ObjectiveTo investigate the risk factors for acute kidney injury （AKI） after liver transplantation， and to establish and validate a risk prediction model， and to provide a basis for early identification of high-risk patients and intervention in clinical practice. MethodsA single-center retrospective study was conducted， and clinical data were collected from 162 patients who received liver transplantation in Liver Transplantation Center of The First Hospital of Shanxi Medical University from March 2020 to June 2025. The patients were divided into AKI group with 69 patients and non-AKI group with 93 patients according to the diagnostic criteria for AKI established by the Kidney Disease： Improving Global Outcomes organization and the presence or absence of AKI within 7 days after surgery. The independent-samples t test was used for comparison of normally distributed continuous data between groups， while the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups， and the chi-square test or the Fisher’s exact test was used for comparison of categorical data between groups. The univariate differential analysis was used to obtain the factors associated with AKI after liver transplantation， and the multivariate logistic regression analysis was used to identify the independent risk factors and establish a nomogram model； the Bootstrap method with 1 000 repeated samples was used to perform internal validation of the model. The dataset was randomly divided into a training set and a validation set at a ratio of 7∶3， and the receiver operating characteristic （ROC） curve， the calibration curve， and decision curve analysis （DCA） were used to assess the discriminatory ability， calibration， and clinical applicability of the predictive model. ResultsBody mass index （BMI） （odds ratio ［OR］=1.281， 95% confidence interval ［CI］： 1.037　—　1.582， P=0.022）， serum creatinine （OR=1.097， 95%CI： 1.020　—　1.181， P=0.013）， intraoperative blood loss （OR=1.005， 95%CI： 1.002　—　1.009， P=0.004）， and cold ischemia time （OR=0.984， 95%CI： 0.976　—　0.991， P<0.001） were independent risk factors for the development of AKI after liver transplantation. The nomogram prediction model established based on the above factors had an area under the ROC curve （AUC） of 0.964 （95%CI： 0.931　—　0.997）， with an optimal cutoff value of 0.319， a sensitivity of 0.971， and a specificity of 0.903. In the training set （n=113）， the nomogram had an AUC of 0.969 （95% CI： 0.933　—　0.971）， while in the validation set （n=49）， the nomogram had an AUC of 0.941 （95%CI： 0.855　—　0.944）. The calibration curve showed good consistency between the predicted incidence rate and the actual incidence rate， and DCA showed that it had good net clinical benefit. ConclusionBMI， serum creatinine， cold ischemia time， and intraoperative blood loss are independent risk factors for the development of AKI after liver transplantation， and the nomogram prediction model established based on these factors performs well and has a good value in predicting the development of AKI after liver transplantation.

OBJECTIVE To establish a method for simultaneous determination of venetoclax， busulfan and voriconazole in plasma of patients with acute myeloid leukemia （AML）， and apply it clinically. METHODS Plasma samples were subjected to protein precipitation using acetonitrile and subsequently analyzed by liquid chromatography-tandem mass spectrometry （LC-MS/MS） using venetoclax-D 8 ， busulfan-D 8 and posaconazole as internal standards. The separation was performed on a Phenomenex Kinetex ® C 18 column with a mobile phase composed of 0.1% formic acid solution （2 mmol/L ammonium acetate）-0.1% formic acid in acetonitrile （gradient elution） at a flow rate of 0.8 mL/min. The column temperature was set at 40 ℃， the sample size was 5 μL， and the total run time was 3.10 min. An electrospray ionization source was employed， and positive ion scanning was conducted using multiple reaction monitoring mode. The ion pairs used for quantitative analysis included m/z 868.4→636.3 （venetoclax）， m/z 264.1→151.1 （busulfan）， and m/z 350.1→224.0 （voriconazole）. The above LC-MS/MS method was adopted to determine plasma concentrations of venetoclax and voriconazole in 10 AML patients， as well as plasma concentration of busulfan in 5 patients undergoing conditioning treatment for allogeneic hematopoietic stem cell transplantation. RESULTS The linear ranges of venetoclax， busulfan and voriconazole were 50-10 000， 15-3 000 and 50-10 000 ng/mL， respectively （ R 2 ≥0.999 0）， with lower limits of quantification of 50， 15 and 50 ng/mL， respectively. The RSDs of intra-day and inter-day precision tests for all three analytes were all less than 10%， with accuracy （relative errors） ranging from －10.00% to 12.96%. The average extraction recovery ranged from 92.54% to 100.95%， and the average matrix effect was 89.98%-101.49%. Dilution reliability covered all dilution factors used in the test samples， and the absolute values of relative errors in stability tests were all≤16.25%. The plasma concentrations of venetoclax， busulfan and voriconazole in enrolled patients were 496.20-4 250.45， 233.48-2 002.28 and 475.51-5 710.18 ng/mL， respectively. CONCLUSIONS The LC-MS/MS method established in this study is rapid， sensitive and easy to operate， and can be used for the therapeutic drug monitoring of venetoclax， busulfan and voriconazole.

OBJECTIVE To develop physiologically based pharmacokinetic （PBPK） model for sodium tanshinone Ⅱ A sulfonate （STS）， clopidogrel （Clo）， and its metabolites， to predict the potential drug-drug interaction （DDI） between STS and Clo during co-administration， and to identify the key factors influencing the predicte d DDI， and provide evidence for rational clinical medication. METHODS Physicochemical and pharmacokinetic parameters of Clo， its metabolites， and STS were retrieved from PubMed， DrugBank， and SwissADME for PBPK model development. The steady-state area under the plasma concentration-time curve （AUC） and maximum concentration （ c max ） of clopidogrel thiol H4 （Clo-AM） were used as indicators to evaluate the DDI between STS and Clo. Single-factor sensitivity analysis was performed to identify key parameters influencing DDI between STS and Clo during co-administration. RESULTS Compared with Clo alone， after 7 days of Clo combined with STS 40 mg， the AUC ratio and c max ratio of Clo-AM were 0.75 and 0.63， respectively. When the dose of STS was increased to 80 mg， the AUC ratio and c max ratio of Clo-AM were 0.62 and 0.56， respectively. Sensitivity analysis indicated that the absolute values of normalized sensitivity coefficients for the lipophilicity of Clo-AM， the inhibition constants of STS for CYP2C19 and CYP3A4， and the hepatic clearance of Clo-AM were 15.19， 11.34， 10.98， 3.08， respectively. These parameters were the highly sensitive parameters in the DDI between STS and Clo during co-administration. CONCLUSIONS The established PBPK model can be used to predict the DDI between STS and Clo during co-administration. Co-administration of STS and Clo may lead to decreased exposure of Clo-AM. The lipophilicity-related parameters of Clo-AM and the inhibition parameters related to CYP3A4 and CYP2C19 are key parameters influencing the prediction of Clo-AM exposure， among which the inhibitory effects of STS on CYP3A4 and CYP2C19 may be an important mechanism mediating the DDI between STS and Clo.

OBJECTIVE To develop physiologically based pharmacokinetic （PBPK） model for sodium tanshinone Ⅱ A sulfonate （STS）， clopidogrel （Clo）， and its metabolites， to predict the potential drug-drug interaction （DDI） between STS and Clo during co-administration， and to identify the key factors influencing the predicte d DDI， and provide evidence for rational clinical medication. METHODS Physicochemical and pharmacokinetic parameters of Clo， its metabolites， and STS were retrieved from PubMed， DrugBank， and SwissADME for PBPK model development. The steady-state area under the plasma concentration-time curve （AUC） and maximum concentration （ c max ） of clopidogrel thiol H4 （Clo-AM） were used as indicators to evaluate the DDI between STS and Clo. Single-factor sensitivity analysis was performed to identify key parameters influencing DDI between STS and Clo during co-administration. RESULTS Compared with Clo alone， after 7 days of Clo combined with STS 40 mg， the AUC ratio and c max ratio of Clo-AM were 0.75 and 0.63， respectively. When the dose of STS was increased to 80 mg， the AUC ratio and c max ratio of Clo-AM were 0.62 and 0.56， respectively. Sensitivity analysis indicated that the absolute values of normalized sensitivity coefficients for the lipophilicity of Clo-AM， the inhibition constants of STS for CYP2C19 and CYP3A4， and the hepatic clearance of Clo-AM were 15.19， 11.34， 10.98， 3.08， respectively. These parameters were the highly sensitive parameters in the DDI between STS and Clo during co-administration. CONCLUSIONS The established PBPK model can be used to predict the DDI between STS and Clo during co-administration. Co-administration of STS and Clo may lead to decreased exposure of Clo-AM. The lipophilicity-related parameters of Clo-AM and the inhibition parameters related to CYP3A4 and CYP2C19 are key parameters influencing the prediction of Clo-AM exposure， among which the inhibitory effects of STS on CYP3A4 and CYP2C19 may be an important mechanism mediating the DDI between STS and Clo.

ObjectiveTo investigate the metabolic mechanisms of Limosilactobacillus reuteri （L. reuteri） in alleviating chemotherapy-induced intestinal mucosal injury （CIMI）. MethodsC57BL/6 mice were randomly divided into the Control group， Model group， and L. reuteri treatment group （n=8 per group）. Mice in the L. reuteri group were intragastrically administered L. reuteri （1 × 10⁹ CFU/mL） for 10 consecutive days. From day 5， mice in the Model and L. reuteri groups were intraperitoneally injected with 5-FU （65 mg/kg） for 6 consecutive days to establish a CIMI model. Body weight changes， colon length， and related indicators were recorded. Intestinal histopathological injury was assessed by HE staining with measurement of villus height and crypt depth. The expression levels of zonula occludens-1 （ZO-1）， Occludin， Claudin-4， Muc1， and Muc2 in ileal tissues were determined by RT-qPCR and immunohistochemistry to evaluate intestinal barrier function. In addition， untargeted metabolomics was performed on cecal contents from each group to analyze metabolic profiles and enrichment of differential metabolic pathways. ResultsL. reuteri intervention significantly alleviated body weight loss （P<0.001） and colon shortening （P<0.05） in CIMI mice， effectively reducing ileal tissue pathological damage， and upregulating the expression of ZO-1， Occludin， Claudin4， Muc1， and Muc2 （P<0.05）. Untargeted metabolomics analysis showed that L. reuteri treatment reversed the abnormal metabolic profile in the cecal contents of CIMI mice， bringing it closer to normal. Various differential metabolites， such as acylcarnitines and polyunsaturated fatty acids， might play an important role in L. reuteri-mediated alleviation of CIMI. These differential metabolites were primarily enriched in key pathways such as linoleic acid metabolism， tryptophan metabolism， and unsaturated fatty acid biosynthesis. ConclusionThis study reveals that L. reuteri improves intestinal barrier function and alleviates CIMI by regulating the intestinal metabolic profile， particularly lipid and amino acid metabolism. It provides a novel potential strategy for the prevention and treatment of CIMI.

Hepatic encephalopathy is a difficult and critical disease with rapid progression and limited treatment methods in the field of liver disease， and it is urgently needed to make breakthroughs in its pathogenesis. Selection of appropriate prevention and treatment strategies is of great importance in delaying disease progression and reducing the incidence and mortality rates. This article reviews the theory of “turbid toxin pathogenesis” and related prevention and treatment strategies for hepatic encephalopathy in traditional Chinese medicine/Zhuang medicine， proposes a new theory of “turbid toxin pathogenesis”， analyzes the scientific connotations of “turbid”， “toxin”， and the theory of “turbid toxin pathogenesis”， and constructs the “four-step” prevention and treatment strategies for hepatic encephalopathy， thereby establishing the new clinical prevention and treatment regimen for hepatic encephalopathy represented by “four prescriptions and two techniques” and clarifying the effect mechanism and biological basis of core prescriptions and techniques in the prevention and treatment of hepatic encephalopathy， in order to provide a reference for the prevention and treatment of hepatic encephalopathy.

BACKGROUND:Cardiac dysfunction due to spinal cord injury is an important factor of death in patients with spinal cord injury;however,the specific mechanism is still not clear.Therefore,revealing the mechanism of cardiac dysfunction in spinal cord injury patients is of great significance to improve their quality of life and survival rate. OBJECTIVE:To investigate the mechanism of luteolin in improving serum-induced myocardial cell death in spinal cord injury rats. METHODS:Allen's impact instrument was used to damage the spine T9-T11 of male SD rats to establish a spinal cord injury model meanwhile a sham operation group was set as the control group.The serum of rats of each group was collected.H9c2 cells were divided into a blank control group,a sham operated rat serum group,a spinal cord injury rat serum group and a luteolin pretreatment group.The cells in blank control group were only cultured with ordinary culture medium.The cells in the sham operated rat serum group were treated with medium containing 10%serum from sham operated rat.The cells in the spinal cord injury rat serum group were treated with medium containing 10%serum from spinal cord injury rat.The cells in the luteolin pretreatment group were precultured with a final concentration of 20 μmol/L luteolin for 4 hours and then changed to a medium containing 10%rat serum from spinal cord injury rat.After 24 hours of culture,the survival rate of each group of H9c2 cells was measured by CCK-8 assay.Western blot assay was used to detect the expression of autophagy related protein LC3 and p62 in H9c2 cells in each group. RESULTS AND CONCLUSION:Compared with the blank control group,there was no significant change in cell survival rate in the sham operated rat serum group(P>0.05).Compared with the sham operated rat serum group,the cell survival rate(P<0.01)and the expression of LC3 protein(P<0.05)in spinal cord injury rat serum group was significantly reduced,and the expression of p62 protein was significantly increased(P<0.05).Compared with the spinal cord injury rat serum group,the survival rate of cells in the luteolin pretreatment group significantly increased(P<0.000 1);the expression of LC3 protein significantly increased(P<0.05),and the expression of p62 protein significantly decreased(P<0.05).The results indicate that luteolin may improve myocardial cell death induced by serum from rats with spinal cord injury by promoting autophagy.

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.

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Objective To investigate the adverse pregnancy outcomes of fetuses with increased nuchal translucency(NT).Methods A total of 376 pregnant women at the Third Affiliated Hospital of Zhengzhou University from May 2023 to January 2024 were selected as research subjects,who had a diagnosis of fetal NT ≥ the 95th percentile and complete pregnancy outcomes for singleton pregnancies.The fetuses were divided into simple thickening group(n=320)and thickening with structural abnormalities group(n=56)based on NT ultrasound results.The interventional prenatal diagnosis outcomes and pregnancy outcomes of two groups were compared.Results The rate of chromosomal abnormalities and the incidence of adverse pregnancy outcomes were higher in thickening with structural abnormalities group compared to simple thickening group with statistically significant differences(P＜0.05).The overall incidence of adverse pregnancy outcomes in NT thickened fetuses was 31.65％,but after excluding chromosomal abnormalities and structural malformations,the good pregnancy outcome rate in NT thickened fetuses was 98.09％.Conclusion NT thickening is associated with adverse pregnancy outcomes in fetuses,and the risk of poor fetal outcome is further increased when NT thickening combined with structural abnormalities in early pregnancy,but the pregnancy outcome is better in fetuses with NT thickening after excluding chromosomal abnormalities and structural malformations.