Objective : To investigate the protective effect of dimethyl fumarate(DMF) on maternal intrahepatic cholestasis(ICP) during pregnancy induced by di(2-ethylhexyl) phthalate(DEHP) exposure and its mechanism. Methods : Thirty-two 8-week-old female institute of cancer research(ICR) mice were randomly divided into 4 groups: Ctrl group, DEHP group, DMF group and DEHP+DMF group. DEHP and DEHP+DMF groups were treated with DEHP(200 mg/kg) by gavage every morning at 9:00 a.m. DMF and DEHP+DMF groups were treated with DMF(150 mg/kg) from day 13 to day 16 of gestation by gavage. After completion of gavage on day 16 of pregnancy, maternal blood, maternal liver, placenta, and amniotic fluid were collected from pregnant mice after a six-hour abrosia. The body weight of the mother rats and the body weight of the fetus rats were sorted and analyzed; the levels of total bile acid(TBA), alkaline phosphatase(ALP), aspartate aminotransferase/alanine aminotransferase(AST/ALT) in serum and TBA in liver, amniotic fluid and placenta were detected by biochemical analyzer; HE staining was used to observe the pathological changes of liver tissue; Quantitative reverse transcription PCR(RT-qPCR) was used to detect the expression levels of tumor necrosis factor-α(TNF-α), interleukin(IL)-6, IL-1, IL-18 and NOD-like receptor thermal protein domain associated protein 3(NLRP3) in the liver; Western blot was used to detect the expression of the nuclear factor KappaB(NF-κB) and NLRP3. Results : Compared with the control group, the body weight of the DEHP-treated dams and pups decreased(P<0.05); the levels of TBA, ALP, AST/ALT in the serum of dams and the levels of TBA in the liver, amniotic fluid, and placenta of dams increased(P<0.05); the histopathological results showed that liver tissue was damaged, bile ducts were deformed, and there was inflammatory cell infiltration around them; the levels of inflammation-related factors TNF-α, IL-6, IL-1, IL-18 and NLRP3 transcription in maternal liver increased(P<0.05); the expression of NF-κB and NLRP3 protein in maternal liver significantly increased( P<0. 05). Compared with the DEHP group,the body weight of both dams and fetuses significantly increased in DEHP + DMF group( P<0. 05); the levels of TBA,ALP,AST/ALT in the serum of dams and amniotic fluid of fetuses decreased( P<0. 05); the degree of liver lesions was improved; the transcription levels of inflammation-related factors TNF-α,IL-6,IL-1,IL-18 and NLRP3 in maternal liver decreased( P<0. 05); the expression of NF-κB and NLRP3 protein in maternal liver significantly decreased( P<0. 05). Conclusion DMF can effectively protect the DEHP exposure to lead to female ICP,and its mechanism may be through inhibiting the NF-κB/NLRP3 pathway and reducing liver inflammation.

Background/Aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) is a chronic liver disease characterized by hepatic steatosis. Ubiquitin-specific protease 29 (USP29) plays pivotal roles in hepatic ischemiareperfusion injury and hepatocellular carcinoma, but its role in MASLD remains unexplored. Therefore, the aim of this study was to reveal the effects and underlying mechanisms of USP29 in MASLD progression. Methods: USP29 expression was assessed in liver samples from MASLD patients and mice. The role and molecular mechanism of USP29 in MASLD were assessed in high-fat diet-fed and high-fat/high-cholesterol diet-fed mice and palmitic acid and oleic acid treated hepatocytes. Results: USP29 protein levels were significantly reduced in mice and humans with MASLD. Hepatic steatosis, inflammation and fibrosis were significantly exacerbated by USP29 deletion and relieved by USP29 overexpression. Mechanistically, USP29 significantly activated the expression of genes related to fatty acid β-oxidation (FAO) under metabolic stimulation, directly interacted with long-chain acyl-CoA synthase 5 (ACSL5) and repressed ACSL5 degradation by increasing ACSL5 K48-linked deubiquitination. Moreover, the effect of USP29 on hepatocyte lipid accumulation and MASLD was dependent on ACSL5. Conclusions USP29 functions as a novel negative regulator of MASLD by stabilizing ACSL5 to promote FAO. The activation of the USP29-ACSL5 axis may represent a potential therapeutic strategy for MASLD.

Background/Aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) is a chronic liver disease characterized by hepatic steatosis. Ubiquitin-specific protease 29 (USP29) plays pivotal roles in hepatic ischemiareperfusion injury and hepatocellular carcinoma, but its role in MASLD remains unexplored. Therefore, the aim of this study was to reveal the effects and underlying mechanisms of USP29 in MASLD progression. Methods: USP29 expression was assessed in liver samples from MASLD patients and mice. The role and molecular mechanism of USP29 in MASLD were assessed in high-fat diet-fed and high-fat/high-cholesterol diet-fed mice and palmitic acid and oleic acid treated hepatocytes. Results: USP29 protein levels were significantly reduced in mice and humans with MASLD. Hepatic steatosis, inflammation and fibrosis were significantly exacerbated by USP29 deletion and relieved by USP29 overexpression. Mechanistically, USP29 significantly activated the expression of genes related to fatty acid β-oxidation (FAO) under metabolic stimulation, directly interacted with long-chain acyl-CoA synthase 5 (ACSL5) and repressed ACSL5 degradation by increasing ACSL5 K48-linked deubiquitination. Moreover, the effect of USP29 on hepatocyte lipid accumulation and MASLD was dependent on ACSL5. Conclusions USP29 functions as a novel negative regulator of MASLD by stabilizing ACSL5 to promote FAO. The activation of the USP29-ACSL5 axis may represent a potential therapeutic strategy for MASLD.

Background/Aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) is a chronic liver disease characterized by hepatic steatosis. Ubiquitin-specific protease 29 (USP29) plays pivotal roles in hepatic ischemiareperfusion injury and hepatocellular carcinoma, but its role in MASLD remains unexplored. Therefore, the aim of this study was to reveal the effects and underlying mechanisms of USP29 in MASLD progression. Methods: USP29 expression was assessed in liver samples from MASLD patients and mice. The role and molecular mechanism of USP29 in MASLD were assessed in high-fat diet-fed and high-fat/high-cholesterol diet-fed mice and palmitic acid and oleic acid treated hepatocytes. Results: USP29 protein levels were significantly reduced in mice and humans with MASLD. Hepatic steatosis, inflammation and fibrosis were significantly exacerbated by USP29 deletion and relieved by USP29 overexpression. Mechanistically, USP29 significantly activated the expression of genes related to fatty acid β-oxidation (FAO) under metabolic stimulation, directly interacted with long-chain acyl-CoA synthase 5 (ACSL5) and repressed ACSL5 degradation by increasing ACSL5 K48-linked deubiquitination. Moreover, the effect of USP29 on hepatocyte lipid accumulation and MASLD was dependent on ACSL5. Conclusions USP29 functions as a novel negative regulator of MASLD by stabilizing ACSL5 to promote FAO. The activation of the USP29-ACSL5 axis may represent a potential therapeutic strategy for MASLD.

ObjectiveTo evaluate the clinical efficacy and safety of Huaban Jiedu Formulation （化斑解毒方， HJF） in treating psoriasis vulgaris with blood-heat syndrome. MethodsA randomized， double-blind， placebo-controlled study was conducted with 60 patients diagnosed with psoriasis vulgaris of blood-heat syndrome. Patients were randomly assigned to either a treatment group or a control group， with 30 cases in each. The treatment group received HJF granules orally， one dose a day， combined with topical Qingshi Zhiyang Ointment （青石止痒软膏）， while the control group received placebo granules， one dose a day， combined with the same topical ointment. Both groups were topically treated twice daily of 28 days treatment cours. Psoriasis area and severity index （PASI）， visual analogue scale for pruritus （VAS）， traditional Chinese medicine （TCM） syndrome scores， dermatology life quality index （DLQI）， and psoriasis life stress inventory （PLSI） were assessed before treatment and on day 14 and day 28. Response rates for PASI 50 （≥50% reduction） and PASI 75 （≥75% reduction）， as well as overall clinical efficacy， were compared between groups. Serum levels of interleukin-6 （IL-6） and interleukin-17 （IL-17） were measured before and after 28 days of treatment. Adverse reactions during treatment were recorded. ResultsAfter 28 days of treatment， both groups showed significant reductions in PASI total score， lesion area score， erythema， scaling， and infiltration scores， pruritus VAS score， TCM syndrome score， DLQI， PLSI， and serum IL-6 and IL-17 levels （P＜0.05）. Compared to the control group， the treatment group had significantly greater improvements in PASI total score and erythema score， TCM syndrome score， serum IL-6 and IL-17 levels， and PASI 50 response rate after 28 days （P＜0.05）. Between-group comparisons of score differences before and after 28-day treatment revealed that the treatment group showed significantly better improvements in PASI total， lesion area score， erythema score， TCM syndrome score， DLQI， PLSI， and inflammatory markers （P＜0.05 or P＜0.01）. The total effective rate on day 14 and day 28 was 40.00% （12/30） and 83.33% （25/30） in the treatment group， versus 6.90% （2/29） and 41.38% （12/29） in the control group， respectively. The clinical efficacy in the treatment group was significantly superior to that in the control group （P＜0.05）. Mild gastric discomfort occurred in 3 patients in the treatment group and 1 in the control group. ConclusionHJF can effectively improve skin lesions and TCM symptoms relieve pruritus， enhance quality of life， and reduce inflammatory markers IL-6 and IL-17， in patients with blood-heat syndrome of psoriasis vulgaris， with a good safety profile.

OBJECTIVE To analyze the influential factors of drug-induced cholestatic liver disease （DIC） related to tigecycline （TGC）， and establish a prediction model for the risk of this adverse reaction. METHODS Data of 707 hospitalized patients who received TGC treatment in our hospital from August 2022 to August 2024 were collected and randomly divided into training set （n＝566） and test set （n＝141） at a ratio of 8∶2. Prediction variables were screened using the least absolute shrinkage and selection operator regression analysis. Multivariate Logistic regression analysis was used to screen the independent risk factors for TGC-related DIC， and a nomogram prediction model was drawn based on the above factors. The prediction performance of the model was evaluated by the receiver operator characteristic curve （ROC curve） and its area under the curve （AUC）. The accuracy of the model was assessed by the Hosmer-Lemeshow goodness-of-fit test and calibration curves. The clinical net benefit of the prediction model were evaluated by decision curve analysis. RESULTS Among the 707 patients， 93 patients developed DIC， with an incidence rate of 13.15%. Gender， age， high-dose administration of TGC， intensive care unit （ICU） admission， duration of medication of TGC， and concurrent use of antifungal drug voriconazole were independent risk factors for the occurrence of TGC-related DIC （P＜0.05）. The AUC of the training set model was 0.745 （95%CI： 0.687-0.801）， with a sensitivity of 76.6% and a specificity of 60.3%. The AUC of ROC curve of the test set model was 0.762 （95%CI： 0.650-0.900）， with a sensitivity of 81.3% and a specificity of 72.0%. The Hosmer-Lemeshow goodness-of-fit test for the training set， the χ 2 value was 5.187 and P was 0.737； and for the test set， the χ 2 value was 9.980 and P was 0.266. The mean absolute error of the calibration curve for the training set was 0.012， and for the test set， it was 0.038. The risk threshold range for the training set was 4%-45%， and for the test set， it was 4%-28%. CONCLUSIONS Age， gender， high-dose administration of TGC， ICU admission， duration of medication of TGC， and concurrent use of antifungal drug voriconazole are independent risk factors for TGC-related DIC. The established TGC-related DIC risk prediction model has good prediction performance and accuracy.

ObjectiveTo investigate whether menaquinone-4 （MK-4） can exert a protective effect against carbon tetrachloride （CCl₄）-induced acute liver injury （ALI） in mice by alleviating ferroptosis. MethodsAfter adaptive feeding， adult male ICR mice， aged 8 weeks， were divided into Control group， MK-4 group， CCl₄ model group （6-hour， 12-hour， and 24-hour）， and MK-4+CCl₄ group （6-hour， 12-hour， and 24-hour）， with 6 mice in each group. The mice in the Control group were given intraperitoneal injection of an equal dose of corn oil； the mice in the MK-4 group were given intraperitoneal injection of 40 mg/kg MK-4 solution， followed by an equal dose of corn oil after 1 hour； the mice in the MK-4+CCl₄ group （6-hour， 12-hour， and 24-hour） were given intraperitoneal injection of 40 mg/kg MK-4 solution， and after 1 hour， the mice in this group and the CCl₄ model group （6-hour， 12-hour， and 24-hour） were given intraperitoneal injection of 0.3 mL/kg CCl₄ solution， with samples collected at 6， 12， and 24 hours. HE staining was used to observe the pathological changes of mouse liver； Prussian blue staining was used to observe iron accumulation in liver tissue； a biochemical analyzer was used to measure the serum levels of aspartate aminotransferase （AST） and alanine aminotransferase （ALT）； related kits were used to measure the levels of tissue iron content and the oxidative stress indices malondialdehyde （MDA） and glutathione （GSH） in liver homogenate； RT-PCR was used to measure the expression levels of ferroptosis marker genes （acyl-CoA synthetase long-chain family member 4 ［ACSL4］， prostaglandin-endoperoxide synthase 2 ［PTGS2］， and glutathione peroxidase 4 ［GPX4］） and iron metabolism-related genes （hemojuvelin ［HJV］， transferrin receptor 1 ［TFR1］， and ferroportin ［FPN］）， and Western blot was used to measure the protein expression level of GPX4. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsIn the aging study， compared with the Control group， the CCl₄ model group （6-hour， 12-hour， and 24-hour） had significant increases in liver weight coefficient and the serum levels of ALT and AST （all P<0.05）， and HE staining also showed that liver injury gradually aggravated over time. Meanwhile， compared with the CCl₄ model group （6-hour， 12-hour， and 24-hour）， the MK-4+CCl₄ （12-hour） group had significant reductions in liver weight coefficient and the serum levels of ALT and AST （all P<0.05）， with a reduction in the necrotic area of liver tissue， and therefore， 12-hour mouse tissue samples were used for detection in the following study. Compared with the Control group， the CCl₄ group had a significant increase in MDA and a significant reduction in GSH （both P<0.05）， and compared with the CCl₄ group， the MK-4+CCl₄ group had a significant reduction in MDA and a significant increase in GSH （both P<0.05）. Compared with the Control group， the CCl₄ group had significant increases in the key ferroptosis indices ASCL4 and PTGS2 and a significant reduction in GPX4 （all P<0.05）； compared with the CCl₄ group， the MK-4+CCl₄ group had significant reductions in the mRNA expression levels of ASCL4 and PTGS2 and a significant increase in the mRNA expression level of GPX4 （all P<0.05）. Western blotting showed that compared with the Control group， the CCl₄ group had a significant reduction in the protein expression level of GPX4 （P<0.05）， and compared with the CCl₄ group， the MK-4+CCl₄ group had a significant increase in the protein expression level of GPX4 （P<0.05）. Prussian blue staining showed that compared with the Control group， the CCl₄ group had a significant increase in iron accumulation； after MK-4 intervention， compared with the CCl₄ group， the MK-4+CCl₄ group had a significant reduction in iron accumulation. As for the measurement of iron metabolism genes in mouse liver， compared with the Control group， the CCl₄ group had a significant increase in iron content， significant reductions in the mRNA expression levels of FPN and HJV， and a significant increase in the mRNA expression level of TFR1 （all P<0.05）； after protection with MK-4， there was a significant reduction in iron content， significant increases in the mRNA expression levels of FPN and HJV， and a significant reduction in the mRNA expression level of TFR1 （all P<0.05）. ConclusionMK-4 intervention in advance can alleviate CCl₄-induced ALI in mice， possibly by inhibiting ferroptosis and improving the expression of iron metabolism-related genes in mouse liver.

Objective:To summarize the clinical, pathological and molecular characteristics of various types of pediatric glioma, and to explore the differences in the morphology and clinical significance among various types of pediatric glioma.Methods:Based on the fifth edition of the World Health Organization classification of central nervous system tumors, this study classified or reclassified 111 pediatric gliomas that were diagnosed at Guangzhou Medical University Affiliated Women and Children′s Medical Center from January 2020 to June 2023. The clinical manifestations, imaging findings, histopathology, and molecular characteristics of these tumors were analyzed. Relevant literature was also reviewed.Results:The 111 patients with pediatric glioma included 56 males and 55 females, with the age ranging from 10 days to 13 years (average age, 5.5 years). Clinically, manifestations presented from 5 days to 8 years before the diagnosis, including epilepsy in 16 cases, increased intracranial pressure in 48 cases and neurological impairment in 66 cases. MRI examinations revealed tumor locations as supratentorial in 43 cases, infratentorial in 65 cases, and spinal cord in 3 cases. There were 73 cases presented with a solid mass and 38 cases with cystic-solid lesions. The largest tumor diameter ranged from 1.4 to 10.6 cm. Among the 111 pediatric gliomas, there were 6 cases of pediatric diffuse low-grade glioma (pDLGG), 63 cases of circumscribed astrocytoma glioma (CAG), and 42 cases of pediatric diffuse high-grade glioma (pDHGG). Patients with pDLGG and CAG were younger than those with pDHGG. The incidence of pDLGG and CAG was significantly lower in the midline of the infratentorial region compared to that of pDHGG. They were more likely to be completely resected surgically. The pDLGG and CAG group included 4 cases of pleomorphic xanthoastrocytoma, showing histological features of high-grade gliomas. Among the high-grade gliomas, 13 cases were diffuse midline gliomas and also showed histological features of low-grade glioma. Immunohistochemical studies of H3K27M, H3K27ME3, p53, ATRX, BRAF V600E, and Ki-67 showed significant differences between the pDLGG and CAG group versus the pDHGG group ( P<0.01). Molecular testing revealed that common molecular variations in the pDLGG and CAG group were KIAA1549-BRAF fusion and BRAF V600E mutation, while the pDHGG group frequently exhibited mutations in HIST1H3B and H3F3A genes, 1q amplification, and TP53 gene mutations. With integrated molecular testing, 2 pathological diagnoses were revised, and the pathological subtypes of 35.3% (12/34) of the pediatric gliomas that could not be reliably classified by histology were successfully classified. Conclusions:There are significant differences in clinical manifestations, pathological characteristics, molecular variations, and prognosis between the pDLGG, CAG and pDHGG groups. The integrated diagnosis combining histology and molecular features is of great importance for the accurate diagnosis and treatment of pediatric gliomas.

OBJECTIVE To explore the molecular mechanism of Compound Dihuang Granule in treating Parkinson's disease(PD)with yin-deficiency and dynamic wind syndrome by regulating the changes of ubiquitin-proteasome system-related proteins.METHODS SPF male SD rats were randomly selected as normal control group and sham operation group,13 rats in each group.The remaining rats were treated with 6-hydroxydopamine lateral brain injection to damage the substantia nigra to establish PD yin-deficien-cy and dynamic wind syndrome rat model.The established rats were randomly divided into model group,madopar group(150 mg·kg-1),low,medium and high dose groups of Compound Dihuang Granule(1.75,3.5,7 g·kg-1),13 rats in each group.Each group was given drugs by intragastric gavage for 28 d.The general conditions and neurobehavioral manifestations of the rats were observed;the expression of ubiquitin(UB),ubiquitin activating enzyme(UBE1),ubiquitin conjugating enzyme(UBE2A)and ubiquitin carboxyl terminal hydrolase(UCH-L1)positive cells,protein and mRNA expression levels in the damaged lateral stria-tum of the brain of rats were detected by immunohistochemistry,Western blot and qPCR methods;changes of dopamine(DA)content in the damaged lateral striatum of the brain of rats were detected by ELISA.RESULTS There was no significant difference in general conditions between the normal control group and the sham operation group,and there was no significant difference in the number of ro-tations,suspension time and number of moving grids.Compared to the sham-op group,the model group rats showed poor spirit,irrita-bility,limb tremor,slow movement,dark yellow fur,less food intake,reduced body weight;the modeling increased number of rota-tions,decreased hanging time and number of moving grids(P<0.01),significantly decreased expression of UB,UBE1,UBE2A,and UCH-L1 positive cells,mRNA and protein expression levels in the damaged lateral striatum(P<0.01),and significantly decreased DA content(P<0.01).Compared with the model group,the general condition of the rats in the madopar group and Compound Di-huang Granule groups was improved,the number of rotations was reduced,the hanging time and number of moving grids were increased(P<0.05,P<0.01),the expression of UB,UBE1,UBE2A,and UCH-L1 positive cells,mRNA and protein expression levels were increased(P<0.05,P<0.01),and the DA content was increased(P<0.01);behavioral tests and the expression levels of various in-dicators were most significantly improved in the madopar group and the high-dose Compound Dihuang Granule group(P<0.05,P<0.01),and there was no statistical significance between the two groups.CONCLUSION Compound Dihuang Granule may play a role in treating PD yin-deficiency and dynamic wind syndrome by regulating the expression of ubiquitin-proteasome system-related proteins,reducing abnormal protein aggregation,and thus alleviating DA content deficiency,and the high-dose Compound Dihuang Granule has the best effect.

Objective To observe the effect of Jinshui Liujun decoction on airway lesions in mice with COPD and explore its possible mechanism.Methods 48 C57BL/6 mice were randomly divided into blank group,model group,Jinshui Liujun decoction group and NAC group,with 12 in each group.The COPD mouse model was established by intranasal drip of LPS and smoking,and the corresponding drugs were given intragastric administration for 14 days after the model was established.Observe the general condition of the mice,measure the MV,PEF and PIF of the mice with the small animal lung function instrument,semi quantitatively evaluate the inflammation of the lung tissue,the thickness of the alveolar septum and the thickness of the airway wall with HE staining,and observe the airway mucus secretion and goblet cell proliferation with PAS staining.The content of MPO,SA and Urea in BALF was detected by the kit,and the ratio of SA and Urea was calculated.The content of MUC5AC in BALF was detected by ELISA.The levels of ROS,GSH,GSSG and GR in lung tissue were detected with the kit,and the ratio of GSH and GSSG was calculated.The expression level of CFTR mRNA in lung tissue was detected by qRT-PCR.Western blot was used to detect the expression level of CFTR protein in lung tissue.Results Compared with the control group,the growth of mice in the model group was poor.The body weight at each time point during the modeling period decreased(P<0.01),and the indexes of MV,PEF and PIF decreased(P<0.01).The lung tissue pathological score,alveolar septal thickness,airway wall thickness,airway mucus and goblet cell increased(P<0.01).The levels of SA,SA/Urea,MUC5AC and MPO in BALF increased(P<0.01),and the level of Urea decreased(P<0.01),The levels of ROS and GSSG in lung tissue increased(P<0.01),and the levels of GSH,GSH/GSSG,and GR decreased(P<0.01).The expression levels of CFTR mRNA and protein in lung tissue decreased(P<0.01).Compared with the model group,the growth condition of COPD mice improved,the body weight increased at each time point during the modeling period(P<0.05,P<0.01),the indexes of MV,PEF and PIF improved significantly(P<0.01),the pathological score of lung tissue,the thickness of alveolar septa,the thickness of airway wall,airway mucus and goblet cell decreased(P<0.01,P<0.05),and the levels of SA,SA/Urea,MUC5AC and MPO in BALF decreased(P<0.01),And an increase in Urea levels(P<0.01),a decrease in ROS and GSSG levels in lung tissue(P<0.01),and an increase in GSH,GSH/GSSG,and GR levels(P<0.01).The expression levels of CFTR mRNA and protein in lung tissue increased(P<0.01).Conclusion Jinshui Liujun decoction can correct CFTR acquired defects through antioxidant effects to improve airway lesions in COPD.