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Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reapproved for heart failure (HF) therapy in patients with and without diabetes. However, the initial glucose-lowering indication of SGLT2i has impeded their uses in cardiovascular clinical practice. A challenge of SGLT2i then becomes how to separate their anti-HF activity from glucose-lowering side-effect. To address this issue, we conducted structural repurposing of EMPA, a representative SGLT2 inhibitor, to strengthen anti-HF activity and reduce the SGLT2-inhibitory activity according to structural basis of inhibition of SGLT2. Compared to EMPA, the optimal derivative JX01, which was produced by methylation of C2-OH of the glucose ring, exhibited weaker SGLT2-inhibitory activity (IC50 > 100 nmol/L), and lower glycosuria and glucose-lowering side-effect, better NHE1-inhibitory activity and cardioprotective effect in HF mice. Furthermore, JX01 showed good safety profiles in respect of single-dose/repeat-dose toxicity and hERG activity, and good pharmacokinetic properties in both mouse and rat species. Collectively, the present study provided a paradigm of drug repurposing to discover novel anti-HF drugs, and indirectly demonstrated that SGLT2-independent molecular mechanisms play an important role in cardioprotective effects of SGLT2 inhibitors.
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OBJECTIVE：To ex plore the protective effects of Longbie capsule contained serum （called“LBJN”for short ）on the apoptosis of chondrocytes induced by YAP inhibitor verteporfin and its mechanism. METHODS ：Primary human knee osteoarthritis（OA）chondrocytes were extracted by two-step enzymatic digestion ，and then identif ied by toluidine blue staining and type Ⅱ collagen immunofluorescence staining. The effects of 2，5 μmol/L verteporfin alone or combined with 5％LBJN on cell apoptosis were detected by flow cytometry. Solvent control （0.1％ DMSO）and 5％ LBJN were set. Western blot assay was adopted to detect the expression of apoptosis related proteins （YAP，Bcl-2，cleaved-caspase-3） after treated with 0.1％DMSO（solvent control ），2 μmol/L verteporfin，2 μmol/L verteporfin+5％LBJN 和 0（blank control ），2.5％ LBJN and 5％ LBJN for 48 h. The expression of autophagy related proteins （mTOR，Beclin-1，LC3A/B） after treated with 0 （blank control ），2.5％，5％ LBJN for 48 h were det ected by Western blot assay. RESULTS ：The isolated cells accorded with the characteristics of chondrocytes. Compared with 0.1％DMSO， the apoptosis rates of cells were increased significantly after treated with 2，5 μmol/L verteporfin（P＜0.05），and the effects of the two concentrations were similar （P＞0.05）. Compared with verteporfin alone ，2，5 μmol/L verteporfin combined with 5％LBJN could significantly decrease the apoptotic rate of cells （P＜0.05）. Compared with 0.1％DMSO，the protein expression of YAP and Bcl-2 were decreased significantly after treated with 2 μ mol/L verteporfin （P＜0.05）， while the protein expression of cleaved-caspase-3 were increased significantly （P＜0.05）. Compared with 2 μmol/L verteporfin，protein expression of YAP and Bcl-2 were increased significantly after treated with 2 μmol/L verteporfin+5％LBJN（P＜0.05），while the protein expression of cleaved-caspase-3 were decreased significantly （P＜0.05）. Compared with blank control ，the protein expression of YAP ，Bcl-2 and Beclin-1 were increased significantly after treated with 2.5％，5％LBJN（P＜0.05），while protein expression of cleaved-caspase- 3 and mTOR were decreased significantly （P＜0.05）. CONCLUSIONS ：LBJN can block the apoptosis of chondrocytes induced by YAP inhibitor verteporfin ，and its mechanism may be related to regulating the expression of apoptosis related proteins and enhancing autophagy of chondrocytes.
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OBJECTIVE:To investigate the possible mechanism of Artemisia capillaries,and to provide reference for further development and utilization of it. METHODS:The effective components and related target protein of A. capillaries were screened by Traditional Chinese Medicine Systems Pharmacology (TCMSP) analysis platform database. The effective compound-target protein visual network of A. capillaries was established by using Cytoscape 3.5.1 software,topology analysis was also performed. The protein-protein interaction (PPI) network was constructed and analyzed by STRING database. KEGG pathway enrichment of target protein coding gene was analyzed by DAVID bioinformatics resource database. RESULTS:A total of 13 kinds of effective compounds,189 target proteins and 34 enrichment pathways were selected. Quercetin,β-glutamol,isorhamnetin and artepillin C were main effective compounds. Prostaglandin G/H sythase 2(PTGS 2),heat shock protein 90(HSP 90),dipeptidyl peptidase Ⅳ, protein kinase A catalytic subunit Cα were main target proteins. Transcription factor AP-1 and cell tumor antigen p53 played a key role in PPI network. The target protein coding gene was rich in TNF-α signaling pathway,HIF-1 signaling pathway,Toll-like receptor signaling pathway,PI3K/Akt signaling pathway,T cell receptor signaling pathway,thyroid hormone signaling pathway, apoptotic signaling pathway,etc. CONCLUSIONS:Quercetin,β-glutamol and isorhamnetin of A. capillaries play an effect on PTGS2,HSP90,transcription factor AP-1 and other target proteins through TNF-α signaling pathway,HIF-1 signaling pathway and PI3K/Akt signaling pathway,so as to play anti-inflammatory and antitumor effect.
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BACKGROUND:Santoni put forward the cortical bone trajectory technology by changing the traditional pedicle screw placement for lumbar internal fixation in order to obtain better control of the screw and bone in 2009. OBJECTIVE:To analyze biomechanical stability of cortical bone trajectory system in the lumbar fusion. METHODS:Twenty fresh newborn calf L3/4, L5/6 motion segment specimens were obtained, and their ranges of motion were detected under different states, as normal controls. Subsequently, twenty samples were divided into cortical bone trajectory screw group and traditional pedicle screw group, which underwent cortical bone trajectory screw fixation combined with posterior lumbar fusion and traditional pedicle screw fixation combined with posterior lumbar fusion, respectively. Without destruction, ranges of motion were detected under different states in both groups. In the revision group, after the test in the traditional pedicle screw group, screw was withdrawn, and cortical bone trajectory screw was used to detect its range of motion under different states. RESULTS AND CONCLUSION:Ranges of motion at bending to the left and right, anteflexion, posterior extension and axial rotation were significantly lower in the cortical bone trajectory screw group and traditional pedicle screw group than in the normal control group (P0.05). These results confirmed that cortical bone trajectory technology combined with posterior lumbar fusion can obtain identical stability as the traditional pedicle screw fixation combined with posterior lumbar fusion. Simultaneously, it is a new choice for revision after traditional pedicle screw fixation.
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Objective To assess the efficacy of combining vestibular rehabilitation with cognitive behavioral therapy in treating chronic subjective dizziness ( CSD) and the associated anxiety. Methods A total of 98 anxious CSD patients were randomly divided into an experimental group ( n=50) and a control group ( n=48) . All of the pa-tients′scores on the Hamilton anxiety scale ( HAMA) were no less than 14 and their scores on the Hamilton depres-sion scale ( HAMD) were less than 18. Systematic vestibular rehabilitation was given to the patients in the control group, while this was combined with cognitive behavioral therapy for the patients in the experimental group. All pa-tients were evaluated using a dizziness handicap inventory ( DHI) and the HAMA before treatment and in the 4th and 8th week of the treatment. Results Before the treatment there was no significant difference between the 2 groups in any of the assessments. After 3 weeks of treatment, the average HAMA score, DHI total score and its factor scores had decreased significantly. Four weeks later, the average HAMA score, DHI total score and its factor scores for som-atization, emotion and function had improved significantly in both groups compared with before treatment and the scores after 3 weeks. After 3 and 7 weeks of treatment, the average HAMA score, DHI total score and its factor scores of the experimental group were significantly lower than those of the control group. Conclusion Cognitive behavioral therapy amplifies the effects of vestibular rehabilitation in treating persons with CSD, in part by significantly relieving their anxiety.
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BACKGROUND:Recently, there are many documents al over the world reporting hypotoxicity infection after fracture internal fixation surgery, but reports are different on whether it is necessary for chronic hypotoxicity infection internal fixation removal post surgery. There are no fixed judgment criteria of curative effects, which leads to inexact conclusion of treatment method. ＜br> OBJECTIVE:To observe the curative effects of taking rifampicin and ciprofloxacin with transfer of skin flap in the treatment of chronic hypotoxicity infection with sinus formation after fracture surgery on tibial plateau and ankle. METHODS:A total of 56 cases of chronic hypotoxicity infection after fracture surgery of tibial plateau and ankle were col ected from September 2005 to December 2012. 30 cases in the therapy group were treated with ＜br> levofloxacin and rifampicin with transfer of skin flap. 26 cases in the control group were treated with conventional intravenous antibiotics with local debridement to remove internal fixation. In both groups, the course of disease was 3 to 6 months. The erythrocyte sedimentation rate, kidney function and radiographic indices were reviewed every 1 to 3 months, and curative effects were evaluated. ＜br> RESULTS AND CONCLUSION:During the fol ow-up visit of 6-24 months, no recurrence happened to the cured and improved patients. In the therapy group, 24 cases were cured, 4 cases were improved, and 2 cases were invalid, with a total effective rate of 93%. In the control group, 11 cases were cured, 6 cases were improved and 9 cases were invalid with the total effective rate of 65%.χ2 test showed that therapeutic effects were significantly better in the therapy group than in the control group (P＜0.05). These data indicated that rifampicin and ciprofloxacin with transfer of skin flap for chronic hypotoxicity infection with sinus formation after fracture surgery of tibial plateau and ankle showed good curative effects.
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BACKGROUND:Rapid prototyping technique has been recently applied in the medical reconstruction and al ows the production of individual implant for patients with tissue defects, achieving an accurate repair. OBJECTIVE:To repair discontinuous mandibular defects in dogs using rapid prototyped titanium plate in combination with autologous cancellous bone graft. METHODS:Nine hybrid canines were used, and the skul was scanned using spiral CT. Then CT data were used to construct three-dimensional digital model, in which virtual partial mandibulectomy was performed, and an individualized bone-grafting plate was designed. A titanium plate was manufactured using rapid prototyping and titanium casting. Animal experiment was then performed. A 40-mm discontinuous defect in the right mandibular body was created in the involved dogs. The defect was restored immediately using the customized plate in combination with autologous cancellous iliac blocks. Sequential radionuclide bone imaging, biomechanical testing, three-dimensional microcomputed tomographic scanning, radiology and histological examination were used to evaluate the turnover of the grafts. RESULTS AND CONCLUSION:A symmetric mandible was reconstructed using the rapid prototyped grafting plate. The grafted bone survived and got corticalized, while a fibrous intermedium was found between the bone graft and the plate. In the reconstruction of mandibular defects, optimal functional and aesthetic outcomes could be achieved using the rapid prototyped grafting plates.
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Objective:To review the treatment of life threatening head and neck space infection.Methods:Retrospective was con-ducted to analyse the patient characterization,signs and symptoms at the time of presentation,presence of concomitant systemic co-morbidities,treatment,prognosis and bacteriology.Results:32 patients from 2007.01 to 2013.01(mean age was 57.71 years)were included.The cases were increased year by year.1 1 (34.37%)patients had breathing difficulty requiring tracheostomy and 19 (59.3%)had concomitant systemic comorbidities.23 cases recovered completely,8 with severe mediastinal infection were trans-ferred to the department of thoracic surgery or the department of respiratory medicine.1 patient died.Pus submission rate was 96.87%,the bacteria detection rate was 37.50%.Pus culture showed mixed infection dominated by streptococci.Staphylococcus au-reus,pseudomonas aeruginosa,enterococcus faecalis,prevotella and neisseria were detected.Conclusion:Annually incidence of life threatening head and neck space infection is increasing.Treatment of the infection should include:①Ensuring the airway patency;②Surgical incision and drainage as early as possible;③ Hypoglycemic control,maintenance of hemodynamic,nutritional support,and multi-disciplinary approach are the key points in the management of such infections;④ Systemic antibiotics.
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Objective To investigate the clinical features of aortic dissection (AD) and emergency treatments. Methods Data from 784 patients with aortic dissection were collected in the Department of Emergency from January 2000 through December 2009. A retrospective analysis was carried out to determine the survival rate, mortality rate and treatment efficiency. Results Pain was the most common onset symptom (77.7% , 609/784). The majority of patients (86.5%) had essential hypertension (678/784). All the patients with preoperative diagnosis of aortic dissection underwent emergency medical intervention by internists resulting in 81.5% survival rate (639/784) and 18.5% mortality rate (145/784). There were 157 patients without improvement (20.0% ) and the total efficiency rate was (83. 1% ). The efficiency rate of conventional treatment was 76.4% , while the efficiency rate of triple four-procedure treatment was 89. 8% (P<0.05). Of them, 139 patients (17. 7% ) died in the hospital. Among them,. 26 patients died within 24 hours (18.4% ) and 47 cases died within 48 hours (33. 8% ) and 66 patients died within 72 hours (47.2% ). There were 92 patients who refused treatments after diagnosis, and among them, 81 patients died within 72 hours (88.04% ). The difference in mortality rate between two groups was significant (P<0.05). Conclusions The diagnosis of aortic dissection depends on detailed history, physical examination and CT or MRI imaging. Analgesia, sedation and control of blood pressure are essential for emergency treatments. Early diagnosis and effective emergency treatments are the critical strategy for the early surgical intervention and time window for further treatment to improve the survival rate of AD.
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An analysis of the characteristics of the facial fractures in children was performed in this paper by investigating the cases of the facial fractures in children.In the study,86 cases of facial fractures in children under 12 years from January 2000 to June 2008 were reviewed,who were treated by the Fourth Military Medical University. The information included the age,gender,time distribution of jury,type of fracture, nerve injury, and associated systemic injuries. The youngest age was 13 months, the ratio of male to female was 2.19∶ 1. The majority of fractures were occurred in summer. The most cases were caused by the traffic accidents, and the mandible fractures were higher than others. The number of conservative treatment were higher than operation,78% cases of condyle fractures were treated conservative, the operation of maxilla and zygomatic arch fracture were less than 50%. The males were higher than the females according to the facial fracture in children.Traffic accident was the main risk factor of condylar fracture. The mandibular fractures were occurred frequently and treated normally by conservative method.
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Objective:To design a new elastic implant-distraction apparatus. Methods:The implant-distraction apparatus consists of tow units, a TiNi shape memory alloy spring and an implant, made of pure titanium TA2.Spring was put into the hollow implant.After horizontal osteotomy, the implant-distraction device was placed into the partial edentulous area of mandible of 6 dogs to distract the alveolar bone.Results: The apparatus was manufactured.It could implement continual autodistraction and kept stable in the in vivo experiment. 10 weeks after application of the apparatus the transport bone segment was vertically augmented by 4.7 mm on average.Conclusion: The implant-distraction device is functional in distraction osteogenesis.
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Objective:To establish an animal model in goats for curved mandibular regeneration by distraction osteogenesis(DO).Methods:Four goats were used.Internally installed curved mandibular distractors were activated 6 days after mandibular osteotomy on the mandibular angles or mandibular symphyses at a rate of l mm/d for 25~34 days.The mandibles were examined by roentgenography.Results:The arched defects of the mandibles in the 4 goats were reconstructed by regenerated bone by the end of DO.Conclusion:Internally installed curved distractor may be used for osteogenesis in the repaire of the arched mandibular defects.
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Objective To analyse the characteristics of maxillofacial injuries resulted in different causes. Methods A retrospective review was done of patients admitted to the Stomatology Hospital of Fourth Military Medical University from January, 1996 to July, 2003. Data was grouped by different causes. Results 1 188 patients were reviewed, the majority of victims caused by different causes were males, the ratio of male and female is 3.34∶1. Most industrial and sport injury occurred in men. Traffic accidents were the major cause of the midface fracture and mandibular fracture. While violence was the major cause of pure soft injure and alveolar bone fracture. Conclusions Traffic accidents and violence were the major causes of facial injury. The facial injury caused by traffic accidents, industrial accidents and fall was more serious than those caused by other causes. More emphasis should be put on the prevention and treatment of these injuries to minimize the maxillofacial malformation.
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Objective: To investigate the distraction osteogenesis technique in correction of severe retro-maxillary deformity following the repair of cleft palate. Methods:10 patients were included in the study. Orthodontic treatment was used as a regular procedure before operation. Distraction osteogenesis technique was used to correct the deformity and malocclusion. 4 of patients applied with the external distractor and others with internal distractor. Latency period was 7 days. Distraction rhythm is 0.8~1 mm/d,2~4 times/d. Consolidation period was 8~12 weeks. Orthognathic surgery was done after distraction finished when necessary. Results:The treatment process was smooth and no severe complication occurred. The maximum of distraction distance is 22 mm, and the minimum of distraction distance was 15 mm. No malunion or ununion occurred in all 10 patients. All the patients were satisfied with the results. Conclusion:Distraction osteogenesis is more suitable for correction of severe retro-maxillary deformity following the repair of cleft palate. Bone transplantation is unnecessary during the operation process with easier handling and lower risk.