BackgroundPatients with schizophrenia experience low quality of life， and internalized stigma is considered an important indicator for quality of life， while the mediating role of self-esteem and severity of negative symptoms in the relationship between internalized stigma and quality of life remains underexplored. ObjectiveTo examine the mediating role of self-esteem and severity of negative symptoms in the relationship between internalized stigma and quality of life， so as to provide references for improving their quality of life. MethodsA total of 342 patients with schizophrenia who were hospitalized in 6 hospitals in Xiangyang City， Siping City and Changchun City from April to September 2023 were included， and all of whom met the diagnostic criteria for schizophrenia according to the International Classification of Diseases， tenth edition （ICD-10）. Internalized Stigma of Mental Illness Scale （ISMI）， Schizophrenia Quality of Life Scale （SQLS）， Self-Esteem Scale （SES） and negative symptom subscale of Positive and Negative Symptom Scale （PANSS） were administered to all patients. Spearman correlation analysis was adopted to determine correlations between the different scales. A structural equation modeling was constructed using Amos 28.0， and Bootstrap method was employed to verify the mediating effect of self-esteem and negative symptom severity in the association between internalized stigma and quality of life. ResultsA total of 309 patients （90.35%） completed questionnaires in this study. The ISMI score of schizophrenia patients was positively correlated with both SQLS score and the PANSS negative symptom subscale score （r=0.612， 0.492， P<0.01）， while was negatively correlated with SES score （r=-0.513， P<0.01）. The SQLS score was negatively associated with the SES score （r=-0.555， P<0.01） and positively associated with PANSS negative symptom subscale score （r=0.672， P<0.01）. The SES score was negatively correlated with PANSS negative symptom subscale score （r=-0.433， P<0.01）.The total effect value of internalized stigma on quality of life was 0.746 （95% CI： 0.680~0.806）. Self-esteem and severity of negative symptoms independently mediated the relationship between internalized stigma and quality of life， and the indirect effect values were 0.151 （95% CI： 0.062~0.254） and 0.126 （95% CI： 0.047~0.205）， accounting for 20.24% and 16.89% of the total effect， respectively. In addition， a chained mediation effect of self-esteem and quality of life was also demonstrated， the indirect effect value was 0.102 （95% CI： 0.049~0.165）， accounting for 13.67% of the total effect）. ConclusionInternalized stigma in patients with schizophrenia patients can not only directly affect the quality of life， but also indirectly affect the quality of life of patients through either separate or chained mediation of self-esteem and the severity of negative symptoms. ［Funded by Hubei Provincial Undergraduate Innovation and Entrepreneurship Project （number， S202410519027）］

BACKGROUND: Retinal ganglion cell (RGC) death caused by acute ocular hypertension is an important characteristic of acute glaucoma. Receptor-interacting protein kinase 3 (RIPK3) that mediates necroptosis is a potential therapeutic target for RGC death. However, the current understanding of the targeting agents and mechanisms of RIPK3 in the treatment of glaucoma remains limited. Notably, artificial intelligence (AI) technologies have significantly advanced drug discovery. This study aimed to discover RIPK3 inhibitor with AI assistance. METHODS: An acute ocular hypertension model was used to simulate pathological ocular hypertension in vivo . We employed a series of AI methods, including large language and graph neural network models, to identify the target compounds of RIPK3. Subsequently, these target candidates were validated using molecular simulations (molecular docking, absorption, distribution, metabolism, excretion, and toxicity [ADMET] prediction, and molecular dynamics simulations) and biological experiments (Western blotting and fluorescence staining) in vitro and in vivo . RESULTS: AI-driven drug screening techniques have the potential to greatly accelerate drug development. A compound called HG9-91-01, identified using AI methods, exerted neuroprotective effects in acute glaucoma. Our research indicates that all five candidates recommended by AI were able to protect the morphological integrity of RGC cells when exposed to hypoxia and glucose deficiency, and HG9-91-01 showed a higher cell survival rate compared to the other candidates. Furthermore, HG9-91-01 was found to protect the retinal structure and reduce the loss of retinal layers in an acute glaucoma model. It was also observed that the neuroprotective effects of HG9-91-01 were highly correlated with the inhibition of PANoptosis (apoptosis, pyroptosis, and necroptosis). Finally, we found that HG9-91-01 can regulate key proteins related to PANoptosis, indicating that this compound exerts neuroprotective effects in the retina by inhibiting the expression of proteins related to apoptosis, pyroptosis, and necroptosis. CONCLUSION AI-enabled drug discovery revealed that HG9-91-01 could serve as a potential treatment for acute glaucoma.
Animals ; Glaucoma/metabolism* ; Neuroprotective Agents/pharmacology* ; Mice ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism* ; Artificial Intelligence ; Retinal Ganglion Cells/metabolism* ; Disease Models, Animal ; Molecular Docking Simulation ; Mice, Inbred C57BL ; Male

OBJECTIVES: To investigate the effect of high glucose on macrophage polarization and the role of immune-responsive gene 1 (IRG1) in mediating its effect. METHODS: RAW264.7 cells were transfected with IRG1-overexpressing plasmid or IRG1 siRNA via electroporation and cultured in either normal or high glucose for 72 h to observe the changes in cell viability and morphology using CCK-8 assay and phase contrast microscopy. The protein levels of IRG1, iNOS, Arg-1, IL-1β and IL-10 in the treated cells were detected with Western blotting, and the fluorescence intensities of iNOS and Arg-1 were detected using immunofluorescence assay. The protein levels of IL-1β and IL-10 in the culture medium were determined with ELISA. RESULTS: High glucose exposure significantly reduced IRG1 and Arg-1 expressions, increased iNOS and IL-1β expressions and IL-1β secretion, and decreased IL-10 level in RAW264.7 cells. Transfection with the IRG1-overexpressing plasmid provided the cells with obvious resistance to high glucose-induced changes in iNOS, Arg-1, IL-1β and IL-10, whereas IRG1 knockdown further enhanced the effects of high glucose exposure on Arg-1 expression and the expression and secretion of IL-10. CONCLUSIONS High glucose promotes M1 polarization of the macrophages possibly through a mechanism to inhibit the expression of IRG1 protein, thus leading to chronic inflammatory response.
Animals ; Mice ; Macrophages/drug effects* ; Glucose/pharmacology* ; Interleukin-10/metabolism* ; Nitric Oxide Synthase Type II/metabolism* ; RAW 264.7 Cells ; Interleukin-1beta/metabolism* ; Arginase/metabolism* ; RNA, Small Interfering/genetics* ; Transfection ; Inflammation

Objective To explore the application value of small airway function measurement in chil-dren with cough variant asthma(CVA).Methods A total of 155 children with chronic cough who visited the hospital from January to December 2022 were selected as the research subjects and divided into the CVA group(n=78)and the non-CVA group(n=77)according to the results of the bronchial provocation test.The small airway function was evaluated by three indicators in the basic lung function:the percentage of the maximum mid-expiratory flow to the predicted value(MMEF％pred),and the percentage of the instantaneous expiratory flow to the predicted value when forcefully exhaling 50％and 75％of the vital capacity(FEF50％％pred,FEF75％％ pred).If any one of the three indicators is lower than the lower limit of the normal value(＜65％),it is determined as small airway dysfunction.The incidence of small airway dysfunction and the indica-tors of atmospheric airway function[percentage of forced expiratory volume in one second to the predicted value(FEV1％pred),percentage of maximum expiratory flow to the predicted value(PEF％ pred)]and small airway(MMEF％pred,FEF50％％pred,FEF75％％)before and after bronchial provocation tests were compared between the two groups.Results Among 55 children with chronic cough,47 cases were found to have small airway dysfunction,with 33 cases in the CVA group and 14 cases in the non-CVA group.The incidence of small airway dysfunction in the CVA group was higher than that in the non-CVA group[42.3％(33/78)vs.18.2％(14/77)],and the difference was statistically significant(P＜0.05).Compared with before the bron-chial provocation test,the levels of large and small airway function indicators in both groups decreased after the bronchial provocation test.The decrease rate in the CVA group was higher than that in the non-CVA group,and the decrease rates of MMEF％pred,FEF50％％pred,and FEF75％％ pred were higher than those of FEV1％ pred and PEF％ pred,the differences were statistically significant(P＜0.05).Conclusion Small air-way function measurement can be performed in children with CVA for early diagnosis and therapeutic effect e-valuation.

Remimazolam is a novel ultra-short-acting benzodiazepine characterized by rapid metabolism via hydrolysis by non-specific esterases.This mechanism enables fast onset and quick recovery,significantly shortening the duration of anesthesia and effectively reducing the risk of drug accumulation in the body.It ex-hibits high binding specificity for the γ-aminobutyric acid(GABA)receptor,leading directly to central nerv-ous system inhibition and producing a pronounced sedative effect.This profile offers a more precise and con-trollable approach to anesthesia in clinical practice.The safety and efficacy of remimazolam have been demon-strated across various clinical settings,including procedural sedation,induction and maintenance of general an-esthesia,and sedation in the intensive care unit(ICU).Its adverse effects are relatively infrequent and highly predictable,as substantiated by numerous clinical trials;however,the optimization of its dosing regimens re-quires further in-depth investigation.This review summarized the pharmacological properties of remimazolam and provides a detailed discussion on the impact of various factors on its pharmacodynamics.These factors in-clude basic patient characteristics(such as gender,age,obesity,hepatic and renal function,and circadian rhythms)and external influences(such as altitude and drug interactions).

Objective: To determine the expression of melanoma-associated antigens D4(MAGED4) and SIRT7 in human glioma, and to analyze the potential effects of MAGED4 and SIRT7 on glioma cell proliferation. Methods: The MAGED4 and SIRT7 expression levels and their correlation were compared by the China glioma genome atlas(CGGA), human protein atlas(HPA), and UALCAN databases. Survival analysis, ROC curve analysis, and Cox regression analysis were used to predict the outcome of MAGED4 and SIRT 7 in glioma patients. Gene ontology(GO) and Kyoto encyclopedia of genes and genomes(KEGG) signaling pathway enrichment analysis were used to explore the biological functions of MAGED4 and SIRT7 in glioma. Western blot experiment was used to investigate whether MAGED4 protein exerted its regulatory effects on the activity of the PI3K/AKT signaling pathway via SIRT7. The effect of MAGED4 on cell proliferation in glioma through SIRT7 was explored by CCK-8. Results: The analysis results of CGGA, UALCAN, and HPA databases showed that the expression levels of MAGED4 and SIRT7 in glioma tissues were higher than those in normal brain tissue, and the expression were positively correlated. Results of survival, ROC, and Cox analysis showed that high expression of MAGED4 and SIRT7 mRNA were risk factors for poor prognosis in glioma. Results of KEGG enrichment analysis showed that MAGED4 and SIRT7 were associated with the PI3K/AKT signaling in glioma, and Western blot results showed that MAGED4 activated the PI3K/AKT signaling pathway by regulating SIRT7. The CCK-8 results showed that MAGED4 promotes the proliferation of glioma cells through SIRT7. Conclusion MAGED4 and SIRT7 are highly expressed in glioma and associated with poor prognosis, and MAGED4 promotes glioma cell proliferation through activation of the PI3K/AKT signaling pathway by SIRT7.

Objective To observe the clinical efficacy of joint needling method combined with ultrasound in the treatment of qi stagnation and blood stasis type of patellofemoral pain syndrome(PFPS).Methods Eighty-six patients with qi stagnation and blood stasis type of PFPS were randomly divided into observation group and control group,with 43 cases in each group.The control group was given western medicine conventional treatment combined with functional exercise,and the observation group was given joint needling method combined with ultrasound treatment on the basis of the control group.Both groups were treated for 2 consecutive weeks.After 2 weeks of treatment,the clinical efficacy of the two groups was evaluated,and the changes in the Visual Analogue Scale(VAS)scores of knee pain and the Kujala scale scores of the two groups were observed before and after treatment.The changes in active range of motion(AROM)of the affected knee joint were compared before and after treatment between the two groups.Results(1)After treatment,the VAS scores of the two groups of patients were significantly improved(P＜0.05),and the observation group was significantly superior to the control group in improving the level of VAS scores,and the difference was statistically significant(P＜0.05).(2)After treatment,the Kujala scores of patients in the two groups were significantly improved(P＜0.05),and the observation group was significantly superior to the control group in improving the level of Kujala scores,and the difference was statistically significant(P＜0.05).(3)After treatment,the AROM of patients in the two groups were significantly improved(P＜0.05),and the observation group was significantly superior to the control group in improving the level of AROM,and the difference was statistically significant(P＜0.05).(4)The total effective rate was 95.35%(41/43)in the observation group and 81.40%(35/43)in the control group.The efficacy of the observation group was superior to that of the control group,and the difference was statistically significant(P＜0.05).Conclusion The joint needling method combined with ultrasound can significantly relieve the pain symptoms of patients with PFPS and promote the recovery of knee joint function,and the clinical efficacy is remarkable.

Objective To observe the effects of electroacupuncture at"Ciliao","Zhongji","Sanyinjiao"and"Dazhui"on urodynamics and expression of ERK/CREB/Bcl-2 pathway in spinal cord tissue of neurogenic bladder rats after suprasacral spinal cord injury.Methods Sixty female SD rats randomly selected 24 and divided into blank group and sham-operation group(12 rats in each group),the remaining 36 rats were subjected to surgical modeling.After modeling,rats were randomly divided into the model group and the electroacupuncture group,with 12 rats in each group.The electroacupuncture group received unilateral electroacupuncture stimulation at acupoints"Ciliao","Zhongji","Sanyinjiao",and"Dazhui"for 30 minutes each time,once a day,for 7 consecutive days.After administration,urodynamic testing was performed,HE staining was used to observe the morphology of bladder detrusor tissue,TUNEL method was used to detected apoptosis in spinal cord tissue,Western blot was used to detected expressions of p-ERK1/2,p-CREB,p-p90Rsk,CRE,Bcl-2,and Bax proteins in spinal cord tissue.Results Compared with the sham-operation group,the basal pressure,maximum pressure,and leakage point pressure of the bladder in the model group increased significantly(P<0.01),while the maximum capacity and compliance of the bladder decreased significantly(P<0.01);the structure of bladder smooth muscle cells was severely damaged and disorderly arranged,accompanied by a large amount of inflammatory cell infiltration;the apoptosis rate of spinal cord tissue cells significantly increased(P<0.01),and the expressions of p-ERK1/2,p-p90Rsk,p-CREB,CRE,and Bcl-2 proteins in spinal cord tissue were significantly decreased,while the expression of Bax protein significantly increased(P<0.01).Compared with the model group,the basal pressure,maximum pressure,and leakage point pressure of the bladder in the electroacupuncture group decreased significantly(P<0.05),while the maximum capacity and compliance of the bladder increased significantly(P<0.05,P<0.01);the integrity of bladder smooth muscle cells was enhanced,the degree of cell edema was reduced,and inflammatory cell infiltration was reduced;the apoptosis rate of spinal cord tissue cells was significantly reduced(P<0.05),and the expressions of p-ERK1/2,p-p90Rsk,p-CREB,CRE,and Bcl-2 proteins in spinal cord tissue significantly increased,while the expression of Bax protein was significantly decreased(P<0.05,P<0.01).Conclusion Electroacupuncture can promote the repair of bladder detrusor tissue in rats with neurogenic bladder model after suprasacral spinal cord injury,increase the maximum capacity and compliance of the bladder,alleviate the high pressure state in the bladder,and its mechanism is related to activating the ERK/CREB/Bcl-2 pathway,reducing secondary apoptosis of damaged neurons,effectively improving bladder innervation,and protecting bladder function.

AIM To study endophytic fungi from Scutellaria baicalensis Georgi.and the enzyme inhibitory activities of their secondary metabolites.METHODS Six different media were used to isolate and purify endophytic fungi from S.baicalensis by tissue homogenate method.The activities of secondary metabolites were evaluated by targeting different enzymes.The highly active strains were identified by molecular biology combined with morphology,and the highly active chemical components were tracked and separated by modern chromatographic separation technology.RESULTS Sixty-four endophytic fungal strains were isolated from S.baicalensis,and one hundred and twenty-eight secondary metabolites were obtained by fermentation.The samples with certain inhibitory activities against adenosine deaminase(ADA),β-lactamase and tyrosinase(TYR)accounted for 14.06%,3.91%and 18.75%,respectively.Strain HTS-23-2 showed high TYR inhibitory activity,and 99%homology with Aspergillus flavus by molecular identification.One compound was isolated from the fermentation samples and identified as kojic acid.CONCLUSION S.baicalensis harbors a rich diversity of endophytic fungi,which serve as a valuable resource for active substances.

AIM To study the chemical constituents from the stems of Gnetum parvifolium(Warb.)C.Y.Cheng ex Chun and their xanthine oxidase inhibitory activities.METHODS The 95%ethanol extract from the stems of G.parvifolium was isolated and purified by silica gel,MCI and preparative HPLC,then the structures of obtained compounds were identified by physicochemical properties and spectral data.The inhibitory activities on xanthine oxidase was determined by ultraviolet spectrophotometry.RESULTS Seventeen compounds were isolated and identified as isorhapontigenin(1),resveratrol(2),4-hydroxybenzaldehyde(3),cycloeucalenol(4),(E)-1-(3',5'-dimethoxyphenyl)-2-(3,4-dimethoxyphenyl)ethene(5),stigmast-4-en-3-one(6),medioresinol(7),chrysin(8),aurantiamide acetate(9),(-)-pinoresinol(10),methyl 4-hydroxybenzoate(11),2-methoxybenzene-1,4-diol(12),gnetumontain C(13),syringaresinol(14),homoeriodictyol(15),vanillin(16),β-sitosterol(17).The IC50 values of compounds 1-3,15-16 were(11.4±0.54),(14.1±1.06),(320.4±0.75),(360.6±0.78),(386.3±0.71)μmol/L,respectively.CONCLUSION Compounds 3-4 are isolated from this plant for the first time.Compounds 5-13 are first isolated from genus Gnetum.Compounds 1-3,15-16 have xanthine oxidase inhibitory activities.