Major vault protein attenuates cardiomyocyte injury in doxorubicin-induced cardiomyopathy through activating AKT.

BACKGROUND: Doxorubicin (DOX) has limited chemotherapy application for malignancies due to cardiotoxicity. The pathogenesis of DOX-induced cardiomyopathy (DiCM) is yet to be elucidated. Increasing studies proved that activation of AKT prevented cardiomyocyte apoptosis and cardiac dysfunction in response to DOX insult. Our previous studies indicated that major vault protein (MVP) deficiency was accompanied by suppressed phosphorylation of AKT in metabolic diseases. This study aimed to investigate the role and underlying mechanism of MVP on cardiomyocyte apoptosis in DiCM. METHODS: Mice were intraperitoneally injected with DOX 5 mg/kg, once a week for 5 weeks, the total cumulative dose was 25 mg/kg. Cardiomyocyte-specific MVP overexpression was achieved using an adeno-associated virus system under the cTnT promoter after the fourth DOX injection. Cardiac function was examined by echocardiography followed by euthanasia. Tissue and serum were collected for morphology analysis and biochemical examination. RESULTS: Herein, we found that MVP expression was upregulated in DOX-treated murine hearts. Cardiac-specific MVP overexpression alleviated DOX-induced cardiac dysfunction, oxidative stress and fibrosis. Mechanistically, MVP overexpression activated AKT signaling and decreased cardiomyocyte apoptosis in DiCM. CONCLUSIONS: Based on these findings, we supposed that MVP was a potential therapeutic agent against DiCM.

Application of Intraoperative Electromyography Intelligent Monitoring in Orthopedic Surgery under General Anesthesia.

To study the application of intraoperative EMG intelligent monitoring in orthopedic surgery under general anesthesia, a total of 53 patients who underwent orthopedic surgery from February 2021 to February 2022 were selected. The combined monitoring of somatosensory evoked potential (SEP), motor evoked potential (MEP), and electromyography (EMG) was used to analyze the monitoring efficiency. In 38 of the 53 patients, the intraoperative signal was normal, and there was no postoperative neurological dysfunction; one case had abnormal signal, and the abnormality still existed after debugging, but no obvious neurological dysfunction was found after operation; the remaining 14 cases had abnormal signal. There were 13 early warnings in SEP monitoring; 12 early warnings in MEP monitoring; 10 early warnings in EMG monitoring. There were 15 cases of early warning in the joint monitoring of the three, and the sensitivity of the combined monitoring of SEP + MEP + EMG was significantly higher than that of the single monitoring of SEP, MEP, and EMG (p < 0.05). There was no significant difference in specificity, positive predictive value, and negative predictive value between combined monitoring and single monitoring (p > 0.05). The combined monitoring of EMG, MEP, and SEP in orthopedic surgery can significantly improve the safety of surgery, its sensitivity and negative predictive value were significantly higher than the monitoring effects of the two alone.

Nanoparticles that target the mitochondria of tumor cells to restore oxygen supply for photodynamic therapy: Design and preclinical validation against breast cancer.

Photodynamic therapy, in which photosensitizers locally generate cytotoxic reactive oxygen species, can treat tumor tissue with minimal effects on surrounding normal tissue, but it can be ineffective because of the anoxic tumor microenvironment. Here we developed a strategy to inactivate the mitochondria of tumor cells in order to ensure adequate local oxygen concentrations for photodynamic therapy. We conjugated the photosensitizer 5-aminolevulinic acid to the lipophilic cation triphenylphosphine, which targets mitochondria. Then we packaged the conjugate into nanoparticles that were based on biocompatible bovine serum albumin and coated with folic acid in order to target the abundant folate receptors on the tumor surface. In studies in cell culture and BALB/c mice bearing MCF-7 xenografts, we found that the nanoparticles helped solubilize the cation-photosensitizer conjugate, prolong its circulation, and enhance its photodynamic antitumor effects. We confirmed the ability of the nanoparticles to target tumor cells and their mitochondria using confocal laser microscopy and in vivo assays of pharmacokinetics, pharmacodynamics, and tissue distribution. Our results not only identify a novel nanoparticle system for treating cancer, but they demonstrate the feasibility of enhancing photodynamic therapy by reducing oxygen consumption within tumors.

Trophoblast Stem-Cell-Derived Exosomes Alleviate Cardiotoxicity of Doxorubicin via Improving Mfn2-Mediated Mitochondrial Fusion.

Doxorubicin (Dox) is an anticancer drug widely used in tumor chemotherapy, but it has the side-effect of cardiotoxicity, which is closely related to mitochondrial damage. Mitochondrial dynamics is a quality control mechanism that usually helps to maintain a healthy mitochondrial pool. Trophoblast stem cell-derived exosomes (TSC-Exos) have been shown to protect cardiomyocytes from DOX-induced cardiotoxicity. To explore whether the cardioprotective role is mediated by the regulation of mitochondrial dynamic mechanism, TSC-Exos were isolated from human trophoblast stem cells by ultracentrifugation and characterized by Western blot and transmission electron microscopy. Cellular experiments of H9c2 cardiomyocytes co-cultured with Dox and TSC-Exos were performed in vitro to determine the levels of reactive oxygen species generation and apoptosis level. An animal model of heart failure was established by intraperitoneal injection of Dox in vivo, therapy mice were received additional intracardiac injection of TSC-Exos, then, the cardiac function, cardiomyocyte apoptosis and mitochondrial fragmentation were ameliorated. Histology assays suggest that Dox caused an increased tendency of mitochondrial fission, which was manifested by a decrease in the average size of mitochondria. By receiving TSC-Exos treatment, this effect was eliminated. In summary, these results suggest that TSC-Exos alleviate DOX-induced cardiotoxicity through antiapoptotic effect and improving mitochondrial fusion with an increase in Mfn2 expression. This study is the first to provide a potential new treatment scheme for the treatment of heart failure from the perspective of the relationship between TSC-Exos and mitochondrial dynamics.

Colchicine Ameliorates Dilated Cardiomyopathy Via SIRT2-Mediated Suppression of NLRP3 Inflammasome Activation.

Background Dilated cardiomyopathy remains a leading cause of heart failure worldwide. Immune inflammation response is recognized as a significant player in the progression of heart failure; however, immunomodulatory strategies remain a long-term challenge. Colchicine, a potent anti-inflammatory drug, has many benefits in ischemic cardiovascular events, but its role in nonischemic heart failure remains unclear. Methods and Results Doxorubicin administration was used to establish a murine dilated cardiomyopathy model, and colchicine or saline was orally given. At the end point, cardiac function and fibrosis were measured to investigate the effects of colchicine. Inflammatory cytokine levels, neutrophil recruitment, and NLRP3 (NOD-like receptor protein 3) inflammasome activation were detected to evaluate the inflammatory response. Furthermore, to examine the downstream target of colchicine, SIRT2 (Sirtuin 2) was pharmacologically inhibited in vitro; thus, changes in the NLRP3 inflammasome were detected by immunoblotting. These results showed that murine cardiac function was significantly improved and fibrosis was significantly alleviated after colchicine treatment. Moreover, the infiltration of neutrophils and the levels of inflammatory cytokines in the failing myocardium were both decreased by colchicine treatment. Mechanistically, colchicine upregulated the expression of SIRT2, leading to the inactivation of the NLRP3 inflammasome in an NLRP3 deacetylated manner. Conversely, the inhibition of SIRT2 attenuated the suppressive effect of colchicine on NLRP3 inflammasome activation. Conclusions This study indicated that colchicine could be a promising therapeutic candidate for dilated cardiomyopathy and other nonischemic heart failure associated with the inflammatory response.

Colchicine alleviates inflammation and improves diastolic dysfunction in heart failure rats with preserved ejection fraction.

PURPOSE: Several studies have reported that colchicine attenuates cardiac inflammation and improves cardiac function in myocardial infarction and atrial fibrillation. However, no study has investigated its effect on heart failure with preserved ejection fraction (HFpEF). Hence, this study aimed to assess its efficacy in a high salt diet (HSD)-induced HFpEF rat model. METHODS: A rat hypertension-induced HFpEF model was created by treating Dahl/SS salt-sensitive rats with an HSD for 6 weeks. Colchicine was given via gavage daily as treatment. Cardiac function and inflammation were assessed using echocardiography, histology, and ELISA. Furthermore, the expression levels of NLRP3 and NF-κB signaling pathways were examined. RESULTS: Treatment with colchicine increased survival and attenuated cardiac dysfunction, as indicated by decreased echocardiographic E/A ratio and longer exercise endurance along with reduced ventricular fibrosis and remodeling in HSD-induced Dahl rats. The treatment also reduced cardiac oxidative stress and inflammatory cell infiltration, as inferred from lower mRNA expressions of TNFα and CCL2 as well as protein expressions of NLRP3 and NF-κB pathways. CONCLUSION: The findings signify that colchicine plays a crucial role in alleviating systemic inflammation and NLRP3 inflammation activation as well as in attenuating cardiac dysfunction and fibrosis in HSD-induced HFpEF model. Colchicine, therefore, holds therapeutic potential for further clinical applications.

Renal Denervation Attenuates Adverse Remodeling and Intramyocardial Inflammation in Acute Myocardial Infarction With Ischemia-Reperfusion Injury.

Background: Inhibition of sympathetic activity and renin-angiotensin system with renal denervation (RDN) was proved to be effective in managing refractory hypertension, and improving left ventricular (LV) performance in chronic heart failure. The inhibition of sustained sympathetic activation prevents or delays the development of cardiac fibrosis and dysfunction that occurs after myocardial infarction and ischemia-reperfusion (I/R) injury. The translational efficiency of RDN remains to be defined in preclinical animal studies. Objectives: This study investigated the therapeutic role of RDN in adverse remodeling and intramyocardial inflammation in myocardial ischemia-reperfusion (MI/R) injury. Methods: Herein, 15 minipigs were subjected to 90-min percutaneous occlusion of the left anterior descending artery followed by reperfusion. Eight animals received simultaneous RDN using catheter-based radiofrequency ablation (MI/R-RDN). Cardiac function and infarct volume were measured in vivo, followed by histological and biochemical analyses. Results: The infarct volume in I/R-RDN pigs reduced at 30 days postreperfusion, compared to I/R-Sham animals. The levels of catecholamine and cytokines in the serum, kidney cortex, the border, and infarcted regions of the heart were significantly reduced in I/R-RDN group. Moreover, the gene expression of collagen and the protein expression of adrenergic receptor beta 1 in heart were also decreased in I/R-RDN mice. Additionally, RDN therapy alleviated myocardial oxidative stress. Conclusion: RDN is an effective therapeutic strategy for counteracting postreperfusion myocardial injury and dysfunction, and the application of RDN holds promising prospects in clinical practice.

Thulium Laser in The Management of Ureteral Fibroepithelial Polyps: A Multicenter Retrospective Study.

Purpose: To retrospectively review the multicenter outcome of patients with ureteral fibroepithelial polyps (UFPs) after endoscopic management with thulium laser. Materials and Methods: A total of 21 adult patients with UFPs were treated in three medical centers between May 2007 and June 2018. We performed ureteroscopy operation and resected the polyps with thulium laser. The Double-J stent was removed 6 weeks after surgery during the 11-year follow-up period. Thereafter, we conducted computed tomography urography (CTU) or ultrasonic checks every 3-6 months. Results: All patients had UFPs resected with thulium laser. The mean length of the UFPs was 3.4 ± 1.43 cm (range 1.8-6.9). They included 12 men and 9 women with a mean age of 41.91 ± 13.56 years. Unilateral polyps were observed in 20 patients (left: n = 13; right: n = 7), whereas 1 patient had bilateral polyps. Back pain was the main symptom (12, 57.14%) identified. The amount of bleeding and the mean surgery time was 8.43 ± 4.02 mL and 42.43 ± 13.53 minutes, respectively. The average length of stay was 4 days (a range of 3-6 days). Notably, no patient exhibited ureteral perforation. We did not observe an increase in hydronephrosis during the follow-up period, ultrasonography showed that it was attenuated 6 weeks later. Besides, 3 months later, CTU revealed favorable recovery without recurrence or ureterostenosis. Conclusions: Ureteroscopy operation combined with thulium laser resection is a minimally invasive and effective method for treating UFPs. Based on our limited multicenter research findings, thulium laser achieves favorable outcomes in restoring drainage from the kidney and reduces recurrence.

Benchmark Problems of Hyper-Elasticity Analysis in Evaluation of FEM.

The paper proposes benchmark problems on exact solutions of hyper-elastic analysis, which can be used to evaluate analysis capabilities of rubber-like materials provided by a finite element program or other approximate solution methods. Special attention was concentrated on analysis and derivation of the exact solutions for the thick-walled rubber cylinders under internal pressure and axial extension, the thick-walled rubber balloons under internal pressure and the rubber cylinders under torsion or tension-torsion. Deformation and stress analysis on the above three cases were conducted to provide equations and methods for data processing. Exact standard solutions of the problems combined with the strain energy function of generalized high-order polynomials are given. Numerical examples and evaluation results of two commercial packages that are in common use (ABAQUS and ANSYS) are presented. Good agreements are found in the comparisons between the present exact standard solutions and the simulation results.

Efficacy between ureteroscopic via urethral Peel-away sheath and transurethral ureteroscopy in treating bladder calculi:A comparative study / 中国内镜杂志

Objective To compare the effectiveness of ureteroscopic via urethral Peel-away sheath and transurethral ureteroscopy in treatment of bladder calculi. Methods Clinical data of 76 cases of bladder calculi patients were collected from January 2013 to December 2015. All the patients were randomly divided into two groups: Group A was performed by ureteroscopic lithotripsy via urethral Peel-away sheath (n = 45). Group B was transurethral ureteroscopic lithotripsy (n = 31). Results 76 cases of bladder calculi were successfully treated by one-time lithotripsy. Lithotripsy time: group A was (17.8 ± 5.9) min, group B was (22.7 ± 8.3) min (t = 2.96, P = 0.004); stone clearance time: group A (12.6 ± 4.9) min, group B (24.5 ± 5.3) min (t = 9.90, P = 0.000);Intraoperative urethral mucosa injury : group A (1.0 ± 0.5), group B (2.1 ± 0.4) (t = 9.47, P = 0.000); VAS score:group A (1.9 ± 0.6), group B (2.6 ± 0.6) points (t = 4.72, P = 0.000); indwelling catheter time: group A (1.0 ± 0.2) d, B group (1.4 ± 0.9) d (t = 2.59, P = 0.012); There was no significant difference in hospitalization expense, group A was (7437.4 ± 356.7), group B was (7296.8 ± 333.8) (t = -1.73, P = 0.087). There were no complications such as hemorrhage, perforation and rupture of the 2 groups, without convertion to open surgery either. After the treatment of oral antibiotic, 1 case of postoperative urinary tract infection was cured in group B. In our study, case of postoperative urinary retention was 1 in group A, versus 5 in group B, with statistical difference (χ2 = 6.43, P = 0.011). Follow up: 13 patients were lost to follow-up, the other patients were followed up for 6 ~ 12 months. There was 1 case of elderly male patient with urinary retention due to BPH in each of the 2 groups, the other patients had no recurrence of calculus. By analyzing the statistical results, it was found that the experimental group had obvious advantages over the control group in the lithotripsy time, stone clearance time, urethral mucosa injury, postoperative pain and postoperative indwelling catheter time. Conclusion There is no significant difference in efficacy of the treatment of bladder calculi between ureteroscopic via urethral Peel-away sheath and transurethral ureteroscopy. However, our study shows the Peel-away ureteroscopy has the advantages of shorter lithotripsy time, shorter time of stone clearance and less injury of urethra mucosa menbrane, there was no significant difference in operation cost between two groups. Therefore, Ureteroscopic via urethral Peel-away sheath is an effective method for endoscopic bladder lithotripsy.

Efficacy between ureteroscopic via urethral Peel-away sheath and transurethral ureteroscopy in treating bladder calculi:A comparative study / 中国内镜杂志

Objective To compare the effectiveness of ureteroscopic via urethral Peel-away sheath and transurethral ureteroscopy in treatment of bladder calculi. Methods Clinical data of 76 cases of bladder calculi patients were collected from January 2013 to December 2015. All the patients were randomly divided into two groups: Group A was performed by ureteroscopic lithotripsy via urethral Peel-away sheath (n = 45). Group B was transurethral ureteroscopic lithotripsy (n = 31). Results 76 cases of bladder calculi were successfully treated by one-time lithotripsy. Lithotripsy time: group A was (17.8 ± 5.9) min, group B was (22.7 ± 8.3) min (t = 2.96, P = 0.004); stone clearance time: group A (12.6 ± 4.9) min, group B (24.5 ± 5.3) min (t = 9.90, P = 0.000);Intraoperative urethral mucosa injury : group A (1.0 ± 0.5), group B (2.1 ± 0.4) (t = 9.47, P = 0.000); VAS score:group A (1.9 ± 0.6), group B (2.6 ± 0.6) points (t = 4.72, P = 0.000); indwelling catheter time: group A (1.0 ± 0.2) d, B group (1.4 ± 0.9) d (t = 2.59, P = 0.012); There was no significant difference in hospitalization expense, group A was (7437.4 ± 356.7), group B was (7296.8 ± 333.8) (t = -1.73, P = 0.087). There were no complications such as hemorrhage, perforation and rupture of the 2 groups, without convertion to open surgery either. After the treatment of oral antibiotic, 1 case of postoperative urinary tract infection was cured in group B. In our study, case of postoperative urinary retention was 1 in group A, versus 5 in group B, with statistical difference (χ2 = 6.43, P = 0.011). Follow up: 13 patients were lost to follow-up, the other patients were followed up for 6 ~ 12 months. There was 1 case of elderly male patient with urinary retention due to BPH in each of the 2 groups, the other patients had no recurrence of calculus. By analyzing the statistical results, it was found that the experimental group had obvious advantages over the control group in the lithotripsy time, stone clearance time, urethral mucosa injury, postoperative pain and postoperative indwelling catheter time. Conclusion There is no significant difference in efficacy of the treatment of bladder calculi between ureteroscopic via urethral Peel-away sheath and transurethral ureteroscopy. However, our study shows the Peel-away ureteroscopy has the advantages of shorter lithotripsy time, shorter time of stone clearance and less injury of urethra mucosa menbrane, there was no significant difference in operation cost between two groups. Therefore, Ureteroscopic via urethral Peel-away sheath is an effective method for endoscopic bladder lithotripsy.