Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

Tranexamic acid is widely used in joint orthopedic surgery.At the same time,it has high safety and few adverse drug reactions.It can effectively improve intraoperative bleeding and promote early functional recovery of patients.This article reviews the mode of administration,safe dose,administration time and adverse drug reactions of tranexamic acid in the perioperative period of joint replacement and arthroscopic surgery,in order to provide reference for the clinical application of tranexamic acid.

Quercetin can mediate the activation of mitogen-activated protein kinase(MAPK)signaling pathways to prevent osteoporosis(OP).This paper comprehensively discusses the interrelationship between MAPK and osteoporosis-related cells based on the latest domestic and international research.Additionally,it elucidates the research progress of quercetin in mediating the MAPK signaling pathway for OP prevention.The aim is to provide an effective foundation for the clinical prevention and treatment of OP and the in-depth development of quercetin.

AIM To explore the clinical effects of Zhenwu Decoction combined with Danshen Drink on patients with chronic heart failure.METHODS Eighty-six patients were randomly assigned into control group(43 cases)for 4-week intervention of conventional treatment,and observation group(43 cases)for 4-week intervention of Zhenwu Decoction,Danshen Drink and conventional treatment.The changes in cardiac function indices(LVFS,LVEDD,LVEF),serum indices(hs-cTnI,sST2,NT-proBNP,MMP-9),inflammatory factors(IL-6,TNF-α,hs-CRP),platelet aggregation rate,QTcd and incidence of adverse reactions were detected.RESULTS After the treatment,the two groups demonstrated increased LVFS,LVEF(P＜0.05),and decreased LVEDD,serum indices,inflammatory factors,platelet aggregation rate,QTcd(P＜0.05),especially for the observation group(P＜0.05).No significant difference in incidence of adverse reactions was found between the two groups(P＞0.05).CONCLUSION For the patients with chronic heart failure,Zhenwu Decoction combined with Danshen Drink can safely and effectively improve hs-cTnI level and platelet aggregation functions.

Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.
Humans ; Female ; Blood Platelets/pathology* ; Biomarkers, Tumor/genetics* ; Ovarian Neoplasms/pathology* ; China

Aim To identify the molecular target of gabapentin in the treatment of postherpetic neuralgia(PHN). Methods The molecular target of gabapentin for PHN was analyzed by network pharmacology and molecular docking and confirmed by coprecipitation test. Rats were randomly divided into control group, model group, model+50 mg·kg-1 gabapentin group, model+100 mg·kg-1 gabapentin group, and model+200 mg·kg-1 gabapentin group, with nine rats in each group. The pain-related behaviors of the rats were measured at different time points. The mRNA and protein expressions of CACNA2D1, Bax, and Bcl-2 in rat spinal cord were determined by immunofluorescence, Western blot, and qPCR. Results CACNA2D1 was the target gene of gabapentin that determined via network pharmacology, molecular docking, and co-precipitation tests. After modeling, mechanical pain threshold and thermal pain threshold significantly decreased, and the number of apoptotic GABA cells significantly increased. However, after intraperitoneal injection of 50, 100, and 200 mg·kg-1 gabapentin, mechanical pain threshold and thermal pain threshold significantly increased(P<0.05), and the number of apoptotic GABA cells significantly decreased(P<0.01). Immunofluorescence and Western blot results showed that compared with the model group, with the increase of gabapentin concentration, the positive expression rate of Bax significantly decreased, and the positive expression rate of Bcl-2 and CACNA2D1 significantly increased. The mRNA expression levels of Bax, Bcl-2 and CACNA2D1 detected by qPCR were consistent with the results of immunofluorescence and Western blot. Conclusions Gabapentin up-regulates the expression of target protein CACNA2D1, inhibits the proapoptotic protein Bax, and promotes the expression of apoptotic inhibitor Bcl-2.

This study primarily concentrated on scientific problems of poor taste caused by unclear critical quality attributes of oral preparations manufactured by Chinese materia medica, successfully established an identification method for taste critical quality attribute and a taste improvement method combining electronic tongue with human senses, and determined the optimal taste formula, to improve patients' oral medication compliance. The study received ethical approval from the Review Committee of the Beijing University of Chinese Medicine. The results showed that the proportion of bitterness of Xiaoer Qingrening Granule was 61.8%, and its bitterness grade was 3.70, it was determined that bitterness is the critical quality attribute that caused the poor taste of Xiaoer Qingrening Granule. Additionally, the optimal taste formula per milliliter of Xiaoer Qingrening sugar-free intermediate was determined with allowable daily intake, solubility, and sweetness as the limiting conditions, which was 40 mg hydroxypropyl β-cyclodextrin, 180 mg trehalose, and 1.5 mg acesulfame potassium. Compared with the Xiaoer Qingrening Granule, the sensory evaluation score of the optimal taste formula was increased by 37.5 points. In conclusion, this study achieved the taste improvement of Xiaoer Qingrening Granule and formed a set of taste improvement strategies including the identification of taste critical quality attribute, the selection of the type and dosage of corrigent, and the optimization of taste formula, which provided a thought reference for the taste improvement of other oral preparations and a new perspective for quality control of intelligent manufacturing of traditional Chinese medicines.

There is still a serious challenge of the measurement of critical quality attributes (CQAs) related to clinical efficacy for Chinese materia medica manufacturing. To overcome this challenge, an integrated strategy of biosensor and ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was proposed using Tongren niuhuang qingxin pills as a trial. Firstly, an original biosensor was created using a semiconductor chip material high electron mobility transistor (HEMT) as the transducer and the macrophage migration inhibitory factor (MIF) as the identification element. By this MIF-HEMT biosensor, the efficacy on stoke of different components from Tongren niuhuang qingxin pills was measured. It was clear that all three components of Tongren niuhuang qingxin pills had strong therapeutic effects on stroke, especially the section A, the K_D of which reached to 8.722×10^-10 g·mL^-1. Furthermore, MIF-HEMT biosensor integrated UPLC-MS/MS was introduced to identify the efficacy CQAs of different components of Tongren niuhuang qingxin pills. As a result, 19 potential CQAs, such as albiforin, paeoniflorin, and prim-O-glucosylcimifugin, were measured as the efficacy CQAs of Tongren niuhuang qingxin pills on stroke treatment by MIF. These results provided vital measurement techniques and methodological guidance for the CQAs study of Tongren niuhuang qingxin pills intervention in MIF-induced stroke treatment. This also provided an essential guideline for the efficient utilization and quality control measurement of high-quality classical recipes.

To identify the bitter compounds of real-world Xiaoer Ganmao Oral Liquid sugar-free intermediates, an integrated strategy has been developed by using ultra-high performance liquid chromatography with linear ion trap-Orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap MSⁿ) method and BitterX database prediction. The chromatographic operating conditions were as follows, chromatographic column: Acquity UPLC BEH C₁₈ (100 mm × 2.1 mm, 1.7 μm), mobile phase: 0.1% formic acid-water solution (A)-acetonitrile (B) with gradient elution. The data were collected in positive and negative ion modes, respectively. The accurate molecular mass and structural information of the target compounds were obtained based on quasi-molecular ions and fragmentation ions provided by high-resolution mass spectrometry. The compounds were identified by combining retention time, reference substances, reports, and other relevant data, and a total of 57 constituents including flavonoids, alkaloids, and phenylpropanoids were finally identified. Further, the BitterX database was used to predict binding probability of compounds to bitter receptors and identify potential bitter critical quality attributes, finally 33 potential bitter compounds, including kukoamine A and linarin, were predicted. This study comprehensively characterized the material basis of Xiaoer Ganmao Oral Liquid sugar-free intermediates, it provides an effective method for bitter compound screening and a reference for further improving the undesirable taste of Xiaoer Ganmao Oral Liquid.

Inductively coupled plasma mass spectrometry (ICP-MS) was applied to determine the concentrations of lead (Pb), cadmium (Cd) and arsenic (As) in Lindera aggregata (Sims) Kosterm. The physiologically based extraction test (PBET) digestion in vitro/Caco-2 cell model was established to investigate the bioaccessible contents of Pb, Cd and As in decoction of Lindera aggregata (Sims) Kosterm. The target-organ toxicity dose modification of HI method (TTD) was used to evaluate the cumulative risk caused by the combined exposure of the total levels of Pb, Cd and As in Lindera aggregata (Sims) Kosterm. and the bioaccessible contents in the decoction. The results showed that the total contents of Pb, Cd and As in 4 batches of samples were in the range of 2.901-3.872, 1.299-1.800 and 0.062-0.216 mg·kg^-1, respectively. After transportation by Cacco-2 cells, the bioaccessible contents of Pb, Cd, and As in the decoction were in the range of 0.045-0.080, 0.070-0.112 and 0.004-0.018 mg·kg^-1. The results of risk assessment showed that calculated by the total amounts of heavy metals in the Lindera aggregata (Sims) Kosterm., for the end points of nervous system, the cumulative risks of co-exposure of heavy metals in 3 batches of samples were of concern. After decoction and transportation by Caco-2 cells, for the end points of cardiovascular system, blood, nervous system, kidney and testis, the TTD modification of HI values of all batches of samples were less than 1, and the health risks were acceptable. The study provided methodology basis for a more objective assessment of the health risks of heavy metals and harmful elements in traditional Chinese medicine and for a more scientific limit standard of heavy metals and harmful elements.