Prusogliptin (DBPR108) monotherapy in treatment-naïve patients with type 2 diabetes: A randomized, double-blind, active and placebo-controlled, phase 3 study.

AIM: This study aimed to assess the efficacy and safety of prusogliptin (DBPR108), a novel and highly selective dipeptidyl peptidase-4 inhibitor, in individuals with type 2 diabetes who had not been using glucose-lowering agents regularly for the 8 weeks before the screening period. MATERIALS AND METHODS: In this multicentre, randomized, double-blind, phase 3 study, adult patients with type 2 diabetes were randomly assigned to receive either DBPR108 100 mg, sitagliptin 100 mg, or placebo once daily during the initial 24-week double-blind treatment period, followed by a 28-week open-label extension period during which all patients received DBPR108 100 mg once daily. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) levels from baseline to week 24. RESULTS: In total, 766 patients were enrolled and received DBPR108 100 mg (n = 462), sitagliptin 100 mg (n = 152), or placebo (n = 152). The mean age of all patients was 54.3 ± 10.5 years, with 58% being men. The median duration of type 2 diabetes was 0.38 (0.02, 2.65) years, and the mean HbA1c (SD) at baseline was 7.94% (0.62), 7.88% (0.61) and 7.83% (0.59) for DBPR108, sitagliptin and placebo groups, respectively. At week 24, the least square mean (SE) changes from baseline in HbA1c were -0.63% (0.04%) for DBPR108, -0.60% (0.07%) for sitagliptin and -0.02% (0.07%) for placebo. The mean treatment difference between DBPR108 and placebo was -0.61% (95% CI -0.77% to -0.44%), and between DBPR108 and sitagliptin was -0.03% (95% CI -0.19% to 0.13%). These results indicate that DBPR108 was superior to placebo and non-inferior to sitagliptin. DBPR108 also significantly reduced fasting and postprandial plasma glucose levels and had little effect on body weight. The mean (SD) changes in HbA1c from baseline to week 52 were -0.50% (0.97%) for the DBPR108 group, -0.46% (0.96%) for the sitagliptin group and -0.41% (0.95%) for the placebo group. The incidence of adverse events was comparable across all three groups. CONCLUSIONS: DBPR108 showed superiority to placebo and non-inferiority to sitagliptin in terms of glycaemic control over the initial 24 weeks in treatment-naïve patients with type 2 diabetes. Furthermore, its efficacy was sustained for up to 52 weeks.

Metabolic profiling of peri-implant crevicular fluid in peri-implantitis.

OBJECTS: This study aims to explore the etiology of peri-implantitis by comparing the metabolic profiles in peri-implant crevicular fluid (PICF) from patients with healthy implants (PH) and those with peri-implantitis (PI). MATERIALS AND METHODS: Fifty-six patients were enrolled in this cross-sectional study. PICF samples were collected and analyzed using both non-targeted and targeted metabolomics approaches. The relationship between metabolites and clinical indices including probing depth (PD), bleeding on probing (BOP), and marginal bone loss (MBL) was examined. Additionally, submucosal microbiota was collected and analyzed using 16S rRNA gene sequencing to elucidate the association between the metabolites and microbial communities. RESULTS: Significant differences in metabolic profiles were observed between the PH and PI groups, with 179 distinct metabolites identified. In the PI group, specific amino acids and fatty acids were significantly elevated compared to the PH group. Organic acids including succinic acid, fructose-6-phosphate, and glucose-6-phosphate were markedly higher in the PI group, showing positive correlations with mean PD, BOP, and MBL. Metabolites that increased in the PI group positively correlated with the presence of Porphyromonas and Treponema and negatively with Streptococcus and Haemophilus. CONCLUSIONS: This study establishes a clear association between metabolic compositions and peri-implant condition, highlighting enhanced metabolite activity in peri-implantitis. These findings open avenues for further research into metabolic mechanisms of peri-implantitis and their potential therapeutic implications.

Ultrasound and computed tomography angiography diagnosis of fetal right atrial isomerism with cardiac total anomalous pulmonary venous connection and intestinal malrotation: a case report and literature review.

Right atrial isomerism is a rare and severe isomerism. It is frequently associated with complex congenital heart disease and various extracardiac anomalies. Imaging diagnosis of right atrial isomerism is a challenge. Multisystem and complex anomalies in a 24-week-old fetus were diagnosed with prenatal ultrasound, postnatal computed tomography angiography (CTA), and autopsy. The ultrasound detected most major cardiovascular anomalies including right atrial isomerism and total anomalous pulmonary venous connection. The CTA further detected thoracic and abdominal malformations such as bilateral morphologically right bronchus, diaphragmatic hernia, asplenia, midline liver, and intestinal malrotation. The autopsy confirmed both ultrasound and CTA findings with additional findings, namely, bilateral trilobed lungs and bilateral morphological right auricles. Prenatal ultrasound and postnatal CTA can be complementary to each other in detecting multi-system complex anomalies. Their combined use can be useful for prenatal counseling and postpartum management.

Dental follicle cells-derived small extracellular vesicles inhibit pathogenicity of Porphyromonas gingivalis.

OBJECTIVE: It aims to explore the effect of dental follicle cells-derived small extracellular vesicles (D-sEVs) with or without lipopolysaccharides (LPS) pretreating on the pathogenicity of Porphyromonas gingivalis (P. gingivalis). METHODS: The antibacterial effects of D-sEV were evaluated by measuring the growth, biofilm formation, gingipains, and type IX secretion system (T9SS) expression of P. gingivalis. And the influence of D-sEV on P. gingivalis adhesion, invasion, cytotoxicity, and host immune response was examined in gingival epithelial cells (GECs). Then P. gingivalis treated with D-sEV was applied to investigate the pathogenicity in experimental periodontitis of mice. RESULTS: It showed that both D-sEV and P. gingivalis LPS-pretreated D-sEV (L-D-sEV) could target P. gingivalis, inhibit their growth and biofilm formation, and hinder the attachment and invasion in GECs, therefore remarkably decreasing P. gingivalis cytotoxicity and the expression of IL-1ß and IL-6 in GECs. In addition, they significantly reduced the expression of P. gingivalis virulence factors (gingipains and T9SS). In vivo, it showed that the bacteria in the gingiva were significantly decreased after sEV treatment. Meanwhile, less bone loss and fewer inflammatory cells infiltration and osteoclast formation in D-sEV and L-D-sEV groups. CONCLUSION: Both D-sEV and L-D-sEV were proven to inhibit the pathogenicity of P. gingivalis and thus prevented the development of periodontitis.

Interpersonal matching of autistic trait levels in typically developed individuals is associated with spontaneous gaze following and initiation during face-to-face social interaction.

OBJECTIVES: People with autism spectrum disorders (ASD) usually exhibit typical behaviours and thoughts that are called autistic traits. Autistic traits are widely and continuously distributed among typically developed (TD) and ASD populations. Previous studies have found that people with ASD have difficulty in following the eye gaze of social peers. However, it remains unknown whether TD adults with high or low autistic traits also differ in spontaneous gaze following and initiation in face-to-face social interactions. To fill this gap, this study used a novel and naturalistic gaze-cueing paradigm to examine this research question. DESIGN: A 4 (group: high-high, high-low, low-high or low-low autistic traits) × 3 (congruency: congruent, neutral, or incongruent) mixed-measures design was used. METHODS: Typically developed adults who were high or low in autistic traits completed a visual search task while a confederate who was high or low in autistic traits sat facing them. Critically, the match of autistic traits within a participant-confederate pair was manipulated. The confederate gazed at (congruent) or away from (incongruent) the location of the target prior to the appearance of the target. Participants were not explicitly instructed to follow the confederate's gaze. RESULTS: Autistic traits were associated with spontaneous gaze following and initiation in face-to-face social interactions. Specifically, only when both the participant and confederate were low in autistic traits did the incongruent gaze cues of confederates interfere with the participants' responses. CONCLUSIONS: Autistic traits impeded gaze following and initiation by TD adults. This study has theoretical and practical implications regarding autistic trait-induced social deficits and indicates a new approach for social skill interventions.

The landscape of T and B lymphocytes interaction and synergistic effects of Th1 and Th2 type response in the involved tissue of IgG4-RD revealed by single cell transcriptome analysis.

OBJECTIVES: To investigate the landscape of T-B cell interaction, immune receptor profiles and effects of different types of immune responses in the involved tissues of IgG4-RD. METHODS: Single cell RNA sequencing, bulk sample RNA sequencing, immune receptor repertoire analysis (both BCR and TCR), multi-color flow cytometry, and in-vitro assays with model cells (e.g. EBV-immortalized B cells from IgG4-RD patient) and histologic methods were applied to investigate the immunopathological features of IgG4-RD from multiple aspects. RESULTS: Ectopic germinal center formation was observed in IgG4-RD patients at advanced disease stage, and a large part of B cells in involved tissue were germinal center B cell-like. Germinal center reaction in IgG4-RD led to the irregularities of both TCR and BCR clones in the involved tissues, and limited clonal overlaps among different samples. Enhanced Th1- and Th2-type responses were observed in involved tissues of IgG4-RD and patients with both increased Th1- and Th2-type response related cell subsets possessed more severe inflammatory indices. Analyses to the origin of IGHG4 transcripts in IgG4-RD indicated that IgG4 could be switched from IgM directly, or from other IgG subclasses. In vitro assays with EBV-immortalized B cells, fibroblasts and epithelial cells revealed the effects of Th1-type and Th2-type responses on germinal center reaction, ectopic expression of MHC-II molecules, and formation of tertiary lymphoid structures. CONCLUSIONS: Synergistic effects of Th1- and Th2-type responses were involved in the pathogenesis of IgG4-RD via their influences on both acute inflammatory processes and the chronicity and complexity of IgG4-RD.

Characterization and associated risk factors of Pneumocystis jirovecii pneumonia in patients with AIRD: a retrospective study.

OBJECTIVES: To explore clinical features of autoimmune inflammatory rheumatic disease (AIRD) patients with Pneumocystis jirovecii pneumonia (PJP) and identify potential risk factors and prognostic factors. METHODS: AIRD patients who had respiratory symptoms and underwent P. jirovecii detection were identified from the database in our department from November 2018 to October 2020. These patients were categorized into PJP and non-PJP groups according to the diagnostic criteria of PJP. Univariate and multivariate analyses were conducted. RESULTS: A total of 173 patients were enrolled and 46 of them had laboratory-confirmed PJP. Glucocorticoid increased the risk of PJP in a dose-dependent manner. In addition, shorter duration of immunosuppressive therapy (IST), combination therapy with CSA and chronic pulmonary comorbidities were also strongly associated with a higher risk of PJP. Combination of IgM and IgA could well identify AIRD patients with PJP from other AIRD patients with respiratory symptoms, with the optimal cut-off value of -0.96 g/l. Seven of 46 AIRD patients with PJP died (15.2%). A higher level of serum LDH, dyspnoea and ARDS, and the presence of extensive ground glass opacity (GGO) in radiologic examinations were more common in deceased patients. CONCLUSIONS: AIRD patients with high-dose glucocorticoid treatment, recent initiation of IST, combination therapy with CSA and history of chronic pulmonary diseases had a greater risk of PJP infection. PJP patients with a higher level of serum LDH, dyspnoea, moderate and severe ARDS, and the presence of extensive GGO in radiologic examinations had poorer prognosis. TRIAL REGISTRATION: Chinese Clinical Trial Register; https://www.chictr.org.cn/; ChiCTR2100044095.

Efficacy and safety of DBPR108 (prusogliptin) as an add-on to metformin therapy in patients with type 2 diabetes: A 24-week, multi-centre, randomized, double-blind, placebo-controlled, superiority, phase III clinical trial.

AIM: To evaluate the efficacy and safety of DBPR108 (prusogliptin), a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, as an add-on therapy in patients with type 2 diabetes (T2D) that is inadequately controlled with metformin. MATERIALS AND METHODS: In this 24-week, multi-centre, randomized, double-blind, placebo-controlled, superiority, phase III study, adult T2D patients with HbA1c levels ranging from 7.0% to 9.5% on stable metformin were enrolled and randomized (2:1) into the DBPR108 + metformin and placebo + metformin groups. The primary endpoint was the change from baseline in HbA1c at week 24 of DBPR108 versus placebo as an add-on therapy to metformin. RESULTS: At week 24, the least-square mean (standard error) change from baseline in HbA1c was significantly greater in the DBPR108 group (-0.70% [0.09%]) than in the placebo group (-0.07% [0.11%]) (P < .001), with a treatment difference of -0.63% (95% confidence interval: -0.87%, -0.39%) on the full analysis set. A higher proportion of patients achieved an HbA1c of 6.5% or less (19.7% vs. 8.5%) and an HbA1c of 7.0% or less (50.0% vs. 21.1%) at week 24 in the DBPR108 + metformin group. Furthermore, add-on DBPR108 produced greater reductions from baseline in fasting plasma glucose and 2-hour postprandial plasma glucose without causing weight gain. The overall frequency of adverse events was similar between the two groups. CONCLUSIONS: DBPR108 as add-on therapy to metformin offered a significant improvement in glycaemic control, was superior to metformin monotherapy (placebo) and was safe and well-tolerated in patients with T2D that is inadequately controlled with metformin.

Increasing the Stability of Metal-Organic Frameworks by Coating with Poly(tetrafluoroethylene).

When compared to industrially stable zeolites, the instability of metal-organic frameworks (MOFs) has been denounced by researchers. Boosting the stability of existing MOFs is highly important for practical applications. In this report, we develop a new strategy to prepare MOFs/poly(tetrafluoroethylene) (PTFE) composites, which can highly improve the chemical, pressure, and photostabilities of zeolitic imidazolate framework (ZIF)-8. Composite materials were prepared by a physical blending of ZIF-8 and PTFE emulsion with different ratios and annealing at 370 °C. Transmission electron microscopy (TEM) studies reveal that the nanoparticles of ZIF-8 are coated by PTFE to form the composite materials. Upon mixing with 20 or 50 wt % PTFE, the ZIF-8/PTFE materials show a superhydrophobic property with water contact angles of around 156°. Pristine ZIF-8 is not stable in water with stirring under acidic, basic, and irradiation conditions, while the ZIF-8/PTFE materials are stable under the same conditions. The ZIF-8/PTFE materials can also maintain their crystalline structure after being compressed with a 10 MPa pressure, while pristine ZIF-8 changes to an amorphous solid after the same pressure treatment. Using water as a solvent, ZIF-8/PTFE can be used as a highly efficient and recyclable catalyst for Knoevenagel reaction at room temperature. The successful preparation of stable ZIF-8/PTFE composite materials provides a useful method to enhance the chemical, pressure, and photostabilities of MOFs.

Gastrodin prevents homocysteine-induced human umbilical vein endothelial cells injury via PI3K/Akt/eNOS and Nrf2/ARE pathway.

In this study, we investigated the protective effects of gastrodin (Gas) against homocysteine-induced human umbilical vein endothelial cell (HUVEC) injury and the role of the phosphoinositide 3-kinase (PI3K)/threonine kinase 1 (Akt)/endothelial nitric oxide synthase (eNOS) and NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathways. We stimulated cells with homocysteine (1 mmol/L, 24 hours) and tested the effects of gastrodin (200-800 µg/mL) on cell viability and the production of malondialdehyde (MDA), lactate dehydrogenase (LDH) and reactive oxygen species (ROS). Then, Nrf2 distribution in the cytoplasm and nucleus as well as the expression of enzymes downstream of Nrf2 was determined. Furthermore, we analysed the expression of bax, bcl-2 and cleaved caspase3, and assessed the involvement of the PI3K/Akt/eNOS pathway by Western blots. Finally, we tested the vasoactive effect of gastrodin in thoracic aortic rings. The results showed that gastrodin decreased MDA, LDH and ROS production and increased cell viability, NO production and relaxation of thoracic aortic rings. Moreover, the protective effects of Gas on NO production and relaxation of thoracic aortic rings were blocked by L-NAME but enhanced by Cav-1 knockdown, and MK-2206 treatment abolished the effect of Gas on the ROS. In addition, treatment with gastrodin increased Nrf2 nuclear translocation, thus enhancing the expression of downstream enzymes. Finally, gastrodin increased the expression of PI3K, p-Akt, and eNOS and decreased Cav-1 protein expression. In conclusion, our study suggested that gastrodin may protect HUVECs from homocysteine-induced injury, and the PI3K/Akt/eNOS and Nrf2/ARE pathways may be responsible for the efficacy of gastrodin.

STAT3 activates the transcription of lncRNA NR2F1-AS1 to promote the progression of melanoma via regulating the miR-493-5p/GOLM1 axis.

BACKGROUND: Long non-coding RNAs (lncRNAs) are vital regulators during the biological processes of melanoma. The present study aimed to uncover biological functions of lncRNA termed NR2F1 antisense RNA 1 (NR2F1-AS1) in melanoma and the potential mechanisms. METHODS: Relative levels of NR2F1-AS1 and miR-493-5p in a total of 137 paired primary melanoma tissues and corresponding non-tumor tissues, as well as three melanoma cell lines, were examined by a real-time polymerase chain reaction. The clinical significance of NR2F1-AS1 expression was analyzed statistically. The STAT3 binding motif in the promoter region of NR2F1-AS1 was identified by JASPAR (http://jaspar.genereg.net). The association between STAT3 and NR2F1-AS1 was determined by dual-luciferase reporter and chromatin immunoprecipitation assays. The effects of NR2F1-AS1 on cell proliferation, migration and were measured by cell counting kit-8 (CCK-8), Edu, transwell and wound healing assays. Dual-luciferase reporter and RNA pull-down assays were applied to validate the interaction among NR2F1-AS1, miR-493-5p and GOLM1. Furthermore, in vivo experiments were conducted to demonstrate the oncogenic role of NR2F1-AS1 in melanoma. RESULTS: Up-regulated NR2F1-AS1 and down-regulated miR-493-5p were detected in melanoma tumors and cells. The overexpression of NR2F1-AS1 was induced by STAT3. High NR2F1-AS1 expression was correlated to advanced tumor stage and poor prognosis of melanoma. Functional studies using CCK-8, Edu, transwell and wound healing assays revealed that the proliferative, migratory and invasive capacities of melanoma cells were attenuated by the by inhibition of NR2F1-AS1. Moreover, NR2F1-AS1 was able to up-regulate GOLM1 through recognizing and binding miR-493-5p. Furthermore, knockdown of miR-493-5p distinctly reversed these inhibitory effects of NR2F1-AS1 down-regulation on the tumorigenesis and progression of melanoma. CONCLUSIONS: Our findings demonstrate a key role for NR2F1-AS1 in melanoma progression via targeting miR-493-5p/GOLM1 axis.

ERP evidence for asymmetric orthographic transfer between traditional and simplified Chinese.

Transferring orthographic processing skills from one language to new languages is important for language learning. However, the specific orthography hypothesis and condition-based transfer hypothesis have debated orthographic transfer. No study has ever examined these debates in a logographic language, and the neural correlates of orthographic transfer in a logographic language remain unknown. Therefore, the present study uses event-related potentials to examine orthographic transfer with Hong Kong (Experiment 1) and mainland China (Experiment 2) participants who only use traditional or simplified Chinese, respectively. The participants sequentially read two of the same (repetition) or different (nonrepetition) traditional or simplified Chinese characters and judged whether they were identical. The results showed that the orthography-related N200 component was smaller in the repetition condition than in the nonrepetition condition. Importantly, for traditional Chinses users, this effect was more salient in traditional Chinese than in simplified Chinese, suggesting limited transfer from traditional to simplified Chinese. For simplified Chinese users, this effect was comparable in traditional and simplified Chinese, suggesting a smooth transfer from simplified to traditional Chinese. The results supported the condition-based transfer hypothesis, and showed asymmetric transfer between simple orthographic rules and complex ones. That is, simple orthographic rules can be transferred to complex ones smoothly, but not vice versa.

The influence of congruency proportion, target eccentricity, and valence strength on the spatial-valence metaphoric congruency effect in a word valence judgment task.

In a word valence judgment task, positive words (e.g., excellence) are judged faster when presented at the top (congruent position) than at the bottom of the screen (incongruent position), whereas the opposite pattern occurs for negative words (e.g., disaster). This spatial-valence metaphoric congruency effect reflects top-positive/bottom-negative metaphoric association and may be attributed to at least three possible mechanisms: spreading activation between spatial and valence concepts (activation account), epistemic function that a conceptual metaphor serves to reduce the uncertainty associated with valence concepts (epistemic account), and/or the extent to which spatial-valence metaphoric association is relevant to task demand (relevance account). In three experiments, we manipulated congruency proportion, target eccentricity, and valence strength in a word valence judgment task to test these three possible accounts. Results showed that the metaphoric congruency effect was larger when a high (vs. equal) proportion of targets appears in congruent, relative to incongruent, position, and for targets with strong (vs. weak) valence. However, the effect in reaction time measure was not modulated by whether the target appeared in the position being near vs. far away from the center of the screen. The overall findings are better accommodated by the relevance account. The implications of the current findings on other theoretical accounts, such as Conceptual Metaphor Theory and polarity correspondence account, are also discussed.

The presence of other-race people disrupts spontaneous level-2 visual perspective taking.

Visual perspective taking is an essential skill for effective social interaction. Previous studies have tested various perceiver-based factors that affect intentional perspective taking; however, the factors affecting spontaneous perspective taking remain unknown. To fill this gap, the present study used a novel spontaneous visual perspective taking paradigm to explore how an agent's race and emotion affect spontaneous level-2 visual perspective taking. In Experiment 1, the participants completed a mental rotation task while a human agent simultaneously gazed at the target with positive, negative, or neutral facial expressions. The agent was African, Caucasian, or Chinese. The results revealed that the other-race agents disrupted the participants' spontaneous level-2 visual perspective taking, while emotion weakly affected it. Experiment 2 retested whether emotion could affect spontaneous level-2 visual perspective taking while only own-race agents were used. The participants completed the same task as that in Experiment 1. The results revealed that emotions weakly affected spontaneous level-2 visual perspective taking. In summary, the present study first examined what target-based factors affect spontaneous level-2 visual perspective taking. The results extend the representation and incorporation of the close others' responses (RICOR) model. Specifically, people routinely construct representations of other people's points of view when they share the same racial group.

Capillary blood reference intervals for platelet parameters in healthy full-term neonates in China.

BACKGROUND: No consensus has been reached on capillary blood reference intervals for platelet parameters in full-term neonates. We aimed to establish neonatal capillary blood reference intervals for platelet parameters and evaluate influences of sex, gestational age and postnatal age on platelet parameters. METHODS: This study was a prospective investigation and implemented in 594 healthy full-term neonates from 12 to 84 h of age, using SYSMEX XN-9000 haematology automatic analyser by means of capillary blood. Reference intervals for platelet parameters were defined by an interval of 2.5th - 97.5th percentiles. RESULTS: Capillary reference interval for platelet count was (152-464) × 109/L. No significance was found between sex-divided reference intervals for platelet parameters. The values of platelet count changed minimally across gestational age (37-41 weeks) and postnatal age (12-84 h). Reference intervals for other platelet parameters were affected by these factors to a different extent. CONCLUSIONS: We established capillary blood reference intervals for platelet parameters in the first days after birth of full-term neonates in China.

Synthesis of CuO/g-C3N4 composites, and their application to voltammetric sensing of glucose and dopamine.

The preparation of 3 kinds of carbonaceous nanocomposites by hydrothermal treatment and subsequent calcination described. The first comprises a nanomaterial of type CuO/g-C3N4, with g-C3N4 in mass fractions of 2, 5 and 7 wt%, respectively. The second comprises CuO/porous carbon (5 wt%), and the third comprises CuO/carbon spheres (5 wt%). All of them were employed to modify a glassy carbon electrode (GCE) to obtain electrochemical sensors for glucose and dopamine. The GCE modified with CuO/g-C3N4 (5 wt%) displays the highest electrocatalytic activity towards glucose and dopamine. Figures of merit for sensing glucose (in 0.1 M NaOH solution) include a wide linear range (0.5 µM to 8.5 mM), a detection limit of 0.150 µM, and a sensitivity of 0.274 µA·µM-1·cm-2 (at a working potential of 0.60 V vs. Ag/AgCl). The respective data for dopamine (in pH 7.0 solution) are linear ranges from 0.2-16.0 µM and 16.0-78.7 µM, a lower detection limit of 60 nM, and an electrochemical sensitivity of 0.834 and 0.331 µA·µM-1·cm-2 (at a working potential of 0.22 V vs. Ag/AgCl). The good performance of the modified GCE is attributed to the synergetic interactions between CuO and the appropriate fraction of g-C3N4, and the improvement of conductivity. Graphical abstract Schematic presentation of a electrochemical sensor based on CuO/g-C3N4 for the determination of glucose and dopamine.

Design, synthesis and activity of novel sorafenib analogues bearing chalcone unit.

Two series of sorafenib derivatives (N-methylpicolinamide-4-oxy) chalcones (5a-o, 7a-e) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR and BRAF kinases. The results indicated that all the compounds showed moderate to good antitumor activity, and the compound 5c showed well cytotoxic activity against HepG2, MCF-7 and PC-3 cell lines with IC50 values of 0.56±0.83µM, 3.88±1.03µM and 3.15±0.81µM, which were 1.03-6.14-fold more active than sorafenib (3.44±1.50µM, 3.18±1.43µM, 3.24±0.45µM), respectively. The compound 5b showed good activity on VEGFR-2/KDR kinase, and its IC50 value was 0.72µM. Structure-activity relationships (SARs) and docking studies indicated that replacement of urea group of sorafenib by chalcone ketones improved the cytotoxic activity, and the results suggested that halogen [3-Br, 4-F] and methoxy (substituted on C-3,4,5 or C-2,3,4 position) substitution was benefit for the activity.

Necrostatin-1 inhibits Hmgb1-IL-23/IL-17 pathway and attenuates cardiac ischemia reperfusion injury.

Ischemia reperfusion (IR) injury is a major issue in cardiac transplantation and inflammatory processes play a major role in myocardial IR injury. Necrostatin-1 (Nec-1) is a small molecule capable of inhibiting RIP1 kinase activity and attenuates inflammation-mediated tissue injury. In our study, hearts of C57Bl/6 mice were flushed and stored in cold Bretschneider solution for 8 h and then transplanted into syngeneic recipients. We found that Nec-1 decreased cardiomyocyte necrosis and recruitment of neutrophils and macrophages. Troponin T (TnT) production on 24 h after myocardial IR injury was reduced by Nec-1 administration. Cardiac output at 60 mmHg of afterload pressure was significantly increased in hearts with Nec-1 administration and the cardiac allograft survival in Nec-1-treated animals was significantly prolonged (MST = 90 days in IR + Nec-1 group, P < 0.05 as compared with IR group, MST = 83.5 days). Nec-1 treatment attenuated ROS generation and increased expression of NOS2 and COX-2. The expression of Hmgb1, IL-23, and IL-17A were also decreased with Nec-1 administration. Furthermore, the decreased TnT expression induced by Nec-1 was abrogated with exogenous Hmgb1 administration. In conclusion, Nec-1 played a protective role in cardiomyocyte IR injury, and this was associated with inhibited Hmgb1-IL-23/IL-17 pathway.

Effectiveness of a school-based physical activity intervention on obesity in school children: a nonrandomized controlled trial.

BACKGROUND: Childhood obesity has been a serious public health problem. An effective school-based physical activity (PA) intervention is still lacking in China. This study aimed to assess the effectiveness of a school-based physical activity intervention during 12 weeks on obesity and related health outcomes in school children. METHODS: It was a non-randomized controlled trial. Altogether 921 children aged 7 to 15 years were recruited at baseline survey. Children in the intervention group (n = 388) participated in a multi-component physical activity intervention during 12 weeks that included improvement of physical education, extracurricular physical activities for overweight/obese students, physical activities at home, and health education lectures for students and parents. Children (n = 533) in the control group participated in usual practice. RESULTS: Participants had mean age of 10.4 years, mean body mass index (BMI) of 19.59 kg/m2, and 36.8 % of them were overweight or obese at baseline survey. The change in BMI in intervention group (-0.02 ± 0.06 kg/m2) was significantly different from that in control group (0.41 ± 0.08 kg/m2). The adjusted mean difference was -0.43 kg/m2 (95% CI: -0.63 to -0.23 kg/m2, P < 0.001). The effects on triceps, subscapular, abdominal skinfold thickness and fasting glucose were also significant in intervention group compared with control group (all P < 0.05). The change in duration of moderate to vigorous physical activity (MVPA) in intervention group (8.9 ± 4.3 min/day) was significantly different from that in control group (-13.8 ± 3.3 min/day). The adjusted mean difference was 22.7 min/day (95% CI: 12.2 to 33.2 min/day, P < 0.001). CONCLUSIONS: The school-based, multi-component physical activity intervention was effective to decreasing levels of BMI, skinfold thickness, fasting glucose and increasing duration of MVPA. These findings provided evidence for the development of effective and feasible school-based obesity interventions. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02074332 (2014-02-26).

Current status of sevoflurane anesthesia in association with microglia inflammation and neurodegenerative diseases.

Sevoflurane is one of the most commonly used volatile anesthetics in clinical practice and is often used in pediatric anesthesia and intraoperative maintenance. Microglia exist in the central nervous system and are innate immune cells in the central nervous system. Under external stimulation, microglia are divided into two phenotypes: proinflammatory (M1 type) and anti-inflammatory (M2 type), maintaining the stability of the central nervous system through induction, housekeeping, and defense functions. Sevoflurane can activate microglia, increase the expression of inflammatory factors through various inflammatory signaling pathways, release inflammatory mediators to cause oxidative stress, damage nerve tissues, and eventually develop into neurodegenerative diseases. In this article, the relationship between sevoflurane anesthesia and microglia inflammation expression and the occurrence of neurodegenerative diseases is reviewed as follows.