OBJECTIVE:To investigate the expression of matrix metallopro teinase-2(MMP-2),tissue inhibitor of metalloproteinase-2(TIMP-2) and collagen Ⅳ(Ⅳ-C) in kidney of diabetic rats and the intervention effect of irbesartan.METHODS:30 male SD rats were randomly divided into three groups:normal control group(NC group),diabetes mellitus group(DM group) and diabetes mellitus+50 mg?kg-1 irbesartan group(DI group).DM and DI group were injected with streptozocin intraperitoneally to reduce diabetic model.After 8 weeks the expression of MMP-2,TIMP-2 and Ⅳ-C in kidney tissure were determined by immunohistochemistry method(SP) and RT-PCR.RESULTS:Compared with NC group,DM group showed the expression of protein and mRNA of MMP-2 significantly reduced while that of TIMP-2 and Ⅳ-C increased(P

objective To investigate the protective effect and possible mechanisms of extract of Gingko biloba(EGB)on early diabetic nephropathy(DN).Methods Fifty-one patients with early DN were randomly divided into control group(n=25)treated by irbesartan alone and treated group(n=26)treated by EGB combined with irbesartan.Serum high sensitive C-reactive protein(hs-CRP)and monocyte chemoattractant protein-1(MCP-1)were determined with ELISA before and after treatment,and urinary albumin excretion rate(UAER),fasting blood glucose (FBG),serum creatinine(SCr),blood urea nitrogen(BUN)and lipid profiles were examined as well.Results Compared with pretreatment,at the end of 6 months'treatment,the values of hs-CRP decreased from(194.37±34.02)and(191.51±27.15)mg/L to(164.13±32.86)and(134.65±20.47)mg/L in control group and treatment group,respectively.MCP-1 was downregulated from(304.23±38.56)and(299.66±44.07)ng/L to (235.43±28.66)and(165.53±21.96)ng/L in control group and treated group(all P＜0.05).After treatment,the decrement of hs-CRP and MCP-1 level in the treated group was more significant than that in control group(P＜0.05).Conclusion EGB could retard the development of early DN,through down-regulating the expresssion of seram MCP-1,decreasing serum hs-CRP concentration and inhibiting inflammatory reaction.

Objective To investigate the effects of Notch1 siRNA on VEGF and angiogenesis of myeloma cell line RPMI-8226 in vitro and in vivo.Methods In vitro,Notch siRNA was transfected into RPMI-8226 cells,and then cell supernatant VEGF secretion was detected using ELISA method.Expression levels of Notch1 and VEGF proteins were assayed by Western blotting.RPMI-8226 cells were subcutaneously transplanted in NOD/SCID mice,and then the tumor mice were divided into three groups randomly:NS group (Notch1 siRNA-transfected group),CS group (Control siRNA-transfected group) and UN group (Untransfected group),and the changes of tumor volume were observed.Immunohistochemical staining was used to detect the changes in expression levels of Notch1,VEGF and CD34.Results Notch1 and VEGF proteins expressions of RPMI-8226 cells were significantly decreased by Notch1 siRNA.At 48 h and 72 h,VEGF secretion level in NS group was significantly different with CS group [(120 ± 25) ng/L ∶ (175 ± 15) ng/L,t =3.27,P ＜ 0.05;(145 ± 24)ng/L ∶ (295 ± 17)ng/L,t =8.83,P＜0.01].At 13 d,17 d and 21 d,tumor volume in NS group was significantly reduced,that was significantly different with CS group [(1 548 ± 218) mm3 ∶ (1 820 ± 64) mm3,t =2.68,P ＜0.05;(1 200 ±75)mm3 ∶ (2 180 ±84)mm3,t =19.46,P＜0.01;(1 150 ±88)mm3 ∶ (2 250 ± 145)mm3,t =14.50,P ＜0.01].The expression levels of Notch1 and VEGF protein were decreased by Notch1 siRNA.The expression levels of Notchl and VEGF in NS group were different with CS group [(16.33 ±2.52)％∶ (75.33 ±2.52)％,t=28.71,P＜0.01;(5.00±1.00)％∶29.67±2.08 ％,t=18.50,P ＜ 0.01].Notch1 siRNA reduced the number of transplanted tumor neovascularization in NS group.Microvascular density in NS group was significantly less than that in CS group [(14.67 ± 2.52) ∶ (30.00 ± 5.00),t =4.74,P ＜ 0.01].Conclusion In vitro,Notch siRNA reduces human myeloma cell RPMI-8226 cell supernatant VEGF secretion.In vivo,Notch siRNA can reduce tumor volume and the number of new blood vessels in transplanted-multiple myeloma mice.Thus,Notchl is an effective molecular target for anti-angiogenesis in myeloma.

Objective:To explore the diagnosis and treatment of posterior shoulder dislocation combined with reverse Hill-Sachs lesion.Methods:Two male patients were treated at Department of Joint Surgery, Affiliated Hospital of Qingdao University for posterior shoulder dislocation combined with reverse Hill-Sachs lesion from August to November 2022. Case 1 was a 46-year-old man, admitted 1 day after right should injury, and case 2 a 57-year-old man, admitted 2 days after right should injury. The injury was caused by electric shock in both, and their fractures were fresh with an injury area>50%. After anatomical reduction of the collapsed humeral head via the pectoralis major deltoid approach, an artificial bone was implanted and fixated with countersunk screws in both cases to reduce the shoulder joint. The Constant-Murley scale and visual analogue scale (VAS) were used to evaluate the functional recovery of the shoulder and pain after treatment.Results:No such perioperative complications as incision infection, brachial plexus injury or vascular injury was observed in either of the 2 patients. Reexamination 3 months after surgery showed in case 1: 110° of shoulder anterior flexion, 90° of shoulder abduction, 30° of external rotation (neutral position), 70° of internal rotation (neutral position), 70 points of Constant-Murley shoulder score, and 3 points of VAS pain score; in case 2: 130° of shoulder anterior flexion, 120° of shoulder abduction, 50° of external rotation (neutral position), 80° of internal rotation (neutral position), 70 points of Constant-Murley shoulder score, and 2 points of VAS pain score.Conclusion:For patients with posterior shoulder dislocation complicated with reverse Hill-Sachs lesion and humeral head collapse greater than 50%, open reduction and screw internal fixation combined with artificial bone grafting can achieve good short-term curative efficacy.

Objective To explore the analysis of the relationship of the serum levels of focal adhe-sion kinase(FAK)and fatty acid-binding protein 4(FABP4)with myocardial injury and cardiac function in elderly patients with acute myocardial infarction(AMI).Methods A total of 211 AMI patients admitted to our hospital from January 2020 to April 2023 were enrolled and assigned into the AMI group,while another 60 healthy volunteers who took routine physical examinations in our hospital during the same period served as the control group.The serum FAK and FABP4 lev-els were compared between the two groups.Multivariate logistic regression analysis was employed to identify influencing factors associated with AMI,and ROC curve was plotted to assess the pre-dictive efficacy of the serum FAK and FABP4 levels for AMI in the elderly population.Pearson correlation analysis was conducted to explore the relationship between serum FAK and FABP4 levels and myocardial injury as well as cardiac function.Results The AMI group exhibited signifi-cantly elevated serum FAK,FABP4,CK-MB,cTnⅠ and CK levels,and larger LVESD and LVEDD,but lower LVEF when compared with the control group(P＜0.05,P＜0.01).For the AMI patients,the serum FAK and FABP4 levels were positively correlated with CK-MB,cTnⅠ and CK levels,as well as LVESD and LVEDD,and negatively with LVEF(P＜0.05).Multivariate logistic regression analysis revealed that both serum levels of FAK(OR=2.872,95％CI:2.230-3.698,P=0.000)and FABP4(OR=2.667,95％CI:1.713-4.154,P=0.000)were influencing factors for AMI.ROC analysis indicated that the cut-off value of FAK level for diagnosing AMI was 25.60 pg/L,with an AUC value of 0.801(95％CI:0.750-0.852).Similarly,the cut-off value of FABP4 in the diagnosis was 23.22 pg/L,with an AUC value of 0.760(95％CI:0.707-0.812).Combined FAK and FABP4 levels yielded,with an AUC value of 0.899(95％CI:0.839-0.918).Conclusion Serum FAK and FABP4 levels are abnormally high in the elderly patients with AMI,which is closely related to myocardial injury and cardiac function.The two indicators alone or in combination can effectively predict the occurrence of AMI.

Objective:To compare the clinical efficacy between modified open wedge high tibial osteotomy (MOWHTO) versus traditional open wedge high tibial osteotomy (TOWHTO) for varus knee osteoarthritis (KOA).Methods:A retrospective study was conducted to analyze the 50 patients (60 knees) with varus KOA who had received high tibial osteotomy at Department of Sports Medicine, The Affiliated Hospital of Qingdao University between September 2019 and December 2020. The patients were divided into 2 groups according to different ways of osteotomy: a traditional group and a modified group. In the traditional group subjected to TOWHTO, there were 25 cases (30 knees); in the modified group subjected to MOWHTO, there were 25 cases (30 knees). In MOWHTO, the bone block attached to the medial collateral ligament (MCL) of the knee was first chiseled at the MCL insertion before osteotomy to reduce excessive stripping of the MCL in the osteotomy area, and then the bone fragment attached to the MCL was filled into the osteotomy area to increase bone filling and bone coverage after the alignment of the lower limb was corrected. The hip-knee-ankle angle (HKAA), medioproximal tibial angle (MPTA), and joint line convergence angle (JLCA) were measured preoperatively and at 18 months postoperatively in both groups to evaluate correction of the alignment of the lower limb. Fracture healing time, bone loss in the osteotomy area, Hospital for Special Surgery (HSS) knee score and visual analogue scale (VAS) were recorded to evaluate the postoperative efficacy.Results:There was no statistically significant difference between the TOWHTO and MOWHTO groups in the general clinical data before operation, showing comparability ( P>0.05). At 18 months after operation, HKAA was (179.1° ± 1.1°) in the TOWHTO group and (179.3° ± 0.7°) in the MOWHTO group while MPTA was (91.9° ± 0.4°) in the TOWHTO group and (91.9° ± 0.4°) in the MOWHTO group, showing no statistically significant difference between the 2 groups ( P>0.05) but a significant difference between preoperation and postoperation in each group ( P<0.05). At 18 months after operation, JLCA was (1.8° ± 0.4°) in the TOWHTO group, significantly larger than that in the MOWHTO group (1.5° ± 0.4°), HSS score was 81.5 (79.5, 83.0) points in the TOWHTO group, significantly lower than that in the MOWHTO group [85.0 (82.5, 87.5) points], and VAS was 1.8 (1.6, 2.0) points in the TOWHTO group, significantly higher than that in the MOWHTO group [1.5 (1.5, 2.0) points] (all P<0.05). At 18 months after operation, the preoperative JLCA was significantly improved in both groups ( P<0.05). The time required for a fracture healing score higher than 4 points was (3.3 ± 0.6) months in the TOWHTO group and (4.5 ± 0.9) months in the MOWHTO group, and the rate of bone loss in the osteotomy area was 20% in the TOWHTO group (6/30) and 0 (0/30) in the MOWHTO group, both showing a significant difference between the 2 groups ( P<0.05). Conclusions:Both TOWHTO and MOWHTO can effectively treat varus KOA. MOWHTO is more effective in promoting bone healing in the osteotomy area, reducing bone defects in the osteotomy area and improving knee function.

Apoptosis ; Cell Hypoxia ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Multiple Myeloma ; pathology

Inhibition of human epidermal growth factor receptor 2 mediated cell signaling pathway is an important therapeutic strategy for HER2-positive cancers. Although monoclonal antibodies are currently used as marketed drugs, their large molecular weight, high cost of production and susceptibility to proteolysis could be a hurdle for long-term application. In this study, we reported a strategy for the development of artificial antibody based on

As a novel and promising antitumor target, AXL plays an important role in tumor growth, metastasis, immunosuppression and drug resistance of various malignancies, which has attracted extensive research interest in recent years. In this study, by employing the structure-based drug design and bioisosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone carboxamide scaffold, of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions. Notably, compound 59 showed a desirable AXL kinase inhibitory activity (IC₅₀: 3.5 nmol/L) as well as good kinase selectivity, and it effectively blocked the cellular AXL signaling. In turn, compound 59 could potently inhibit BaF3/TEL-AXL cell viability (IC₅₀: 1.5 nmol/L) and significantly suppress GAS6/AXL-mediated cancer cell invasion, migration and wound healing at the nanomolar level. More importantly, compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-