Acute liver injury (ALI) serves as a critical precursor and major etiological factor in the progression and ultimate manifestation of various hepatic disorders. The prevention and treatment of ALI is still a serious global challenge. Given the limited therapeutic options for ALI, exploring novel targeted therapeutic agents becomes imperative. The potential therapeutic efficacy of inhibiting RIPK2 is highlighted, as it may provide significant benefits by attenuating the MAPK pathway and NF-κB signaling. Herein, we propose a CMD-OPT model, a two-stage molecular optimization tool for the rapid discovery of RIPK2 inhibitors with optimal properties. Compound RP20, which targets the ATP binding site, demonstrated excellent kinase specificity, ideal oral pharmacokinetics, and superior therapeutic effects in a model of APAP-induced ALI, positioning RP20 as a promising preclinical candidate. This marks the first application of RIPK2 inhibitors in ALI treatment, opening a novel therapeutic pathway for clinical applications. These results highlight the efficacy of the CMD-OPT model in producing lead compounds from known active molecules, showcasing its significant potential in drug discovery.

Based on CT scan data,a bionic model of lumbar spine injuries with high biofidelity is developed and validated through cadaver experiments.Decoupling the constraint system that affects occupants during collisions due to inertial forces and the subsequent pressure exerted by the seat upon returning to position,a simulated fall experiment is designed.The simulated outcomes are trained and predicted using deep learning algorithms,and the accuracy of the trained neural network prediction model is verified.Key parameters are analyzed for correlation using principal component analysis and cross-reverse methods.The results shows that the predicted lumbar spine injury model obtained from training has high reliability(R2>0.9).Comprehensive analysis reveals that after experiencing axial impact,the L4 vertebral body bears the highest impact load and can be used as a representative measure of lumbar spine injury.Among the environmental variables,the axial force on the L4 lumbar spine is mainly affected by torso mass and fall height,both of which have positive correlations.Torso mass,fall height,and posture angle all have positive effects on internal energy.Conversely,torso mass and fall height have negative correlations with stress.These research findings provide a scientific basis for further elucidating lumbar spine injury mechanisms in intelligent cockpit environments,devising corresponding safety protection measures,and evaluating occupant safety in automobiles.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital vaginal hypoplasia and primordial uterus caused by Müllerian anomalies. Case reports concerning adenomyosis associated with MRKH syndrome are limited, and the formation and intervention of adenomyosis without endometrium are unclear. Here, we present the case of a patient with MRKH syndrome complicated with adenomyosis without endometrium, a hypoechoic solid mass next to the right ovary. According to the intraoperative observation and histopathological examination findings, the mass were diagnosed as adenomyosis of the primordial uterus. Moreover, our report provides insights about its mechanism of occurrence and interventions in MRKH syndrome combined with adenomyosis without endometrium.

OBJECTIVE To study how resveratrol(Res)mitigates acute lung injury(ALI)in mice induced by sulfur mustard(SM)and potential mechanism.METHODS Male C57BL/6N mice were randomly divided into the control group(50 μL physiological saline via nebulization),SM group(SM 5 mg·kg-1 via nebulization),SM+Res 10 or 20 mg·kg-1 groups(1 h after administration of SM 5 mg·kg-1,Res 10 or 20 mg·kg-1 was administered via nebulization).Mice in each group were weighed 0,24,48 and 72 h after SM administration.Mice were sacrificed 72 h after SM administration,and lung tissues were collected,weighed for wet and dry weights,and the wet/dry ratio was calculated.HE staining was employed to detect the pathological changes of lung tissues while real-time quantitative PCR(RT-qPCR)was used to detect the mRNA expression levels of interleukin 6(IL-6)and IL-1β.Transcriptomic changes of the SM group and the SM+Res 20 mg·kg-1 group were detected with the next-generation sequencing technology.RT-qPCR was used to detect the mRNA expression changes of adenosine 5'-monophos-phate-activated protein kinase(AMPK)and silence information regulator 1(SIRT1)in lung tissues.RESULTS 72 h after SM administration,the body mass of mice in the SM group was significantly decreased compared with normal control group,while the wet/dry ratio of the lung was significantly increased,so were the mRNA expression levels of IL-6 and IL-1β in lung tissues were also significantly increased.Pathological changes of lung tissues included alveolar cavity atrophy,marked parenchymal tissues,and diffuse infiltration of local inflammatory cells.Compared with the SM group,the body mass of mice in the SM+Res 10 and 20 mg·kg-1 groups significantly increased,the wet/dry ratio of lung tissues was significantly reduced,and expressions of IL-6 and IL-1β mRNA were significantly decreased in SM+Res 10 and 20 mg·kg-1 groups.Compared with the normal control group,the mRNA expression levels of AMPK and SIRT1 in lung tissues of the SM group were significantly decreased.Compared with the SM group,the mRNA expression levels of AMPK in lung tissues of the SM+Res 10 and 20 mg·kg-1 groups were significantly increased while the mRNA expression level of SIRT1 was significantly decreased.CONCLUSION Res can mitigate ALI in mice induced by SM,and the mechanism may be related to the inhibition of cell apoptosis by regulating the AMPK/SIRT1 signaling pathway.

OBJECTIVE To compare the efficacy and safety of different daily doses of aspirin in the prevention of preeclampsia （PE）. METHODS The case-control studies and prospective randomized controlled trials on aspirin with daily dose ≥ 100 mg （trial group） vs. ＜100 mg （control group） in the prevention of PE were retrieved from PubMed， Medline， Embase， the Cochrane Library， CNKI， China Biomedical Literatue Database and Wanfang Data from base-building to January 2025. After literature screening， data extraction and quality evaluation， meta-analysis was performed by using RevMan 5.3 software. RESULTS A total of 11 literatures were included， involving 3 052 pregnant women. Meta-analysis showed the incidence of PE [RR＝0.63， 95%CI （0.53，0.76）， P＜0.000 01]， gestational hypertension [RR＝0.69， 95%CI （0.50，0.94），P＝0.02]， preterm birth [RR＝0.56， 95%CI （0.47，0.66）， P＜0.000 01]， and intrauterine growth retardation [RR＝0.73，95%CI （0.61，0.87），P＝0.000 5] in trial groups were significantly lower than control group. The incidence of postpartum hemorrhage between the two groups had no statistically significant difference [RR＝1.17， 95%CI （0.90，1.53），P＝0.25]. Subgroup analysis showed that the incidence of PE in Chinese pregnant women taking 150 mg of aspirin was significantly higher than taking 100 mg of aspirin [RR＝3.40， 95%CI （1.29， 8.93）， P＝0.01]； but there was no significant difference between the two groups in the incidences of postpartum hemorrhage， preterm birth （P＞0.05）. CONCLUSIONS Aspirin with daily dose ≥100 mg is more effective in preventing PE than daily dose ＜100 mg， with lower rates of gestational hypertension， preterm birth， and intrauterine growth retardation. It does not increase the risk of postpartum hemorrhage. For pregnant women in China， daily dose 100 mg of aspirin may be more effective in preventing PE than 150 mg.

Andrographolide sulfonate (AS) is a sulfonated derivative of andrographolide extracted from Andrographis paniculata (Burm.f.) Nees, and has been approved for several decades in China. The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis. Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling, improved body weights, and attenuated pathological changes in joints of rats with adjuvant-induced arthritis. Additionally, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β in the serum and ankle joints were reduced. Bioinformatics analysis, along with the spleen index and measurements of IL-17 and IL-10 levels, suggested a potential relationship between AS and Th17 cells under arthritic conditions. In vitro, AS was shown to block Th17 cell differentiation, as evidenced by the reduced percentages of CD4⁺ IL-17A⁺ T cells and decreased expression levels of RORγt, IL-17A, IL-17F, IL-21, and IL-22, without affecting the cell viability and apoptosis. This effect was attributed to the limited glycolysis, as indicated by metabolomics analysis, reduced glucose uptake, and pH measurements. Further investigation revealed that AS might bind to hexokinase2 (HK2) to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or pyruvate kinase M2 (PKM2), and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation. Furthermore, AS impaired the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signals in vivo and in vitro, which was abolished by the addition of lactate. In conclusion, AS significantly improved adjuvant-induced arthritis (AIA) in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.
Animals ; Th17 Cells/immunology* ; Diterpenes/pharmacology* ; Arthritis, Rheumatoid/metabolism* ; Proto-Oncogene Proteins c-akt/immunology* ; Glycolysis/drug effects* ; Cell Differentiation/drug effects* ; Phosphatidylinositol 3-Kinases/genetics* ; Rats ; Male ; Rats, Sprague-Dawley ; Humans ; Andrographis paniculata/chemistry* ; Arthritis, Experimental/drug therapy* ; Interleukin-17/immunology* ; Signal Transduction/drug effects*

Penicillin G acylases (PGAs) are industrially important enzymes primarily used for the synthesis of first- and second-generation cephalosporins or penicillins. This study aims to establish a high-efficiency biosynthetic system for cefradine on the purpose of significantly enhancing its catalytic efficiency in cefradine synthesis and developing its potentials for industrial application. In this study, we identified and engineered penicillin G acylase and obtained a highly active mutant KsPGA M7(M168F/F313G) for the synthesis of cefradine. The mutant achieved a conversion rate over 95% in the scaled-up reaction. To validate its industrial applicability, we immobilized both the wild-type and mutant enzymes and applied them in continuous flow reactions, which achieved a space-time yield of 2 800 g/(L·d). This study lays a foundation for the future applications of penicillin G acylases in the industrial synthesis of cefradine.
Penicillin Amidase/biosynthesis* ; Protein Engineering/methods* ; Cephradine/metabolism* ; Escherichia coli/metabolism* ; Enzymes, Immobilized/metabolism* ; Recombinant Proteins/biosynthesis*

ObjectiveTo investigate the pathogenic spectrum and epidemiological characteristics of diarrheal disease in Fengxian District of Shanghai, and to provide scientific basis for the prevention and control of diarrheal diseases. MethodsBasic information of the initial adult cases visited diarrheal disease surveillance sentinel hospital in Fengxian District, Shanghai, was collected from August 2013 to 2023, and fecal samples were collected at 1∶5 sampling intervals to isolate and identify 5 kinds of diarrheagenic Escherichia coli (DEC), Salmonella (SAL), Vibrio parahaemolyticus, Campylobacter, Vibrio cholerae, Shigella and Yersinia enterocolitica (YE). Simultaneously, nucleic acid detection was performed for 3 kinds of rotavirus, 2 kinds of norovirus, intestinal adenovirus, astrovirus and sapovirus. ResultsA total of 1 861 cases of newly diagnosed diarrheal disease were reported, with the peak in July to August. Additionally, 704 surveillance samples were detected, with a total positive detection rate of 50.57%. The detection rates of bacterial, viral and mixed infection were 25.14%, 21.02% and 4.40%, respectively. Among the pathogens detected, DEC accounted for the highest (17.61%, 124/704), followed by norovirus (16.48%, 116/704), rotavirus (6.39%, 45/704), SAL (5.97%, 42/704) and Campylobacter (3.84%, 27/704). DEC detected were mainly enteroaggregative Escherichia coli and enterotoxigenic Escherichia coli, with no detection of Vibrio cholerae, Shigella and YE. The highest total pathogen detection rate was observed from June to September, and the detection peaks of norovirus were from March to June and from October to December, whereas that of DEC was from June to October. The detection rate of rotavirus peaked from January to February, but which was not detected between 2020‒2023. The SAL positive rate peak was in September, whereas that of Campylobacter was from July to September. ConclusionThe main pathogens detected in Fengxian District from 2013‒2019 are DEC, norovirus, rotavirus, SAL and Campylobacter. Different pathogens have different detection peaks, with bacteria predominating in summer and viruses in winter and spring. Prevention and control measures should be carried out according to the epidemiological characteristics of different seasons.

Objective To explore the mediating role of mobile phone dependency and self-rated health in the relationship between adverse childhood experiences(ACEs)and mental health among young adults.Methods A cross-sectional study was conducted using cluster random sampling among 1 611 young adults(mean age 26.30 years)from a region in Hainan Province.Participants completed the childhood trauma questionnaire(short form),the mobile phone addiction index,the depression-anxiety-stress scale(simplified Chinese version),and a self-rated health questionnaire.Pearson correlation analysis and mediation effect analysis were employed to examine the relationships among ACEs,mobile phone dependency,self-rated health,and mental health.Results ACEs,mobile phone dependency,and self-rated health were all significantly correlated with mental health(all P＜0.01).ACEs had a direct negative effect on mental health(direct effect=0.221,95%confidence interval[CI]0.150-0.293).Furthermore,ACEs exerted indirect effects on mental health through 3 pathways:the independent mediation of mobile phone dependency(indirect effect=0.081,95%CI 0.035-0.130),the independent mediation of self-rated health(indirect effect=0.034,95%CI 0.011-0.062),and the chain mediation of mobile phone dependency and self-rated health(indirect effect=0.009,95%CI 0.004-0.015).Conclusion ACEs have a significant impact on the mental health of young adults,with mobile phone dependency and self-rated health serving as key mediators.Interventions aimed at reducing mobile phone dependency and improving health status may help mitigate the negative impact of childhood trauma on mental health,thereby promoting psychological well-being in this population.

OBJECTIVE To study how resveratrol(Res)mitigates acute lung injury(ALI)in mice induced by sulfur mustard(SM)and potential mechanism.METHODS Male C57BL/6N mice were randomly divided into the control group(50 μL physiological saline via nebulization),SM group(SM 5 mg·kg-1 via nebulization),SM+Res 10 or 20 mg·kg-1 groups(1 h after administration of SM 5 mg·kg-1,Res 10 or 20 mg·kg-1 was administered via nebulization).Mice in each group were weighed 0,24,48 and 72 h after SM administration.Mice were sacrificed 72 h after SM administration,and lung tissues were collected,weighed for wet and dry weights,and the wet/dry ratio was calculated.HE staining was employed to detect the pathological changes of lung tissues while real-time quantitative PCR(RT-qPCR)was used to detect the mRNA expression levels of interleukin 6(IL-6)and IL-1β.Transcriptomic changes of the SM group and the SM+Res 20 mg·kg-1 group were detected with the next-generation sequencing technology.RT-qPCR was used to detect the mRNA expression changes of adenosine 5'-monophos-phate-activated protein kinase(AMPK)and silence information regulator 1(SIRT1)in lung tissues.RESULTS 72 h after SM administration,the body mass of mice in the SM group was significantly decreased compared with normal control group,while the wet/dry ratio of the lung was significantly increased,so were the mRNA expression levels of IL-6 and IL-1β in lung tissues were also significantly increased.Pathological changes of lung tissues included alveolar cavity atrophy,marked parenchymal tissues,and diffuse infiltration of local inflammatory cells.Compared with the SM group,the body mass of mice in the SM+Res 10 and 20 mg·kg-1 groups significantly increased,the wet/dry ratio of lung tissues was significantly reduced,and expressions of IL-6 and IL-1β mRNA were significantly decreased in SM+Res 10 and 20 mg·kg-1 groups.Compared with the normal control group,the mRNA expression levels of AMPK and SIRT1 in lung tissues of the SM group were significantly decreased.Compared with the SM group,the mRNA expression levels of AMPK in lung tissues of the SM+Res 10 and 20 mg·kg-1 groups were significantly increased while the mRNA expression level of SIRT1 was significantly decreased.CONCLUSION Res can mitigate ALI in mice induced by SM,and the mechanism may be related to the inhibition of cell apoptosis by regulating the AMPK/SIRT1 signaling pathway.