Xanthine oxidase (XO) is an important therapeutic target for the treatment of hyperuricemia and gout. Based on the previously identified potent XO inhibitor 1, seventeen oxadiazoles and their ring-opening analogues were designed and synthesized via the bioisostere replacement strategy. Among them, compounds 2l, 2n, and 3b showed obvious XO inhibitory activity at the concentration of 10 μmol·L^-1, and compound 3b exhibited an IC₅₀ value of 1.45 μmol·L^-1.

Aim To explore the mechanism of the effect of rosiglitazone(Rsg)on the pancreatic cancer in diabetic mice based on the impact of PPARγ on glu-cose transport and metabolism.Methods A high-fat and high sugar diet combined with STZ was used to construct T2DM model;T2DM mice and normal mice were subcutaneously injected with PANC02 cells to construct a transplanted tumor model.T2DM trans-planted tumor mice and normal transplanted tumor mice were divided into the following groups:Rsg,PPARy inhibitor(PIN-2),rosiglitazone+PPARγ in-hibitor(Rsg+PIN-2),and normal transplanted tumor mice(NDM)and T2DM transplanted tumor mice(DM)were used as control groups,respectively.Tis-sue samples were collected after intervention.Tissue pathological changes were observed by HE staining.The expressions of Ki67 and PCNA proteins were de-tected by immunohistochemistry.Cell apoptosis was detected by TUNEL assay.The expression of PPARγwas detected by immunofluorescence.The expressions of Glucokinase,GLUT2,Nkx6.1,PDX-1RT-PCR were determined by Western blot.Results Rsg could significantly reduce the tumor mass,pathological chan-ges,Ki67 and PCNA expression of transplanted tumors(P＜0.05),increase cell apoptosis and the expression of PPARγ,Glucokinase,GLUT2,Nkx6.1,PDX-1 proteins in NDM and DM mice(P＜0.05).PIN-2 could reverse the indicator changes caused by Rsg in NDM and DM mice.However,compared with NDM mice,the above related indicators of the DM group mice were more sensitive to Rsg and PIN-2.Conclu-sions Compared to non-diabetic pancreatic cancer,rosiglitazone can more sensitively inhibit the prolifera-tion of pancreatic cancer with T2DM,induce apopto-sis,and reprogram the metabolism of pancreatic cancer with T2DM by activating PPA Rγ and altering the ex-pression of glucose and lipid metabolism genes,there-by exerting an anti-cancer effect.

Aim To explore the mechanism and mate-rial basis of Shenkang injection(SKI)in the treatment of renal fibrosis(RF)by bioinformatics and in vitro experiments.Methods The differentially expressed genes of RF were screened by GEO database.With the help of CMAP database,based on the similarity princi-ple of gene expression profile,the drugs that regulated RF were repositioned,and then the components of SKI potential treatment RF were screened by molecular fin-gerprint similarity analysis.At the same time,the core targets and pathways of SKI regulating RF were predic-ted based on network pharmacology.Finally,it was verified by molecular docking and cell experiments.Results Based on the GEO database,two RF-related data sets were screened,and CMAP was relocated to three common RF therapeutic drugs(saracatinib,da-satinib,pp-2).Molecular fingerprint similarity analysis showed that RF therapeutic drugs had high structural similarity with five SKI components such as salvianolic acid B and hydroxysafflor yellow A.Molecular docking results showed that salvianolic acid B,hydroxysafflor yellow A and other components had good binding abili-ty with MMP1 and MMP13,which were the core targets of SKI-regulated potential treatment of RF.Network pharmacology analysis suggested that the core targets of SKI were mainly enriched in signaling pathways such as Relaxin and AGE-RAGE.Cell experiments showed that SKI could significantly reduce the mRNA expres-sion levels of AGER,NFKB1,COL1A1,SERPINE1,VEGFC in AGE-RAGE signaling pathway and MMP1 and MMP13 in Relaxin signaling pathway in RF model cells,and significantly increase the mRNA expression level of RXFP1.Conclusions SKI can play a role in the treatment of RF by regulating Relaxin and AGE-RAGE signaling pathways,and its material basis may be salvianolic acid B,hydroxysafflor yellow A and other components.

Objective To compare the efficacies of retrograde tibial nailing(RTN)versus minimally invasive percutaneous plate osteosynthesis(MIPPO)in the treatment of distal tibial fractures.Methods A retrospective analysis was conducted on the clinical data of 55 patients with distal tibial fractures who underwent surgery in our hospital.Patients were divided into two groups based on the different surgical methods,patients in the RTN group(n=25)were treated with RTN,and patients in the MIPPO group(n=30)were treated with MIPPO.The surgical parameters(operation time,intraoperative blood loss,intraoperative fluoroscopy times,and success rate of closed reduction),fracture healing time,ankle dorsiflexion range of motion and American Orthopaedic Foot and Ankle Society(AOFAS)ankle-hindfoot scores 6 months after operation and at the last follow-up,and the incidence of complications during perioperative period and follow-up were compared between the two groups.Results The operation time,intraoperative blood loss,and intraoperative fluoroscopy times in the RTN group were significantly shorter/less than those in the MIPPO group(P＜0.05).The ankle dorsiflexion range of motion and AOFAS ankle-hindfoot score 6 months after operation in the RTN group were significantly greater/higher than those in the MIPPO group(P＜0.05).There was no statistically significant difference in the fracture healing time,or ankle dorsiflexion range of motion and AOFAS ankle-hindfoot score at the last follow-up between the two groups(P＞0.05).The success rate of closed reduction in the RTN group was 72.00％,which was lower than that of 96.67％in the MIPPO group(P＜0.05).The incidence of soft tissue-related complications in the RTN group was signifi-cantly lower than that in the MIPPO group(P＜0.05),while there was no statistically significant difference in the overall incidence of complica-tions between the two groups(P＞0.05).Conclusion RTN is an effective minimally invasive surgical technique for the treatment of distal tibial fractures,characterized by minimal trauma,low incidence of soft tissue complications,and fast recovery of joint function compared with MIPPO.

For the past 30 years,percutaneous balloon mitral valve dilatation has been performed under the guidance of X-rays and bedside ultrasound.However,there are still some cases of mitral valve stenosis in the large atrium where balloon dilation failed.Intraperitoneal ultrasound-guided percutaneous balloon mitral valve plasty is accurate and feasible,which can reduce the occurrence of complications and improve the success rate of such elderly complex cases.Two patients with severe mitral stenosis underwent percutaneous balloon mitral valve plasty guided by intracardiac ultrasound.The operations were successful without any complications,which can provide reference for clinical treatment of mitral stenosis.

Objective:To study the incidence and risk factors of herpes zoster in patients with multiple myeloma and to evaluate the preventive effect of antiviral therapy.Methods:The clinical features of multiple myeloma patients with herpes zoster were retrospectively analyzed,the risk factors of herpes zoster and the effect of antiviral prophylaxis were analyzed.Results:Among 180 patients with multiple myeloma,23 cases developed herpes zoster(12.8％).The incidence of herpes zoster was 19.1％in patients with renal dysfunction and 23.5％after autologous hematopoietic stem cell transplantation(ASCT).The incidence of herpes zoster was higher in patients receiving bortezomib-containing regimens(21/137,15.3％)than that in those without bortezomib(2/43,4.7％),but there was no statistical difference(P=0.067).Antiviral prophylaxis was associated with fewer zoster infections,8/111(7.2％)developed herpes zoster in patients who received antiviral prophylaxis,and 15/69(21.7％)in those receiving no prophylaxis(P=0.005).65.2％of patients with herpes zoster did not receive antiviral prophylaxis.Multivariate analysis showed that bortezomib treatment,AHSCT and renal dysfunction were independent risk factors for multiple myeloma with herpes zoster,while antiviral prophylaxis was independently associated with reducing the risk of herpes zoster.Herpes zoster had no effect on OS in patients with multiple myeloma.Conclusion:The risk of herpes zoster in multiple myeloma patients was increased.Antiviral prophylaxis can reduce the risk of herpes zoster in patients on bortezomib-based therapy.

Objective:To investigate the clinical efficacy and prognosis of Rituximab combined with DHAX and CHOP regimen in the first-line treatment of elderly patients with newly diagnosed diffuse large B-cell lymphoma(DLBCL).Methods:A total of 36 elderly patients with DLBCL who were admitted and treated with 3 of more courses of treatment from August 2011 to August 2021 were retrospectively analyzed,and they were divided into rituximab± DHAX(R±DHAX)regimen group(18 cases)and rituximab±CHOP(R-CHOP)regimen group(18 cases)according to the treatment plan,and clinical features,efficacy and survival of the patients were observed.Results:Compared with R-CHOP group,patients of the R±DHAX group were older,and had worse performance status and higher IPI score,the differences between two groups in age,ECOG score and IPI score were statistically significant(P=0.005,P=0.018,P=0.035),but there were no significant differences be ween two groups in gender,whether there were B symptoms,whether LDH was elevated,whether there was extranodal involvement,cell origin,bone marrow infiltration,and whether rituximab was combined(P=0.738,P=1,P=0.315,P=0.305,P=0.413,P=0.177,P=0.711,P=0.229).The efficacy could be evaluated in 36 cases,including CR 14(38.9％),PR 17(47.2％),PD 5(13.9％),and ORR of 86.1％(31/36).There were no statistically significant differences in CR[(27.8％(5/18)vs 50.0％(9/18);P＞0.05]and PR[44.4％(8/18)vs 50.0％(9/18);P＞0.05]of R±DHAX group and R-CHOP group,there was statistically significant difference in ORR[72.2％(13/18)vs 100.0％(18/18);P=0.045]between two groups.The 1-year OS of R±DHAX group and R-CHOP group was(38.9+11.5％)％and(94.4±7.4％)％,respectively,2-year OS was(16.7±8.8)％and(72.2±10.6)％,respectively,and the differences between two groups were statistically significant(P=0.001,P=0.002).The median survival time in the R±DHAX group was 11 months(95％CI;8.9-13.1),and the median survival time in the R-CHOP group was not reached,and there was a statistically significant difference between the groups(P＜0.001).Conclusion:For elderly DLBCL patients,R± DHAX may not be superior to R-CHOP in OS,and ECOG score,IPI score and age may affect the survival of elderly DLBCL patients.However,R±DHAX regimen is safe,tolerable and has a certain efficacy,which can be used as one of the clinical treatment options for elderly DLBCL.

Objective:To investigate the prognostic value of minimal residual disease(MRD)detected by multi-parameter flow cytometry(MFC)in pediatric patients with acute myeloid leukemia(AML)after induction chemotherapy.Methods:A retrospective study was conducted on 97 pediatric patients initially diagnosed with AML at Wuhan Children's Hospital from August 2015 to December 2022.The study analyzed the results of MRD detection using MFC after the first and second cycles of induction chemotherapy,and its association with prognosis were analyzed.Results:Following the first cycle of induction treatment,57 of the 97 patients tested positive for MRD(MRD1+,58.8％).Subsequently,19 patients remained MRD positive(MRD2+,19.6％)after the second cycle of induction treatment.Kaplan-Meier survival analysis showed that the estimated 3-year overall survival(OS)rate of the 37(64.9％)MRD1+patients who underwent transplantation was significantly higher than that of the 20(35.1％)MRD1+patients who did not undergo transplantation(84.6％vs 40.0％,P=0.0001).Among the 35 MRD1+MRD2-patients,the 3-year OS rate of the 25 children who underwent transplantation was higher than that of the 10 children who did not undergo transplantation(87.2％vs 70.0％,P=0.3229).The 3-year OS rate of the 19 MRD1+MRD2+patients was lower than that of the 35 MRD1+MRD2-patients(57.4％vs 81.8％,P=0.059).In the 19 MRD2+patients,the 3-year OS rate of the 12 children who underwent transplantation was significantly higher than that of the 7 children who did not undergo transplantation(80.8％vs 14.3％,P=0.0007).There was no significant difference in 3-year OS between the 12 MRD1+MRD2+patients and 25 MRD1+MRD2-patients,both treated with transplantation(80.8％vs 87.2％,P=0.8868).In those not treated with transplantation,the 7 MRD1+MRD2+patients had a significantly lower 3-year OS compared with the 10 MRD1+MRD2-patients(14.3％vs 70.7％,P=0.0114).Further multivariate analysis indicated that MRD2 positivity and transplantation were both independent prognostic factors(P=0.031,0.000),while MRD1 positivity was not significantly associated with the overall prognosis of 97 patients(P=0.902).Conclusion:MRD positivity following the second cycle of induction chemotherapy is an independent risk factor for unfavorable outcomes in children with AML.MRD2 positivity indicates a poorer prognosis and can help to identify the candidates requiring transplantation.MRD2 positivity is not a contraindication for transplantation in pediatric patients,and early transplantation significantly improves the prognosis of high-risk patients.

Objective:To investigate the mechanism of polygonatum and astragalus compound(PA)in inhibiting the progression of lung adenocarcinoma. Methods:CCK-8 assay was used to assess the inhibitory rate of proliferation in A549 and H1299 cells treated with PA at different concentrations and to calculate the half maximal inhibitory concentration(IC50).C57BL/6 mice(KRASG12D/+;TP53flox/flox)were treated with adenovirus carrying Cre enzyme via nasal inhalation to establish a mouse model of primary lung adenocarcinoma.The model mice were fed with PA-containing diet to directly observe the effect of PA on the lung adenocarcinoma tissue.Immunohistochemical staining was used to examine the pathological status of the lung tissue.Bioinformatics analysis indicated that PA affects the progression of lung adenocarcinoma through the apelin-peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC1α)-mitochondrial brown fat uncoupling protein 1(UCP1).Real-time quantitative PCR and Western blotting analysis were used to study the effect of PA on the mRNA and protein expression levels of apelin-PGC1α-UCP1 signaling pathway related genes.An ATP detection kit and flow cytometry were used to evaluate the effect of PA on the ATP and mitochondrial ROS production,respectively,in A549 and H1299 cells.siUCP1 was used to silent the expression of UCP1 while Z160 was used to induce UCP1 overexpression in A549 and H1299 cells,and the changes in ATP and mitochondrial ROS production were examined to further investigate whether PA acts on apelin-PGC1α-UCP1 signaling pathway to affect the progression of lung adenocarcinoma. Results:PA could obviously inhibit the proliferation of A549 and H1299 cells with the IC50 values of 10.66 mg/mL for A549 cells and 9.66 mg/mL for H1299 cells.In the mouse primary lung adenocarcinoma model,PA could effectively inhibit the growth of tumor,downregulate apelin-PGC1α-UCP1 signaling pathway and inhibit the expression of lung adenocarcinoma-promoting gene UCP1.In A549 and H1299 cells,PA could significantly inhibit the expression of apelin,PGC1α and UCP1(P＜0.05),promote the production of ATP(P＜0.000 1)and ROS,restore mitochondrial oxidative phosphorylation,and inhibit aerobic glycolysis(P＜0.01).UCP1 silencing could increase the production of ATP(P＜0.01)and mitochondrial ROS and decrease the expression of key glycolysis enzymes hexokinase 2(HK2)and pyruvate kinase isozyme type M2(PKM2)(P＜0.05).Increasing the expression of UCP1 could reduce the ATP production(P＜0.01)and mitochondrial ROS generation in cells while increase the expression of HK2 and PKM2(P＜0.05).Treating cells with PA and Z160 simultaneously(PA+Z160)could reverse the inhibitory effect of PA on the ATP production and glycolysis of tumor cells(P＜0.05). Conclusion:PA can downregulate the apelin-PGC1α-UCP1 signaling pathway,inhibit mitochondrial uncoupling,restore mitochondrial oxidative phosphorylation,inhibit aerobic glycolysis,reverse the Warburg effect,and thus inhibit lung adenocarcinoma progression.

This study aimed to investigate the effect of iron overload on the transplant outcomes of pediatric patients with severe aplastic anemia (SAA) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). A retrospective analysis was conducted on the clinical data of 74 children with SAA who received allo-HSCT at the Hematology Department of Wuhan Children’s Hospital between January 2018 and August 2022. Children with iron overload (serum ferritin >1 000 μg/L) before transplantation had a longer disease course, received more red blood cell transfusions, and had a higher number of CD34 + cells infused. Moreover, iron overload significantly delayed the reconstitution of regulatory T cells after transplantation, increasing the incidence of hemorrhagic cystitis and grade Ⅲ-Ⅳ acute graft-versus-host disease after transplantation. However, iron overload did not significantly affect the overall survival and failure-free survival rates of the children.