin. Changes in cell viability, apoptosis, and ROS were analysed by MTT assay, flow cytometry assay, and fluorescent probe DCFH-DA. Expression of proteins and mRNA was determined by Western blotting and real-time RT-PCR. Growth of xenografted tumours was measured. Spleens and other vital organs were analysed with histological and immunohistochemical techniques.Key Results: Diosmetin induced selective apoptotic death in NSCLC cells but spared normal cells, via ROS accumulation. Diosmetin induced ROS production in NSCLC cells probably via reducing Nrf2 stability through disruption of the PI3K/Akt/GSK-3β pathway. The in vitro and in vivo xenograft studies showed that combined treatment of diosmetin and paclitaxel synergistically suppressed NSCLC cells. Histological analysis of vital organs showed no obvious toxicity of diosmetin, which matched our in vitro findings.Conclusions and Implications: Diosmetin selectively induced apoptosis and enhanced the efficacy of paclitaxel in NSCLC cells via ROS accumulation through disruption of the PI3K/Akt/GSK-3β/Nrf2 pathway. Therefore, diosmetin may be a promising candidate for adjuvant treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Graphical abstract Aiming to exploring potent XO inhibitor with optimal heterocycle, we have identified a new 2-phenylthiazole-4-carboxylic acid scaffold by evaluating 5 heterocycle scaffolds unexplored in this field, exemplified by the potent and orally bioavailable XO inhibitor 8. Highlights • 2-Phenylthiazole-4-carboxylic acid was identified as a novel scaffold of xanthine oxidase inhibitors. • Compound 8 revealed equivalent XO inhibitory activities with the analog of Febuxostat (compound 7). • Compound 8 exhibited significantly hypouricemic effect in hyperuricemic mice. Abstract The xanthine oxidase (XO) plays an important role in producing uric acid, and therefore XO inhibitors are considered as one of the promising therapies for hyperuricemia and gout. We have previously reported a series of XO inhibitors with pyrazole scaffold to extend the chemical space of current XO inhibitors. Herein, we describe further structural optimization to explore the optimal heterocycle by replacing the thiazole ring of Febuxostat with 5 heterocycle scaffolds unexplored in this field. All of these efforts resulted in the identification of compound 8 , a potent XO inhibitor (IC 50 = 48.6 nM) with novel 2-phenylthiazole-4-carboxylic acid scaffold. Moreover, lead compound 8 exhibited hypouricemic effect in potassium oxonate-hypoxanthine-induced hyperuricemic mice. These results promote the understanding of ligand-receptor interaction and might help to design more promising XO inhibitors. [ABSTRACT FROM AUTHOR]

Non-rigid soils (e.g., Vertisols) present dynamics of bulk density (ρ b) due to high shrinkage and swelling. However, the in-situ measurement and prediction of the dynamic of ρ b in non-rigid soils are still great challenges. The objectives were to (1) evaluate the performance of the combined soil moisture and thermal property sensors in estimating in-situ ρ b dynamics under different tillage practices, (2) and establish mathematic equations to predict the ρ b dynamics associated with soil subsidence and shrink-swelling processes during wetting and drying cycles. The in-situ ρ b monitoring and periodical intact soil core sampling were conducted in the 0–10 cm and 10–20 cm layers in a Vertisol under three tillage treatments, containing no-tillage (NT), rotary tillage (RT) and deep ploughing (DP). Our results showed that the dual-sensor combination provided accurate ρ b estimates in the field over 2021–2022 year (R2 > 0.487, RMSE < 0.177 g cm−3), except for the early stage after deep tillage. The ρ b dynamics in the 0–20 cm in the NT and the 10–20 cm layer in RT treatment were mainly caused by shrink-swelling. Whereas the ρ b dynamics in the 0–10 cm and 10–20 cm in the DP and the 0–10 cm layer in RT treatment were predominantly determined by soil subsidence first and then shrink-swelling when the accumulative rainfall (P t) reached 131.8 mm, 186.1 mm, and 79.3 mm, respectively. The ρ b dynamics during soil subsidence were well-fitted by an exponential equation related to accumulative rainfall (R2 > 699, P < 0.01), while the ρ b dynamics during shrink-swelling were well-fitted by a newly proposed SSC ρb equation derived from the Peng and Horn soil shrinkage model (R2 > 589, P < 0.05). Combined with the long-term monitored rainfall and soil moisture, The SSC ρb equation and the two-stage equation involving subsidence and SSC ρb exhibited good prediction of ρ b dynamic from 2017 to 2022 (R2 > 0.453, RMSE < 0.070 g cm−3). The soil subsidence and shrink-swelling process accounted for 3.32%− 12.5% and 2.84%− 14.8% of the ρ b variation in tilled non-rigid soils, respectively. Our results demonstrated that the dual-sensor combination can be applied for field ρ b monitoring in non-rigid soil. The proposed two-stage equation has great potential for predicting the field dynamics of ρ b. • The dual-sensor combination showed good estimation of in-situ ρ b dynamic in a Vertisol. • The dynamic of ρ b was predominantly driven by shrink-swelling in the no-tillage treatment. • A two-stage equation involving both soil subsidence and shrink-swelling was established. • The ρ b dynamic was well predicted by the two-stage equation in the deep tillage treatment. [ABSTRACT FROM AUTHOR]

Platelet-derived growth factor receptors (PDGFRs) are abundantly expressed by stromal cells in the non-small cell lung cancer (NSCLC) microenvironment, and in a subset of cancer cells, usually with their overexpression and/or activating mutation. However, the effect of PDGFR inhibition on lung cancer cells themselves has been largely neglected. In this study, we investigated the anticancer activity of CP-673451, a potent and selective inhibitor of PDGFRβ, on NSCLC cell lines (A549 and H358) and the potential mechanism. The results showed that inhibition of PDGFRβ by CP-673451 induced a significant increase in cell apoptosis, accompanied by ROS accumulation. However, CP-673451 exerted less cytotoxicity in normal lung epithelial cell line BEAS-2B cells determined by MTT and apoptosis assay. Elimination of ROS by NAC reversed the CP-673451-induced apoptosis in NSCLC cells. Furthermore, CP-673451 down-regulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) probably through inhibition of PI3K/Akt pathway. Rescue of Nrf2 activity counteracted the effects of CP-673451 on cell apoptosis and ROS accumulation. Silencing PDGFRβ expression by PDGFRβ siRNA exerted similar effects with CP-673451 in A549 cells, and when PDGFRβ was knockdowned by PDGFRβ siRNA, CP-673451 produced no additional effects on cell viability, ROS and GSH production, Nrf2 expression as well as PI3K/Akt pathway activity. Specifically, Nrf2 plays an indispensable role in NSCLC cell sensitivity to platinum-based treatments and we found that combination of CP-673451 and cisplatin produced a synergistic anticancer effect and substantial ROS production in vitro . Therefore, these results clearly demonstrate the effectiveness of inhibition of PDGFRβ against NSCLC cells and strongly suggest that CP-673451 may be a promising adjuvant chemotherapeutic drug. [ABSTRACT FROM AUTHOR]

As one kind of clean and widely distributed unconventional energy resource, natural gas hydrate (NGH) is attracting increasing attention these years. In this study, the methods of depressurization and thermal stimulation are adopted to dissociate the NGH experimentally, when the initial temperature is 1.0 °C, the initial pressure is 3.1 MPa, the porosity is 0.35 and initial NGH saturation is 32%. The results reveal that during the depressurization process, there exists a pressure difference threshold (Δ P = 0.19 MPa), and similarly a temperature difference threshold (Δ T = 1.4 °C) exists during the process of thermal stimulation. NGH will not dissociate until pressure difference or temperature difference outweighs the corresponding threshold value. In addition, the influencing factors of driving force on the gas production performance have been studied. When thermal stimulation is adopted, the driving force of the temperature difference will grow with the increasing hot-brine injection rate and the brine temperature, in which case the gas production rate will drive up. When depressurization is used, the pressure difference driving force will go up with the increasing depressurizing range and depressurizing rate. Driving force is a major factor during NGH dissociation by depressurization and thermal stimulation. [ABSTRACT FROM AUTHOR]

Surface electromyography (sEMG) is a kind of biological signal that records muscle activity noninvasively, which is of great significance in advanced human-computer interaction, prosthetic control, clinical therapy, and biomechanics. However, the number of hand gestures that can be recognized is limited and the recognition accuracy needs to be further improved. These factors lead to the fact that sEMG products are not widely used in practice. The main contributions of this paper are as follows. Firstly, considering the increasing number of gestures to be recognized and the complexity of gestures, an extensible two-stage machine learning lightweight framework was innovatively proposed for multi-gesture task recognition. Secondly, the multivariate variational mode decomposition (MVMD) is applied to extract the spatial–temporal features from the multiple channels to the EMG signals, and the separable convolutional neural network is used for modelling. In this work, the experimental results for 52 hand gestures recognition task show that the average accuracy on each stage is about 90%. The potential movement information is mainly contained in the low-frequency oscillator of the sEMG signal, and the model performs better with the low-frequency oscillation from the MVMD algorithm on the second stage classification than that of other decomposition methods. [ABSTRACT FROM AUTHOR]

Fluxes and composition dynamics of atmospheric nitrogen deposition play key roles in better balancing economic development and ecological environment. However, there are some knowledge gaps and difficulties in urban ecosystems, especially for small and medium-sized cities. In this study, both flux and composition (ratio of NH 4 +-N to NO 3 −-N, R N) of wet-deposited dissolved inorganic nitrogen (DIN, sum of NO 3 −-N and NH 4 +-N) were estimated and sources were identified at a long-term urban observation station in Tongling, a typical medium-sized city in eastern China during 2010–2016, respectively. Results showed that wet-deposited DIN fluxes were 33.20 and 28.15 kgN ha−1 yr−1 in Tongling city during 2010–2011 and 2015–2016, respectively. Compared to these two periods, both DIN and NO 3 −-N fluxes decreased by 15.2% and 31.8% for a series of NOx abatement measures applied effectively, respectively. At the same time, the NH 4 +-N flux remained stable and ranged from 19.53 to 20.62 kgN ha−1 yr−1, and the R N increased from 1.7 to 2.2. Seasonally, winds from the southwest and west-southwest with higher frequencies and speeds in spring and summer brought more NH 4 +-N and DIN wet deposition from an ammonia plant, which could threaten the safety of regional hydrosphere ecosystems. On the whole, the wet-deposited NH 4 +-N was threatening regional ecosystems of both the hydrosphere and forest. The wet-deposited DIN including NH 4 +-N in Tongling city stemmed mainly from a combined source of coal combustion and dust from Cu extraction and smelting, ammonia production, and roads. Therefore, production lines should be updated for Cu extraction and smelting industries, thermal power generations and the ammonia plant, old vehicles should be eliminated, and the use of new energy vehicles should be promoted for regional sustainable development and human health in the medium-sized city. Unlabelled Image • Deposited DIN was characterized and compared at a typical medium–sized city. • Deposited DIN and NO 3 −-N declined by 10.5% and 10.5% during 2010–2016, respectively. • Ratio of NH 4 +-N/NO 3 −-N increased by 10.5% during 2010–2016. • Deposited NH 4 +-N kept stable and treated eco-safety of water and forests. [ABSTRACT FROM AUTHOR]

Current extraction methods often extract DNA and RNA separately, and few methods are capable of co-extracting DNA and RNA from sputum. We established a nucleic acid co-extraction method from sputum based on magnetic beads and optimized the method by evaluating influencing factors, such as the guanidinium thiocyanate (GTC) and dithiothreitol (DTT) concentrations, magnetic bead amount, incubation temperature, lysis buffer pH and RNA carrier type. The feasibility of the simultaneous nucleic acid co-extraction method was evaluated by amplifying DNA and RNA viruses from a single clinical specimen with a multiplex RT-qPCR method. Both DNA and RNA were most efficiently extracted when the GTC and DTT concentrations were 2.0 M and 80 mM, respectively, 20 μl magnetic beads were added, the incubation temperature was 80 °C, the pH was 8 or 9, and RNA carrier A was used. Therefore, we established a simple method to extract nucleic acids from two important respiratory viruses compared with other commercial kits. This magnetic beads-based co-extraction method for sputum followed by a multiplex RT-qPCR can rapidly and precisely detect DNA and RNA viruses from a single clinical specimen and has many advantages, such as decreased time, low cost, and a lack of harmful chemicals. [ABSTRACT FROM AUTHOR]