OBJECTIVES: To study the effect of prophylactic phenytoin (PHT) or levetiracetam (LEV) on busulfan (BU) blood concentration in children undergoing hematopoietic stem cell transplantation. METHODS: Pediatric patients conditioned with BU plus cyclophosphamide and fludarabine at the First People's Hospital of Chenzhou from September 2023 to February 2025 were retrospectively included. Patients were grouped by prophylactic antiepileptic regimen into PHT (n=24) and LEV (n=26). BU blood concentrations at the end of infusion (0 hour) and at 1, 2, and 4 hours post-infusion were compared between groups. RESULTS: At 0 hour post-infusion, BU blood concentrations did not differ significantly between groups (P>0.05). At 1, 2, and 4 hours post-infusion, BU blood concentrations were higher in the LEV group than in the PHT group (P<0.05). The area under the concentration-time curve from 0 to ∞ (AUC_0-∞) was greater in the LEV group (P<0.001), and the attainment rate of AUC_0-∞ was higher in the LEV group than in the PHT group (73% vs 21%, P<0.001). No significant differences were observed between groups in time to hematopoietic engraftment or in the incidence of BU-related adverse drug reactions (P>0.05). CONCLUSIONS Compared with PHT, LEV prophylaxis is associated with higher BU blood concentration and a higher AUC_0-∞ attainment rate. There is no observed difference in BU efficacy or safety between PHT and LEV.
Humans ; Levetiracetam/therapeutic use* ; Busulfan/pharmacokinetics* ; Hematopoietic Stem Cell Transplantation ; Male ; Female ; Child ; Child, Preschool ; Phenytoin/pharmacology* ; Infant ; Retrospective Studies ; Anticonvulsants/pharmacology* ; Adolescent

The interaction between m⁶A-methylated RNA and chromatin modification remains largely unknown. We found that targeted inhibition of bromodomain-containing protein 4 (BRD4) by siRNA or its inhibitor (JQ1) significantly decreases mRNA m⁶A levels and suppresses the malignancy of breast cancer (BC) cells via increased expression of demethylase AlkB homolog 5 (ALKBH5). Mechanistically, inhibition of BRD4 increases the mRNA stability of ALKBH5 via enhanced binding between its 3' untranslated regions (3'UTRs) with RNA-binding protein RALY. Further, BRD4 serves as a scaffold for ubiquitin enzymes tripartite motif containing-21 (TRIM21) and ALKBH5, resulting in the ubiquitination and degradation of ALKBH5 protein. JQ1-increased ALKBH5 then demethylates mRNA of extra spindle pole bodies like 1 (ESPL1) and reduces binding between ESPL1 mRNA and m⁶A reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), leading to decay of ESPL1 mRNA. Animal and clinical studies confirm a critical role of BRD4/ALKBH5/ESPL1 pathway in BC progression. Further, our study sheds light on the crosstalks between histone modification and RNA methylation.

OBJECTIVES: To explore the active components that mediate the therapeutic effect of Centella asiatica on psoriasis and their therapeutic mechanisms. METHODS: TCMSP, TCMIP, PharmMapper, Swiss Target Prediction, GeneCards, OMIM and TTD databases were searched for the compounds in Centella asiatica and their targets and the disease targets of psoriasis. A drug-active component-target network and the protein-protein interaction network were constructed, and DAVID database was used for pathway enrichment analysis. In a RAW264.7 macrophage model of LPS-induced inflammation, the anti-inflammatory effect of 7.5, 15, 30, and 60 μmol/L quercetin, asiaticoside, and asiatic acid, which were identified as the main active components in Centella asiatica, were tested by measuring cellular production of NO, TNF‑α and IL-6 using Griess method and ELISA and by detecting mRNA expressions of IL-23, IL-17A, TNF-α and IL-6 and protein expressions of p-STAT3 (Tyr705) and p-STAT3 (Ser727) with RT-qPCR and Western blotting. RESULTS: A total of 139 targets of Centella asiatica and 4604 targets of psoriasis were obtained, and among them CASP3, EGFR, PTGS2, and ESR1 were identified as the core targets. KEGG analysis suggested that quercetin, asiaticoside, and asiatic acid in Centella asiatica were involved in cancer and IL-17 and MAPK signaling pathways. In the RAW264.7 macrophage model of inflammation, treatment with quercetin significantly reduced cellular production of NO, TNF‑α and IL-6, and lowered mRNA expressions of IL-23, IL-17A, TNF‑α and IL-6 and protein expressions of p-STAT3 (Tyr705) and p-STAT3 (Ser727). CONCLUSIONS Quercetin, asiaticoside and asiatic acid are the main active components in Centella asiatica to mediate the therapeutic effect against psoriasis, and quercetin in particular is capable of suppressing cellular production of NO, TNF‑α and IL-6 and regulating the IL-23/IL-17A inflammatory axis by mediating STAT3 phosphorylation to inhibit inflammatory response.
Quercetin/pharmacology* ; Psoriasis/metabolism* ; STAT3 Transcription Factor/metabolism* ; Mice ; Animals ; Centella/chemistry* ; Triterpenes/pharmacology* ; Phosphorylation ; Interleukin-17/metabolism* ; Interleukin-23/metabolism* ; RAW 264.7 Cells ; Pentacyclic Triterpenes/pharmacology* ; Macrophages/drug effects* ; Signal Transduction ; Plant Extracts

OBJECTIVES: To study the effect of CDC20 knockdown on proliferation, migration and invasion of cervical cancer cells and its underlying mechanism. METHODS: CDC20 expression in cervical cancer tissues was analyzed using the TCGA database, and the protein expressions of CDC20 and β-Catenin in clinical specimens of cervical cancer and adjacent tissues were detected using immunohistochemistry. A dual target sgRNA2&7 sequence for CDC20 gene was designed for CDC20 gene knockdown in cervical cancer C33A cells using CRISPR/Cas9 technology, and CDC20 mRNA and protein expression levels in the transfected cells were detected using qRT-PCR and Western blotting. The changes in proliferation, cell cycle, apoptosis, migration and invasiveness of the transfected cells were evaluated using colony-forming assay, fluorescence activated cell sorting (FACS) and Transwell assay. In the animal experiment, naïve C33A cells and the cells with CDC20 knockdown were injected subcutaneously into the left and right axillae of nude mice (n=5) to observe tumor growth. The expressions of CDC20 and β-Catenin proteins in transfected cells and the xenograft were analyzed using Western blotting, and their interaction was confirmed by co-immunoprecipitation (CoIP) and immunofluorescence co-localization assays. RESULTS: Cervical cancer tissues expressed significantly higher CDC20 and β‑Catenin levels than the adjacent tissues. C33A cells with CDC20 knockdown showed reduced proliferation, increased apoptosis, and lowered migration and invasion abilities. CDC20 knockdown significantly suppressed the growth of C33A cell xenograft in nude mice, and the tumor-bearing mice did not exhibit obvious body mass changes. CDC20 and β-Catenin levels were both significantly lowered in C33A cells with CDC20 knockdown. Co-immunoprecipitation and co-localization assays confirmed the interaction between CDC20 and β‑Catenin. CONCLUSIONS CDC20 is highly expressed in cervical cancer tissues, and CDC20 knockdown can suppress proliferation, invasion, and metastasis while enhancing apoptosis of C33A cells, which is closely related with the regulation of the Wnt/β-Catenin signaling pathway.
Humans ; Uterine Cervical Neoplasms/metabolism* ; Female ; Cdc20 Proteins/genetics* ; Cell Proliferation ; Animals ; Cell Movement ; Neoplasm Invasiveness ; Apoptosis ; Mice, Nude ; beta Catenin/metabolism* ; CRISPR-Cas Systems ; Mice ; Cell Line, Tumor ; Gene Knockout Techniques ; Neoplasm Metastasis

OBJECTIVES: To explore the therapeutic mechanism of compound Centella asiatica formula (CCA) for alleviating Schistosoma japonicum (Sj)-induced liver fibrosis in mice. METHODS: The active components and targets of CCA were identified using the TCMSP database with cross-analysis of Sj-related liver fibrosis targets. A "drug-component-target-pathway-disease" network was constructed using Cytoscape 3.9.1. Functional enrichment analysis (GO/KEGG) was performed using DAVID. Molecular docking study was carried out to validate interactions between the core targets and the key compounds. For experimental validation of the results, 36 mice were divided into control group, Sj-infected model group, and CCA-treated groups. In the latter two groups, liver fibrosis was induced via abdominal infection with Sj cercariae for 8 weeks, followed by 8 weeks of daily treatment with CCA decoction or saline. Hepatic pathology of the mice was assessedwith HE and Masson staining, and hepatic expressions of collagen-I and collagen-III were detected using immunohistochemistry; serum IL-6 and TNF-α levels were determined with ELISA. Hepatic expressions of TLR4 and MyD88 proteins were analyzed with Western blotting. RESULTS: We identified a total of 107 bioactive CCA components and 791 targets, including 37 intersection targets linked to Sj-induced fibrosis. The core targets included TNF, TP53, JUN, MMP9, and CXCL8, involving the IL-17 signaling, lipid metabolism, TLR4/MyD88 axis, and cancer pathways. Molecular docking study confirmed strong binding affinity between quercetin (a primary CCA component) and TNF/TP53/JUN/MMP9. In Sj-infected mouse models, CCA treatment significantly attenuated hepatic inflammatory cell infiltration, reduced collagen-I and collagen-III deposition, improved tissue architecture, reduced serum IL-6 and TNF-α levels, and downregulated TLR4 and MyD88 expressions in the liver. CONCLUSIONS CCA mitigates Sj-induced liver fibrosis by targeting TNF, TP53, JUN, and MMP9 to modulate the TLR4/MyD88 pathway, thereby suppressing pro-inflammatory cytokine release, inhibiting hepatic stellate cell activation, reducing collagen deposition, and preventing granuloma formation in the liver.
Animals ; Toll-Like Receptor 4/metabolism* ; Mice ; Myeloid Differentiation Factor 88/metabolism* ; Schistosoma japonicum ; Liver Cirrhosis/parasitology* ; Schistosomiasis japonica ; Signal Transduction ; Molecular Docking Simulation ; Inflammation ; Centella/chemistry* ; Drugs, Chinese Herbal/pharmacology* ; Tumor Necrosis Factor-alpha/metabolism*

OBJECTIVE: To investigate the differences in indwelling duration, clinical scenarios, and complications between the modified midline catheter (MMC) and the central venous catheter (CVC) in the treatment of patients in the medical intensive care unit (ICU) and the risk factors for complications based on real-world data. METHODS: A retrospective cohort study was conducted. The adult patients admitted to the medical ICU of the Third Xiangya Hospital of Central South University and had undergone placement of either a MMC or a CVC between January 1, 2023, and July 31, 2024, were consecutively enrolled by querying the hospital's electronic medical record system. Based on the type of catheter inserted, the patients were divided into the MMC group and the CVC group. The two groups were compared regarding the selection of catheters in the context of different underlying diseases, the actual clinical application after catheterization, catheter-related complications, the international normalized ratio (INR) and platelet count (PLT) during puncture and catheterization, the length of ICU stay, total length of hospital stay, catheter indwelling duration, and mortality during hospitalization. Multivariate Logistic regression analysis was employed to identify independent risk factors for catheter removal. RESULTS: Among the 274 patients, 52 received a MMC and 222 received a CVC. The utilization rate of MMC was significantly higher than that of CVC in patients with acute respiratory distress syndrome (ARDS), cardiovascular disease, and cancer [ARDS: 92.3% (48/52) vs. 70.3% (156/222), cardiovascular disease: 84.6% (44/52) vs. 54.5% (121/222), cancer: 30.8% (16/52) vs. 17.1% (38/222), all P < 0.05]. However, the use of MMC was significantly lower than CVC when vasoactive drug infusion was required [57.7% (30/52) vs. 79.7% (177/222), P < 0.05]. A significantly higher proportion of patients in the MMC group had a catheter indwelling time ≥ 12 days as compared with the CVC group [32.7% (17/52) vs. 13.5% (30/222), P < 0.05]. There were no statistically significant differences in other underlying diseases, venous access usage, INR and PLT during puncture and catheterization, length of ICU stay, total length of hospital stay, and in-hospital mortality of patients between the two groups. Regarding catheter-related complications, although the incidence of partial or complete catheter removal in the MMC group was significantly higher than that in the CVC group [36.5% (19/52) vs. 5.4% (12/222), P < 0.05], the incidence of puncture site fluid leakage, puncture site skin allergy, and deep vein thrombosis were significantly lower than those in the CVC group [puncture site fluid leakage: 1.9% (1/52) vs. 22.1% (49/222), puncture site skin allergy: 0% (0/52) vs. 20.7% (46/222), deep vein thrombosis: 3.8% (2/52) vs. 16.7% (37/222), all P < 0.05]. Furthermore, the proportion of patients experiencing three or more types of complications in the MMC group was significantly lower than that in the CVC group [5.8% (3/52) vs. 17.6% (39/222), P < 0.05]. Multivariate Logistic regression analysis of risk factors for catheter removal identified the use of a MMC [odds ratio (OR) = 8.518, 95% confidence interval (95%CI) was 3.710-19.560, P < 0.001] and a catheter indwelling time ≥ 12 days (OR = 3.133, 95%CI was 1.297-7.567, P = 0.011) as independent risk factors. CONCLUSIONS MMC was more frequently used in patients with ARDS, cardiovascular disease, and cancer, whereas CVC was primarily employed for vasoactive drug infusion. The use of MMC and a longer indwelling time were identified as independent risk factors for catheter removal. Despite a higher removal rate, the overall incidence of complications was significantly lower with MMC than with CVC. These findings suggest that MMC could serve as a routine alternative to CVC in most of clinical scenarios, provided that measures are implemented to prevent removal.
Humans ; Retrospective Studies ; Intensive Care Units ; Catheterization, Central Venous/methods* ; Central Venous Catheters ; Risk Factors ; Length of Stay ; Male ; Female ; Middle Aged ; Adult ; Catheters, Indwelling ; Aged

Objective To understand the medical decision-making preferences of doctors in tertiary grade A hospitals,providing evidence to promote clinical guidelines and improve healthcare service value.Methods A discrete choice model was constructed using the Delphi method.A total of 106 valid samples were collected via a questionnaire survey.The mixed logit model was used to assess doctors' preferences in medical decision-making across scenarios of hypertension,abdominal infection,and IgA nephropathy,analyzing heterogeneity in decision-making preferences based on doctors' characteristics.Results Overall,treatment efficacy,patient preference,and the value of medical exploration significantly influenced doctors' decision-making preferences(P＜0.05).In hypertension and IgA nephropathy scenarios,adverse reactions had a significant impact on decision-making preferences(P＜0.001).The relative importance of decision-making attributes was treatment efficacy＞adverse reactions＞patient preference＞medical exploration value＞cost control.Doctors with higher education levels valued treatment efficacy more in abdominal infection and IgA nephropathy scenarios(P＜0.05)and adverse reactions more in hypertension scenarios(P＜0.05).Conclusion Treatment efficacy is the primary factor in medical decision-making.Cost control plays a limited role in current decision-making,and preferences vary by disease specificity across different clinical practice scenarios.

Objective To understand the medical decision-making preferences of doctors in tertiary grade A hospitals,providing evidence to promote clinical guidelines and improve healthcare service value.Methods A discrete choice model was constructed using the Delphi method.A total of 106 valid samples were collected via a questionnaire survey.The mixed logit model was used to assess doctors' preferences in medical decision-making across scenarios of hypertension,abdominal infection,and IgA nephropathy,analyzing heterogeneity in decision-making preferences based on doctors' characteristics.Results Overall,treatment efficacy,patient preference,and the value of medical exploration significantly influenced doctors' decision-making preferences(P＜0.05).In hypertension and IgA nephropathy scenarios,adverse reactions had a significant impact on decision-making preferences(P＜0.001).The relative importance of decision-making attributes was treatment efficacy＞adverse reactions＞patient preference＞medical exploration value＞cost control.Doctors with higher education levels valued treatment efficacy more in abdominal infection and IgA nephropathy scenarios(P＜0.05)and adverse reactions more in hypertension scenarios(P＜0.05).Conclusion Treatment efficacy is the primary factor in medical decision-making.Cost control plays a limited role in current decision-making,and preferences vary by disease specificity across different clinical practice scenarios.

Objective To evaluate the impact of the eastern healthy diet pattern (EHDP) on body weight, blood pressure, blood lipids, and glucose in type 2 diabetes mellitus (T2MD) patients and compare it with the effect of traditional diabetes diet (TDD). Methods A total of 140 inpatients with T2DM admitted to Chenzhou First People's Hospital from May 2022 to December 2022 were selected and randomly assigned to EHDP (n = 70) group or TDD group (n = 70). Both groups were served with three meals a day by the dietitian department of the hospital for 8 weeks. The TDD group followed the guidelines of the Chinese diabetes society, while the EHDP group optimized diversified food intake and increased aquatic products, olive oil, and dairy products. Results There was no statistically significant difference between the two groups of patients in baseline data including age, gender, blood pressure, blood glucose, and hypoglycemic and lipid-lowering treatment between the two groups (P value 0.238~0.795). After 8 weeks of dietary intervention, compared with before the intervention, the body weight, fasting blood glucose, 2-hour postprandial blood glucose, glycosylated hemoglobin, blood lipids and blood pressure of both groups showed statistically significant decreases (P<0.05). The reductions in weight, BMI, blood lipids, blood pressure and fasting blood glucose in the EHDP group were greater than those in the TDD group (P<0.05). Conclusion EHDP is better than the traditional diabetic diet in reducing blood glucose, weight, blood pressure, and blood lipids compared to traditional diets. Both diet patterns effectively improve 2h PG and HbA1c with no significant difference.

OBJECTIVE: To explore the mechanisms that mediate the anti-inflammatory activity of Eurycoma longifolia. METHODS: Kunming mouse models of xylene-induced ear swelling and lipopolysaccharide (LPS)-induced acute pneumonia were used to compare the anti- inflammatory activities of aqueous and ethanol extracts of Eurycoma longifolia. UPLC-Q-TOF-MS/MS was used to identify the chemical composition in the ethanol extract of Eurycoma longifolia, based on which the potential antiinflammatory targets of Eurycoma longifolia were screened using the databases including SwissADME, SwissTargetPrediction, and Genecards. The String database was used to generate the protein-protein interaction (PPI) network, and Cytoscape was used for network topology analysis and screening the core targets. The enrichment of the core targets was analyzed using Metascape database, the core components and targets were docked with Autodock software, and the docking results were visualized using Pymol software. In a RAW264.7 cell model of LPS-induced inflammation, the Griess reagent was used to measure NO level, and Western blotting was performed to detect the expression levels of MAPK1, JAK2, and STAT3 proteins to verify the anti- inflammatory mechanism of Eurycoma longifolia. RESULTS: The ethanol extract (75%) of Eurycoma longifolia (ELE) was the active site, which contained a total of 37 chemical components. These chemical compounds and diseases had 541 targets, involving the JAK/STAT3, cAMP and other signaling pathways. Twelve indicator components were identified, which all showed good results of molecular docking with two core targets involved in the signaling pathways. In the cell validation experiment, treatment of the cells with low-, medium-, and high-dose ELE significantly reduced NO release in the cells, and ELE at the medium dose significantly decreased the cellular expressions of JAK2 and STAT3. CONCLUSION The anti-inflammatory activity of Eurycoma longifolia is attributed primarily to its active ingredients bitter lignin and alkaloids, which may regulate the JAK/STAT3 signaling pathway by targeting JAK2 and STAT3.
Animals ; Mice ; Network Pharmacology ; Eurycoma ; Lipopolysaccharides ; Molecular Docking Simulation ; Tandem Mass Spectrometry ; Anti-Inflammatory Agents/pharmacology* ; Ethanol ; Plant Extracts/pharmacology*