Search

Bicuculline is a natural isoquinoline alkaloid that works as a gamma‐aminobutyric acid receptor antagonist. It is widely found in Papaveraceae plants used in traditional Chinese medicines. Bicuculline not only has been shown to have favorable analgesic, memory‐improving, and anxiolytic effects but may also cause adverse effects such as convulsions and epilepsy. A simple, rapid, and sensitive method was developed and validated for the determination of bicuculline in the plasma and tissue samples in rats by ultra‐high‐performance liquid chromatography–tandem mass spectrometry (MS/MS). The chromatographic separation was performed on a Thermo Scientific C18 column. The MS/MS system was operated in the positive multiple reaction monitoring mode, and the precursor–product ion transitions were optimized as m/z 368.0 → 307.1 for bicuculline and as 354.1 → 188.1 for protopine (internal standard). The linearity, accuracy, precision, recovery, and matrix effect were within acceptable limits. The experimental data showed that bicuculline was rapidly absorbed and eliminated in rats, with a moderate plasma protein binding ratio and low bioavailability. The main tissues of distribution were the kidney, liver, and brain; bicuculline could exert its pharmacological effects across the blood–brain barrier. This study has positive implications for the clinical use of herbal medicines containing bicuculline and for further development. [ABSTRACT FROM AUTHOR]

Aim: To develop a personalized nomogram and risk score to predict the 5‐year risk of diabetes among Chinese adults with prediabetes. Methods: There were 26 018 participants with prediabetes at baseline in this retrospective cohort study. We randomly stratified participants into two cohorts for training (n = 12 947) and validation (n = 13 071). The least absolute shrinkage and selection operator (LASSO) model was applied to select the most significant variables among candidate variables. And we further established a stepwise Cox proportional hazards model to screen out the risk factors based on the predictors chosen by the LASSO model. We presented the model with a nomogram. The model's discrimination, clinical use and calibration were assessed using the area under the receiver operating characteristic (ROC) curve, decision curve and calibration analysis. The associated risk factors were also categorized according to clinical cut‐points or tertials to create the diabetes risk score model. Based on the total score, we divided it into four risk categories: low, middle, high and extremely high. We also evaluated our diabetes risk score model's performance. Results: We developed a simple nomogram and risk score that predicts the risk of prediabetes by using the variables age, triglyceride, fasting blood glucose, body mass index, alanine aminotransferase, high‐density lipoprotein cholesterol and family history of diabetes. The area under the ROC curve of the nomogram was 0.8146 (95% CI 0.8035‐0.8258) and 0.8147 (95% CI 0.8035‐0.8259) for the training and validation cohort, respectively. The calibration curve showed a perfect fit between predicted and observed diabetes risks at 5 years. Decision curve analysis presented the clinical use of the nomogram, and there was a wide range of alternative threshold probability spectrums. A total risk score of 0 to 2.5, 3 to 4.5, 5 to 7.5 and 8 to 13.5 is associated with low, middle, high and extremely high diabetes risk status, respectively. Conclusions: We developed and validated a personalized prediction nomogram and risk score for 5‐year diabetes risk among Chinese adults with prediabetes, identifying individuals at a high risk of developing diabetes. Doctors and other healthcare professionals can easily and quickly use our diabetes score model to assess the diabetes risk status in patients with prediabetes. In addition, the nomogram model and risk score we developed need to be validated in a prospective cohort study. [ABSTRACT FROM AUTHOR]

The new reform of power system promotes the market‐oriented operation of microgrids. The ubiquitous power internet of things provide support in information, data, and computation to microgrids in market operation, energy management, and coordination interaction. This study takes the park microgrid with multi‐stakeholder as the object, establishes a two‐level optimisation model of microgrid bidding transaction based on multi‐agent system. In the lower level optimisation, considering the deviation penalty of power generation and the previous round bidding results, the optimal bidding strategy model is established by the bidding unit agent to maximise its benefit. In the upper‐level model, bidding strategies of distributed energy resources (DERs) as constraints, a multiple objective mixed‐integer linear programming model was built to optimise the overall objectives of clearing price and imbalanced deviation, searching for the optimal clearing price and the generation plan of DERs. The results were fed back to the DERs to help them form the next round of strategies until the result reaches equilibrium. The proposed optimised operation mode is compared with the traditional operation mode in the case study, verifying that the proposed method can realise the optimal operation of the microgrid and the coordinated interaction with the main grid, increasing the benefit of stakeholders. [ABSTRACT FROM AUTHOR]

Abstract: Wilms tumor (WT) is a genetically heterogeneous childhood kidney tumor. Several genetic mutations have been identified in WT patients, including inactivation of WTX, somatic stabilizing CTNNB1, and p53 mutations. However, the molecular mechanisms in tumorigenesis remain largely unexplored. Stat3 is a transcription factor that can promote oncogenesis. Stat3 activation is commonly viewed as crucial for multiple tumor proliferation and metastasis. We show that Stat3 is highly activated in Wilms tumor tissues compared to those in adjacent tissues. IL-6 treatment or transfection of a constitutively activated Stat3 in G401 cells promotes cell proliferation. At the molecular level, we further elucidate that Stat3 inhibits WTX expression through up-regulation of microRNA-370. Our results suggest that Stat3/miR-370/WTX regulatory axis might be a critical mechanism in Wilms tumor cells. [Copyright &y& Elsevier]

Abstract The possible effects on the morphine withdrawal signs of the nonspecific corticotropin-releasing factor (CRF) receptor antagonist α-helical CRF, the selective CRF receptor subtype 1 antagonist CP-154,526 and the selective CRF receptor subtype 2 antagonist antisauvagine-30 (AS-30) were investigated in rats. The most withdrawal signs, including jumping, teeth chatter, writhing, shakes, lacrimation, piloerection, irritability and diarrhoea, were attenuated by pretreatment with α-helical CRF (10 µg i.c.v.) and CP-154,526 (30 mg/kg i.p.). However, no morphine withdrawal signs except for diarrhea were significantly affected by pretreatment with AS-30 (10 µg, i.c.v.). To investigate the possible role of different CRFR antagonists (α-helical CRF, CP-154,526 and AS-30) in relapse to opiate dependence, the 28-day extinction of morphine-conditioned place preference (CPP) was used. The morphine-CPP disappeared following a 28-day extinction and then was reactivated by a single injection of 10 mg/kg morphine. Pretreatment with α-helical CRF (10 µg, i.c.v.) and CP-154,526 (30 mg/kg, i.p.) could significantly block this reactivation of morphine-CPP. In contrast, pretreatment with AS-30 (1 or 10 µg i.c.v.) did not affect this reactivation of morphine-CPP. The present study demonstrated that activation of the CRF receptor is involved in morphine withdrawal signs and relapse to morphine dependence, and that the role of CRF receptor subtypes 1 and 2 in withdrawal and reactivation of morphine dependence is not identical. CRF receptor subtype 1, but not subtype 2, is largely responsible for the action of the CRF system on opiate dependence. These results suggest that the CRF receptor antagonists, particularly the CRF receptor subtype 1 antagonist, might be of some value in the treatment and prevention of drug dependence. [ABSTRACT FROM AUTHOR]