BACKGROUND: T-cell lymphoblastic lymphoma/acute lymphoblastic leukemia (T-LBL/ALL) is an aggressive form of hematological malignancy associated with poor prognosis in adult patients. Histone deacetylases (HDACs) are aberrantly expressed in T-LBL/ALL and are considered potential therapeutic targets. Here, we investigated the antitumor effect of a novel HDAC inhibitor, chidamide, on T-LBL/ALL. METHODS: HDAC1, HDAC2 and HDAC3 levels in T-LBL/ALL cell lines and patient samples were compared with those in normal controls. Flow cytometry, transmission electron microscopy, and lactate dehydrogenase release assays were conducted in Jurkat and MOLT-4 cells to assess apoptosis and pyroptosis. A specific forkhead box O1 (FOXO1) inhibitor was used to rescue pyroptosis and upregulated gasdermin E (GSDME) expression caused by chidamide treatment. The role of the FOXO1 transcription factor was evaluated by dual-luciferase reporter and chromatin immunoprecipitation assays. The efficacy of chidamide in vivo was evaluated in a xenograft mouse. RESULTS: The expression of HDAC1, HDAC2 and HDAC3 was significantly upregulated in T-LBL/ALL. Cell viability was obviously inhibited after chidamide treatment. Pyroptosis, characterized by cell swelling, pore formation on the plasma membrane and lactate dehydrogenase leakage, was identified as a new mechanism of chidamide treatment. Chidamide triggered pyroptosis through caspase 3 activation and GSDME transcriptional upregulation. Chromatin immunoprecipitation assays confirmed that chidamide led to the increased transcription of GSDME through a more relaxed chromatin structure at the promoter and the upregulation of FOXO1 expression. Moreover, we identified the therapeutic effect of chidamide in vivo . CONCLUSIONS This study suggested that chidamide exerts an antitumor effect on T-LBL/ALL and promotes a more inflammatory form of cell death via the FOXO1/GSDME axis, which provides a novel choice of targeted therapy for patients with T-LBL/ALL.
Humans ; Pyroptosis/drug effects* ; Forkhead Box Protein O1/genetics* ; Aminopyridines/pharmacology* ; Animals ; Mice ; Benzamides/pharmacology* ; Cell Line, Tumor ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Phosphate-Binding Proteins/metabolism* ; Histone Deacetylase Inhibitors/pharmacology* ; Jurkat Cells ; Histone Deacetylases/metabolism* ; Apoptosis/drug effects* ; Gasdermins

This study aimed to explore the therapeutic mechanisms of Colquhounia Root Tablets(CRT) in treating diabetic kidney disease(DKD) by integrating biomolecular network mining with animal model verification. By analyzing clinical transcriptomics data, an interaction network was constructed between candidate targets of CRT and DKD-related genes. Based on the topological eigenvalues of network nodes, 101 core network targets of CRT against DKD were identified. These targets were found to be closely related to multiple pathways associated with type 2 diabetes, immune response, and metabolic reprogramming. Given that immune-inflammatory imbalance driven by metabolic reprogramming is one of the key pathogenic mechanisms of DKD, and that many core network targets of CRT are involved in this pathological process, receptor for advanced glycation end products(RAGE)-reactive oxygen species(ROS)-phosphatidylinositol 3-kinase(PI3K)-protein kinase B(AKT)-nuclear factor-κB(NF-κB)-NOD-like receptor family pyrin domain containing 3(NLRP3) signaling axis was selected as a candidate target for in-depth research. Further, a rat model of DKD induced by a high-sugar, high-fat diet and streptozotocin was established to evaluate the pharmacological effects of CRT and verify the expression of related targets. The experimental results showed that CRT could effectively correct metabolic disturbances in DKD, restore immune-inflammatory balance, and improve renal function and its pathological changes by inhibiting the activation of the RAGE-ROS-PI3K-AKT-NF-κB-NLRP3 signaling axis. In conclusion, this study reveals that CRT alleviates the progression of DKD through dual regulation of metabolic reprogramming and immune-inflammatory responses, providing strong experimental evidence for its clinical application in DKD.
Animals ; Diabetic Nephropathies/metabolism* ; Receptor for Advanced Glycation End Products/genetics* ; NF-kappa B/genetics* ; Signal Transduction/drug effects* ; Rats ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Proto-Oncogene Proteins c-akt/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Phosphatidylinositol 3-Kinases/genetics* ; Reactive Oxygen Species/metabolism* ; Humans ; Plant Roots/chemistry* ; Rats, Sprague-Dawley ; Tablets/administration & dosage*

OBJECTIVE: To explore clinical efficacy of membrane-induced technique combined with gastrocnemius muscle flap transposition in treating traumatic osteomyelitis of the upper tibia. METHODS: A retrospective analysis was conducted on 7 patients with traumatic osteomyelitis of the upper tibia who were treated with membrane-induced technique combined with gastrocnemius muscle flap transposition from January 2022 to December 2023. Among them, there were 4 males and 3 females; aged from 29 to 57 years old; 4 patients were treated after open fracture, 2 patients were treated after closed fracture, and 1 patient was treated after scalding; the courses of disease ranges from 2 weeks to 8 years; sinus tracts were present in all patients, and the lesion range of the tibia ranged from 5 to 9 cm. The results of deep tissue bacterial culture showed that 2 patients were negative, 3 patients were staphylococcus aureus, 1 patient was methicillin-resistant staphylococcus aureus, and 1 patient was pseudomonas aeruginosa and 1 patient was klebsiella pneumoniae. After debridement, the range of bone defect ranged from 8 to 12 cm, and the cortical defect accounted for approximately 30% of the circumference. The area of soft tissue defect ranged from 8.0 cm×2.0 cm to 10.0 cm×6.0 cm. At the first stage, vancomycin-loaded/meropenem/gentamicin-loaded bone cement was implanted. The gastrocnemius muscle flap was repositioned to cover the wound surface and free skin grafting was performed. After an interval of 7 to 10 weeks, the stageⅡsurgery was performed to remove bone cement. Autologous iliac bone mixed with vancomycin/gentamicin and calcium sulfate artificial bone was transplanted, and the wound was sutured. One patient retained the original internal plants, one patient removed the internal plants and replaced them with steel plate external fixation, one patient replaced the internal plants and added steel plate external fixation, and three patients were simply fixed with steel plate external fixation. One year after operation, the recovery of knee joint and ankle joint functions was evaluated by using Hospital for Special Surgery (HSS) knee joint score and Kofoed ankle joint function score respectively. RESULTS: All patients had their wounds closed simultaneously with bone cement implantation and healed well. All patients were followed up for 12 to 17 months after operation, and satisfactory bone healing was achieved at 6 months after stageⅡsurgery. Twelve months after operation, all patients had good bone healing without obvious limping was observed when walking. At 12 months after operation HSS knee joint score ranged from 93 to 100 points, and Kofoed ankle function score ranged from 96 to 100 points. CONCLUSION For traumatic osteomyelitis of the upper tibia, a staged treatment plan combining membrane-induced technique and gastrocnemius flap transposition on the basis of thorough debridement could safely cover the wound surface, effectively control bone infection and achieve satisfactory bone healing, without adverse effects on limb function.
Humans ; Male ; Female ; Middle Aged ; Osteomyelitis/surgery* ; Adult ; Surgical Flaps ; Retrospective Studies ; Tibia/injuries* ; Muscle, Skeletal/surgery*

Objective To investigate the predictive value of heparin-binding protein(HBP)in Kawasaki disease complicated with bacterial infection.Methods A total of 148 children with Kawasaki disease in this hospital from April 2021 to June 2022 were selected as Kawasaki disease group.According to the results of pathogen detection during hospitalization,the children were divided into three subgroups:Mycoplasma pneu-moniae group(36 cases),bacteria group(19 cases),and non-infection group(93 cases).In addition,35 chil-dren with fever and upper respiratory tract infection were randomly selected as the case control group.HBP and other inflammatory markers[white blood cell count(WBC),neutrophil percentage(NE％),procalcitonin(PCT),C reactive protein(CRP),interleukin-6(IL-6)]in each group were detected and analyzed.Receiver operating characteristic(ROC)curve was used to analyze the predictive value of HBP and PCT for bacterial infection in children with Kawasaki disease.Results The levels of HBP,WBC,NE％,CRP and IL-6 in the Ka-wasaki disease group were significantly higher than those in the case control group(P＜0.05),while there was no significant difference in PCT level between the two groups(P＞0.05).The levels of HBP,WBC,NE％,PCT,CRP and IL-6 in children with Kawasaki disease after treatment were significantly lower than those at admission(P＜0.05).The levels of HBP and PCT in the bacterial group were higher than those in the Mycoplasma pneumoniae group and the non-infection group,and the differences were statistically signifi-cant(P＜0.05),while there were no statistically significant differences in WBC,NE％,CRP and IL-6 levels a-mong the three groups(P＞0.05).ROC curve results showed that the area under the curve(AUC)and 95％CI of HBP for predicting bacterial infection in children with Kawasaki disease was 0.77(0.68-0.86),when HBP was 499.65 ng/mL,the sensitivity and specificity were 84.2％and 66.7％,respectively.When PCT was 0.85 ng/mL,the AUC(95％CI)for predicting bacterial infection in children with Kawasaki disease was 0.65(0.52-0.78),and the sensitivity and specificity were 63.2％and 65.9％,respectively.Conclusion HBP is associated with Kawasaki disease,and it has certain predictive value for Kawasaki disease complicated with bacterial infection.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and joint damage, accompanied by the accumulation of plasma cells, which contributes to its pathogenesis. Understanding the genetic alterations occurring during plasma cell differentiation in RA can deepen our comprehension of its pathogenesis and guide the development of targeted therapeutic interventions. Here, our study elucidates the intricate molecular mechanisms underlying plasma cell differentiation by demonstrating that PRDX1 interacts with DOK3 and modulates its degradation by the autophagy-lysosome pathway. This interaction results in the inhibition of plasma cell differentiation, thereby alleviating the progression of collagen-induced arthritis. Additionally, our investigation identifies Salvianolic acid B (SAB) as a potent small molecular glue-like compound that enhances the interaction between PRDX1 and DOK3, consequently impeding the progression of collagen-induced arthritis by inhibiting plasma cell differentiation. Collectively, these findings underscore the therapeutic potential of developing chemical stabilizers for the PRDX1-DOK3 complex in suppressing plasma cell differentiation for RA treatment and establish a theoretical basis for targeting PRDX1-protein interactions as specific therapeutic targets in various diseases.

OBJECTIVE: This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study. METHODS: A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants. RESULTS: Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m ²) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m ²) and obesity (≥ 28.0 kg/m ²) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m ² ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses. CONCLUSION This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans ; Body Mass Index ; China/epidemiology* ; Male ; Female ; Middle Aged ; Prospective Studies ; Rural Population/statistics & numerical data* ; Aged ; Follow-Up Studies ; Adult ; Mortality ; Cause of Death ; Obesity/mortality* ; Overweight/mortality*

Objective:To explore the current status of hospital-acquired rhinosinusitis (HAR) in Neurocritical Care Unit (NCU) patients and to analyze its risk factors.Methods:From January 2021 to December 2022, 819 NCU patients of Nanfang Hospital, Southern Medical University were selected by whole population sampling method, of which 125 patients met the inclusion and exclusion criteria for analysis. Patients were categorized into HAR group ( n=69) and non-HAR group ( n=56) based on the occurrence of HAR. Differences in demographic and clinical data of the two groups of patients were compared. Logistic regression analysis was used to explore the risk factors for the HAR in patients. Results:HAR occurred in 69 NCU patients, with an incidence of 55.2% (69/125) . There were statistically significant differences in gender, smoking history, Glasgow Coma Scale score on admission, whether or not there was pneumonia, whether or not a nasogastric tube was indwelt before the occurrence of HAR, whether or not tracheal intubation was performed before the occurrence of HAR, whether or not mechanical ventilation was conducted before the occurrence of HAR, whether or not tracheotomy was performed, and the length of NCU stay between patients in HAR group and non-HAR group ( P<0.05) . Logistic regression analysis showed that indwelling nasogastric tube before the occurrence of HAR, failure to quit smoking before admission, and prolonged NCU stay were risk factors for HAR ( OR=6.291, 3.976, 1.089; P<0.05) . Conclusions:NCU patients have a high incidence of HAR, and indwelling nasogastric tube, failure to quit smoking before admission, and prolonged NCU stay are risk factors for HAR in NCU patients.

AIM:To investigate the efficacy of Shenxiankang(SXK)in mitigating renal fibrosis in unilateral ureteral obstruction(UUO)mice,and elucidate its regulatory mechanism targeting the differentiation antagonizing non-protein coding RNA(DANCR)/TGF-β1/Smad3 signaling axis.METHODS:Mice were randomly assigned to:normal group(NC),model group(UUO),low,medium and high doses(1 500,3 000 and 4 500 mg·kg-1·d-1)of SXK group,and benazepril(10 mg·kg-1·d-1)group.Chronic kidney disease was modeled via unilateral ureteral ligation.Renal DAN-CR overexpression was induced using tail vein injection coupled with ultrasound microbubble technology.In vitro,human renal tubular epithelial cells(HK-2)were stimulated with TGF-β1;DANCR was either knocked down or overexpressed,followed by SXK intervention in both in vivo and in vitro models.Renal tissues were harvested for pathological assessment.DANCR expression and localization were analyzed using fluorescence in situ hybridization.Fibrosis deposition was evaluat-ed by immunohistochemistry(IHC).Western blot quantified the expression of fibrosis markers(α-SMA,FN)and key components of the TGF-β1/Smad3 signaling axis(p-Smad3,Smad3,TGF-β1).RESULTS:UUO mice exhibited signifi-cant renal tubular dilation.SXK intervention ameliorated renal lesions and reduced fibrosis.In UUO mice with DANCR overexpression,levels of renal fibrosis markers(α-SMA,FN)and TGF-β1/Smad3 signaling axis proteins(p-Smad3,Smad3,TGF-β1)were increased;these effects were reversed by SXK.In vitro,DANCR knockdown decreased the expres-sion of fibrotic proteins/mRNA and TGF-β1/Smad3 signaling axis components.SXK treatment effectively counteracted the fibrotic injury and TGF-β1/Smad3 signaling axis activation induced by DANCR overexpression.CONCLUSION:SXK ef-fectively mitigates renal fibrosis in UUO mice,potentially through regulation of the DANCR/TGF-β1/Smad3 signaling axis.

AIM:To establish methods for the isolation,identification,primary culture and evaluation of gas-tric smooth muscle cells(GSMC)from rat and mouse.METHODS:Thirty SD rats and thirty C57BL/6 mice were random-ly assigned into three groups,with 10 rats or mice in each group.Three parallel experiments were conducted to isolate pri-mary GSMC under aseptic conditions.The isolated cells were identified through morphological observation,immunofluo-rescence and Western blot.Flow cytometry was employed to analyze the purity of the cells.Additionally,trypan blue ex-clusion test was utilized to evaluate the viability of the cells after resuscitation.RESULTS:Isolated rat and mouse GSMC exhibited a fusiform or polygonal morphology.Immunofluorescence and Western blot results demonstrated the expression of α-smooth muscle actin(α-SMA).Flow cytometry showed that the positive expression rate of α-SMA was 99.6%in rat GSMC and 97.4%in mouse GSMC.Moreover,the viability rates of rat and mouse GSMC after cryopreservation were found to be greater than 97%.CONCLUSION:A stable and reliable method for the isolation,culture and evaluation of primary GSMC from rat and mouse has been established.