OBJECTIVES: To investigate the impact of prenatal fear stress on placental amino acid transport and emotion and cognition development in offspring rats. METHODS: Thirty pregnant Wistar rats were randomized equally into control and fear stress (induced using an observational foot shock model) groups. In each group, placental and serum samples were collected from 6 dams on gestational day 20, and the remaining rats delivered naturally and the offspring rats were raised under the same conditions until 8 weeks of age. Emotional and cognitive outcomes of the offspring rats were assessed with behavioral tests, and placental structure was examined using HE staining. Bioinformatics analysis was used to identify differentially expressed placental transporter genes under fear stress. The expressions of system A and system L amino acid transporters, along with other specialized transporters, were detected using qRT-PCR and Western blotting. Fetal serum amino acid concentrations were determined by HPLC. The correlations between fetal amino acid levels and behavioral outcomes of the offspring rats were analyzed. RESULTS: The dams with fear stress showed reduced open-field activity and increased freezing behavior with significantly decreased placental weight, fetal weight, and fetal-to-placental ratio. Bioinformatics analysis revealed 28 differentially expressed transporter genes involved mainly in amino acid transport. In the fear stress group, fetal serum amino acid levels were significantly lowered and Slc38a1, Slc43a1, Slc43a2, Slc7a8, Slc6a6, Slc1a1 and Slc6a9 mRNA and protein expressions were all downregulated. The offspring rats in fear stress group exhibited decreased novel object preference and spontaneous alternation with reduced open arm exploration and increased immobility in emotional tests. Lower early-life amino acid levels was found to correlate with impaired adult cognition. CONCLUSIONS Prenatal fear stress in rats impairs placental amino acid transporter expression and reduces fetal serum amino acid levels, potentially contributing to long-term cognitive deficits in the offspring rats.
Animals ; Female ; Pregnancy ; Placenta/metabolism* ; Fear ; Rats ; Rats, Wistar ; Cognition ; Prenatal Exposure Delayed Effects ; Stress, Psychological ; Amino Acids/blood* ; Amino Acid Transport Systems/metabolism*

•A strategy for in situ metabolically synthesized active drug-based probes was proposed.•The potential purgative targets of SA were successfully hooked and identified.•The work provided a new insight for studying the direct targets of unstable active drugs.

Objective To investigate the common molecular features of immunothrombosis, thus enhancing the comprehension of thrombosis triggered by immune and inflammatory responses and offering crucial insights for identifying potential diagnostic and therapeutic targets. Methods Differential gene expression analysis and functional enrichment analysis were conducted on datasets of systemic lupus erythematosus (SLE) and venous thromboembolism (VTE). The intersection of differentially expressed genes in SLE and VTE with those of neutrophil extracellular traps (NET) yielded cross-talk genes (CG) for SLE-NET and VTE-NET interaction. Further analysis included functional enrichment and protein-protein interaction (PPI) network assessments of these CG to identify hub genes. Venn diagrams and receiver operating characteristic (ROC) curve analysis were employed to pinpoint the most effective shared diagnostic CG, which were validated using a graft-versus-host disease (GVHD) dataset. Results Differential expression genes in SLE and VTE were associated with distinct biological processes, whereas SLE-NET-CG and VTE-NET-CG were implicated in pathways related to leukocyte migration, inflammatory response, and immune response. Through PPI network analysis, several hub genes were identified, with matrix metalloproteinase 9 (MMP9) and S100 calcium-binding protein A12 (S100A12) emerging as the best shared diagnostic CG for SLE (AUC: 0.936 and 0.832) and VTE (AUC: 0.719 and 0.759). Notably, MMP9 exhibited good diagnostic performance in the GVHD dataset (AUC: 0.696). Conclusion This study unveils the common molecular features of SLE, VTE, and NET, emphasizing MMP9 and S100A12 as the optimal shared diagnostic CG, thus providing valuable evidence for the diagnosis and therapeutic strategies related to immunothrombosis. Additionally, the expression of MMP9 in GVHD highlights its critical role in the risk of VTE associated with immune system disorders.
Humans ; Computational Biology/methods* ; Lupus Erythematosus, Systemic/immunology* ; Protein Interaction Maps/genetics* ; Venous Thromboembolism/therapy* ; Matrix Metalloproteinase 9/genetics* ; Extracellular Traps/metabolism* ; Gene Regulatory Networks ; Thrombosis/immunology* ; Graft vs Host Disease/genetics* ; Gene Expression Profiling

Esculetin, a natural dihydroxy coumarin derived from the Chinese herbal medicine Cortex Fraxini, has demonstrated significant pharmacological activities, including anticancer properties. Ferroptosis, an iron-dependent form of regulated cell death, has garnered considerable attention due to its lethal effect on tumor cells. However, the exact role of ferroptosis in esculetin-mediated anti-hepatocellular carcinoma (HCC) effects remains poorly understood. This study investigated the impact of esculetin on HCC cells both in vitro and in vivo. The findings indicate that esculetin effectively inhibited the growth of HCC cells. Importantly, esculetin promoted the accumulation of intracellular Fe²⁺, leading to an increase in ROS production through the Fenton reaction. This event subsequently induced lipid peroxidation (LPO) and triggered ferroptosis within the HCC cells. The occurrence of ferroptosis was confirmed by the elevation of malondialdehyde (MDA) levels, the depletion of glutathione peroxidase (GSH-Px) activity, and the disruption of mitochondrial morphology. Notably, the inhibitor of ferroptosis, ferrostatin-1 (Fer-1), attenuated the anti-tumor effect of esculetin in HCC cells. Furthermore, the findings revealed that esculetin inhibited the Nrf2-xCT/GPx4 axis signaling in HCC cells. Overexpression of Nrf2 upregulated the expression of downstream SLC7A11 and GPX4, consequently alleviating esculetin-induced ferroptosis. In conclusion, this study suggests that esculetin exerts an anti-HCC effect by inhibiting the activity of the Nrf2-xCT/GPx4 axis, thereby triggering ferroptosis in HCC cells. These findings may contribute to the potential clinical use of esculetin as a candidate for HCC treatment.
Umbelliferones/administration & dosage* ; Ferroptosis/drug effects* ; Carcinoma, Hepatocellular/physiopathology* ; NF-E2-Related Factor 2/genetics* ; Humans ; Liver Neoplasms/physiopathology* ; Phospholipid Hydroperoxide Glutathione Peroxidase/genetics* ; Animals ; Cell Line, Tumor ; Mice ; Amino Acid Transport System y+/genetics* ; Mice, Inbred BALB C ; Male ; Signal Transduction/drug effects* ; Lipid Peroxidation/drug effects* ; Reactive Oxygen Species/metabolism* ; Mice, Nude

Clinical trials have demonstrated that kilohertz-frequency transcutaneous spinal cord stimulation (TSCS) can be used to facilitate the recovery of sensory-motor function for patients with spinal cord injury, whereas the neural mechanism of TSCS is still undetermined so that the choice of stimulation parameters is largely dependent on the clinical experience. In this paper, a finite element model of transcutaneous spinal cord stimulation was used to calculate the electric field distribution of human spinal cord segments T ₁₂ to L ₂, whereas the activation thresholds of spinal fibers were determined by using a double-cable neuron model. Then the variation of activation thresholds was obtained by varying the carrier waveform, the interphase delay, the modulating frequency, and the modulating pulse width. Compared with the sinusoidal carrier, the usage of square carrier could significantly reduce the activation threshold of dorsal root (DR) fibers. Moreover, the variation of activation thresholds was no more than 1 V due to the varied modulating frequency and decreases with the increased modulating pulse width. For a square carrier at 10 kHz modulated by rectangular pulse with the frequency of 50 Hz and the pulse width of 1 ms, the lowest activation thresholds of DR fibers and dorsal column fibers were 27.6 V and 55.8 V, respectively. An interphase delay of 5 μs was able to reduce the activation thresholds of the DR fibers to 20.1 V. The simulation results can lay a theoretical foundation on the selection of TSCS parameters in clinical trials.
Humans ; Spinal Cord Stimulation/methods* ; Nerve Fibers/physiology* ; Finite Element Analysis ; Spinal Cord/physiology* ; Computer Simulation ; Spinal Cord Injuries/physiopathology* ; Lumbosacral Region ; Lumbar Vertebrae ; Transcutaneous Electric Nerve Stimulation/methods* ; Models, Neurological

BACKGROUND:Hydrogels have become a research hotspot due to their unique advantages in the biomedical field due to their superior mechanical and biological properties.At present,related research involves tissue engineering,wound dressing and so on. OBJECTIVE:To review the advantages and properties of hydrogels and the research progress of their application in the repair of oral and maxillofacial defects,discuss the current limitations and challenges of hydrogels in application and promotion,and provide new ideas for future research directions. METHODS:Relevant literature was searched in PubMed,CNKI,and WanFang database by computer.The search terms were"hydrogel,oral and maxillofacial defects,mechanical properties,tissue engineering,wound dressing"in Chinese and"hydrogel,oral and maxillofacial defects,mechanical properties,guided tissue regeneration,wound dressing"in English.Preliminary screening was carried out by reading titles and abstracts,and articles not related to the topic of the article were excluded.According to the inclusion and exclusion criteria,108 articles were finally included for the result analysis. RESULTS AND CONCLUSION:(1)The hydrogel has good biological activity,mechanical controllability,and stimulation response.(2)Polymer,metal,and ceramic hydrogel composites have appropriate mechanical properties,biodegradability,and controlled release rate,which are suitable for maxillofacial bone tissue engineering.(3)Fibrin-based hydrogel could fill the hollow nerve conduit through the nerve defect area and promote the regeneration and growth of axons to restore the function of maxillofacial nerve.(4)Controlling the interaction between nanomaterials and hydrogels can improve the formation of muscle fiber oriented structure to promote maxillofacial muscle tissue regeneration.(5)Polysaccharide hydrogel has gradually become the first choice for repairing irregular periodontal defects due to its ability to control drug delivery,carry bioactive molecules,and combine with other materials to produce the best scaffold matching the extracellular matrix.(6)Calcium phosphate or calcium carbonate-based hydrogels can be used to fill irregular or fine tissue defects and remineralize hard tissues.The self-assembled hydrogels are simple to prepare and have good biological activity.(7)Salivary gland-derived extracellular matrix-like gel is expected to participate in the treatment of many salivary gland diseases.(8)Hydrogels can be used as wound dressings in combination with biological adhesives,acellular biomaterials,antimicrobials,antioxidants,or stem cells to treat various wounds.(9)Fibrin-based hydrogel has the most potential in the repair of oral and maxillofacial defects.It has excellent biocompatibility,flexibility,and plasticity.It can combine with cells,extracellular matrix proteins,and various growth factors,and promote the osteogenic differentiation of mesenchymal stem cells,axon regeneration and growth,angiogenesis,myotube differentiation,salivary gland tissue regeneration,and periodontal tissue regeneration.It has a broad prospect in the repair of oral and maxillofacial defects.However,its therapeutic effect depends on the function of the substance carried.The complex preparation process,its safety and long-term efficacy,and the special anatomical oral and maxillofacial structure is the problem that hinders its promotion,which also provides directions for future research.

BACKGROUND:This study provided insight into the molecular mechanisms by which exogenous basic fibroblast growth factor(bFGF)promotes wound healing. OBJECTIVE:To investigate the effect of exogenous bFGF on macrophage phenotype transition and granulation regeneration during wound repair in rats. METHODS:(1)In vitro experiment:Cells were divided into normal control group,low-dose bFGF group,high-dose bFGF group,and bFGF+valproic acid group.100 and 200 μg/L bFGF was added into the cell culture medium of low-dose bFGF group and high-dose bFGF group,respectively,while 200 μg/L bFGF and 20 mmol/L valproic acid were added into the cell culture medium of valproic acid group.EdU test,scratch test and tubule formation test were used to detect the effects of bFGF on proliferation,migration and angiogenesis of human umbilical vein endothelial cells.(2)In vivo experiment:Sprague-Dawley rats were randomly divided into model group,low-dose bFGF group,high-dose bFGF group and bFGF+valproic acid group.The open wound model of full-thickness skin defect was established in low-dose bFGF group,high-dose bFGF group and bFGF+valproic acid group.Rats in the low-and high-dose bFGF groups were given 100 and 200 μg/L bFGF through subcutaneous injection,while those in the bFGF+valproic acid group received subcutaneous injection of 200 μg/L bFGF and intraperitoneal injection of 10 mg/kg valproic acid.The wound healing rate of rats was detected at 7 and 14 days of administration.TUNEL was used to detect the apoptosis of cells in wound tissue.Enzyme linked immunosorbent assay was used to detect the serum levels of malondialdehyde,superoxide dismutase,tumor necrosis factor-α and interleukin-10.Immunofluorescence detection was conducted to detect the phenotypic transformation of macrophages in wound tissue.Immunohistochemistry was used to detect the expression of proliferating cell nuclear antigen,platelet endothelial cell adhesion molecule-1(CD31)and vascular endothelial growth factor in wound tissue.Western blot was used to detect the expression of Notch1 and Jagged1 in wound tissue. RESULTS AND CONCLUSION:(1)Compared with the normal control group,bFGF could significantly promote the proliferation,migration and angiogenesis of human umbilical vein endothelial cells in a dose-dependent manner.(2)Compared with the model group,bFGF could significantly promote wound healing,downregulate the rate of apoptosis in wound tissue,decrease the levels of malondialdehyde and tumor necrosis factor-α in serum,increase the levels of superoxide dismutase and interleukin-10,promote the conversion of macrophages to type M2 in wound tissue,upregulate the expression of proliferating cell nuclear antigen,CD31 and vascular endothelial growth factor in wound tissue,and inhibit the expression of Notch1 and Jagged1 in a dose-dependent manner.Valproic acid could partially reverse the promoting effect of bFGF on wound healing.To conclude,bFGF can significantly promote wound healing and granulation regeneration and induce the conversion of macrophages to M2,which may be related to the regulation of Notch1/Jagged1 signaling pathway.

Objective:To explore the impacts of different frequencies of orthogonal image-guided verification on set-up error correction and the reference values of planning target volume (PTV) margins in postoperative radiotherapy for breast cancer, in order to provide recommendations of the verification frequency in clinical practice.Methods:A total of 80 breast cancer patients who received postoperative intensity-modulated radiotherapy for breast cancer at the Affiliated Union Hospital of Fujian Medical University from January 2021 to January 2022 were enrolled. Orthogonal image-guided verification was conducted before each radiation treatment to determine initial and residual set-up errors. The error data were statistically analyzed by categorizing patients into groups A, B, C, D, E, and F, based on assumed verification frequencies (daily, every 2, 3, 4, and 5 d, and no correction). The magnitude, distribution, and differences of set-up errors of various groups were analyzed, and the PTV margins were calculated using a reference formula.Results:The collected initial set-up errors of the 80 patients were (3.49±3.43), (2.87±2.88), and (2.75±2.35) mm, in x, y, and z directions, respectively. The residual set-up errors decreased gradually with increasing verification frequency. In the case of daily image-guided verification, the residual set-up errors in x, y, and z directions decreased to (1.63±0.90), (1.63±0.93), and (1.55±0.90)mm, respectively. The reference values of PTV margins calculated under different verification frequencies decreased with an increase in the verification frequency. Under daily verification, the reference values of PTV margins calculated based on set-up errors decreased from initial 6.60, 6.29, and 4.22 mm (without correction) to 1.27, 1.37, and 1.28 mm, respectively. Differences in the reference values under verification frequencies every 3, 4, and 5 d were less than 0.81 mm. Conclusions:Daily image-guided verification (including correction) can effectively reduce set-up errors in image-guided radiotherapy for breast cancer. The set-up errors differ under varying verification frequencies, with a higher frequency corresponding to better correction effects and smaller PTV margins required.

Immune thrombocytopenia (ITP) is a disease characterized by an imbalance between immune-mediated platelet destruction and production. Its clinical management has long been confronted with core challenges such as insufficient diagnostic specificity, significant individual differences in treatment response, and difficulties in prognosis assessment. In recent years, researches have systematically revealed the multi-dimensional pathological mechanisms of this disease: in terms of immunology, autoantibodies mediate platelet clearance, and the imbalance of T cell subsets exacerbates the disorder of immune homeostasis. Proteomic techniques have identified plasma markers such as matrix metallopeptidase 9 and CXCL11. Genomic studies have revealed that miR-199a-5p, lncRNA MALAT1, etc., are involved in the pathogenesis by regulating the immune-thrombopoiesis axis. Metabolism research has shown features such as lipid metabolism disorders, abnormal tryptophan pathways in the bone marrow, and excessive T cell glycolysis. Although multi-omics techniques have promoted the progress of biomarker research, the clinical translation of biomarkers is still limited by high heterogeneity, insufficient validation, and lack of standardization. In the future, it is expected that through the integration of multi-omics data and the development of artificial intelligence algorithms, combined with single-cell technologies to analyze the heterogeneity of the immune microenvironment, and multi-dimensional prediction models can be constructed to optimize precision diagnosis and treatment strategies.

Objective:To investigate the clinical-epidemiological characteristics of connective tissue diseases (CTD) complicated with pulmonary hypertension in Shanxi province from 2018 to 2021.Methods:This was a cross-sectional study. Data of CTD patients with pulmonary hypertension from 2018 to 2021 were collected from the Shanxi Provincial Health Statistics Direct Reporting System based on inpatient medical records. The demographic and clinical data of patients with different CTD types were analyzed.Results:A total of 1 697 CTD patients with pulmonary hypertension were included, among whom there were 451 cases (26.58%) of Sj?gren′s syndrome, 392 cases (23.10%) of systemic lupus erythematosus, 289 cases(17.03%) of systemic sclerosis, 109 cases (6.42%) of mixed CTD, 69 cases (4.07%) of Takayasu arteritis, and 387 cases (22.80%) of other CTD. The majority of patients were female (1 410 (83.09%)), and 783 cases (46.14%) were aged between 41 and 65 years, and 6 cases (0.35%) were performed right heart catheterization. The prevalence of CTD with pulmonary hypertension increased from 0.06/10 4 in 2018 to 0.20/10 4 in 2021. There were significant differences in the severity of pulmonary hypertension, New York Heart Association (NYHA) functional class, length of hospital stay, medical costs, and clinical outcomes among patients with different CTD subtypes (all P<0.001). Patients with systemic sclerosis had the highest proportion of NYHA functional class Ⅲ/Ⅳ(65.1%(188/289)), the longest length of hospital stays (13 (9, 18) days), the highest average medical costs (13 622.67 (8 636.38, 20 597.75) ￥(RMB)), and the lowest rate of improvement and discharge (51.90%(150/289)). Conclusions:Between 2018 and 2021, Shanxi province, where CTD is more common in Sj?gren′s syndrome, has a high proportion of women, a high proportion of people aged 41-65 years, and a low prevalence of right ventricular catheterization in patients with CTD complicated with pulmonary hypertension. The prevalence of CTD complicated with pulmonary hypertension shows a rising trend in Shanxi province from 2018 to 2021, while patients with systemic sclerosis exhibit the most severe cardiac impairment and poorer clinical outcomes compared to other subtypes.