Due to patient compliance and convenience, oral medication is likely the most common and acceptable method of drug administration. However, traditional dosage forms such as tablets or capsules may lead to low drug bioavailability and poor therapeutic efficiency. Therefore, with advancements in material science and micro/nano manufacturing technology, various carriers have been developed to enhance drug absorption in the gastrointestinal tract. In this context, we initially discuss the key biological factors that hinder drug transport and absorption (including anatomical, physical, and biological factors). Building on this foundation, recent progress in both conventional and innovative oral drug delivery routes aimed at improving drug bioavailability and targeting is reviewed. Finally, we explore future prospects for oral drug delivery systems as well as potential challenges in clinical translation.

BACKGROUND: Doxorubicin hydrochloride (DOX) is extensively used in the treatment of various tumors. However, its clinical application is limited due to dose-dependent cardiotoxicity. Currently, few effective strategies exist to mitigate or eliminate DOX-induced cardiomyopathy (DIC). Although ferroptosis is implicated in DIC and its inhibition partially alleviates the condition, the direct targets of DOX in the progression of cardiotoxicity remain unclear. This study aimed to discover the direct targets of DOX in ferroptosis-mediated DIC. METHODS: A DOX pulldown assay was performed to identify proteins specifically binding to DOX in murine hearts, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify candidate proteins. A cardiac injury mouse model was established by DOX treatment. Based on this, multiple ferroptosis biomarkers were detected by flow cytometry, quantitative real-time polymerase chain reaction, western blotting, immunochemistry, etc. Besides, specific activator and inhibitor of signaling pathways were applied to illuminate molecular mechanisms. RESULTS: Glutathione S-transferase P1 (GSTP1) was identified as a DOX target. GSTP1 activity was inhibited in DOX-treated cardiomyocytes, while its overexpression significantly alleviated DIC. Moreover, GSTP1 overexpression inhibited acyl-CoA synthetase long-chain family member 4 (ACSL4)-dependent ferroptosis. Mechanistically, GSTP1 overexpression suppressed c-Jun N-terminal kinase (JNK) phosphorylation, thereby reducing reactive oxygen species (ROS) production and inhibiting ferroptosis in DIC. CONCLUSIONS This study identifies the DOX/GSTP1/JNK axis as a critical pathway mediating ACSL4-dependent ferroptosis in DIC. GSTP1 is highlighted as a potential key mediator of ferroptosis and a promising therapeutic target for DIC.

OBJECTIVES: To assess the preliminary efficacy and safety of a dose-intensified C5VD regimen (cisplatin, 5-fluorouracil, vincristine, and doxorubicin) in children with locally advanced hepatoblastoma. METHODS: This prospective study enrolled 24 children with newly diagnosed, locally advanced hepatoblastoma who received the dose-intensified C5VD regimen at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, and Shanghai Children's Hospital between January 2020 and December 2023. Clinical characteristics, treatment outcomes, and chemotherapy-related toxicities were analyzed. RESULTS: Of the 24 patients, 13 were male and 11 were female, with a median age at diagnosis of 18.7 months (range: 3.5-79.4 months). All patients achieved complete macroscopic resection of hepatic lesions without liver transplantation. Serum alpha-fetoprotein levels decreased significantly after two chemotherapy cycles. During a median follow-up of 38.4 months (range: 15.8-50.7 months), all patients maintained continuous complete remission, with 3-year event-free survival and overall survival rates of 100%. Across 144 chemotherapy cycles, the incidence rates of grade 3-4 neutropenia, thrombocytopenia, and infections were 97%, 77%, and 71%, respectively; no treatment-related deaths occurred. Notably, 5 patients (21%) developed Brock grade ≥3 hearing loss, of whom 1 required a hearing aid. CONCLUSIONS The dose-intensified C5VD regimen demonstrates significant efficacy with an overall favorable safety profile in the treatment of newly diagnosed, locally advanced pediatric hepatoblastoma. Grade 3-4 myelosuppression and infection are the predominant toxicities. However, high‑dose cisplatin-induced ototoxicity remains a concern, highlighting the need for improved otoprotective strategies.
Humans ; Hepatoblastoma/pathology* ; Male ; Female ; Infant ; Liver Neoplasms/pathology* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Child, Preschool ; Prospective Studies ; Doxorubicin/adverse effects* ; Child ; Cisplatin/adverse effects* ; Vincristine/adverse effects* ; Fluorouracil/adverse effects*

Ovarian cancer is the most lethal malignancy affecting the female reproductive system. Pharmacological inhibitors targeting CDK4/6 have demonstrated promising efficacy across various cancer types. However, their clinical benefits in ovarian cancer patients fall short of expectations, with only a subset of patients experiencing these advantageous effects. This study aims to provide further clinical and biological evidence for antineoplastic effects of a CDK4/6 inhibitor (TQB4616) in ovarian cancer and explore underlying mechanisms involved. Patient-derived ovarian cancer organoid models were established to evaluate the effectiveness of TQB3616. Potential key genes related to TQB3616 sensitivity were identified through RNA-seq analysis, and TRIM4 was selected as a candidate gene for further investigation. Subsequently, co-immunoprecipitation and GST pull-down assays confirmed that TRIM4 binds to hnRNPDL and promotes its ubiquitination through RING and B-box domains. RIP assay demonstrated that hnRNPDL binded to CDKN2C isoform 2 and suppressed its expression by alternative splicing. Finally, in vivo studies confirmed that the addition of siTRIM4 significantly improved the effectiveness of TQB3616. Overall, our findings suggest that TRIM4 modulates ubiquitin-mediated degradation of hnRNPDL and weakens sensitivity to CDK4/6 inhibitors in ovarian cancer treatment. TRIM4 may serve as a valuable biomarker for predicting sensitivity to CDK4/6 inhibitors in ovarian cancer.
Humans ; Female ; Ovarian Neoplasms/pathology* ; Animals ; Tripartite Motif Proteins/genetics* ; Mice ; Cyclin-Dependent Kinase 4/antagonists & inhibitors* ; Cell Line, Tumor ; Cyclin-Dependent Kinase 6/antagonists & inhibitors* ; Protein Kinase Inhibitors/pharmacology* ; Ubiquitin/metabolism* ; Xenograft Model Antitumor Assays ; Ubiquitination ; Antineoplastic Agents/pharmacology*

Cellular force transducer plays a crucial role in normal development of the follicles,which consists of integrin,focal adhesion,signal pathways and cytoskeleton.In follicle development,cellular force transducer converts force stimulation into biochemical signal,and activates the signal pathways to make cytoskeleton respond to stimulation.This process promotes various biological functions of germ cells,such as migration,meiosis and ovulation.This review summarizes the mechanism of follicles'development from two aspects,the role of cellular force transducer in the development of follicles and the related signal pathways,so as to provide a new idea for the further study of follicle development.

Objective:To analyze the types and functions of CD34 + cells in full-thickness skin defect wounds of normal mice and diabetic mice by single-cell RNA sequencing. Methods:This study was an experimental study. The CD34 + cell lineage tracing mouse was produced, and the visualization of CD34 + cells under the fluorescent condition was realized. Six male CD34 + cell lineage tracing mice aged 7-8 weeks (designated as diabetic group) were intraperitoneally injected with streptozotocin to establish a diabetic model, and full-thickness skin defect wounds were prepared on their backs when they reached 13 weeks old. Another 6 male CD34 + cell lineage tracing mice aged 13 weeks (designated as control group) were also subjected to full-thickness skin defect wounds on their backs. On post-injury day (PID) 4, wound tissue was collected from 3 mice in control group and 2 mice in diabetic group, and digested to prepare single-cell suspensions. CD34 + cells were screened using fluorescence-activated cell sorting, followed by single-cell RNA sequencing. The Seurat 4.0.2 program in the R programming language was utilized for dimensionality reduction, visualization, and cell clustering analysis of CD34 + cell types, and to screen and annotate the marker genes for each CD34 + cell subpopulation. Kyoto encyclopedia of genes and genomes (KEGG) and gene ontology (GO) enrichment analysis was performed to analyze the differentially expressed genes (DEGs) of CD34 + fibroblasts (Fbs), smooth muscle cells (SMCs), keratinocytes (KCs), and chondrocyte-like cells (CLCs) in the wound tissue of two groups of mice for exploring cellular functions. Results:On PID 4, CD34 + cells in the wound tissue of both groups of mice were consisted of 7 cell types, specifically endothelial cells, Fbs, KCs, macrophages, T cells, SMCs, and CLCs. Among these, Fbs were further classified into 5 subpopulations. Compared with those in control group, the proportions of CD34 + endothelial cells, Fbs subpopulation 1, Fbs subpopulation 4, KCs, and CLCs in the wound tissue of mice were increased in diabetic group, while the proportions of CD34 + Fbs subpopulation 2, Fbs subpopulation 3, and SMCs were decreased. The marker genes for annotating CD34 + CLCs, endothelial cells, Fbs subpopulation 1, Fbs subpopulation 2, Fbs subpopulation 3, Fbs subpopulation 4, Fbs subpopulation 5, KCs, macrophages, SMCs, and T cells were respectively metastasis-associated lung adenocarcinoma transcript 1, fatty acid binding protein 4, Gremlin 1, complement component 4B, H19 imprinted maternally expressed transcript, Dickkopf Wnt signaling pathway inhibitor 2, fibromodulin, keratin 5, CD74 molecule, regulator of G protein signaling 5, and inducible T-cell co-stimulator molecule. KEGG and GO enrichment analysis revealed that, compared with those in control group, DEGs with significant differential expression (SDE) in CD34 + Fbs from the wound tissue of mice in diabetic group on PID 4 were significantly enriched in terms related to inflammatory response, extracellular matrix (ECM) organization, regulation of cell proliferation, and aging (with Pvalues all <0.05), DEGs with SDE in CD34 + SMCs were significantly enriched in terms related to cell migration, apoptotic process, positive regulation of transcription, and phagosome (with P values all <0.05), DEGs with SDE in CD34 + KCs were significantly enriched in terms related to mitochondrial function, transcription, and neurodegenerative diseases (with P values all <0.05), and DEGs with SDE in CD34 + CLCs were significantly enriched in terms related to rhythm regulation, ECM, and viral infection (with P values all <0.05). Conclusions:CD34 + cells display high heterogeneity in the healing process of full-thickness skin defect wounds in both normal mice and diabetic mice. The significantly enriched functions of DEGs with SDE in CD34 + cell subpopulations in the wound tissue of the two mouse groups are closely related to the wound healing process.

Objective:To evaluate the effects of antibiotics alone and combined with Longqing tablets and antibiotics on stent-related symptoms (SRS), urinary tract infection (UTI), and quality of life in patients who underwent ureteroscopic lithotripsy (URL) with indwelling ureteral stents.Methods:The clinical data of 160 patients who underwent URL with indwelling ureteral stents in the Department of Urology, Xuanwu Hospital, Capital Medical University from January 2022 to December 2023 were retrospectively analyzed. According to the postoperative application of antibiotics and Longqing tablets, they were divided into two groups: control group and observation group, with 80 cases in each group. The control group took Levofloxacin tablets orally, and the observation group took Longqing tablets combined with Levofloxacin tablets orally. The SRS of the two groups was compared according to the degree of urinary tract irritation symptoms, low back pain, and dysuria. UTI was evaluated by the incidence of fever, hematuria, pyuria, positive rate of urine culture, and specific bacterial classes. The Chinese version of the ureteral stent symptom questionnaire (USSQ) and the quality of life score were evaluated in the two groups. Normally distributed quantitative data were expressed as mean ± standard deviation ( ± s), and the t-test was used for comparison between groups; non-normally distributed quantitative data were expressed as median (interquartile range) [ M( Q1, Q3)], and the non-parametric test was used for comparison between groups. Count data were expressed as the number of cases and percentage, and the Chi-square test was used for comparison between groups. Results:Among the 160 patients, 141 (88.13%) developed SRS, including 71 cases (88.75%) in the control group, and 70 cases (87.50%) in the observation group, there was no significant difference between the two groups ( P=0.724). In terms of SRS, the urinary tract irritation symptom scores [3.0 (1.0, 5.0) points vs 5.0 (3.0, 7.0) points], low back pain scores [1.5 (1.0, 2.0) points vs 2.5 (2.0, 3.0) points] and dysuria scores [1.5 (1.0, 2.0) points vs 3.5 (2.5, 4.0) points] of the observation group were significantly lower than those of the control group, the differences were statistically significant ( P<0.05). The Chinese version of USSQ showed that the urinary tract symptoms of the observation group were significantly relieved compared with the control group [15(12, 19) points vs 22 (15, 28) points], and the difference was statistically significant ( P=0.037). In terms of UTI, the incidence of fever (6.25% vs 7.50%), the incidence of hematuria (20.00% vs 22.50%), the incidence of pyuria (30.00% vs 33.75%), and positive rate of urine culture (11.25% vs 15.00%) between the two groups were not statistically significant ( P> 0.05), but the number was reduced to a certain extent. There was no statistically significant difference in the scores of physiological function, emotional function and social function between the two groups before surgery ( P> 0.05); however, the scores of the above three items in both groups were improved 2 weeks after surgery, and the improvement of the observation group was significantly higher than that of the control group, with statistical significance ( P<0.01). Conclusion:Longqing tablets combined with antibiotics are more effective in improving SRS in patients who receive URL and have indwelling ureteral stents than antibiotics alone, and can prevent UTI and improve the quality of life to a certain extent.

Objective To explore the relationship between C1q tumor necrosis factor related protein 13(CTRP13)and gestational diabetes mellitus(GDM),and the predictive value of CTRP13 for adverse pregnancy outcomes in GDM patients.Methods A total of 163 pregnant women who underwent prenatal examination in the Second Affiliated Hospital of Zhengzhou University from January to May 2023 were enrolled in GDM group(n=83)and normal glucose tolerance(NGT)group(n=80)according to the results of oral glucose tolerance test at 24-28 weeks of gestation.Collect general information,biochemical data,and adverse pregnancy outcomes from two groups of subjects.Analyze the correlation between serum CTRP13 and glucose and lipid metabolism indicators in GDM pregnant women.The receiver operating characteristic(ROC)curve was drawn to analyze the predictive value of CTRP13 for adverse pregnancy outcomes in GDM pregnant women.Results The pre pregnancy body mass index,prenatal body mass index,triglycerides,total cholesterol,low density lipoprotein,fasting blood glucose,2-hours plasma glucose,glycosylated hemoglobin,fasting insulin,and homeostasis model assessment of insulin resistanc index in GDM group was significantly higher than those in NGT group,while CTRP13 was significantly lower than that in NGT group(P＜0.05).Serum CTRP13 was negatively correlated with total cholesterol,triglycerides,low density lipoprotein,2-hours plasma glucose,and glycosylated hemoglobin in GDM patients(P＜0.05).The incidence of adverse pregnancy outcomes such as gestational hypertension and premature rupture of membranes in GDM group were significantly higher than those in NGT group(P＜0.05).The area under the curve of serum CTRP13 for predicting adverse pregnancy outcomes in GDM pregnant women was 0.805,with sensitivity and specificity of 75.80％and 76.00％,respectively.Conclusion Serum CTRP13 is associated with glucose and lipid metabolism in GDM pregnant women,and is a potential biomarker for predicting adverse pregnancy outcomes in GDM pregnant women.

Objective:To assess the effectiveness of a 6-month Ba Duan Jin exercise program in improving the balance of community-dwelling older adults.Methods:A two arms, parallel-group, cluster randomized controlled trial was conducted in 1 028 community residents aged 60-80 years in 40 communities in 5 provinces of China. Participants in the intervention group (20 communities, 523 people) received Ba Duan Jin exercise 5 days/week, 1 hour/day for 6 months, and three times of falls prevention health education, and the control group (20 communities, 505 people) received falls prevention health education same as the intervention group. The Berg balance scale (BBS) score was the leading outcome indicator, and the secondary outcome indicators included the length of time of standing on one foot (with eyes open and closed), standing in a tandem stance (with eyes open and closed), the closed circle test, and the timed up to test.Results:A total of 1 028 participants were included in the final analysis, including 731 women (71.11%) and 297 men (28.89%), and the age was (69.87±5.67) years. After the 3-month intervention, compared with the baseline data, the BBS score of the intervention group was significantly higher than the control group by 3.05 (95% CI: 2.23-3.88) points ( P<0.001). After the 6-month intervention, compared with the baseline data, the BBS score of the intervention group was significantly higher than the control group by 4.70 (95% CI: 4.03-5.37) points ( P<0.001). Ba Duan Jin showed significant improvement ( P<0.05) in all secondary outcomes after 6 months of exercise in the intervention group compared with the control group. Conclusions:This study showed that Ba Duan Jin exercise can improve balance in community-dwelling older adults aged 60-80. The longer the exercise time, the better the improvement.

Objective To study the expression levels of serum complement C1q/tumor necrosis factor-related protein 6(CTRP6)in women in early pregnancy and to explore its relationship with gestational diabetes mellitus(GDM).Methods Women at the Second Affiliated Hospital of Zhengzhou University from March 2021 to March 2022 were prospectively and consecutively selected from 10 to 13 weeks gestation for outpatient obstetric check-ups.The age,height,weight,and time of last menstruation of pregnant women were collected,and the levels of total cholesterol(TC),triglyceride(TG),high density lipoprotein(HDL),low density lipoprotein(LDL),fasting plasma glucose(FPG),glycosylated hemoglobin(HbA1c),fasting insulin(FINS)and CTRP6 were measured in early pregnancy,and the pre-pregnancy body mass index(BMI),baseline BMI,prenatal BMI,and homeostatic model assessment of insulin resistance(HOMA-IR)were calculated.All pregnant women underwent a 75g oral glucose tolerance test at 24-28 weeks of gestation and were divided into GDM group and normal glucose tolerance(NGT)group according to the test results.The clinical data and laboratory indexes of the two groups in early pregnancy were compared,and the correlation between serum CTRP6 and various indexes in early pregnancy and its relationship with GDM were analyzed.Results A total of 213 maternal cases were enrolled,and 203 cases were completed for follow-up.Among them,52 mothers were diagnosed with GDM,with a GDM prevalence rate of 25.62%.Serum CTRP6,age,pre-pregnancy BMI,baseline BMI,antenatal BMI,TC,LDL,FPG,HbA1c,FINS,and HOMA-IR were higher in GDM group compared to NGT group,with a statistically significant difference(P<0.05).CTRP6 in early pregnancy was positively correlated with age,pre-pregnancy BMI,baseline BMI,prenatal BMI,TG,LDL,FPG,HbA1c,FINS,HOMA-IR,and negatively correlated with HDL(P<0.05).After correcting for age,BMI,glycolipid metabolism index and HOMA-IR,CTRP6 in early pregnancy remained an independent factor in the development of GDM.Conclusion Elevated serum CTRP6 in early pregnancy is associated with GDM and is an independent risk factor for GDM.