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BACKGROUND: Osteoporotic thoracolumbar burst fracture (OTLBF) is common in seniors. Due to the fracture of the posterior vertebra and spinal canal occupancy, the risk of cement leakage and spine injury is high in OTLBF patients, thus the application of vertebroplasty and kyphoplasty is limited in these patients. This study aims to investigate the efficacy and safety of the modified percutaneous kyphoplasty (MPKP) in the treatment of OTLBF. METHODS: Clinical data of the OTLBF patients treated with MPKP and the osteoporotic thoracolumbar compression fracture (OTLCF) patients undergone PKP from January 2014 to June 2016 were collected. The key procedure of the MPKP was to fill the bone cavity with gel-foam by the first balloon inflation and to press the gel-foam by a second balloon inflation. Pain intensity, Oswestry disability index (ODI), and bone cement leakage of the patients in the two groups were analyzed. RESULTS: In the burst fracture group, the overall spinal canal occupancy was relatively low, and the maximum occupancy was 1/3 of the sagittal diameter of the spinal canal. The surgical duration was longer in the burst fracture group (39.0 ± 5.0 min with 95% CI: 37.7, 40.3) than in the compression fracture group (31.7 ± 4.3 min with 95% CI: 31.1, 32.3), and the difference between the two groups was statistically significant (Z = -8.668 and P = 0.000). Both the Oswestry disability index (ODI) and the visual analog scales (VAS) were apparently improved, but there was no significant difference between the two groups. Cement leakage occurred in 13 out of the 53 cases (24.5%) in the burst fracture group and 35 out of the 193 cases (18.1%) in the compression fracture group, and there was no significant difference between the two groups (Z = - 1.038 and P = 0.299). Neither group had consequential symptoms, such as spinal cord lesion, pain, and numbness of the peripheral nerve. CONCLUSION: Similar to the efficacy of PKP in the treatment of OTLCF, MPKP efficiently reduced the cement leakage rate and improved the safety of the surgery, although it prolonged the surgical duration and introduced more surgical steps.
Assuntos
Cimentos Ósseos , Fraturas por Compressão/cirurgia , Cifoplastia/métodos , Fraturas por Osteoporose/cirurgia , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fraturas da Coluna Vertebral/cirurgia , Vértebras Torácicas/cirurgia , Resultado do Tratamento , Vertebroplastia/métodos , Escala Visual AnalógicaRESUMO
Blood-retinal barrier breakdown is the main pathological characteristics of diabetic retinopathy (DR). Asymmetric dimethylarginine (ADMA) was reported to be elevated in DR patients. In this study, we observed the dynamic profile of ADMA, retinal morphology and permeability of BRB at 2, 4 or 8 week of diabetic rats induced by a single intraperitoneal injection of streptozocin (60 mg/kg) and in cultured rat retinal pericytes pretreated with D-glucose (30 mM) for 1, 3, 5 and 7 days or ADMA (3, 10, 30 µM) for 24, 48 and 72 h, trying to explore the effects of ADMA on blood-retinal barrier in DR. Gap junction intercellular communication (GJIC) and the expression of blood-retinal barrier-specific component connexin 43 (Cx43) were examined in diabetic rats or cultured retinal pericytes to elucidate whether ADMA impacted blood-retinal barrier function via damaging Cx43-GJIC. The results showed that with increasing duration of diabetes, the ultrastructure of blood-retinal barrier of diabetic rats appeared cell junction damage, apoptosis of retinal pericytes and breakdown of barrier successively. The increases in retinal permeability, ADMA levels and Cx43 expression, and abnormal GJIC were observed in diabetic rats and retinal pericytes exposed to D-glucose (30 mM). A glucose-like effect was seen using ADMA or another L-arginine analogue NG-monomethyl-L-arginine or dimethylarginine dimethylaminohydrolases (DDAHs) siRNA, implicating that ADMA aggravated the breakdown of blood-retinal barrier via damaging Cx43-GJIC.
Assuntos
Arginina/análogos & derivados , Barreira Hematorretiniana/patologia , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/patologia , Pericitos/patologia , Animais , Apoptose , Arginina/metabolismo , Barreira Hematorretiniana/metabolismo , Comunicação Celular , Permeabilidade da Membrana Celular , Células Cultivadas , Conexina 43/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/induzido quimicamente , Retinopatia Diabética/metabolismo , Junções Comunicantes/patologia , Glucose/metabolismo , Masculino , Pericitos/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina/administração & dosagem , Estreptozocina/toxicidadeRESUMO
Myeloperoxidase (MPO)-derived product hypochlorous acid (HOCl) is able to induce cellular senescence and MPO is also expressed in endothelial cells besides the well-recognized immune cells. This study aims to clarify the association of endothelium-derived MPO with endothelial senescence in hyperlipidemia. The rats were fed with high-fat diet for 8 weeks to establish a hyperlipidemic model, which showed an increase in plasma lipids, endothelium-derived MPO expression, endothelial senescence and endothelial dysfunction concomitant with a reduction in glycogen synthase kinase 3 beta (GSK-3ß) activity and phosphorylated ß-catenin (p-ß-catenin) level as well as an increase in ß-catenin and p53 levels within the endothelium. Next, human umbilical vein endothelial cells (HUVECs) were incubated with oxidized low density lipoprotein (ox-LDL, 100 µg/ml) for 24 h to establish a senescent cell model in vitro. Consistent with the finding in vivo, ox-LDL-induced MPO expression and HUVECs senescence, accompanied by a decrease in GSK-3ß activity and p-ß-catenin level as well as an increase in HOCl content, ß-catenin and p53 levels; these phenomena were attenuated by MPO inhibitor. Replacement of ox-LDL with HOCl could also induce HUVECs senescence and activate the ß-catenin/p53 pathway. Based on these observations, we conclude that endothelium-derived MPO is upregulated in hyperlipidemic rats, which may contribute to the accelerated vascular endothelial senescence through a mechanism involving the ß-catenin/p53 pathway.
Assuntos
Células Endoteliais/metabolismo , Hiperlipidemias/metabolismo , Ácido Hipocloroso/metabolismo , Lipoproteínas LDL/metabolismo , Peroxidase/metabolismo , beta Catenina/metabolismo , Animais , Senescência Celular , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Endotélio Vascular/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Hiperlipidemias/patologia , Ácido Hipocloroso/farmacologia , Lipídeos/sangue , Lipoproteínas LDL/farmacologia , Masculino , Peroxidase/química , Ratos Sprague-Dawley , Proteína Supressora de Tumor p53/metabolismoRESUMO
Background: In observational studies, the relationship between coffee intake and bone mineral density (BMD) is contradictory. However, residual confounding tends to bias the results of these studies. Therefore, we used a two-sample Mendelian randomization (MR) approach to further investigate the potential causal relationship between the two. Methods: Genetic instrumental variables (IVs) associated with coffee intake were derived from genome-wide association studies (GWAS) of the Food Frequency Questionnaire (FFQ) in 428,860 British individuals and matched using phenotypes in PhenoScanner. Summarized data on BMD were obtained from 537,750 participants, including total body BMD (TB-BMD), TB-BMD in five age brackets ≥60, 45-60, 30-45, 15-30, and 0-15 years, and BMD in four body sites: the lumbar spine, the femoral neck, the heel, and the ultradistal forearm. We used inverse variance weighting (IVW) methods as the primary analytical method for causal inference. In addition, several sensitivity analyses (MR-Egger, Weighted median, MR-PRESSO, Cochran's Q test, and Leave-one-out test) were used to test the robustness of the results. Results: After Bonferroni correction, Coffee intake has a potential positive correlation with total body BMD (effect estimate [Beta]: 0.198, 95% confidence interval [Cl]: 0.05-0.35, P=0.008). In subgroup analyses, coffee intake was potentially positively associated with TB-BMD (45-60, 30-45 years) (Beta: 0.408, 95% Cl: 0.12-0.69, P=0.005; Beta: 0.486, 95% Cl: 0.12-0.85, P=0.010). In addition, a significant positive correlation with heel BMD was also observed (Beta: 0.173, 95% Cl: 0.08-0.27, P=0.002). The results of the sensitivity analysis were generally consistent. Conclusion: The results of the present study provide genetic evidence for the idea that coffee intake is beneficial for bone density. Further studies are needed to reveal the biological mechanisms and offer solid support for clinical guidelines on osteoporosis prevention.
Assuntos
Densidade Óssea , Café , Humanos , Densidade Óssea/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Colo do FêmurRESUMO
Background: Observational studies have shown that changes in circulating cytokine/growth factor levels occur throughout the initiation and progression of ankylosing spondylitis (AS), yet whether they are etiologic or downstream effects remains unclear. In this study, we performed a summarized-level bidirectional Mendelian randomization (MR) analysis to shed light on the causal relationship between the two. Methods: Genetic instrumental-variables (IVs) associated with circulating cytokine/growth factor levels were derived from a genome-wide association study (GWAS) of 8,293 European individuals, whereas summary data for the AS were obtained from a FinnGen GWAS of 166,144 participants. We used the inverse-variance-weighted (IVW) method as the main analysis for causal inference. Furthermore, several sensitivity analyses (MR-Egger, weighted median, MR-PRESSO and Cochran's Q test) were utilized to examine the robustness of the results. Finally, reverse MR analysis was performed to assess reverse causality between AS and circulating cytokine/growth factor levels. Results: After Bonferroni correction, circulating levels of Cutaneous T-cell attracting (CTACK) and Monocyte specific chemokine 3 (MCP-3) were positively associated with a higher risk of AS (odds ratio [OR]: 1.224, 95% confidence interval [95% Cl]: 1.022 ~ 1.468, P = 0.028; OR: 1.250, 95% Cl: 1.016 ~ 1.539, P = 0.035). In addition, elevated circulating levels of Basic fibroblast growth factor (FGF-basic), Granulocyte colony-stimulating factor (G-CSF) and MCP-3 was considered a consequence of AS disease (ß = 0.023, P = 0.017; ß = 0.017, P = 0.025; ß = 0.053, P = 0.025). The results of the sensitivity analysis were generally consistent. Conclusion: The present study supplies genetic evidence for the relationship between circulating cytokine levels and AS. Targeted interventions of specific cytokines may help to reduce the risk of AS initiation and progression.
Assuntos
Citocinas , Espondilite Anquilosante , Humanos , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Espondilite Anquilosante/genética , Fator Estimulador de Colônias de GranulócitosRESUMO
Tumor-associated macrophages (TAMs) play critical roles in reprogramming other immune cells and orchestrating antitumor immunity. However, the interplay between TAMs and tumor cells responsible for enhancing immune evasion remains insufficiently understood. Here, we revealed that interleukin (IL)-1ß was among the most abundant cytokines within the in vitro tumor-macrophage coculture system, and enhanced IL-1ß expression was associated with impaired cytotoxicity of CD8+ T cells in human ovarian cancer, indicating the possibility that IL-1ß mediated immunosuppression during tumor-TAMs crosstalk. Mechanistically, we demonstrated that IL-1ß significantly boosted programmed death-ligand 1 (PD-L1) expression in tumor cells via the activation of the nuclear factor-κb signaling cascade. Specifically, IL-1ß released from TAMs was triggered by lactate, the anaerobic metabolite of tumor cells, in an inflammasome activation-dependent manner. IL-1ß sustained and intensified immunosuppression by promoting C-C motif chemokine ligand 2 secretion in tumor cells to fuel TAMs recruitment. Importantly, IL-1ß neutralizing antibody significantly curbed tumor growth and displayed synergistic antitumor efficacies with anti-PD-L1 antibody in tumor-bearing mouse models. Together, this study presents an IL-1ß-centered immunosuppressive loop between TAMs and tumor cells, highlighting IL-1ß as a candidate therapeutic target to reverse immunosuppression and potentiate immune checkpoint blockade.
RESUMO
Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.
Assuntos
Plaquetas , Neoplasias Ovarianas , Humanos , Feminino , Plaquetas/patologia , Biomarcadores Tumorais/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , ChinaRESUMO
OBJECTIVES: To determine whether functional polymorphisms of glutathione S-transferase µ type 1 (GSTM1) and aldehyde dehydrogenase-2 (ALDH2) affect the isosorbide 5-mononitrate (IS-5-MN) response, and the role of the calcitonin gene-related peptide (CGRP) in IS-5-MN response in healthy volunteers. METHODS: A two-phase, placebo-controlled study was carried out in 24 healthy Chinese volunteers with their ALDH2 and GSTM1 genotypes known. During each phase, either 20-mg IS-5-MN tablet or placebo was orally administered; blood pressure (BP), heart rate, and plasma concentration of CGRP was determined before and at several time points after drug administration. Pharmacokinetic parameters of IS-5-MN were determined. RESULTS: GSTM1 null individuals showed significantly lower systolic BP (SBP) and diastolic BP (DBP), and higher degree of decreases in SBP (ΔSBP) and DBP (ΔDBP) after IS-5-MN administration. GSTM1 null individuals showed significantly decreased IS-5-MN area under the plasma concentration-time curve than GSTM1 wild-type individuals (P<0.05). Plasma concentration of CGRP was increased significantly at 0.5 (P<0.01), 1 (P<0.05), and 2 h (P<0.05) after IS-5-MN administration in GSTM1 null individuals but not wild-type individuals. GSTM1 null individuals also showed significantly higher degree of percentage increase in the plasma concentration of CGRP than GSTM1 wild-type individuals at 1 h after IS-5-MN administration (P<0.05). IS-5-MN upregulated CGRP I and CGRP II mRNA expressions in cultured peripheral blood mononuclear cells, and the IS-5-MN-induced CGRP II mRNA expression was inhibited by GSTs inhibitor, ethacrynic acid. No difference in the IS-5-MN response was observed between ALDH2 genotypes. CONCLUSION: We suggest that GSTM1, but not ALDH2, may interfere with the bioactivation of IS-5-MN, and CGRP contributes to the IS-5-MN response in a GSTM1 genotype-dependent manner.
Assuntos
Aldeído Desidrogenase/genética , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Sistema Cardiovascular/efeitos dos fármacos , Glutationa Transferase/genética , Dinitrato de Isossorbida/análogos & derivados , Doadores de Óxido Nítrico/administração & dosagem , Vasodilatadores/administração & dosagem , Adulto , Aldeído Desidrogenase/metabolismo , Aldeído-Desidrogenase Mitocondrial , Pressão Sanguínea/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/sangue , China , Glutationa Transferase/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Humanos , Dinitrato de Isossorbida/administração & dosagem , Dinitrato de Isossorbida/sangue , Dinitrato de Isossorbida/farmacologia , Masculino , Doadores de Óxido Nítrico/sangue , Doadores de Óxido Nítrico/farmacocinética , Vasodilatadores/sangue , Vasodilatadores/farmacocinéticaRESUMO
Ferroptosis is an iron-dependent regulated necrosis. This study aims to evaluate the contribution of ferroptosis to ischemia or reperfusion injury, and lay a basis for precise therapy of myocardial infarction. The Sprague-Dawley (SD) rat hearts were subjected to ischemia for different duration or the hearts were treated with 1 h-ischemia plus different duration of reperfusion. The myocardial injury was assessed by biochemical assays and hematoxylin & eosin (HE) staining. The ferroptosis was evaluated with the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), iron, and malondialdehyde. Iron chelator (deferoxamine) was applied to verify the contribution of ferroptosis to ischemia and reperfusion injury. The results showed that ischemic injury (infarction and CK release) was getting worse with the extension of ischemia, but no significant changes in ferroptosis indexes (ACSL4, GPX4, iron, and malondialdehyde) in cardiac tissues were observed. Differently, the levels of ACSL4, iron, and malondialdehyde were gradually elevated with the extension of reperfusion concomitant with a decrease of GPX4 level. In the ischemia-treated rat hearts, no significant changes in myocardial injury were observed in the presence of deferoxamine, while in the ischemia/reperfusion-treated rat hearts, myocardial injury was markedly attenuated in the presence of deferoxamine concomitant with a reduction of ferroptosis. Based on these observations, we conclude that ferroptosis occurs mainly in the phase of myocardial reperfusion but not ischemia. Thus, intervention of ferroptosis exerts beneficial effects on reperfusion injury but not ischemic injury, laying a basis for precise therapy for patients with myocardial infarction.
Assuntos
Ferroptose , Isquemia , Traumatismo por Reperfusão Miocárdica , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Coenzima A Ligases/metabolismo , Creatina Quinase/sangue , Desferroxamina/farmacologia , Ferro/metabolismo , Isquemia/metabolismo , Masculino , Malondialdeído/metabolismo , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Ratos Sprague-Dawley , Sideróforos/farmacologiaRESUMO
Iron overload triggers the ferroptosis in the heart following ischemia/reperfusion (I/R) and transferrin receptor 1 (TfR1) charges the cellular iron uptake. Bioinformatics analysis shows that the three molecules of ubiquitin-specific protease 7 (USP7), p53 and TfR1 form a unique pathway of USP7/p53/TfR1. This study aims to explore whether USP7/p53/TfR1 pathway promotes ferroptosis in rat hearts suffered I/R and the underlying mechanisms. The SD rat hearts were subjected to 1 h-ischemia plus 3 h-reperfusion, showing myocardial injury (increase in creatine kinase release, infarct size, myocardial fiber loss and disarray) and up-regulation of USP7, p53 and TfR1 concomitant with an increase of ferroptosis (reflecting by accumulation of iron and lipid peroxidation while decrease of glutathione peroxidase activity). Inhibition of USP7 activated p53 via suppressing deubiquitination, which led to down-regulation of TfR1, accompanied by the decreased ferroptosis and myocardial I/R injury. Next, H9c2 cells underwent hypoxia/reoxygenation (H/R) in vitro to mimic the myocardial I/R model in vivo. Consistent with the results in vivo, inhibition or knockdown of USP7 reduced the H/R injury (decrease of LDH release and necrosis) and enhanced the ubiquitination of p53 along with the decreased levels of p53 and TfR1 as well as the attenuated ferroptosis (manifesting as the decreased iron content and lipid peroxidation while the increased GPX activity). Knockdown of TfR1 inhibited H/R-induced ferroptosis without p53 deubiquitination. Based on these observations, we conclude that a novel pathway of USP7/p53/TfR1 has been identified in the I/R-treated rat hearts, where up-regulation of USP7promotes ferrptosis via activation of the p53/TfR1 pathway.
Assuntos
Ferroptose , Coração , Peptidase 7 Específica de Ubiquitina/genética , Animais , Isquemia , Ratos , Ratos Sprague-Dawley , Receptores da Transferrina , Reperfusão , Proteína Supressora de Tumor p53/genéticaRESUMO
Necroptosis, ferroptosis and cyclophilin D (Cyp D)-dependent necrosis contribute to myocardial ischemia/reperfusion (I/R) injury, and ponatinib, deferoxamine and cyclosporine are reported to inhibit necroptosis, ferroptosis and Cyp D-dependent necrosis, respectively. This study aims to explore whether the any two combination between ponatinib, deferoxamine and cyclosporine exerts a better cardioprotective effect on I/R injury than single medicine does. The H9c2 cells were subjected to 10 h of hypoxia (H) plus 4 h of reoxygenation (R) to establish H/R injury model. The effects of any two combination between ponatinib, deferoxamine and cyclosporine on H/R injury were examined. On this basis, a I/R injury model in rat hearts was established to focus on the effect of ponatinib, deferoxamine and their combination on myocardial I/R injury and the underlying mechanisms. In H/R-treated H9c2 cells, all three medicines can attenuate H/R injury (decrease in LDH release and necrosis percent). However, only the combination of ponatinib with deferoxamine exerted synergistic effect on reducing H/R injury, showing simultaneous suppression of necroptosis and ferroptosis. Expectedly, administration of ponatinib or deferoxamine either before or after ischemia could suppress necroptosis or ferroptosis in the I/R-treated rat hearts as they did in vitro, concomitant with a decrease in myocardial infarct size and creatine kinase release, and the combination therapy is more efficient than single medication. Based on these observations, we conclude that the combination of ponatinib with deferoxamine reduces myocardial I/R injury via simultaneous inhibition of necroptosis and ferroptosis.
Assuntos
Desferroxamina/farmacologia , Ferroptose/efeitos dos fármacos , Imidazóis/farmacologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Necroptose/efeitos dos fármacos , Piridazinas/farmacologia , Animais , Linhagem Celular , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
1. It has been reported that resveratrol exerts the inhibitory effects on aging through activation of sirtuin 1 (SIRT1) and dimethylarginine dimethylaminohydrolase (DDAH)/asymmetric dimethylarginine (ADMA) pathway involved in the high glucose-induced endothelial cell senescence. 2. The aims of this work were to explore whether BTM-0512, a novel derivative of resveratrol, was able to exert the beneficial effect on high glucose-induced cellular senescence through regulating the DDAH/ADMA pathway and to explore whether the regulatory effect of BTM-0512 on DDAH/ADMA pathway was related to the activation of SIRT1. 3. The senescence model of endothelial cells was induced by high glucose and the cells were collected for the determination of beta-galactosidase and DDAH activity, ADMA level, DDAH and SIRT1 mRNA expression. 4. The results showed that high glucose significantly increased the ratio of senescent cells concomitantly with the decreased DDAH activity, the downregulated DDAH2 and SIRT1 mRNA expressions and the increased ADMA levels, which were attenuated by pretreatment with BTM-0512. 5. The beneficial effects of BTM-0512 on high glucose-induced senescence were blocked by splimtomicin, the specific inhibitor of SIRT1, or by silencing DDAH2 expression. 6. The results suggest that BTM-0512 was able to exert the beneficial effects on high glucose-induced cellular senescence through regulating the DDAH/ADMA pathway, and its regulatory effect on DDAH/ADMA pathway was related to the activation of SIRT1.
Assuntos
Amidoidrolases/metabolismo , Antioxidantes/farmacologia , Arginina/análogos & derivados , Senescência Celular/efeitos dos fármacos , Glucose/efeitos adversos , Estilbenos/análise , Estilbenos/farmacologia , Amidoidrolases/genética , Arginina/metabolismo , Técnicas de Cultura de Células , Linhagem Celular , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/enzimologia , Células Endoteliais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Endotélio Vascular/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase/metabolismo , RNA Mensageiro/genética , Espécies Reativas de Oxigênio/metabolismo , Resveratrol , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sirtuína 1/metabolismoRESUMO
OBJECTIVE: To study effects of postoperative regular training of core muscle strength guided by the concept of enhanced recovery after surgery (ERAS) on the rehabilitation of elderly patients with osteoporotic lumbar vertebral compression fracture after vertebroplasty (PVP) and kyphoplasty(PKP). METHODS: Ninety-four elderly patients with osteoporotic lumbar compression fractures who underwent PKP or PVP from January 2016 to January 2018 and met inclusion criteria were divided into observation group and control group. All the patients were treated with routine anti osteoporosis therapy after operation. There were 47 patients in the observationgroup, including 18 males and 29 females, with an average age of (62.62±3.21) years old;in the control group, there were 47 cases, including 17 males and 30 females, with an average age of (62.38±2.84) years old. The patients in the control group were trained by traditional way, and the patients in observation group were instructed to conduct regular training of core muscle strength according to ERAS concept. The patients were followed up for 1, 3 and 6 months after operation. Patients' conditions were quantitatively evaluated according to Barthel scale, JOA low back pain score and Oswestry Disability Index, and the differences in treatment effects between two groups were statistically analyzed and compared. RESULTS: All the patients were followed up, and the Barthel scale, JOA low back pain score and Oswestry Disability Index score of the observation group were all better than those of the control group on the 1st and the 3rd months after surgery(P< 0.05). The Oswestry Disability Index score of the observation group on the 6th month after surgery were superior to those of the control group (P<0.05). However, there was no significantly difference in JOA low back pain score and Barthel scale between two groups at 6 months after surgery (P>0.05). The comparison of Barthel scale, JOA low back pain score and Oswestry Disability Index before and after the operation of 1, 3 and 6 months between the two groups were significantly improved (P<0.05). CONCLUSION: Early regular core strength training has a positive effect on early functional recovery and improvement of life ability after PKP or PVP for elderly patients with osteoporotic lumbar compression fractures, which is in line with the concept of accelerated rehabilitation surgery.
Assuntos
Fraturas por Compressão , Cifoplastia , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Vertebroplastia , Idoso , Recuperação Pós-Cirúrgica Melhorada , Feminino , Fraturas por Compressão/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Fraturas por Osteoporose/cirurgia , Fraturas da Coluna Vertebral/cirurgia , Resultado do TratamentoRESUMO
OBJECTIVE: From the perspective of clinical application to analyze the effectiveness and reliability of CPC/PMMA bone cement in percutaneous kyphoplasty (PKP) for the treatment of elderly patients with osteoporotic thoracolumbar fractures. METHODS: A retrospective analysis was performed on 62 patients with osteoporotic compression fracture of single-vertebral thoracic or lumbar segment who underwent PKP surgery and had a bone density less than or equal to -3.0 SD from February 2016 to December 2016. Among them, 23 patients were in CPC/PMMA group, with an average age of (77.6±2.2) years old, 39 patients in PMMA group, with an average age of (77.1±1.1) years old. The indexes between two groups were compared, including the visual analogue scale (VAS), height ratio of anterior vertebra (AVHR), local Cobb angle, cement leakage, new adjacent vertebral fracture(NAVF). RESULTS: There were no significant difference in gender, age, follow-up time and preoperative VAS, AVHR, local Cobb angle between two groups (P>0.05), at the 1 day after operation, VAS, AVHR, local Cobb angle in all patients got obvious improvement (P<0.05), which was no significant difference at 1 day after operation and final follow-up (P>0.05). At the same time, there was no statistically significant difference in the incidence of new adjacent vertebral fracture and cement leakage (P>0.05). The pain in both groups continued to improve at follow up after operation (P<0.05), the local Cobb angle increased (P<0.05) and AVHR decreased slightly (P<0.05). However, the images of conventional methods (X-ray or CT) could not find signs about CPC degeneration and new bone ingrowth. CONCLUSION: CPC/PMMA composite bone cement is safe and reliablein PKP for treatment of elderly patients with osteoporotic thoracolumbar fractures, which can effectively relieve pain and maintain vertebral body stability. It has the same curative effect as PMMA bone cement. It was worthy to research more in future, although no direct evidences support the CPC/PMMA composite bone cement can reduce the incidence of adjacent vertebral fracture, CPC degeneration or new bone ingrowth.
Assuntos
Fraturas por Compressão , Cifoplastia , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Vertebroplastia , Idoso , Humanos , Cimentos Ósseos , Polimetil Metacrilato , Reprodutibilidade dos Testes , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: By comparing the clinical efficacy of short-segment and long-segment fixation for single-segment thoracic and lumbar spine III stage Kümmell disease to explore a more suitable fixed segment for the disease. METHODS: The clinical data of 46 patients with single-segment thoracic and lumbar spine III stage Kümmell disease treated from July 2013 to December 2016 were retrospectively analyzed. Forty-six patients were divided into short-segment fixation group(one vertebra above and below the diseased vertebra) and long-segment fixation group(two vertebrae on the upper and lower of the diseased vertebra) according to different methods of cement stick fixation. There were 25 patients in the short-segment fixation group, including 9 males and 16 females, with an average age of (75.3±4.5) years old, lumbar spine bone mineral density T-value of (-3.1±0.3) g/cm³, follow-up time of (13.0±2.3) months; there were 21 patients in long-segment fixation group, 6 males and 15 females, with an average age of (74.5±3.9) years old, lumbar spine bone mineral density T-value of (-3.2±0.3) g/cm³, follow-up time of (14.7±3.6) months.The gender, age, follow-up time, operation time, intraoperative blood loss, cement leakage, and the rate of adjacent vertebrae fractures were compared between two groups, as well as pain VAS score, ODI, and kyphosis angle before and after surgery. RESULTS: There were no significant differences in age, gender, bone density, pain VAS score, ODI, and kyphosis between two groups before surgery. The operation time and intraoperative blood loss of short-segment fixation group were less than that of long-segment fixation group. The pain VAS score, ODI and kyphosis of the two groups were significantly improved at 7 days after the operation and at the latest follow-up, there was no significant difference between two groups. There were no significant differences in bone cement leakage(9/25 vs 11/21) and adjacent vertebrae fractures(4/25 vs 3/21). CONCLUSIONS: Both long-segment fixation and short-segment fixation can effectively relieve pain, correct kyphosis, improve functional index, and achieve better clinical results, but short-segment fixation has less operation time and less intraoperative blood. So single-segment thoracic and lumbar spine III stage Kümmell disease does not need to extend the fixed segment, short-segment fixation is more in line with clinical needs and worthy of further study.
Assuntos
Cifose , Fraturas da Coluna Vertebral , Idoso , Feminino , Fixação Interna de Fraturas , Humanos , Vértebras Lombares , Masculino , Estudos Retrospectivos , Vértebras Torácicas , Resultado do TratamentoRESUMO
In the present study, the efficacy of unilateral transverse process-pedicle and bilateral puncture techniques in percutaneous kyphoplasty (PKP) for Kummell disease was compared. Between March 2015 and June 2017, 63 patients with Kummell disease were recruited and underwent PKP with two different puncture techniques: A total of 38 patients were treated by unilateral transverse process-pedicle PKP and 25 patients were treated by bilateral PKP. The operative time, intra-operative fluoroscopy time, volume of bone cement injection and bone cement leakage were recorded. Prior to surgery and 1 day post-surgery, the visual analogue scale (VAS) pain score and Oswestry disability index (ODI) were determined, and the vertebral body height and Cobb angle were measured. The results indicated that the incidence of bone cement leakage in the unilateral group was similar with the bilateral group (15.79% vs. 16.00%), with no statistically significant difference between the two groups. None of the patients in the two groups had any obvious damage of the spinal cord. The operative time, intra-operative fluoroscopy time and volume of bone cement injection in the unilateral group were lower than those in the bilateral group. A chest X-ray examination at 1 day post-surgery revealed no pulmonary embolism in the two groups. The VAS score, ODI, vertebral body height and Cobb angle were significantly improved in the unilateral and bilateral groups at 1 day post-surgery and at the last follow-up (12 months post-surgery) as compared with these parameters prior to surgery. In conclusion, the unilateral transverse process-pedicle and bilateral puncture techniques in PKP exhibited good efficacy as a treatment for Kummell disease. The operative time, intra-operative fluoroscopy time and volume of bone cement injection were lower in the unilateral group.
RESUMO
OBJECTIVE: To study the postmortem stability of cTnT as well as its expression alteration, and to evaluate it in the diagnosis of early myocardial ischemia in forensic practice. METHODS: Animal model of early myocardial ischemia was established by rabbit coronary artery ligation. The expression of cTnT in myocardium at different postmortem intervals was detected using immunohistochemistry and analyzed using imaging technique and statistics. The results were then compared between the experimental and control groups. RESULTS: In ischemic myocardium, the expression of cTnT showed prominent focal or flaky depletion in myocardial cytoplasm with no expression detected in interstitium. The expression level showed a linear decrease with prolonged postmortem interval, and disappeared completely on day 14 after death while stored at 4 degrees C. However, there were significant differences in the expression levels of cTnT between experimental and control groups from day 1 to day 7 after death. CONCLUSION: Immunohistochemical detection of cTnT for diagnosis of early myocardial ischemia in corpses stored at 4 degrees C must be performed within 7 days after death.
Assuntos
Isquemia Miocárdica/metabolismo , Mudanças Depois da Morte , Troponina T/metabolismo , Animais , Feminino , Imuno-Histoquímica , Masculino , Miocárdio/metabolismo , Coelhos , Distribuição Aleatória , Fatores de Tempo , Troponina T/genéticaRESUMO
Statins are reported to exert benefits on endothelial function through a mechanism involving in prevention of endothelial senescence. This study aims to explore whether atorvastatin exerts inhibitory effect on endothelial senescence in hyperlipidemic rats or ox-LDL-treated HUVECs through a mechanism involving suppress of miR-21-5p/203a-3p expression and their downstream pathway. The rats were fed with high-fat diet to establish a hyperlipidemic model, which showed an increase in plasma lipids and endothelial senescence, accompanied by the elevation in plasma levels of miR-21-5p/203a-3p, down-regulation of Drp1 and up-regulation of p53 in the aorta of hyperlipidemic rats; these phenomena were reversed by atorvastatin. Next, HUVECs were incubated with ox-LDL to establish a senescent model in vitro. Consistent with the finding in vivo, atorvastatin treatment decreased the level of miR-21-5p and miR-203a-3p in the ox-LDL-treated HUVECs, restored Drp1 expression and mitochondrial function, as well as suppressed p53 and p16 expression and endothelial senescence. Based on these observations, we conclude that atorvastatin exerts inhibitory effect on endothelial senescence in hyperlipidemic rats through a mechanism involving down-regulation of miR-21-5p/203a-3p, which leads to the restoration of Drp1 level and recovery of mitochondrial function. Our findings highlight a novel non-lipid effect for atorvastatin besides its function in modulation of lipids.
Assuntos
Aorta/metabolismo , Atorvastatina/farmacologia , Senescência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais/metabolismo , Hiperlipidemias/metabolismo , MicroRNAs/biossíntese , Animais , Aorta/patologia , Dinaminas/biossíntese , Células Endoteliais/patologia , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Proteína Supressora de Tumor p53/biossínteseRESUMO
BACKGROUND AND AIMS: Vascular peroxidase 1 (VPO1) plays a key role in mediation of cardiovascular oxidative injury. This study aims to determine whether VPO1 can promote programmed necrosis of endothelial cells and the underlying mechanisms. METHODS AND RESULTS: Human umbilical vein endothelial cells (HUVECs) were incubated with oxidized low-density lipoprotein (ox-LDL, 100⯵g/mL) for 48â¯h to induce cell injury, which showed an elevation in cell necrosis (reflected by the increased propidium iodide (PI) positive-staining cells, LDH release and decreased cell viability), concomitant with an increase in programmed necrosis-relevant proteins including receptor-interacting protein kinase 1/3 (RIPK1/3), p-RIPK3 and mixed lineage kinase domain like (MLKL); these phenomena were attenuated by necrostatin-1(Nec-1) and RIPK3 siRNA. Meanwhile, VPO1 was up-regulated in ox-LDL-treated endothelial cells accompanied by a decrease in GSK-3ß activity and p-ß-catenin levels, and an elevation of ß-catenin levels; these phenomena were reversed in the presence of VPO1 siRNA or hypochlorous acid (HOCl) inhibitor; replacement of ox-LDL with HOCl could also induce endothelial programmed necrosis and activate the ß-catenin signaling; ß-catenin inhibitor could also suppress ox-LDL-induced RIPK-dependent necrosis. In hyperlipidemic patients, the plasma level of VPO1 was obviously increased concomitant with an elevation in plasma levels of RIPK1, RIPK3 and MLKL, and they were positively correlated. CONCLUSIONS: VPO1 plays an important role in promotion of endothelial programmed necrosis under hyperlipidemic conditions through activation of ß-catenin signaling. It may serve as a novel therapeutic target for prevention of endothelial dysfunction in hyperlipidemia.