According to General Chapter 1145 of Division IV in the Chinese Pharmacopoeia (2020 Edition), the test for depressor substances is a common method for drug testing. It determines whether the level of depressor substances in a test sample complies with the specified standards by comparing the extent of blood pressure reduction in anesthetized cats induced by the histamine reference substance and the test sample. If an out-of-specification (OOS) result occurs in the test for depressor substances, it may be caused by inherent quality issues of the drug or errors in the testing process. Therefore, analyzing the causes of OOS is particularly important for confirming the test results and evaluating drug quality. Cats are used as experimental animals in the test for depressor substances. Compared with conventional laboratory animals, they are less stable, surgery procedures are more challenging, and the testing process is more complex. These factors make it more difficult to investigate the causes of OOS in this test. Based on a review of the literature and practical work experience, this article analyzes the causes of OOS in the test for depressor substances from the following five aspects: (1) an analysis of the impact of drug standards on OOS from three aspects: standard determination, standard content, and standard drafting; (2) personnel qualifications, including pre-employment training, compliance with standard operating procedures during experimental operations, and the ability to operate instruments; (3) factors related to cats, used as experimental animals in the test for depressor substances, including physiological characteristics, genetic background, and abnormal conditions during the experiment; (4) reference substances, reagents, test samples, and key instruments such as the multi-channel physiological signal instrument; (5) experimental operations including animal anesthesia, arterial and venous catheterization, drug administration, and data processing. This article aims to provide reference approaches for professionals engaged in the testing of pharmaceuticals and biological products when analyzing the causes of OOS in the test for depressor substances.

According to General Chapter 1145 of Division IV in the Chinese Pharmacopoeia (2020 Edition), the test for depressor substances is a common method for drug testing. It determines whether the level of depressor substances in a test sample complies with the specified standards by comparing the extent of blood pressure reduction in anesthetized cats induced by the histamine reference substance and the test sample. If an out-of-specification (OOS) result occurs in the test for depressor substances, it may be caused by inherent quality issues of the drug or errors in the testing process. Therefore, analyzing the causes of OOS is particularly important for confirming the test results and evaluating drug quality. Cats are used as experimental animals in the test for depressor substances. Compared with conventional laboratory animals, they are less stable, surgery procedures are more challenging, and the testing process is more complex. These factors make it more difficult to investigate the causes of OOS in this test. Based on a review of the literature and practical work experience, this article analyzes the causes of OOS in the test for depressor substances from the following five aspects: (1) an analysis of the impact of drug standards on OOS from three aspects: standard determination, standard content, and standard drafting; (2) personnel qualifications, including pre-employment training, compliance with standard operating procedures during experimental operations, and the ability to operate instruments; (3) factors related to cats, used as experimental animals in the test for depressor substances, including physiological characteristics, genetic background, and abnormal conditions during the experiment; (4) reference substances, reagents, test samples, and key instruments such as the multi-channel physiological signal instrument; (5) experimental operations including animal anesthesia, arterial and venous catheterization, drug administration, and data processing. This article aims to provide reference approaches for professionals engaged in the testing of pharmaceuticals and biological products when analyzing the causes of OOS in the test for depressor substances.

The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating many physiological processes. Activating the AhR-CYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases. Here, a practical in situ cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators, via functional sensing of CYP1A1 activities in live cells. Firstly, a cell-permeable, isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for in-situ visualizing the dynamic changes of CYP1A1 function in living systems, which was subsequently used for discovering the efficacious modulators of the AhR-CYP1A1 axis. Following screening of a compound library, LAC-7 was identified as an efficacious activator of the AhR-CYP1A1 axis, which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines. LAC-7 also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages. Animal tests showed that LAC-7 could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice, and markedly reduced the levels of multiple inflammatory factors. Collectively, an optimized fluorometric cell-based assay was devised for in situ functional imaging of CYP1A1 activities in living systems, which strongly facilitated the discovery of efficacious modulators of the AhR-CYP1A1 axis as novel anti-inflammatory agents.

Advancements in artificial intelligence (AI) and emerging technologies are rapidly expanding the exploration of chemical space, facilitating innovative drug discovery. However, the transformation of novel compounds into safe and effective drugs remains a lengthy, high-risk, and costly process. Comprehensive early-stage evaluation is essential for reducing costs and improving the success rate of drug development. Despite this need, no comprehensive tool currently supports systematic evaluation and efficient screening. Here, we present druglikeFilter, a deep learning-based framework designed to assess drug-likeness across four critical dimensions: 1) physicochemical rule evaluated by systematic determination, 2) toxicity alert investigated from multiple perspectives, 3) binding affinity measured by dual-path analysis, and 4) compound synthesizability assessed by retro-route prediction. By enabling automated, multidimensional filtering of compound libraries, druglikeFilter not only streamlines the drug development process but also plays a crucial role in advancing research efforts towards viable drug candidates, which can be freely accessed at https://idrblab.org/drugfilter/.

Background::Intrauterine valvuloplasty is an innovative therapy, which promotes ventricular growth and function in some congenital heart diseases (CHDs). The technique remains challenging and can only be performed in a few centers. This study aimed to assess the feasibility and mid-term outcomes of fetal cardiac intervention (FCI) in fetuses with critical CHD in an experienced tertiary center.Methods::Five fetal aortic valvuloplasty (FAV) or fetal pulmonary valvuloplasty (FPV) procedures were performed in our fetal heart center between August 2018 and May 2022. Technical success was defined as crossing the aortic or pulmonary valve and balloon inflation, followed by evidence of increased blood flow across the valve and/or new regurgitation. Follow-up clinical records and echocardiography were obtained during the prenatal and postnatal periods.Results::Five fetuses received FAV or FPV, including critical aortic stenosis ( n = 2) and pulmonary atresia with intact ventricular septum ( n = 3). The mean maternal age was 33.0 ± 2.6 years. The median gestational age (GA) at diagnosis was 24 weeks (range, 22-26 weeks). The median GA at intervention was 29 weeks (range, 28-32 weeks). All five cases underwent successful or partially successful procedures. One patient had pulmonary valve perforation without balloon dilation. No procedure-related deaths or significant complications occurred. However, one neonatal death occurred due to heart and renal failure. The median follow-up period was 29.5 months (range, 8.0-48.0 months). The four surviving patients had achieved biventricular circulation, exhibited improved valve, and ventricular development at the last follow-up visit. Conclusion::Intrauterine FCI could be performed safely with good prognosis in critical CHD.

Amyloidosis is a rare disease.This paper reports a case of localized secondary hypopharyngeal amyloidosis presenting with pulmonary tuberculosis as the initial symptom.The patient lacked specific clinical manifestations and primarily exhibited symptoms such as cough,sputum production,acid reflux,belching,and abdominal pain.Chest CT indicated bronchiectasis with infection and pulmonary tuberculosis.Digestive endoscopy revealed a white mucosal elevation at the right pyriform sinus of the hypopharynx.Pathological diagnosis confirmed amyloid deposits in the hypopharyngeal mucosal tissue.The patient tested positive for anti-amyloid A antibodies,Congo red staining(+),and periodate Schiff staining(+).Amyloidosis commonly affects the digestive system and may have various etiologies,often presenting with symptoms that overlap with other digestive system diseases,leading to frequent misdiagnosis and missed optimal treatment opportunities.The hypopharynx,a highly folded and narrow chamber that serves as a common passage for the digestive and respiratory tracts,can be effectively evaluated for amyloidosis using digestive endoscopy.

Kirsten rat sarcoma viral oncogene homolog(KRAS)gene is one of the most commonly mutated oncogenes.It has been found that KRAS inhibitors have the potential therapeutic effect on cancer patients with this gene mutation.In this study,machine learning was applied to develop a QSAR(quantitative structure-activity relationship)model for KRAS small molecule inhibitors.A total of 1857data points of IC50 and SMILES(simplified molecular input line entry system)for KRAS inhibitors were collected from three databases:ChEMBL,BindingDB,and PubChem.And nine different classifiers were constructed using three different feature screening methods combined with three machine learning models,namely,random forest,support vector machine,and extreme gradient boosting machine.The results showed that the SVM model combined with mutual information feature selection exhibited the best performance:AUCtest=0.912,ACCtest=0.859,F1test=0.890.Moreover,it also demonstrated good predictive performance on the external validation set(AUCExt=0.944,RecallExt=0.856,FPRExt=0.111).This study provides a new technical route for KRAS inhibitor screening in natural product databases using artificial intelligence methods.

Currently,human health due to corona virus disease 2019(COVID-19)pandemic has been seriously threatened.The coronavirus severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)spike(S)protein plays a crucial role in virus transmission and several S-based therapeutic approaches have been approved for the treatment of COVID-19.However,the efficacy is compromised by the SARS-CoV-2 evolvement and mutation.Here we report the SARS-CoV-2 S protein receptor-binding domain(RBD)inhibitor licorice-saponin A3(A3)could widely inhibit RBD of SARS-CoV-2 variants,including Beta,Delta,and Omicron BA.1,XBB and BQ1.1.Furthermore,A3 could potently inhibit SARS-CoV-2 Omicron virus in Vero E6 cells,with EC50 of 1.016 pM.The mechanism was related to binding with Y453 of RBD deter-mined by hydrogen-deuterium exchange mass spectrometry(HDX-MS)analysis combined with quan-tum mechanics/molecular mechanics(QM/MM)simulations.Interestingly,phosphoproteomics analysis and multi fluorescent immunohistochemistry(mIHC)respectively indicated that A3 also inhibits host inflammation by directly modulating the JNK and p38 mitogen-activated protein kinase(MAPK)path-ways and rebalancing the corresponding immune dysregulation.This work supports A3 as a promising broad-spectrum small molecule drug candidate for COVID-19.

Vascular biomechanics mainly explores how vascular cells perceive mechanical stimuli,how mechanics affects the development of diseases,and the exploitation of various mathematical models to analyze the effects of mechanical factors on diseases.In recent years,researches in the field of vascular biomechanics are developing rapidly,and various research teams have analyzed the mechanical and biological processes of blood vessels from different directions,in order to gain a deeper understanding of the regulatory mechanisms of vascular biomechanical factors affecting the progression of various vascular diseases,and provide a theoretical basis based on the mechanobiology for the prevention and treatment of cardiovascular and cerebrovascular diseases.This article summarizes and discusses the recent research hotspots and emerging trends in the field of vascular mechanobiology based on domestic and foreign expert teams and combined with the work of this research team,thus providing a systematic framework for grasping hotspots and exploring new research directions in the field of vascular mechanobiology.

Objective : To learn the epidemiological characteristics of acute hepatitis B in Jiangxi Province from 2014 to 2021, so as to provide insights into perfecting hepatitis B prevention and control strategy. Methods: Data pertaining to acute hepatitis B was collected through the Chinese Disease Prevention and Control Information System. The temporal, spatial and population distributions of acute hepatitis B were analyzed using a descriptive epidemiological method. The trend in incidence of acute hepatitis B was analyzed using annual percent change (APC). Results: Totally 8 890 cases of acute hepatitis B were reported in Jiangxi Province from 2014 to 2021, with the reported incidence showing a tendency towards a decline (APC=-11.730%, P<0.05). The average annual reported incidence rate of acute hepatitis B was 2.42/105. Acute hepatitis B occurred all the year round, without obvious seasonal characteristics. The top three highest incidence rates were reported in Pingxiang City (7.12/105), Ganzhou City (3.12/105) and Fuzhou City (2.87/105). The lowest and highest incidence rates of acute hepatitis B were seen among residents aged under 10 years (0.30/105) and 20-29 years (3.86/105). The incidence rate of males was higher than that of females (3.25/105 vs. 1.55/105, P<0.05). Farmers were predominant population affected acute hepatitis B (5 764 cases, 64.84%). Conclusions The incidence of acute hepatitis B showed a downward trend in Jiangxi Province from 2014 to 2021, and the disease predominantly affected young males, farmers. Health education should be strengthened, and hepatitis B vaccination coverage should be promoted.