| 1 | Targeting ferroptosis suppresses osteocyte glucolipotoxicity and alleviates diabetic osteoporosis显示文摘Diabetic osteoporosis(DOP) is the leading complication continuously threatening the bone health of patients with diabetes. A key pathogenic factor in DOP is loss of osteocyte viability. However, the mechanism of osteocyte death remains unclear. Here, we identified ferroptosis, which is iron-dependent programmed cell death, as a critical mechanism of osteocyte death in murine models of DOP. The diabetic microenvironment significantly enhanced osteocyte ferroptosis in vitro, as shown by the substantial lipid peroxidation, iron overload, and aberrant activation of the ferroptosis pathway. RNA sequencing showed that heme oxygenase-1(HO-1) expression was notably upregulated in ferroptotic osteocytes. Further findings revealed that HO-1 was essential for osteocyte ferroptosis in DOP and that its promoter activity was controlled by the interaction between the upstream NRF2 and c-JUN transcription factors. Targeting ferroptosis or HO-1 efficiently rescued osteocyte death in DOP by disrupting the vicious cycle between lipid peroxidation and HO-1 activation, eventually ameliorating trabecular deterioration. Our study provides insight into DOP pathogenesis, and our results provide a mechanism-based strategy for clinical DOP treatment. | Yiqi Yang Yixuan Lin Minqi Wang Kai Yuan Qishan Wang Pei Mu Jingke Du Zhifeng Yu Shengbing Yang Kai Huang Yugang Wang Hanjun Li Tingting Tang | 2022 | Bone Research2022，10，3： | 19 |
| 2 | Staged angioplasty versus regular carotid artery stenting in patients with carotid artery stenosis at high risk of hyperperfusion:a randomised clinical trial显示文摘Background and purpose Hyperperfusion(HP)is a devastating complication associated with carotid artery stenting(CAS)or endarterectomy.The efficacy and safety of staged angioplasty(SAP)in patients with CAS at high risk of HP remains unclear.We sought to determine whether SAP is superior to regular CAS in patients with high risk of HP.Methods A randomised,multicentre open-label clinical trial with blinded outcome assessment(STEP)was conducted.Patients with severe carotid stenosis at high risk of HP were randomly assigned(1:1)to the SAP or regular CAS group.The primary endpoint was hyperperfusion syndrome(HPS)and intracerebral haemorrhage(ICH)within 30 days after the procedure.Results From November 2014 to January 2017,a total of 64 patients were enrolled in 11 centres.33 patients were allocated to the SAP group and 31 to the regular CAS group.At 30 days,the rate of primary endpoint was 0.0%(0/33)in the SAP group and 9.7%(3/31)in the regular CAS group(absolute risk reduction(ARR),9.7%;95%CI−20.1% to 0.7%;p=0.11).As one of the secondary endpoints,the incidence of HP phenomenon(HPP)was lower in the SAP group than the regular CAS group(0.0%vs 22.6%,ARR,−22.6%;95% CI−36.8%to−10.2%;p=0.04).Conclusion The rate of HPS and ICH was not significantly lower in SAP group;the extended secondary endpoint of HPP,however,significantly reduced,which suggested that SAP may be a safe and effective carotid revascularisation procedure to prevent HP. | Dapeng Mo Baixue Jia Huaizhang Shi Yaxuan Sun Qingan Liu Chengzhe Fan Jianping Deng Jinglin Yuan Wei Wu Changchun Jiang Guilian Zhang Hanjun Du Ning Ma Feng Gao Xuan Sun Ligang Song Lian Liu Guangge Peng Yongjun Wang Yilong Wang Zhongrong Miao the STEP Study Group | 2021 | Stroke & Vascular Neurology2021，6，1： | 3 |
| 3 | Irisin Attenuates Osteoarthritis by Inhibiting Apoptosis of Osteocytes Through Activating Erk Signaling Pathway显示文摘Osteoarthritis(OA)is an inflammatory disease involving the joints that is prevalent in the global aging population.The purpose of this study is to determine whether irisin can attenuate osteoarthritis(OA)progression in anterior cruciate ligament transection(ACLT)mice models and the mechanism of irisin therapy effect on OA by increase the resistance of apoptosis in MLO-Y4 cells induced by mechanical stretch in vitro.Methods For in vivo study,3-month-old male C57BL/6 J mice were randomized to three groups,sham-operated,anterior cruciate ligament transection(ACLT)-operated treated with vehicle,and ACLT-operated treated with irisin by intraperitoneal injection once a week.Cartilage erosion was observed by HE staining.Osteoarthritis Research Society International(OARSI)scores were evaluated according to the safranin O stai-ning.The microstructure of tibia cortical bone,trabecular bone,and subchondral bone was analyzed by micro-CT and the bone histomorphometry has been administrated including mineral apposition rate(MAR).Edu staining and cck-8 were used for the detection of the proliferation of MLO-Y4 cells.For mechanical stress,cells were seeded on the collagen-I coated chamber subjected with a peak biaxial stretch of 20%at 1 Hz for 16 hours to induce apoptosis.Flow cytometry was used for the detection of apoptosis and cell cycle.TUNNEL was used for staining the apoptotic cells and rt-PCR was applied for quantifying the expression of mRNA such as Bax,Bcl-2,SOST,c-myc,Opg.Western blot was utilized to confirm the mechanism of how irisin decrease the osteocyte apoptosis.Results In vivo,irisin can attenuate articular cartilage degeneration.Irisin maintains the proportion of hyaline cartilage and calcified cartilage and keep fewer cartilage erosions in ACLT-operated mice.For immunohistochemical(IHC)staining,irisin reduced the expression of caspase3,Bax and matrix metalloproteinase-13 in both cartilage and subchondral bone.Irisin-treated ACLT group shows higher Trabecular number(Tb.N)and bone volume fraction(BV/TV)compared to the vehicle-treated ACLT group.In vitro, irisin significantly increased the proliferation of MLO-Y4 cells detected by Edu and Ki67 staining,and irisin can protect the cells from both mechanical stretchinduced apoptosis detected by FITC-PI flow cytometry and maintain the cell activity by regulating the expression of Bax,Bcl-2,and c-myc.Transcriptome sequencing shows that irisin significantly activates the MAPK signaling pathway and we confirm the result by western blot:irisin effectively activates the Erk signaling pathway through phosphorylation and has a certain activation effect on p38 signaling pathway,no activation was observed for FAK signaling pathway.Conclusions Irisin can attenuate the progression of OA by decrease the apoptosis of osteocyte,which can improve the microarchitecture of subchondral bone.Erk pathway activation plays an important role in reducing the apoptosis of osteocyte. | Zihao He Hanjun Li Feng Zhou Jingke Du Shuhong Zhang Tingting Tang Zhifeng Yu | 2019 | 医用生物力学2019，34，A01： | 0 |
| 4 | Renal Effects of Prosthetic Abdominal Aortic Aneurysm in Dogs显示文摘To provide experimental model for abdominal aortic aneurysm research and to optimize design of stent-graft,the authors established an animal models of prosthetic abdominal aortic aneurysm (PAAA) in dogs,evaluated its biofunction,biocompatibility and renal effect.The PAAA was sutured using aneurysm neck (Φ 6 mm artificial blood vessel) and aneurysm body (Φ 29 and 31mm artificial blood vessel,respectively). Sixteen healthy adult dogs,with weight of 13. 5 ± 0. 66 kg,were randomly divided into 2 groups: group 29 mm and group 31 mm,8 in each group. Infrarenal aortic artery was reconstructed with PAAA to establish abdominal aortic aneurysm (AAA) animal model. Blood coagulation index such as prothrombin time (PT),activated partial thromboplatin time (APTT),thrombin time (TT) and Fibrinogen (Fbg) were detected pre-operation,1,7 and 14 days post-operation,respectively. Blood routine parameters were detected pre-operation 11,3 and 7 days post-operation. Renal function parameters such as blood urea nitrogen (BUN),creatinine (CREA),urea acid (UA) and urea/ creatinine (BU/CREA) were evaluated pre-operation and 30,90,150 days post-operation,respectively. PAAA were removed en bloc to determinine its biofuction and biocompatibility after 5 months of surgery. Kidneys were fixed in neutral buffered formalin solution,pathological slice were conducted to observate pathological changes of kidneys by HE stain.The results are as follows:1. Animal model: The PAAA was implanted to the infrarenal abdominal aortic artery without extensive bleeding after anastomosis. One dog died 2,25 and 127 days post-operation in group 31 mm,respectively,and the overall success rate was 62. 5%. One dog died 7 days post-operation in group 29 mm,the overall success rate was 87. 5%.2. Biofunction and biocompatibility of PAAA: Autopsy showed that there were no abdominal adhesions around the PAAAs,the lumen was patent without blood clots,there were no bleeding in PAAAs in two groups. Biocompatibility was poor because the outer layer of PAAA was enclosed by tissues,which was easy to strip,in group 31 mm. Excellent biocompatibility was proved by vascular endothelial cells growth in the inner layer of PAAA in group 29 mm.3. Coagulation examination: ATPP reduced significantly 1 day post-operation,and returned to normal after 7 days;there was no significant difference on TT in two groups. Fbg increased significantly 1 day post-operation (3. 16 ± 0. 56g/L,P<0. 05),and returned to normal after 7 days; PT and INR have no significant difference in group 29 mm. Value of PT and INR was 7. 92 ± 0. 57s and 0. 655 ± 0. 49,respectively,which reduced significantly compared with base value (P<0. 05),and returned to normal after 7 days; Fbg increased extremely 1 day post-operation (3. 28 ± 0. 49 g /L) (P<0. 01),which still increased significantly after 7 and 14 days in group 31 mm.4. Blood routine examination: Red blood cell count (RBC) and hemoglobin (HGB) reduced significantly 1 and 3days post-operation (P<0. 05); white blood cell count (WBC) and intermediate cell rate (MID%) increased extremely 1 day post-operation; there was no significant change in platelet count in group 29 mm. Mean corpuscular volume (MCV),RBC,HGB reduced significantly 1 and 3 days post-operation; WBC and MID% increased extremely 1 day after surgery; platelet (PLT),thrombocytocrit (PCT%) and platelet distribution width (PDW%) increased significantly1 day post-operation in group 31 mm.5. Renal function: BUN was 3. 995 ± 0. 36 mmol/L,which reduced extremely (P<0. 01),CREA was 104. 5 ±13. 85 μmol/L,which increased significantly (P<0. 05) after 150 days. BU/CREA reduced 90 and 150 days post-operation; UA reduced significantly or extremely 30,90 and 150 days post-operation (P<0. 05,P<0. 01),Its' values were 309. 61 ± 40. 8 μmol/L,160. 26 ± 28. 73 μmol/L and 23. 69 ± 12. 66 μmol/L,respectively in group 29 mm.In group 31 mm,BUN were 5. 51 ± 0. 43 mmol/L and 5. 36 ± 0. 32 mmol/L,which reduced significantly (P <0. 05); BU/CREA reduced significantly (P<0. 05),CREA were 106. 83 ± 7. 0 μmol/L、113. 17 ± 9. 79 μmol/L (P< 0. 05),which increased significantly compared with base values (P<0. 05) 90 and 150 days post-operation. UA reduced significantly or extremely 30,90 and 150 days post-operation (P<0. 05,P<0. 01),its' values were 303. 17 ±39. 2 μmol/L,144. 17. 26 ± 31. 06 μmol/L and 20. 83 ± 11. 52 μmol/L,respectively.6. Pathologic observation of kidney: Glomerular atrophy and granular degeneration in renal tubule with luminal narrowing was observed under microscope. Red thrombosis could be seen in part of renal tubule and renal glomerulus.Animal model of PAAA in dogs was successfully established. Biofunction and biocompatibility of PAAA in group 29mm is better than that of group 31mm. There were great changes in renal function,and obvious pathological changes appeared on kidney post-operation. | LV Yu-huan XU Zai-pin XU Wanli MA Zhe PENG Yao DU Peihang SUN Anqiang Deng Xiaoyan LOU Hanjun | 2012 | 畜牧与兽医2012，44，S2： | 0 |
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