Background: Diabetic pain patients have increased pain at night. Exosomes can relieve neuropathic pain. This study aimed to investigate the efficacy of exosome administration at different time points in relieving diabetic neuropathic pain (DNP) in rats. Methods: M2 macrophages from bone marrow were induced in mice and exosomes were extracted. A diabetic rat model was induced using streptozotocin, with the mechanical withdrawal threshold (MWT) of the rats beingmeasured at ≤ 80% of the basal value after 14 days, indicating successful construction of the DNP rat model.Exosomes were administered on three consecutive days at ZT0 (zeitgeber time) and ZT12. Parameters including blood glucose levels, body weight, MWT, and thermal withdrawal latency (TWL) were assessed in the rats. The lumbar spinal cord of rats was examined on days 21 and 28 to measure inflammatory factors and observe the expression of M1 and M2 microglia. Furthermore, microglia were exposed to lipopolysaccharide (LPS) and LPS + exosomes in a controlled in vitro setting to assess alterations in microglia phenotype involving the NF-kB p65 andIKBα inflammatory signaling pathways. Results: The findings revealed that administration of exosomes during the rat resting period at ZT12 resulted in increased MWT and TWL, as well as a shift in microglia polarization towards the M2 phenotype. In vitro analysis indicated that exosomes influenced microglia polarization and suppressed the phosphorylation of NF-kB p65 andIKBα.  Conclusions Temporal therapy with exosomes effectively reduces pain in DNP rats by polarizing microglia andaffecting NF-kB p65 and IKBα signaling pathways.

Background: Diabetic pain patients have increased pain at night. Exosomes can relieve neuropathic pain. This study aimed to investigate the efficacy of exosome administration at different time points in relieving diabetic neuropathic pain (DNP) in rats. Methods: M2 macrophages from bone marrow were induced in mice and exosomes were extracted. A diabetic rat model was induced using streptozotocin, with the mechanical withdrawal threshold (MWT) of the rats beingmeasured at ≤ 80% of the basal value after 14 days, indicating successful construction of the DNP rat model.Exosomes were administered on three consecutive days at ZT0 (zeitgeber time) and ZT12. Parameters including blood glucose levels, body weight, MWT, and thermal withdrawal latency (TWL) were assessed in the rats. The lumbar spinal cord of rats was examined on days 21 and 28 to measure inflammatory factors and observe the expression of M1 and M2 microglia. Furthermore, microglia were exposed to lipopolysaccharide (LPS) and LPS + exosomes in a controlled in vitro setting to assess alterations in microglia phenotype involving the NF-kB p65 andIKBα inflammatory signaling pathways. Results: The findings revealed that administration of exosomes during the rat resting period at ZT12 resulted in increased MWT and TWL, as well as a shift in microglia polarization towards the M2 phenotype. In vitro analysis indicated that exosomes influenced microglia polarization and suppressed the phosphorylation of NF-kB p65 andIKBα.  Conclusions Temporal therapy with exosomes effectively reduces pain in DNP rats by polarizing microglia andaffecting NF-kB p65 and IKBα signaling pathways.

Background: Diabetic pain patients have increased pain at night. Exosomes can relieve neuropathic pain. This study aimed to investigate the efficacy of exosome administration at different time points in relieving diabetic neuropathic pain (DNP) in rats. Methods: M2 macrophages from bone marrow were induced in mice and exosomes were extracted. A diabetic rat model was induced using streptozotocin, with the mechanical withdrawal threshold (MWT) of the rats beingmeasured at ≤ 80% of the basal value after 14 days, indicating successful construction of the DNP rat model.Exosomes were administered on three consecutive days at ZT0 (zeitgeber time) and ZT12. Parameters including blood glucose levels, body weight, MWT, and thermal withdrawal latency (TWL) were assessed in the rats. The lumbar spinal cord of rats was examined on days 21 and 28 to measure inflammatory factors and observe the expression of M1 and M2 microglia. Furthermore, microglia were exposed to lipopolysaccharide (LPS) and LPS + exosomes in a controlled in vitro setting to assess alterations in microglia phenotype involving the NF-kB p65 andIKBα inflammatory signaling pathways. Results: The findings revealed that administration of exosomes during the rat resting period at ZT12 resulted in increased MWT and TWL, as well as a shift in microglia polarization towards the M2 phenotype. In vitro analysis indicated that exosomes influenced microglia polarization and suppressed the phosphorylation of NF-kB p65 andIKBα.  Conclusions Temporal therapy with exosomes effectively reduces pain in DNP rats by polarizing microglia andaffecting NF-kB p65 and IKBα signaling pathways.

Background: Diabetic pain patients have increased pain at night. Exosomes can relieve neuropathic pain. This study aimed to investigate the efficacy of exosome administration at different time points in relieving diabetic neuropathic pain (DNP) in rats. Methods: M2 macrophages from bone marrow were induced in mice and exosomes were extracted. A diabetic rat model was induced using streptozotocin, with the mechanical withdrawal threshold (MWT) of the rats beingmeasured at ≤ 80% of the basal value after 14 days, indicating successful construction of the DNP rat model.Exosomes were administered on three consecutive days at ZT0 (zeitgeber time) and ZT12. Parameters including blood glucose levels, body weight, MWT, and thermal withdrawal latency (TWL) were assessed in the rats. The lumbar spinal cord of rats was examined on days 21 and 28 to measure inflammatory factors and observe the expression of M1 and M2 microglia. Furthermore, microglia were exposed to lipopolysaccharide (LPS) and LPS + exosomes in a controlled in vitro setting to assess alterations in microglia phenotype involving the NF-kB p65 andIKBα inflammatory signaling pathways. Results: The findings revealed that administration of exosomes during the rat resting period at ZT12 resulted in increased MWT and TWL, as well as a shift in microglia polarization towards the M2 phenotype. In vitro analysis indicated that exosomes influenced microglia polarization and suppressed the phosphorylation of NF-kB p65 andIKBα.  Conclusions Temporal therapy with exosomes effectively reduces pain in DNP rats by polarizing microglia andaffecting NF-kB p65 and IKBα signaling pathways.

Background: Diabetic pain patients have increased pain at night. Exosomes can relieve neuropathic pain. This study aimed to investigate the efficacy of exosome administration at different time points in relieving diabetic neuropathic pain (DNP) in rats. Methods: M2 macrophages from bone marrow were induced in mice and exosomes were extracted. A diabetic rat model was induced using streptozotocin, with the mechanical withdrawal threshold (MWT) of the rats beingmeasured at ≤ 80% of the basal value after 14 days, indicating successful construction of the DNP rat model.Exosomes were administered on three consecutive days at ZT0 (zeitgeber time) and ZT12. Parameters including blood glucose levels, body weight, MWT, and thermal withdrawal latency (TWL) were assessed in the rats. The lumbar spinal cord of rats was examined on days 21 and 28 to measure inflammatory factors and observe the expression of M1 and M2 microglia. Furthermore, microglia were exposed to lipopolysaccharide (LPS) and LPS + exosomes in a controlled in vitro setting to assess alterations in microglia phenotype involving the NF-kB p65 andIKBα inflammatory signaling pathways. Results: The findings revealed that administration of exosomes during the rat resting period at ZT12 resulted in increased MWT and TWL, as well as a shift in microglia polarization towards the M2 phenotype. In vitro analysis indicated that exosomes influenced microglia polarization and suppressed the phosphorylation of NF-kB p65 andIKBα.  Conclusions Temporal therapy with exosomes effectively reduces pain in DNP rats by polarizing microglia andaffecting NF-kB p65 and IKBα signaling pathways.

OBJECTIVE: To explore the significance of thrombus biomarkers in evaluating the progression of immunoglobulin A vasculitis (IgAV) in children. METHODS: A total of 193 children who were diagnosed as IgAV from September 2021 to June 2023 in the Children's Hospital of Soochow University were enrolled. The levels of plasma thrombomodulin (TM), thrombin-antithrombin complex (TAT), plasmin-α2-plasmin inhibitor complex (PIC), tissue plasminogen activator-plasminogen activator inhibitor-1 complex (t-PAIC) and D-dimer (D-D) were analyzed retrospectively. And, 140 healthy children were selected as controls during the same period. The receiver operating characteristic (ROC) curves were drawn to analyze the role of thrombus parameters in estimating the progression of IgAV in children. Univariate and multivariate logistic regression analysis were used to assess the independent risk factors influencing the progression of pediatric IgAV in acute phase. RESULTS: The levels of D-D, TAT, PIC and t-PAIC in plasma of IgAV group were higher than those in control group (all P <0.001). The levels of D-D, TAT and PIC in acute phase children were significantly higher than those in non acute phase children (all P <0.001), while the levels of kidney injury related indicators such as 24h-UTP, urine albumin/creatinine ratio, positive urinary blood on dipstick, serum creatinine and cystatin C were lower (all P <0.05). ROC analysis showed that the area under curve (AUC) of PIC was 0.743 when the cut-off value was 0.93 μg/ml with 71.8% sensitivity and 78.3% specificity, while the AUC of D-D was 0.756 when the cut-off value was 550.0 μg/L with 81.3% sensitivity and 73.4% specificity. Univariate and multivariate logistic regression analysis showed that PIC≥0.93 μg/ml (OR =4.64, P =0.012) and D-D≥550.0 μg/L (OR =3.60, P =0.035) were the independent risk factors for the progression of IgAV in acute phase. CONCLUSION The pediatric patients with IgAV have shown hyperfibrinolysis in the acute stage. Furthermore, the levels of PIC and D-D should be of diagnostic value for evaluating the progression of IgAV in the acute phase.
Humans ; Biomarkers/blood* ; Child ; Fibrin Fibrinogen Degradation Products ; Retrospective Studies ; Thrombosis ; Female ; Male ; Disease Progression ; Thrombomodulin/blood* ; ROC Curve ; Vasculitis/blood* ; Antithrombin III ; Plasminogen Activator Inhibitor 1/blood* ; IgA Vasculitis/blood* ; alpha-2-Antiplasmin ; Adolescent ; Child, Preschool ; Fibrinolysin

OBJECTIVE: To evaluate the efficacy and safety of denosumab in the treatment of prostate cancer with bone metastases. METHODS: Relevant studies were retrieved from PubMed, EMBASE, Cochrane, Web of Science, Sinomed , CNKI and Wanfang databases. The Cochrane risk-of-bias assessment tool was used to evaluate the quality of included studies, and relevant data were extracted. meta-analysis was performed using RevMan 5.4 and RStudio software, and forest plots were generated. RESULTS: Six randomized controlled trials (RCTs) were included. Compared with the control group, denosumab significantly reduced the risk of skeletal-related events (HR=0.78, 95% CI: 0.62-0.93). In terms of safety, denosumab did not increase the risk of total adverse events, severe adverse events and the adverse events higher than CTC grade 3. CONCLUSION Denosumab can delay the time to first skeletal-related event with good safety. However, due to the limitations of this study, further high-quality, large-sample, multicenter RCTs are needed to confirm these findings.
Humans ; Denosumab/therapeutic use* ; Bone Neoplasms/drug therapy* ; Prostatic Neoplasms/drug therapy* ; Male ; Randomized Controlled Trials as Topic ; Bone Density Conservation Agents/therapeutic use*

OBJECTIVE: To investigate the anti-tumor effects of cinobufacini (CINO) on hepatocellular carcinoma (HCC) induced by des-gamma-carboxy-prothrombin (DCP) and to uncover the underlying mechanisms. METHODS: The inhibitory effect of CINO on HCC cell proliferation was evaluated using the cell counting kit-8 method, and the apoptosis rate was quantified using flow cytometry. Immunofluorescence and Western blot analyses were used to investigate the differential expression of proteins associated with cell growth, apoptosis, migration, and invasion pathways after CINO treatment. The therapeutic potential of CINO for HCC was confirmed, and the possibility of combining cinobufacini with c-Met inhibitor for the treatment of primary HCC was further validated by in vivo experiments. RESULTS: Under the induction of DCP, CINO inhibited the activity of HCC cells, induced apoptosis, and inhibited migration and invasion. Upon the induction of DCP, CINO regulated c-Met activation and the activation of the phosphatidylinositol-3 kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways. In a mouse model of HCC, CINO exhibited significant antitumor effects by inhibiting the phosphorylation of c-Met and the downstream PI3K/AKT and MEK/ERK pathways in tumor tissues. CONCLUSIONS CINO inhibited HCC cell growth, promoted apoptosis, and suppressed HCC cell invasion and migration by targeting c-Met and PI3K/AKT and MEK/ERK signaling pathways under DCP induction.
Carcinoma, Hepatocellular/drug therapy* ; Proto-Oncogene Proteins c-met/metabolism* ; Liver Neoplasms/drug therapy* ; Signal Transduction/drug effects* ; Animals ; Humans ; Cell Movement/drug effects* ; Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Amphibian Venoms/therapeutic use* ; Cell Line, Tumor ; Neoplasm Metastasis ; Cell Survival/drug effects* ; Proto-Oncogene Proteins c-akt/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Neoplasm Invasiveness ; Mice, Inbred BALB C ; Mice, Nude ; Mice ; Male ; Bufanolides/therapeutic use* ; Protein Precursors ; Prothrombin ; Biomarkers