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In S1 mouse proximal tubular cells, rKL treatment ameliorated HG-mediated cellular and mitochondrial damage and enhanced oxidative phosphorylation, with an increase in PGC1α-AMPK-induced mitochondrial recovery. Our data suggest that klotho exerts a mitochondrial protective effect in diabetic kidney disease by inducing AMPK-PGC1α expression.Anti-tuberculosis drug-induced liver injury (ATB-DILI) is a common adverse reaction of anti-tuberculosis drug treatment. Studies have shown that isoniazid (INH) and rifampicin (RFP) are mainly metabolized in the liver and a large amount of intracellular glutathione is used up during the metabolism of these drugs, resulting in lipid peroxidation and hepatocyte death. Ferroptosis is a novel form of programmed cell death caused by iron-ion-dependent lipid peroxidation. In this study, we explored lipid peroxidation and ferroptosis during ATB-DILI. Morphology of ferroptosis was discovered in ATB-DILI mouse livers by transmission electron microscopy. Flow cytometry was used to assess the molecular markers of lipid peroxidation and ferroptosis including reactive oxygen species, lipid peroxidation, and cellular iron content. Glutathione peroxidase 4 (GPX4) was depleted, while acyl-CoA synthetase long chain family member 4 (ACSL4) was overexpressed in the ATB-DILI tissues. And glutathione supplementation significantly reduced the level of lipid peroxidation and the risk of liver damage. Retrospective study of tuberculosis patients who underwent INH and RFP treatment also revealed an association between the intake of glutathione and a negative ATB-DILI rate. In addition, iron supplementation enhanced the degree of lipid peroxidation and liver injury induced by INH and RFP in vivo and clinical retrospective study. Taken together, these results indicate that lipid peroxidation and evidence suggestive of ferroptosis occurs during ATB-DILI, and glutathione replenishment prevents this process while iron supplementation augmenting this effect.circRNAs have been shown to be involved in cancer progression. It is unclear whether circPGAM1 exerts its effect on laryngocarcinoma drug resistance. In this study, we employed colony formation and MTT assay to determine colony number and cell viability under cisplatin treatment. TUNEL experiment was used to evaluate apoptosis of laryngocarcinoma cells in the presence of cisplatin. Xenograft tumor experiment was performed to assess in vivo tumor growth of SNU46 cells. We found that circPGAM1 enhanced colony formation and viability of SNU46 and M4E cells. In contrast, circPGAM1 caused attenuated cell apoptosis. Furthermore, we also confirmed that circPGAM1 played a key role in tumor growth in animal model and clinical patients. miR-376a was identified and proved to act as key effector for circPGAM1-mediated drug resistance. Disufenton chemical Finally, autophagy-related gene ATG2A was shown to rescue miR-376a-modulated drug resistance of laryngocarcinoma cells. Herein, we illuminate the role of circPGAM1 in laryngocarcinoma drug resistance, thereby facilitating development of targeted therapy for treating laryngocarcinoma.DNA target search is a key step in cellular transactions that access genomic information. How DNA binding proteins combine 3D diffusion, sliding and hopping into an overall search strategy remains poorly understood. Here we report the use of a single molecule DNA tethering method to characterize the target search kinetics of the type II restriction endonuclease NdeI. The measured search rate depends strongly on DNA length as well as salt concentration. Using roadblocks, we show that there are significant changes in the DNA sliding length over the salt concentrations in our study. To explain our results, we propose a model including cycles of 3D and 1D search in which salt concentration modulates the strategy by varying the length of DNA probed per 1D scan. At low salt NdeI makes a single non-specific encounter with DNA followed by an effective and complete 1D scan. At higher salt, NdeI must execute multiple cycles of target search due to the reduced efficacy of 1D search.DNase coatings show great potential to prevent biofilm formation in various applications of the medical implant, food and marine industry. However, straightforward and quantitative methods to characterize the enzymatic activity of these coatings are currently not available. We here introduce the qDNase assay, a quantitative, real-time method to characterize the activity of DNase coatings. The assay combines (1) the use of an oligonucleotide probe, which fluoresces upon cleavage by coated DNases, and (2) the continuous read-out of the fluorescent signal within a microplate fluorometer format. The combination of these two properties results in a real-time fluorescent signal that is used to directly quantify the activity of DNase coatings. As a proof of concept, bovine DNase I coatings were immobilized on titanium by means of chemical grafting and their activity was estimated at 3.87 × 10-4 U. To our knowledge, the qDNase assay provides the first approach to report the activity of a DNase coating in absolute DNase activity units. This assay will not only serve to compare existing DNase coating methods more accurately, but will also enable the rational design of new DNase coating methods in the future.Farnesoid X receptor (FXR) is considered as a potential target for the treatment of several liver disorders such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Tropifexor is a highly potent and non-steroidal FXR agonist that has progressed into phase II clinical trials in patients with PBC. The clinical trials demonstrate that tropifexor improved serum markers of patients with liver diseases and lower side effect such as pruritus that might be implicated with TGR5 activation. However, the molecular mechanism of the potency and selectivity of tropifexor remains unclear. In this study, the binding affinity of FXR and tropifexor is measured by isothermal titration calorimetry (ITC) assays. The crystal structure of the FXR/tropifexor complex is determined at 2.7 Å resolution to explain the molecular mechanism of tropifexor bound to FXR-LBD. Structural comparison with other FXR/agonists structures reveals the conformational change in the FXR/tropifexor structure. Moreover the structural superposition of TGR5/tropifexor indicates that the steric hindrance between tropifexor and TGR5 might be a possible explanation for the impotency arises of tropifexor to TGR5. Overall, our analyses might provide an insight into the molecular mechanism of tropifexor binding to FXR-LBD and account for the high selectivity of tropifexor for FXR versus TGR5.
This study sought to investigate the sensitivity of electroanatomical mapping (EAM) to detect scar as identified by late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR).
Previous studies have shown correlation between low voltage electrogram amplitude and myocardial scar. However, voltage amplitude is influenced by the distance between the scar and the mapping surface and its extent. The aim of this study is to examine the reliability of low voltage EAM as a surrogate for myocardial scar using LGE-derived scar as the reference.
Twelve swine underwent anterior wall infarction by occlusion of the left anterior descending artery (LAD) (n=6) or inferior wall infarction by occlusion of the left circumflex artery (LCx) (n=6). Subsequently, animals underwent CMR and EAM using a multielectrode mapping catheter. CMR characteristics, including wall thickness, LGE location and extent, and EAM maps, were independently analyzed, and concordance between voltage maps and CMR characteristics was assessed.hlighted the limitations of the current EAM system to detect scar in thick myocardial wall regions.
This study sought to analyze safety and outcomes of ventricular tachycardia (VT) substrate ablation during sinus rhythm (SR), without baseline VT induction.
Safety and outcomes after scar-related VT ablation during SR are not well known. Hemodynamic instability and need for electrical cardioversion can compromise safety of VT ablation procedures.
Four hundred twelve consecutive patients with structural heart disease undergoing VT ablation were included in a prospective multicenter registry. Substrate ablation during SR, without baseline VT induction, was the first step of the ablation procedure and the standard protocol. Scar dechanneling was the substrate ablation technique used. VT inducibility was tested after substrate ablation.
VT induction protocol was negative after substrate ablation in 289 patients (70.1%), completing the procedure in SR. Procedure-related complication rate was 6.5%, including 1 death (0.2%). Thirty-day mortality after first VT ablation procedure was 1.7%. Overall survival wang 1 death (0.2%). Thirty-day mortality after first VT ablation procedure was 1.7%. Overall survival was 95.8% and 88.6% at 1 and 3 years of follow-up, respectively. In a multivariable proportional hazards regression model, age ≥70 years (hazard ratio [HR] 4.95 [2.59 to 9.47]; p less then 0.001), chronic obstructive pulmonary disease (HR 2.37 [1.24 to 4.52]; p = 0.008), left ventricular ejection fraction less then 30% (HR 2.43 [1.37 to 4.33]; p = 0.002), and incomplete substrate ablation (HR 2.37 [1.24 to 4.52]; p = 0.026) were independent predictors of overall mortality. At 12 months' follow-up, VT-free survival was 82.5% after 1 procedure and 87.8% after n procedures CONCLUSIONS Substrate ablation during SR avoiding multiple VT induction has low procedure-related complications and low early mortality. Age, chronic obstructive pulmonary disease, and reduced left ventricular ejection fraction, but also incomplete substrate elimination, are predictors of mortality.
The aim of this study was to assess the long-term efficacy and outcomes of retrograde venous ethanol ablation in treating ventricular arrhythmias (VAs).
Retrograde coronary venous ethanol ablation (RCVEA) can be effective for radiofrequency ablation (RFA)-refractory VAs, particularly those arising in the LV summit (LVS).
Patients with drug and RFA-refractory VAs were considered for RCVEA after RF failure attempts. Intramural coronary veins (tributaries of the great cardiac, anterior interventricular, lateral cardiac, posterolateral, and middle cardiac) were mapped using an angioplasty wire. Ethanol infusion was delivered in veins with appropriate signals.
Of 63 patients (age 63 ± 14 years; 60% men) with VAs (71% extrasystole, 29% ventricular tachycardia, 76% LVS origin), RCVEA was performed in 56 patients who had suitable vein branches. These were defined as those amenable to cannulation and with intramural signals that preceded those mapped in the epicardium or endocardium and had better matching pace maps or entrainment responses. Seven patients had no suitable veins and underwent RFA. In 38 of 56 (68%) patients, the VAs were successfully terminated exclusively with ethanol infusion. In 17 of 56 (30%) patients, successful ablation was achieved using ethanol with adjunctive RFA in the vicinity of the infused vein due to acute recurrence or ethanol-induced change in VA morphology. Overall, isolated or adjuvant RCVEA was successful in 55 of 56 (98%) patients. At 1-year follow-up, 77% of patients were free of recurrent arrhythmias. Procedural complications included 2 venous dissections that led to pericardial effusions.
RCVEA offers a significant long-term effective treatment for patients with drug and RF-refractory VAs.
RCVEA offers a significant long-term effective treatment for patients with drug and RF-refractory VAs.
