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.

ObjectiveTo investigate the expression level of lysophosphatidyllecithin acyltransferase 4 （LPCAT4） in pancreatic cancer and its effect on the proliferation of pancreatic cancer cells. MethodsIn this study， the differentially expressed genes of patients with KRAS mutant and wild-type pancreatic cancer were analyzed by online database LinkedOmics. The LPCAT4 expression in pancreatic cancer tissues was analyzed online by the University of Alabama at Birmingham Cancer Data Analysis （UALCAN）， Sangerbox and gene expression profile interaction analysis 2 （GEPIA2）. Kaplan-Meier Plotter database was used to explore the correlation between LPCAT4 and the prognosis of patients with pancreatic cancer. The expression of LPCAT4 in human pancreatic cancer cells were detected by quantitative real-time PCR and Western blot analysis. LPCAT4 was knocked down in the high-expressing SW1990 cell line and overexpressed in the low-expressing MIA PaCa-2 cell line. The effects of LPCAT4 expression on cell proliferation were assessed using CCK-8 and EdU assays. STRING and GEPIA2 databases were used to obtain LPCAT4 binding and coexpressed genes in tumors， which were then analyzed by GO and KEGG. ResultsAnalysis of the LinkedOmics online database revealed a significant upregulation of LPCAT4 in patients with KRAS mutant pancreatic cancer compared to patients with KRAS wild-type pancreatic cancer. The online analysis of GEPIA2， UALCAN and Sangerbox 3.0 showed that the expression of LPCAT4 was higher in pancreatic cancer than in normal tissues. Analysis of the Kaplan-Meier Plotter database revealed that high LPCAT4 expression was associated with poorer prognosis in pancreatic cancer patients.Western blot and qPCR results showed that expression of LPCAT4 in pancreatic cancer cell lines was significantly higher than in normal pancreatic ductal epithelial cells. Knockdown of LPCAT4 in SW1990 cells inhibited proliferation， while overexpression in MIA PaCa-2 cells promoted proliferation. Enrichment analysis indicated that LPCAT4 was closely related to sulfur metabolism. ConclusionsLPCAT4 is highly expressed in pancreatic cancer and is associated with poor prognosis of patients. It plays a significant regulatory role in the proliferation of pancreatic cancer cells， with its expression level closely correlated with cell proliferation capacity. These findings reveal the critical role of LPCAT4 in the malignant progression of pancreatic cancer and provide important evidence for its potential as a therapeutic target.

Objective:To explore the influence factors of neurodevelopmental disorders in children with SCN8A-related early-onset epilepsy through analyzing their clinical characteristics and following up their neurodeve-lopmental status. Methods:A retrospective analysis was carried out on 21 children (13 males and 8 females, the age ranged from 4 months to 8 years, average 31.6 months)with SCN8A-related early-onset epilepsy treated in Guangzhou Women and Children′s Medical Center and Kunming Children′s Hospital between January 2017 and February 2021.All patients underwent whole-exome sequencing and Sanger sequencing.The pathogenicity was estimated according to the American College of Medical Genetics and Genomics guidelines.The clinical data of all patients were also collected, including the age of onset of the disease, forms of seizures, seizure frequency, neurological development at onset, electroencephalogram (EEG) and brain magnetic resonance imaging (MRI). Besides, the patients were followed up to acquire the effect of sodium channel blockers after the onset of seizures, the process or improvement of neurodeve-lopment, EEG evaluation and neurodevelopmental outcomes.Patients were grouped based on data analysis results.The Fisher′s exact test was conducted to measure the effect of various factors on the neurodevelopmental process and outcome, and corresponding coe-fficients were calculated. Results:The average onset age of 21 patients was 0-9 months.The follow-up duration was 4 months-8 years.Three cases died.Sixteen cases (76.2%) had early infantile epileptic encephalopathy (EIEE), 5 cases (23.8%) had epilepsy without encephalopathy, and 1 case had benign infantile epilepsy.Fourteen cases (66.7%) belonged to drug resistant epilepsy.Only one child showed normal neurodevelopment.Eleven children showed delayed neurodevelopment, but improvement was observed.Nine children were retrogressed and stagnated in terms of neurodevelopment.Small age at onset ( Fisher=9.517, P=0.020, r=0.571), high seizure frequency ( Fisher=10.512, P=0.003, r=0.572), EEG background ( Fisher=10.512, P=0.003, r=0.572), epileptic discharges ( Fisher=8.288, P=0.008, r=0.542), and EEG changes before and after treatment ( Fisher=10.437, P=0.009, r=0.586) were important factors affecting the neurodevelopmental process.Neurodevelopmental outcome was normal in only 1 case, 1 child belonged to mild mental retardation (MR), 7 children belonged to moderate MR, 3 children belonged to severe MR, and 9 children belonged to profound MR.Statistical analysis indicated that the clinical phenotype ( Fisher=10.059, P=0.004, r=0.739) and drug resistance ( Fisher=13.706, P=0.001, r=0.640) were significantly correlated with neurodevelopmental outcomes.However, the forms of seizures, EEG findings at onset and mutation sites were not related to neurodevelopmental disorders. Conclusions:Most children with SCN8A-related early-onset epilepsy are accompanied with neurodevelopmental retardation of varying degrees.Epileptic encephalopathy and poor response to drug treatment will lead to severe neurodevelopmental disorders.

Objective To investigate the influence of Zhenqing Recipe(ZQR)and Ligustri Lucidi Fructus(LLF)on diabetic rats and its possible mechanism.Methods The model of type 2 diabetic rats was established by feeding a high-sucrose-high-fat diet and injecting a low dose of Streptozotocin in Wistar rats.The model rats were randomly divided into three groups: diabetic model,ZQR-treated,and LLF-treated groups for 8-weeks treatment.The normal Wistar rats were as a normal control group.Results The level of fasting blood glucose in ZQR and LLF groups was decreased compared with model group(P < 0.01,0.05,respectively).Both ZQR and LLF markedly reduced serum triglycerides(P < 0.01,0.05,respectively),and increased the insulin sensitivity index(P < 0.05).Histopathology revealed that ZQR and LLF reduced pancreatic damage.Immunohistochemistry evaluation showed that the percentage of insulin positive cells in pancreatic island was higher than model group(P < 0.01,0.05,respectively).The mRNA and protein expression of SREBP-1c in pancreas were significantly decreased in ZQR and FLL group(P < 0.01).Conclusion ZQR has therapeutic effect on type 2 diabetes,it ameliorates the histopathologlcal changes of pancreas,protects β cells,improves insulin resistance,and attenuates the expression of SREBP-1c.This study also provides the anti-diabetic evidence of FLL even its effects are weaker than ZQR.

OBJECTIVE To investigate the distribution and drug resistance status of urinary tract infections in diabetics and offer scientific basis for reasonable usage of antibiotics.METHODS Pathogenic bacteria isolated from specimens of 236 cases with urinary tract infections were identified and drug susceptibility tests were performed.RESULTS Among 236 strains of pathogenic bacteria,Escherichia coli rated the top one,59.7%.Then Enterococcus rated the second and accounted for 10.6%.The isolates were susceptible to imipenem and amikacin and showed higher drug-resistance to the other common antibiotics.CONCLUSIONS Diabetics easily suffer from urinary tract infections.Drug-resistance of pathogenic bacteria to antibiotics is higher.Therefore,we should take precautions to control the urinary tract infections in diabetics.

AIM: To construct human GPI-B7-1 fusion protein and investigate the therapeutic potentials in the treatment of tumors. METHODS: The chimeric GPI anchored-B7-1 gene was obtained by overlap PCR and inserted into expressing vector pcDNA3.1, named pc3.1/GPI-B7-1. pc3.1/GPI-B7-1was transfected into CHO cells by lipofectamine ~2 000 reagent. The CHO cells, expressing GPI-B7-1 on membranes, were obtained after selecting by G418. That was confirmed by flow cytometry, SDS-PAGE and Western blot. RESULTS: Recombinant vector pc3.1/GPI-B7-1 was successfully constructed and sequence result indicated that it was identical with reference sequence. The protein on transfected CHO cell membrane selected by G418 was confirmed to be GPI-anchored protein by flow cytometry, and GPI-B7-1 approximately 60 kD was conformed by SDS-PAGE and Western blot. CONCLUSION: A large amount of GPI-B7-1 fusion protein was obtained and will be further studied in the treatment of tumors.2? [