Glycyrrhizin attenuates myocardial ischemia reperfusion injury by suppressing Inflammation, oxidative stress, and ferroptosis via the HMGB1-TLR4-GPX4 pathway.

Ferroptosis, a form of regulated cell death process, play an important role in myocardial ischemia‒reperfusion (I/R) injury. Glycyrrhizin (GL), a natural glycoconjugate triterpene, has the property to improve growth rate, immune regulation, antioxidant, anti-inflammatory. However, whether GL can attenuate myocardial I/R injury by modulating ferroptosis or other mechanisms are still unclear. In this study, SD rats underwent in vivo myocardial ischemia/reperfusion (I/R) surgery, while H9C2 cells were subjected to the hypoxia/reoxygenation (H/R) model for in vitro experiments. In addition, TAK-242, a TLR4-specific antagonist, and GL were also used to evaluate the effect and mechanisms of GL on the cardiac function and expression of ferroptosis-related gene and protein in vivo and vitro. The results show that GL decreased not only the expression of the inflammation-related factors (HMGB1, TNF-α, IL-6, IL-18 and IL-1ß), but also reduced the number of TUNEL-positive cardiomyocytes, and mitigated pathological alterations in I/R injury. In addition, GL decreased the levels of MDA, promoted antioxidant capacity such as GSH, CAT, Cu/Zn-SOD, Mn-SOD, and SOD in vivo and vitro. More importantly, GL and TAK-242 regulate ferroptosis-related protein and gene expression in I/R and H/R model. Surprisingly, GL may ameliorate cardiomyocyte ferroptosis and ultimately improves cardiac function induced by H/R via the HMGB1-TLR4-GPX4 axis. Therefore, we have highlighted a novel mechanism by which GL regulates inflammation, oxidative stress, and ferroptosis via the HMGB1-TLR4-GPX4 pathway to prevent myocardial I/R injury. GL appears to be a potentially applicable drug for the treatment of myocardial I/R injury.

Bimetallic H2 Addition and Intramolecular Caryl-H Activation Mediated by an Iron-Zinc Hydride.

Heteronuclear Fe(µ-H)Zn hydride Cp*Fe(1,2-Cy2PC6H4)HZnEt (3) undergoes reversible intramolecular Caryl-H reductive elimination through coupling of the cyclometalated phosphinoaryl ligand and the hydride, giving rise to a formal Fe(0)-Zn(II) species. Addition of CO intercepts this equilibrium, affording Cp*(Cy2PPh)(CO)Fe-ZnEt that features a dative Fe-Zn bond. Significantly, this system achieves bimetallic H2 addition, as demonstrated by the transformation of the monohydride Fe(µ-H)Zn to a deuterated dihydride Fe-(µ-D)2-Zn upon reaction with D2.

The impact of lipidome on breast cancer: a Mendelian randomization study.

OBJECTIVE: This study aims to investigate the association between specific lipidomes and the risk of breast cancer (BC) using the Two-Sample Mendelian Randomization (TSMR) approach and Bayesian Model Averaging Mendelian Randomization (BMA-MR) method. METHOD: The study analyzed data from large-scale GWAS datasets of 179 lipidomes to assess the relationship between lipidomes and BC risk across different molecular subtypes. TSMR was employed to explore causal relationships, while the BMA-MR method was carried out to validate the results. The study assessed heterogeneity and horizontal pleiotropy through Cochran's Q, MR-Egger intercept tests, and MR-PRESSO. Moreover, a leave-one-out sensitivity analysis was performed to evaluate the impact of individual single nucleotide polymorphisms on the MR study. RESULTS: By examining 179 lipidome traits as exposures and BC as the outcome, the study revealed significant causal effects of glycerophospholipids, sphingolipids, and glycerolipids on BC risk. Specifically, for estrogen receptor-positive BC (ER+ BC), phosphatidylcholine (P < 0.05) and phosphatidylinositol (OR: 0.916-0.966, P < 0.05) within glycerophospholipids play significant roles, along with the importance of glycerolipids (diacylglycerol (OR = 0.923, P < 0.001) and triacylglycerol, OR: 0.894-0.960, P < 0.05)). However, the study did not observe a noteworthy impact of sphingolipids on ER+BC. In the case of estrogen receptor-negative BC (ER- BC), not only glycerophospholipids, sphingolipids (OR = 1.085, P = 0.008), and glycerolipids (OR = 0.909, P = 0.002) exerted an influence, but the protective effect of sterols (OR: 1.034-1.056, P < 0.05) was also discovered. The prominence of glycerolipids was minimal in ER-BC. Phosphatidylethanolamine (OR: 1.091-1.119, P < 0.05) was an important causal effect in ER-BC. CONCLUSIONS: The findings reveal that phosphatidylinositol and triglycerides levels decreased the risk of BC, indicating a potential protective role of these lipid molecules. Moreover, the study elucidates BC's intricate lipid metabolic pathways, highlighting diverse lipidome structural variations that may have varying effects in different molecular subtypes.

Nanofluidic Device for Detection of Lysine Methylpeptides and Sensing of Lysine Methylation.

Protein methylation is the smallest possible yet vitally important post-translational modification (PTM). This small and chemically inert addition in proteins makes the analysis of methylation more challenging, thus calling for an efficient tool for the sake of recognition and detection. Herein, we present a nanofluidic electric sensing device based on a functionalized nanochannel that was constructed by introducing monotriazole-containing p-sulfonatocalix[4]arene (TSC) into a single asymmetric polymeric nanochannel via click chemistry. The device can selectively detect lysine methylpeptides with subpicomole sensitivity, distinguish between different lysine methylation states, and monitor the lysine methylation process by methyltransferase at the peptide level in real time. The introduced TSC molecule, with its confined asymmetric configuration, presents the remarkable ability to selectively bind to lysine methylpeptides, which, coupled with the release of the complexed Cu ions, allows the device to transform the molecular-level recognition to the discernible change in ionic current of the nanofluidic electric device, thus enabling detection. This work could serve as a stepping stone to the development of a new methyltransferase assay and the chemical that specifically targets lysine methylation in PTM proteomics.

QM Calculations Revealed that Outer-Sphere Electron Transfer Boosted O-O Bond Cleavage in the Multiheme-Dependent Cytochrome bd Oxygen Reductase.

The cytochrome bd oxygen reductase catalyzes the four-electron reduction of dioxygen to two water molecules. The structure of this enzyme reveals three heme molecules in the active site, which differs from that of heme-copper cytochrome c oxidase. The quantum chemical cluster approach was used to uncover the reaction mechanism of this intriguing metalloenzyme. The calculations suggested that a proton-coupled electron transfer reduction occurs first to generate a ferrous heme b595. This is followed by the dioxygen binding at the heme d center coupled with an outer-sphere electron transfer from the ferrous heme b595 to the dioxygen moiety, affording a ferric ion superoxide intermediate. A second proton-coupled electron transfer produces a heme d ferric hydroperoxide, which undergoes efficient O-O bond cleavage facilitated by an outer-sphere electron transfer from the ferrous heme b595 to the O-O σ* orbital and an inner-sphere proton transfer from the heme d hydroxyl group to the leaving hydroxide. The synergistic benefits of the two types of hemes rationalize the highly efficient oxygen reduction repertoire for the multi-heme-dependent cytochrome bd oxygen reductase family.

[Left Main Trunk Orifice Reconstruction Using Aortic flap and Autologous Pulmonary Arterial Patch for Severe Left Main Trunk Stenosis After Arterial Switch Operation].

A 6-year-old boy with left main trunk (LMT) stenosis, who had undergone arterial switch operation (ASO) for transposition of the great arteries( TGA) before 6 years, underwent LMT orifice reconstruction. Coronary angiography showed severe stenosis of LMT, already when he was hospitalized with heart failure after 3 months of ASO. He was stable with oral treatment, therefore we performed the LMT reconstruction, before starting school, in terms of the risk of coronary ischemic event. We reconstructed the LMT ostium using an aortic flap and autologous pulmonary arterial patch. The postoperative computed tomography showed neither stenosis nor kinking at the repair site of LMT. He remains asymptomatic for over 6 months. We have reported that this method is effective to repair coronary artery anomalies (CAAs), since using an aortic flap. We could form a coronary artery floor, which is affixed to the aortic wall. This method allows us to change the coronary orifice position and the angle, so it is very useful method not for only CAAs, but also for coronary stenosis after ASO.

[Midterm Outcomes of Pulmonary Valve Leaflet Augmentation using Fresh Autologous Pericardium for Transannular Patch Repair of Tetralogy of Fallot].

BACKGROUND: Although valve sparing (VS) for patients with smaller pulmonary valves has been increasing, transannular patch repair( TAP) accounts for more than half of the total tetralogy of Fallot corrections worldwide. We use fresh autologous pericardial patches to perform a modified TAP procedure with pulmonary valve leaflet augmentation as proposed by Sung et al. We aimed to explore the early and midterm outcomes of this procedure. METHODS: We retrospectively reviewed 37 patients( group TAP:12;group VS:25) who underwent total tetralogy of Fallot corrections from April 2018 to December 2021. RESULTS: No midterm mortality was observed at a median observation period of 20.4 months in both groups. The midterm rates of freedom from moderate or more pulmonary regurgitation( PR) were 64.2 % and 21.4% in group TAP and 100% and 100% in group VS at 1 and 3 years, respectively( p<0.001). The midterm rates of freedom from pulmonary stenosis reintervention were 100% and 100% in group TAP and 96% and 96% in group VS at 1 and 3 years, respectively( p=0.51). CONCLUSIONS: TAP showed acceptable midterm survival and reintervention rate. Longer follow-up is essential considering the significantly higher PR in the postoperative period in group TAP.

Apex rotation as a risk factor for total anomalous pulmonary connection repair in single ventricle.

BACKGROUND: The high incidence of postoperative pulmonary venous obstruction (PVO) is a major mortality-associated concern in patients with right atrial isomerism and extracardiac total anomalous pulmonary venous connection (TAPVC). We evaluated new anatomical risk factors for reducing the space behind the heart after TAPVC repair. METHODS: Eighteen patients who underwent TAPVC repair between 2014 and 2020 were enrolled. Sutureless technique was used in 12 patients and conventional repair in six patients. The angle between the line perpendicular to the vertebral body and that from the vertebral body to the apex was defined as the "vertebral-apex angle (V-A angle)." The ratio of postoperative and preoperative angles, indicating the apex's lateral rotation, was compared between patients with and without PVO. RESULTS: The median (interquartile range) age and body weight at repair were 102 (79-176) days and 3.8 (2.6-4.8) kg, respectively. The 1-year survival rate was 83% (median follow-up, 29 [11-36] months). PVO occurred in seven patients (39%), who showed an obstruction of one or two branches in the apex side. The postoperative V-A angle (46° [45°-50°] vs. 36° [29°-38°], p = 0.001) and the ratio of postoperative and preoperative V-A angles (1.27 [1.24-1.42] vs. 1.03 [0.98-1.07], p = 0.001) were significantly higher in the PVO group than in the non-PVO group. The cut-off values of the postoperative V-A angle and ratio were 41° and 1.17, respectively. CONCLUSION: A postoperative rotation of the heart apex into the ipsilateral thorax was a risk factor for branch PVO after TAPVC repair.

[Modified Carpentier Technique is Useful Method for Tricuspid Regurgitation in Hypoplastic Left Heart Syndrome].

Management of tricuspid regurgitation( TR) before right ventricular dysfunction is critical in patients with hypoplastic left heart syndrome (HLHS);however, appropriate tricuspid valvuloplasty (TVP) is challenging. We report a TVP technique for TR in a 4-year-old girl with HLHS, who had undergone Norwood operation, bidirectional cavopulmonary shunt, and TVP. Preoperative echocardiography revealed the etiology of TR as anterior leaflet prolapse, annulus dilatation, and relative tethering of the septal leaflet. We performed surgical reconstruction of the anterior leaflet with artificial chordae. Before annuloplasty, the posterior leaflet and a part of the septal leaflet were detached from the annulus with a 1 mm margin using the Key-Reed technique. Furthermore, the posterior leaflet was slid to augment the septal leaflet. We managed to regulate the TR by enlarging the septal leaflet, thus increasing the coaptation zone. We believe that this technique will be useful for TR with annulus dilatation in HLHS.

Representations and Benchmarking of Modern Visual SLAM Systems.

Simultaneous Localisation And Mapping (SLAM) has long been recognised as a core problem to be solved within countless emerging mobile applications that require intelligent interaction or navigation in an environment. Classical solutions to the problem primarily aim at localisation and reconstruction of a geometric 3D model of the scene. More recently, the community increasingly investigates the development of Spatial Artificial Intelligence (Spatial AI), an evolutionary paradigm pursuing a simultaneous recovery of object-level composition and semantic annotations of the recovered 3D model. Several interesting approaches have already been presented, producing object-level maps with both geometric and semantic properties rather than just accurate and robust localisation performance. As such, they require much broader ground truth information for validation purposes. We discuss the structure of the representations and optimisation problems involved in Spatial AI, and propose new synthetic datasets that, for the first time, include accurate ground truth information about the scene composition as well as individual object shapes and poses. We furthermore propose evaluation metrics for all aspects of such joint geometric-semantic representations and apply them to a new semantic SLAM framework. It is our hope that the introduction of these datasets and proper evaluation metrics will be instrumental in the evaluation of current and future Spatial AI systems and as such contribute substantially to the overall research progress on this important topic.

[Aortic Regurgitation and Stenosis Associated with Ventricular Septal Defect in the Elderly;Report of a Case].

A 63-year-old man had ventricular septal defect (VSD) and had been followed up without heart failure. Recently, he had palpitation caused by atrial fibrillation and the echocardiography revealed moderate aortic valve regurgitation and stenosis with right coronary cusp prolapse due to subpulmonary ventricular septal defect. He underwent patch closure of VSD, aortic valve replacement with mechanical valve, and maze procedure. In recent years, advanced case like this patient is rare because most of patients with subpulmonary VSD and right coronary cusp prolapse are operated in childhood.

[Open Aortic Arch Surgery for Type â Endoleak after Thoracic Endovascular Aortic Repair Using Fenestrated Stent Graft;Report of a Case].

Thoracic endovascular aortic repair (TEVAR) has become a major procedure for thoracic aortic aneurysm and its indication is expanding. On the other hand, TEVAR specific complication is rather critical and its treatment is of increasing interest. Especially, open repair after TEVAR is sometimes demanding and case based strategy is mandatory. We experienced a case of open repair for aneurysm infection and endoleak after fenestrated TEVAR in 76-year-old man. He underwent initial aneurysmal repair using fenestrated graft 2 years ago. Five months later, debridment of infected tissue was performed because of aneurysmal infection. Type Ⅰ endoleak appeared after the surgery and expansion of the aneurysm made us decide extensive open repair. The operation was done under hypothermic circulatory arrest and selective cerebral perfusion. Partial removal of stent-graft and insertion of the open stent-graft, replacement of ascending aorta and reconstruction of neck vessels were done. Postoperative course was smooth. Open repair after TEVAR is often demanding. Sophisticated strategy for each case has to be planned.

Neutron Drip Line in the Ca Region from Bayesian Model Averaging.

The region of heavy calcium isotopes forms the frontier of experimental and theoretical nuclear structure research where the basic concepts of nuclear physics are put to stringent test. The recent discovery of the extremely neutron-rich nuclei around ^{60}Ca O. B. Tarasov et al. [Phys. Rev. Lett. 121, 022501 (2018)10.1103/PhysRevLett.121.022501] and the experimental determination of masses for ^{55-57}Ca S. Michimasa et al. [Phys. Rev. Lett. 121, 022506 (2018)10.1103/PhysRevLett.121.022506] provide unique information about the binding energy surface in this region. To assess the impact of these experimental discoveries on the nuclear landscape's extent, we use global mass models and statistical machine learning to make predictions, with quantified levels of certainty, for bound nuclides between Si and Ti. Using a Bayesian model averaging analysis based on Gaussian-process-based extrapolations we introduce the posterior probability p_{ex} for each nucleus to be bound to neutron emission. We find that extrapolations for drip-line locations, at which the nuclear binding ends, are consistent across the global mass models used, in spite of significant variations between their raw predictions. In particular, considering the current experimental information and current global mass models, we predict that ^{68}Ca has an average posterior probability p_{ex}≈76% to be bound to two-neutron emission while the nucleus ^{61}Ca is likely to decay by emitting a neutron (p_{ex}≈46%).

Surgical treatment of cardiac fibroma in a child with left ventricular noncompaction.

Surgical treatment of cardiac fibroma is rare in patients with left ventricular noncompaction (LVNC). Although several case reports regarding cardiac fibroma have been published, resection in a patient with LVNC has not been described. Here, we describe the surgical treatment of left ventricular fibroma in a child with LVNC. We resected a cardiac fibroma in a 10-year-old boy with LVNC to control ventricular arrhythmia. Partial resection with careful tumor dissection was performed to avoid endocardial damage and entering the ventricular cavity. The postoperative course was uneventful, and the patient remains asymptomatic without heart failure or arrhythmia. Surgical excision of cardiac fibroma can be performed safely with excellent results, even in a child with LVNC.

[Mitral Valve Repair in a Jehovah's Witnesses Patient with Post Myocardial Infarction Papillary Muscle Rupture;Report of a Case].

A 70-years old man was referred to our department for acute heart failure due to post myocardial infarction papillary muscle rupture. We planned emergent surgery, but he refused blood transfusion because of religious reason( Jehovah's Witness). Therefore, we chose medical therapy using intra-aortic balloon pumping and catecholamine. He was also treated with subcutaneous erythropoietin and intravenous iron supplement to increase preoperative hemoglobin. One month later, we decided to undergo mitral valve repair because he was stabilized with medical treatment. The patient underwent mitral valve repair with artificial chordae through median sternotomy. The mitral valve A3 prolapse was caused by posterior papillary muscle rupture. No blood transfusion was given and postoperative course was uneventful. We experienced successful mitral repair for post infarction papillary muscle rupture in a Jehova's Witnessess patient.

[Aortopulmonary Fistula Caused by Rupture of an Aortic Arch Aneurysm Successfully Treated by Surgery;Report of a Case].

An 81-year-old woman who presented with chest and back pain was diagnosed as aortopulmonary fistula caused by rupture of an aortic arch aneurysm and was transferred to our hospital for surgical treatment. Additionally, she was diagnosed with aortic dissection( Stanford type B). Total arch replacement with open stent-grafting and direct closure of aortopulmonary fistula were performed because of her exacerbation of congestive heart failure. Manual compression of fistula during cardiopulmonary bypass was effective to control massive shunt. The patient recovered uneventfully and was transferred to other hospital for rehabilitation on postoperative day 24.

[Infective Endocarditis in Right Ventricle( RV)-Pulmonary Artery( PA) Conduit Late after the Ross Procedure;Report of a Case].

Ross procedure has been found to have a lower incidence of infective endocarditis compared to other aortic replacement procedure using prosthetic valves. We report a case of 25-year-old man who underwent Ross procedure for congenital aortic stenosis and regurgitation when he was 7 years old. He presented with fever and was highly suspected of infective endocarditis. All sets of blood cultures were positive for Heamophilus parainfluenzae. Autologous pericardial pulmonary valve was severely stenotic and computed tomography (CT) scan and radio isotope (RI) scan revealed infection at the stenotic valve. We performed right ventricle (RV)-pulmonary artery (PA) conduit replacement and he was discharged after completion of intravenous antibiotic treatment. We experienced a rare case of infective endocarditis in a patient late after Ross procedure. Prophylaxis against infective endocarditis is mandatory even in patients with infection resistant Ross procedure.

Quantification of complanatoside A in rat plasma using LC-MS/MS and its application to a pharmacokinetic study.

Complanatoside A is a flavonol glycoside isolated from Astragalus complanatus, and currently it is used as a quality control index for A. complanatus in the 2010 edition of the Chinese Pharmacopoeia. For the first time, a simple and sensitive LC-MS/MS method was developed for the determination of complanatoside A in rat plasma over the range of 2.3-575 ng/mL. Complanatoside A was extracted from plasma by a protein precipitation procedure, separated by LC and detected by MS/MS in positive electrospray ionization mode. The method was validated for selectivity, carryover, sensitivity, linearity, extraction recovery, matrix effect, accuracy, precision and stability studies. The lower limit of quantification was established at 2.3 ng/mL. Intra- and inter-day precisions (LLOQ, low-QC, med-QC and high-QC) were <7.9%, and accuracies were between 94.0 and 105.1%. Matrix effect was acceptable (97.9-103.0%) and extraction recovery was reproducible (88.5-94.4%). Complanatoside A was stable in the investigated conditions. The method was applied to the pharmacokinetics of complanatoside A in rats. Copyright © 2015 John Wiley & Sons, Ltd.

Development of a folate receptor (FR)-targeted indenoisoquinoline using a pH-sensitive N-ethoxybenzylimidazole (NEBI) bifunctional cross-linker.

This Communication describes the synthesis and evaluation of a folate-conjugated drug delivery system (DDS) that incorporates an acid-sensitive N-ethoxybenzylimidazole (NEBI) bifunctional linker and a novel imidazole-containing indenoisoquinoline. Indenoisoquinolines are a class of TOP1 inhibitors that exhibit broad anticancer activity. Here, we examined whether a DDS that comprised an indenoisoquinoline attached to a folate moiety could help target activity to cancer cells that naturally overexpress the folate receptor (FR), thereby increasing the specificity of these compounds. Evaluation of the DDS revealed an 11-fold increased toxicity in folate receptor (FR)-overexpressing cells compared to in FR-knockdown cancer cells. Microscopy studies demonstrate enhanced internalization and localization of the DDS in acidic lysosomal compartments of FR-overexpressing cells, supporting a receptor-mediated mechanism for uptake and activation. Together with control experiments, the results support that the cytotoxic activity of this DDS is dependent on both the presence of the folate group as well as the presence of the acid-sensitive hydrolyzable group. This work represents the first example of a cell receptor-targeted indenoisoquinoline, which could help pave the way for the use of this class of compounds in anticancer therapy.

Exploring the NRF2-TP53 Signaling Network Through Machine Learning and Pan-Cancer Analysis: Identifying Potential targets for Cancer Prognosis Related to Oxidative Stress.

Oxidative stress (OXS) is closely related to tumor prognosis and immune response, while TP53 integrated with NRF2 is closely associated with the regulation of cancer-related OXS. Hence, constructing a TP53-NRF2 integrated OXS signature of pan-cancer is essential in predicting survival prognosis and facilitating cancer drug treatment. The pan-cancer analysis acquired the Cancer Genome Atlas (TCGA) transcriptome sequencing data from UCSC Xena, which consisted of 33 cancer types (n = 10 440). The Random Forest, Lasso regression, and Cox regression analyses are used to construct an OXS score based on 25 OXS genes. Following this, based on the OXS signature, patients are categorized into low- and high-risk groups. The disparities between the two cohorts regarding survival prognosis, immune infiltration, and drug sensitivity are delved deeply. The expression level of genes is confirmed using immunohistochemistry. The prognosis of pan-cancer patients is adequately predicted by the OXS signature with the assistance of the machine-learning algorithm. A highly accurate nomogram is developed by combining the OXS signature and clinical features. The presence of immune cells indicated that the OXS signature can be associated with the critical pathways of immunotherapy for all types of cancer, and BCL2 showed promising results. Distinct inter-group differences are observed in the OXS signature for frequently utilized antineoplastic medications in clinical settings, including first-line drugs suggested in the guidelines. In summary, by conducting a thorough analysis of OXS genes, a new model based on OXSscore is successfully developed. This model can predict the clinical prognosis and drug sensitivity of pan-cancer with high accuracy. Potential stars in the field of cancer-related anti-OXS may include drugs that target BCL2.