Dry eye is a chronic ocular surface disease caused by multiple factors. It is caused by the instability of tear film and the imbalance of the microenvironment of ocular surface, and may be accompanied by ocular surface inflammation, damage, and abnormal nerve sensation. The instability of tear film is its core characteristic. Mucin is an important component of the tear film and plays a role in stabilizing the tear film. The reduction of its secretion and the change of its structure lead to the occurrence and development of dry eye. The intracellular Ca2+ signal is the key to controlling the secretion of water and enzymes by exocrine glands. A decrease in the Ca2+ signal can cause dry eye. Conjunctival goblet cells are the main cells that secrete mucin. By activating the intracellular PLC-IP3-Ca2+ pathway, RyRs pathway, cAMP signaling pathway, P2X receptor, BLT1 and ChemR23 receptors, cholinergic receptor, and ALX signaling pathway, the content of Ca2+ can be increased, and the replenishment of mucin granules can be accelerated, thereby relieving the symptoms of dry eye. The Ca2+ signaling pathway may be an important target for the treatment of dry eye. This article reviews the role of mucin in dry eye and the influence of the Ca2+ signal on the secretion of mucin by conjunctival goblet cells.

ObjectiveTraditional Chinese medicine (TCM) constitutes a valuable cultural heritage and an important source of antitumor compounds. Poria (Poria cocos (Schw.) Wolf), the dried sclerotium of a polyporaceae fungus, was first documented in Shennong’s Classic of Materia Medica and has been used therapeutically and dietarily in China for millennia. Traditionally recognized for its diuretic, spleen-tonifying, and sedative properties, modern pharmacological studies confirm that Poria exhibits antioxidant, anti-inflammatory, antibacterial, and antitumor activities. Pachymic acid (PA; a triterpenoid with the chemical structure 3β-acetyloxy-16α-hydroxy-lanosta-8,24(31)-dien-21-oic acid), isolated from Poria, is a principal bioactive constituent. Emerging evidence indicates PA exerts antitumor effects through multiple mechanisms, though these remain incompletely characterized. Neuroblastoma (NB), a highly malignant pediatric extracranial solid tumor accounting for 15% of childhood cancer deaths, urgently requires safer therapeutics due to the limitations of current treatments. Although PA shows multi-mechanistic antitumor potential, its efficacy against NB remains uncharacterized. This study systematically investigated the potential molecular targets and mechanisms underlying the anti-NB effects of PA by integrating network pharmacology-based target prediction with experimental validation of multi-target interactions through molecular docking, dynamic simulations, and in vitro assays, aimed to establish a novel perspective on PA’s antitumor activity and explore its potential clinical implications for NB treatment by integrating computational predictions with biological assays. MethodsThis study employed network pharmacology to identify potential targets of PA in NB, followed by validation using molecular docking, molecular dynamics (MD) simulations, MM/PBSA free energy analysis, RT-qPCR and Western blot experiments. Network pharmacology analysis included target screening via TCMSP, GeneCards, DisGeNET, SwissTargetPrediction, SuperPred, and PharmMapper. Subsequently, potential targets were predicted by intersecting the results from these databases via Venn analysis. Following target prediction, topological analysis was performed to identify key targets using Cytoscape software. Molecular docking was conducted using AutoDock Vina, with the binding pocket defined based on crystal structures. MD simulations were performed for 100 ns using GROMACS, and RMSD, RMSF, SASA, and hydrogen bonding dynamics were analyzed. MM/PBSA calculations were carried out to estimate the binding free energy of each protein-ligand complex. In vitro validation included RT-qPCR and Western blot, with GAPDH used as an internal control. ResultsThe CCK-8 assay demonstrated a concentration-dependent inhibitory effect of PA on NB cell viability. GO analysis suggested that the anti-NB activity of PA might involve cellular response to chemical stress, vesicle lumen, and protein tyrosine kinase activity. KEGG pathway enrichment analysis suggested that the anti-NB activity of PA might involve the PI3K/AKT, MAPK, and Ras signaling pathways. Molecular docking and MD simulations revealed stable binding interactions between PA and the core target proteins AKT1, EGFR, SRC, and HSP90AA1. RT-qPCR and Western blot analyses further confirmed that PA treatment significantly decreased the mRNA and protein expression of AKT1, EGFR, and SRC while increasing the HSP90AA1 mRNA and protein levels. ConclusionIt was suggested that PA may exert its anti-NB effects by inhibiting AKT1, EGFR, and SRC expression, potentially modulating the PI3K/AKT signaling pathway. These findings provide crucial evidence supporting PA’s development as a therapeutic candidate for NB.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Objective To discuss the methods,efficacy,and safety of endovascular treatment for ruptured pseudoaneurysm hemorrhage of internal carotid artery(ICA)after radiotherapy for nasopharyngeal carcinoma(NPC).Methods The clinical data of 21 patients with ruptured pseudoaneurysm hemorrhage of ICA after radiotherapy for NPC,who were admitted to the Affiliated Union Hospital,Fujian Medical University of China,were retrospectively analyzed.The patient's surgical strategies were analyzed,the therapeutic results and the clinical and imaging follow-up results were summarized.Of the 21 patients,covered stent implantation was carried out in 8,stent-assisted coil embolization was employed in 6,and direct occlusion of parent artery was adopted in 7.Results Successful endovascular treatment was accomplished in all the 21 patients.Excellent hemostatic effect was obtained immediately after surgery.Aneurysm neck residue was observed in 2 patients,and aneurysm body residue was seen in one patients.Postoperative bleeding recurred in 5 patients,in 4 of them the bleeding stopped after once more occlusion of the parent artery,and one patient developed internal leakage after covered stent implantation and the bleeding stopped after balloon dilation,and this patient died of unknown cause one month later.One patient developed coma after covered stent implantation,CT scan demonstrated subarachnoid hemorrhage and brain swelling,and this patient showed no improvement after treatment and was self-discharged from hospital.ICA occlusion was seen in 3 patients during follow-up period,and 2 patients did not receive a postoperative follow-up visit.In the 19 patients who were followed up,the mRS score was 0 point(n=9),1 point(n=6),2 points(n=2),5 points(n=1),and 6 points(n=1).Conclusion For the ruptured pseudoaneurysm hemorrhage of ICA after radiotherapy for NPC,endovascular treatment is highly safe with reliable efficacy.The covered stent implantation carries good short-term efficacy,but there are also problems such as aneurysm recurrence,internal endoleak,etc.The direct occlusion of parent artery may have more reliable long-term efficacy.(J Intervent Radiol,2024,33:304-308)

ObjectiveTo explore the effects of different emulsion mixtures and emulsification methods on the inflammation severity in an experimental autoimmune uveitis （EAU） model in rats， and to analyze the characteristics of the current EAU model. MethodEAU was induced in Lewis rats by subcutaneous injection of interphotoreceptor retinoid-binding protein （IRBP） 1177-1191 emulsified with Freund's complete adjuvant （CFA）， with or without intraperitoneal injection of pertussis toxin （PTX）. Slit lamp examination， HE staining， and optical coherence tomography were used to evaluate factors affecting EAU modeling， including different doses of the emulsion mixture （IRBP1177-1191， PTX， and inactivated Mycobacterium tuberculosis） and four different emulsification methods. The classification， characteristics， modeling methods， advantages， and disadvantages of EAU animal models were summarized and analyzed based on the clinical diagnostic criteria and syndrome characteristics of chronic uveitis in both traditional Chinese medicine （TCM） and western medicine， to evaluate the consistency between TCM and western medical syndromes. ResultIncreasing the dose of inactivated M. tuberculosis and antigen peptide in the emulsion mixture exacerbated the anterior segment inflammation in EAU rats. Increasing the injection of PTX also exacerbated anterior segment inflammation and increased retinal thickness in EAU rats. The severity of the EAU model was closely related to the emulsification method used. All four emulsification methods successfully induced EAU in rats. Comparatively， the ultrasonic cell disruptor and T10 basic disperser achieved successful emulsification in a short time. The degree of emulsification of the mixture also influenced the severity of the EAU model in rats. The existing EAU animal model shows a high degree of consistency with western medical diagnoses and the main ocular syndromes in TCM. ConclusionIRBP1177-1191， PTX， inactivated M. tuberculosis， and emulsification methods can affect the severity of the EAU model through different pathways. The existing EAU animal models can simulate the clinical characteristics of western medicine well but lack the etiology， pathogenesis， and syndrome characteristics of TCM. Therefore， it is necessary to construct an EAU animal model that combines disease and syndrome characteristics.

Thrombocytopenia is one of the common complications of cirrhotic patients, which can induce an increasing bleeding risk and closely correlate with bleeding following invasive procedures. Consequently, how to respond to thrombocytopenia is crucial for improving the prognosis of patients with cirrhosis. This article reviews the main mechanisms of cirrhosis concurrent with thrombocytopenia, as well as the corresponding clinical management strategies.

Objective lo investigate the predictive value of serum growth differentiation factor 11(GDF-11)and calprotectin A4(S100A4)for contrast-induced nephropathy(CIN)after coronary angiography(CAG).Methods A total of 528 patients who underwent CAG in the First Affiliated Hospital of Xi'an Jiao-tong University from December 2020 to November 2023 were selected as the research objects.According to whether the patients had CIN,they were divided into non-nephropathy group(472 cases)and nephropathy group(56 cases).Enzyme-linked immunosorbent assay was used to detect serum levels of GDF-11 and S100A4.Multivariate Logistic regression analysis was used to explore the influencing factors of CIN after CAG.Receiver operating characteristic(ROC)curve was used to evaluate the predictive value of serum GDF-11 and S100A4 for CIN after CAG.Results The serum levels of GDF-11 and S100A4 in nephropathy group were higher than those in non-nephropathy group(P＜0.05).The contrast agent dose and postoperative ser-um creatinine level in the nephropathy group were higher than those in the non-nephropathy group(P＜0.05).Multivariate Logistic regression analysis showed that contrast agent dose ≥131.84 mL(OR=2.158,95％CI 1.284-3.627),postoperative serum creatinine ≥ 87.57 μmol/L(OR=2.445,95％CI 1.533-3.898),GDF-1 1 ≥4 50.84 ng/mL(OR=2.445,95％CI 1.533-3.898)were the influencing factors of CIN af-ter CAG(P＜0.05).The area under the curve(95％CI)of serum GDF-11 and S100A4 for predicting CIN af-ter CAG was 0.861(95％CI 0.810-0.912)and 0.798(95％CI 0.747-0.849),respectively.The optimal cut-off values were 450.84 ng/mL and 86.98 μg/mL,the specificity were 65.89％and 57.62％,and the sensi-tivity were 94.74％and 94.74％,respectively.The area under the curve of the combination of the two was 0.906(95％CI 0.856-0.957),the specificity was 87.09％,and the sensitivity was 84.26％.Conclusion The elevated levels of serum GDF-11 and S100A4 are closely related to the occurrence of CIN in patients after CAG surgery,which can be used as biological indicators to evaluate the occurrence of CIN in patients after CAG surgery,and the combined prediction efficiency of GDF-11 and S100A4 is higher.

AIM To evaluate the quality of Changmaile Capsules(Ⅰ).METHODS The analysis was performed on a 35℃ thermostatic Thermo Scientific AccucoreTM XL C18 column(4.6 mm×250 mm,4 μm),with the mobile phase comprising of methanol-acetonitrile-0.5% phosphoric acid flowing at 1 mL/min in a gradient elution manner,and the detection wavelengths were set at 230,280 nm.The contents of gastrodin,danshensu,quercetin-3-O-β-D-glucose-7-O-β-D-gentiobioside,3′-hydroxypuerarin,puerarin,3′-methoxypuerarin,puerarin apioside,daidzin,rosmarinic acid,lithospermic acid,ononin,daidzein,salvianolic acid B,calycosin,paeoniflorin and isoquercitrin were determined,after which HPLC fingerprints were established,along with the calculation of similarities.RESULTS Sixteen constituents showed good linear relationships within their own ranges(r≥0.999 0),whose average recoveries were 87.4%-103.9% with the RSDs of 0.54%-3.10% .At 230 nm,the fingerprints of ten batches of samples demonstrated similarities of 0.954-0.999,which displayed obvious differences at 280 nm.3′-Hydroxypuerarin,puerarin,3′-methoxypuerarin,puerarin apioside,daidzin and daidzein were main differential constituents,paeoniflorin and isoquercitrin exhibited stable contents in various batches of samples.CONCLUSION This simple,accurate and reliable method can be used for the quality control of Changmaile Capsules(Ⅰ).

Acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had caused a global pandemic since 2019, and posed a serious threat to global health security. Traditional Chinese medicine (TCM) has played an indispensable role in the battle against the epidemic. Many components originated from TCMs were found to inhibit the production of SARS-CoV-2 3C-like protease (3CLpro) and papain-like protease (PLpro), which are two promising therapeutic targets to inhibit SARS-CoV-2. This study describes a systematic investigation of the roots and rhizomes of Sophora tonkinensis, which results in the characterization of 12 new flavonoids, including seven prenylated flavanones (1-7), one prenylated flavonol (8), two prenylated chalcones (9-10), one isoflavanone (11), and one isoflavan dimer (12), together with 43 known compounds (13-55). Their structures including the absolute configurations were elucidated by comprehensive analysis of MS, 1D and 2D NMR data, and time-dependent density functional theory electronic circular dichroism (TDDFT ECD) calculations. Compounds 12 and 51 exhibited inhibitory effects against SARS-CoV-2 3CLpro with IC₅₀ values of 34.89 and 19.88 μmol·L^-1, repectively while compounds 9, 43 and 47 exhibited inhibitory effects against PLpro with IC₅₀ values of 32.67, 79.38, and 16.74 μmol·L^-1, respectively.
Flavonoids/chemistry* ; SARS-CoV-2 ; Rhizome ; COVID-19 ; Peptide Hydrolases ; Antiviral Agents/chemistry*

Objective To investigate the effect of silencing E6-associated protein(E6AP)on the level of p53 protein in human papilloma virus(HPV)negative cervical cancer cells(C33A cells).Methods The siRNA sequence silencing E6AP(siE6AP)and silencing control disordered siRNA sequence(siControl)were transfected into C33A cells with the mediation of LipofectamineTM2000 transfection reagent respectively.The silencing effect of siRNA on E6AP and the expression of p53and cleaved-caspase-3 proteins were detected by Western blot.Results The levels of E6AP protein in C33A cells of siE6AP group were significantly lower(t =-4.597,P<0.05),while the levels of p53 and cleaved-caspase-3 proteins were significantly higher than those of siControl group(t = 4.533 and 7.099 respectively,each P<0.05).Conclusion Silencing of E6AP significantly increased the expression of p53 protein in C33A cells,indicating that silencing of E6AP may restore the activity and function of p53 protein in C33A cells.