Engineering of IF1 -susceptive bacterial F1 -ATPase.

IF1 , an inhibitor protein of mitochondrial ATP synthase, suppresses ATP hydrolytic activity of F1 . One of the unique features of IF1 is the selective inhibition in mitochondrial F1 (MF1 ); it inhibits catalysis of MF1 but does not affect F1 with bacterial origin despite high sequence homology between MF1 and bacterial F1 . Here, we aimed to engineer thermophilic Bacillus F1 (TF1 ) to confer the susceptibility to IF1 for elucidating the molecular mechanism of selective inhibition of IF1 . We first examined the IF1 -susceptibility of hybrid F1 s, composed of each subunit originating from bovine MF1 (bMF1 ) or TF1 . It was clearly shown that only the hybrid with the ß subunit of mitochondrial origin has the IF1 -susceptibility. Based on structural analysis and sequence alignment of bMF1 and TF1 , the five non-conserved residues on the C-terminus of the ß subunit were identified as the candidate responsible for the IF1 -susceptibility. These residues in TF1 were substituted with the bMF1 residues. The resultant mutant TF1 showed evident IF1 -susceptibility. Reversely, we examined the bMF1 mutant with TF1 residues at the corresponding sites, which showed significant suppression of IF1 -susceptibility, confirming the critical role of these residues. We also tested additional three substitutions with bMF1 residues in α and γ subunits that further enhanced the IF1 -susceptibility, suggesting the additive role of these residues. We discuss the molecular mechanism by which IF1 specifically recognizes F1 with mitochondrial origin, based on the present result and the structure of F1 -IF1 complex. These findings would help the development of the inhibitors targeting bacterial F1 .

Midterm outcomes of transcatheter aortic valve replacement in patients with active cancer.

OBJECTIVES: The clinical outcomes of transcatheter aortic valve replacement (TAVR) in patients with aortic stenosis (AS) and concomitant active cancer remain insufficiently explored. This study aimed to assess the midterm outcomes of TAVR in patients diagnosed with AS and active cancer. METHODS: Data from the OCEAN-TAVI, a prospective Japanese registry of TAVR procedures, was analysed to compare prognoses and clinical outcomes in patients with and without active cancer at the time of TAVR. RESULTS: Of the 2336 patients who underwent TAVR from October 2013 to July 2017, 89 patients (3.8%) had active cancer, whereas 2247 did not. Among patients with active cancer, 49 had limited-stage cancer (stage 1 or 2). The prevalent cancers identified before TAVR were colon (21%), prostate (18%), lung (15%), liver (11%) and breast (9%). Although the periprocedural complications and 30-day mortality rates were comparable between the groups, the 3-year survival rate after TAVR was notably lower in patients with active cancer (64.7%) than in those without active cancer (74.7%; p=0.016). Nevertheless, the 3-year survival rate of patients with limited-stage cancer (stage 1 or 2) did not significantly differ from those without cancer (70.6% vs 74.7%, p=0.50). CONCLUSIONS: The patients with active cancer exhibited significantly reduced midterm survival rates. However, no distinct disparity existed in those with limited-stage cancer (stage 1 or 2). Although TAVR is a viable treatment in patients with AS with active cancer, the type and stage of cancer and prognosis should be carefully weighed in the decision-making process.

The series of conformational states adopted by rotorless F1-ATPase during its hydrolysis cycle.

F1Fo ATP synthase interchanges phosphate transfer energy and proton motive force via a rotary catalytic mechanism and isolated F1-ATPase subcomplexes can also hydrolyze ATP to generate rotation of their central γ rotor subunit. As ATP is hydrolyzed, the F1-ATPase cycles through a series of conformational states that mediates unidirectional rotation of the rotor. However, even in the absence of a rotor, the α and ß subunits are still able to pass through a series of conformations, akin to those that generate rotation. Here, we use cryoelectron microscopy to establish the structures of these rotorless states. These structures indicate that cooperativity in this system is likely mediated by contacts between the ß subunit lever domains, irrespective of the presence of the γ rotor subunit. These findings provide insight into how long-range information may be transferred in large biological systems.

Rationale and design of Non-antithrombotic Therapy After Transcatheter Aortic Valve Implantation (NAPT) Trial.

BACKGROUND: Despite the wide implementation of transcatheter aortic valve implantation (TAVI), the optimal antithrombotic therapy after TAVI has not been established yet. Owing to the accumulating evidence supporting the efficacy and safety of single antiplatelet therapy (SAPT) over dual antiplatelet therapy, the latest guideline recommends life-long SAPT. However, there is scarce evidence supporting SAPT compared with non-antithrombotic therapy. Given the vulnerability of patients undergoing TAVI in terms of high bleeding risk, the benefit of SAPT may be canceled out by its potential increased bleeding risk. STUDY DESIGN AND OBJECTIVES: Non-antithrombotic Therapy After Transcatheter Aortic Valve Implantation (NAPT) Trial is a prospective, randomized controlled, open-label blinded endpoint multicenter trial conducted in Japan, testing the non-inferiority of non-antithrombotic therapy compared with aspirin monotherapy in patients who underwent TAVI and had no indications for long-term oral anticoagulation therapy (OAC). Patients who successfully underwent trans-femoral TAVI for severe aortic stenosis with either balloon-expandable or self-expandable valves are eligible for inclusion. Key exclusion criteria are (i) occurrence of perioperative complications (ii) indications of taking antithrombotic drugs for other reasons; (iii) eGFR <30 ml/min/1.73 m2 or hemodialysis or peritoneal dialysis. A total of 360 patients will be randomized (1:1) to aspirin monotherapy vs. non-antithrombotic therapy. The primary outcome is a composite of all-cause mortality, myocardial infarction, stroke, and bleeding. All bleeding events based on the Valve Academic Research Consortium 3 are included as a component of the primary outcome. CONCLUSION: The NAPT trial will determine the non-inferiority of a non-antithrombotic therapy compared with aspirin monotherapy after TAVI.

Digital Cascade Assays for ADP- or ATP-Producing Enzymes Using a Femtoliter Reactor Array Device.

Digital enzyme assays are emerging biosensing methods for highly sensitive quantitative analysis of biomolecules with single-molecule detection sensitivity. However, current digital enzyme assays require a fluorogenic substrate for detection, which limits the applicability of this method to certain enzymes. ATPases and kinases are representative enzymes for which fluorogenic substrates are not available; however, these enzymes form large domains and play a central role in biology. In this study, we implemented a fluorogenic cascade reaction in a femtoliter reactor array device to develop a digital bioassay platform for ATPases and kinases. The digital cascade assay enabled quantitative measurement of the single-molecule activity of F1-ATPase, the catalytic portion of ATP synthase. We also demonstrated a digital assay for human choline kinase α. Furthermore, we developed a digital cascade assay for ATP-synthesizing enzymes and demonstrated a digital assay for pyruvate kinase. These results show the high versatility of this assay platform. Thus, the digital cascade assay has great potential for the highly sensitive detection and accurate characterization of various ADP- and ATP-producing enzymes, such as kinases, which may serve as disease biomarkers.

Prognostic Impact of Polypharmacy following Trans-Catheter Aortic Valve Replacement.

BACKGROUND: Polypharmacy in elderly patients with various comorbidities is associated with mortality and morbidity. However, the prognostic impact of polypharmacy in patients with severe aortic stenosis receiving trans-catheter aortic valve replacement remains unknown. METHODS: Patients with severe aortic stenosis who received trans-catheter aortic valve replacement between 2015 and 2022 and were followed up at our institute following index discharge were included in this retrospective study. The impact of polypharmacy, which was defined as medication numbers ≥10 at index discharge, upon 2-year all-cause death was investigated. RESULTS: A total of 345 patients (median age 85 [83, 89] years old, 99 (29%) men) were included. Median medication number was 9 (7, 10) at the index discharge and 88 (26%) were classified as receiving polypharmacy. Frailty index, including mini-mental state examination and CSHA score, were not significantly different between those with and without polypharmacy (p > 0.05 for both). Polypharmacy was associated with higher 2-year cumulative mortality with an adjusted hazard ratio of 21.4 (95% confidence interval, 6.06-74.8, p < 0.001). As a sub-analysis, the number of cardiovascular medications was not associated with 2-year mortality (hazard ratio 1.12, 95% confidence interval 0.86-1.48, p = 0.46), whereas a higher number of non-cardiovascular medications was associated with an incremental increase in 2-year mortality with a hazard ratio of 1.39 (95% confidence interval, 1.15-1.63, p < 0.001). CONCLUSIONS: In elderly patients with severe aortic stenosis, polypharmacy was associated with worse short-term survival following trans-catheter aortic valve replacement. Prognostic implication of aggressive intervention to decrease the amount of medication among those receiving TAVR requires further prospective studies.

Molecular mechanism on forcible ejection of ATPase inhibitory factor 1 from mitochondrial ATP synthase.

IF1 is a natural inhibitor protein for mitochondrial FoF1 ATP synthase that blocks catalysis and rotation of the F1 by deeply inserting its N-terminal helices into F1. A unique feature of IF1 is condition-dependent inhibition; although IF1 inhibits ATP hydrolysis by F1, IF1 inhibition is relieved under ATP synthesis conditions. To elucidate this condition-dependent inhibition mechanism, we have performed single-molecule manipulation experiments on IF1-inhibited bovine mitochondrial F1 (bMF1). The results show that IF1-inhibited F1 is efficiently activated only when F1 is rotated in the clockwise (ATP synthesis) direction, but not in the counterclockwise direction. The observed rotational-direction-dependent activation explains the condition-dependent mechanism of IF1 inhibition. Investigation of mutant IF1 with N-terminal truncations shows that the interaction with the γ subunit at the N-terminal regions is crucial for rotational-direction-dependent ejection, and the middle long helix is responsible for the inhibition of F1.

Comparison of perioperative serum osteocrin concentrations between surgical techniques in dogs with cranial cruciate ligament rupture.

The cranial cruciate ligament (CCL) rupture is a common orthopedic disease in dogs that is usually managed with tibial plateau leveling osteotomy (TPLO) or extracapsular lateral suture (ECLS). Osteotomy is generally associated with some complications, including nonunion. The periosteum plays an important role in bone growth and remodeling. Osteocrin (OSTN), which was recently identified and is involved in bone formation and differentiation, is produced in the periosteum and osteoblasts. The aimed to investigate whether the concentrations of serum OSTN change before and after stifle surgery in dogs and compare the OSTN concentrations in the two surgical techniques (TPLO: n = 20 vs. ECLS: n = 36). The postoperative serum OSTN concentration in the TPLO group was significantly lower than the preoperative value (p < 0.05), while serum OSTN concentrations differed statistically between the preoperative and suture-removal periods. In contrast, no significant differences were observed in the ECLS group. In conclusion, osteotomy affects serum OSTN concentrations during the perioperative period in dogs, which may be related to periosteal injury.

Impact of the elevated angiopoietin-2 levels during Impella support on the short-term prognosis.

Elevated serum angiopoietin-2 levels in patients with acute myocardial infarction-related cardiogenic shock with and without intra-aortic balloon pump as well as acute decompensated heart failure are associated with short-term mortality. However, its prognostic impact in patients with cardiogenic shock supported by Impella-incorporated mechanical circulatory support (MCS) remains unknown. Patients who received temporary MCS (Impella alone or Impella and veno-arterial extracorporeal membrane oxygenation) in our institute between August 2018 and January 2022 were included in this prospective study. The serum levels of angiopoietin-2 were measured just before and following the initiation of temporary MCS therapy. Association between the levels of serum angiopoietin-2 and 30-day mortality was investigated. A total of 38 patients (median 72 years old, 63% men) were included. The median levels of serum angiopoetin-2 tended to decrease from baseline to 4 days following the initiation of temporary MCS from 5.2 (3.3, 10.5) ng/mL to 4.8 (2.7, 6.8) ng/mL (p = 0.132). A higher angiopoietin-2 (> 6.8 ng/mL) following the initiation of temporary MCS was associated with higher 30-day mortality (89.7% versus 44.4%, p = 0.0048) with an odds ratio 18.946 (95% confidence interval 1.624-218.695, p = 0.018) adjusted for potential confounders. A higher serum angiopoietin-2 level following the initiation of Impella-incorporated temporary MCS, instead of baseline angiopoetin-2 level, was associated with higher short-term mortality.

Direct identification of the rotary angle of ATP cleavage in F1-ATPase from Bacillus PS3.

F1-ATPase is the world's smallest biological rotary motor driven by ATP hydrolysis at three catalytic ß subunits. The 120° rotational step of the central shaft γ consists of 80° substep driven by ATP binding and a subsequent 40° substep. In order to correlate timing of ATP cleavage at a specific catalytic site with a rotary angle, we designed a new F1-ATPase (F1) from thermophilic Bacillus PS3 carrying ß(E190D/F414E/F420E) mutations, which cause extremely slow rates of both ATP cleavage and ATP binding. We produced an F1 molecule that consists of one mutant ß and two wild-type ßs (hybrid F1). As a result, the new hybrid F1 showed two pausing angles that are separated by 200°. They are attributable to two slowed reaction steps in the mutated ß, thus providing the direct evidence that ATP cleavage occurs at 200° rather than 80° subsequent to ATP binding at 0°. This scenario resolves the long-standing unclarified issue in the chemomechanical coupling scheme and gives insights into the mechanism of driving unidirectional rotation.

Initial report of percutaneous left atrial appendage closure in hemodialysis patients with atrial fibrillation and high risk of bleeding in Japan.

In the countries like Japan where anticoagulation is not recommended in hemodialysis patients, the feasibility of percutaneous left atrial appendage closure (LAAC) in hemodialysis patients with non-valvular atrial fibrillation (NVAF) accompanying high risks of thromboembolic stroke and bleeding remains unknown. Peri-procedural and 45-day clinical outcomes following LAAC using WATCHMAN system, which were performed in our institute between Jun 2020 and April 2022 according to the Japanese Circulation Society guidelines, were retrospectively compared between those with and without hemodialysis. 118 patients (median 79 years, 81 men) consisting of 25 hemodialysis patients and 93 non-hemodialysis patients were included. CHADS score was 3 (2, 4) in the hemodialysis patients and 3 (2, 4) in the non-hemodialysis patients (p = 0.98). HAS-BREAD score was 4 (3, 5) in the hemodialysis patients and 3 (2, 3) in the non-hemodialysis patients (p < 0.001). All procedures were successful, except for a non-hemodialysis patient with a larger left atrial appendage. There were no major complications during index hospitalization and 45-day observational period, except for a hemodialysis patient with suspected bleeding and a non-hemodialysis patient who died due to cardiac amyloidosis. LAAC seems to be feasible in hemodialysis patients with high risks of thromboembolic events and bleedings.

Evaluation of enamel thickness of mandibular incisors

ABSTRACT Objective: To measure enamel thickness at the proximal surfaces of the mandibular incisors, using micro-computed tomography (micro-CT) scans. Material and Methods: Forty-one single-rooted mandibular incisors were selected and analyzed according to anatomical characteristics, to form three groups: Group 1 - central incisors (n = 18); Group 2 - right lateral incisors (n = 10); and Group 3 - left lateral incisors (n = 13). First, enamel thickness at the proximal contact areas of the mandibular incisors was measured. Second, the mesial and distal surfaces of the lateral incisors were compared. Finally, the relationship between the tooth width and the mean enamel thickness was determined. Each tooth was scanned with a micro-CT scanner, and the image was processed with SCANCO micro-CT onboard analysis software. Results: There were no statistically significant differences in mean enamel thickness between the mesial and distal surfaces for each lateral incisor, or between contralateral lateral incisors. In all surfaces analyzed, the upper zones had statistically significantly thinner enamel (0.52 ± 0.10 mm) when compared to the middle and lower zones (0.60 ± 0.08 mm and 0.59 ± 0.08 mm, respectively). There was no correlation (r =0.07) between enamel thickness of the mandibular incisor and the tooth width. Conclusions: The enamel thickness of the mandibular incisors is similar on the mesial and distal surfaces, with the thinnest layer located at the upper zone.

RESUMO Objetivo: Medir a espessura do esmalte nas superfícies proximais dos incisivos inferiores, usando imagens de microtomografia computadorizada (micro-CT). Material e Métodos: Quarenta e um incisivos inferiores com raiz única foram selecionados e analisados de acordo com as características anatômicas, formando três grupos: Grupo 1 - incisivos centrais (n = 18); Grupo 2 - incisivos laterais direitos (n = 10); e Grupo 3 - incisivos laterais esquerdos (n = 13). Primeiro, foi medida a espessura do esmalte nas áreas de contato proximal dos incisivos inferiores. Em segundo lugar, as faces mesial e distal dos incisivos laterais foram comparadas. Por fim, foi determinada a relação entre a largura do dente e a espessura média do esmalte. Cada dente foi escaneado com um scanner micro-CT, e a imagem foi processada com o software de análise SCANCO micro-CT. Resultados: Não houve diferenças estatisticamente significativas na espessura média do esmalte entre as superfícies mesial e distal de cada incisivo lateral, ou entre os incisivos laterais contralaterais. Em todas as superfícies analisadas, as zonas superiores apresentaram esmalte significativamente mais fino (0,52 ± 0,10 mm) quando comparadas às zonas média e inferior (0,60 ± 0,08 mm e 0,59 ± 0,08 mm, respectivamente). Não houve correlação (r = 0,07) entre a espessura do esmalte do incisivo inferior e a largura do dente. Conclusões: A espessura do esmalte dos incisivos inferiores é semelhante nas faces mesial e distal, com a camada mais fina localizada na zona superior.

Structural Elements Involved in ATP Hydrolysis Inhibition and ATP Synthesis of Tuberculosis and Nontuberculous Mycobacterial F-ATP Synthase Decipher New Targets for Inhibitors.

The F1FO-ATP synthase is required for the viability of tuberculosis (TB) and nontuberculous mycobacteria (NTM) and has been validated as a drug target. Here, we present the cryo-EM structures of the Mycobacterium smegmatis F1-ATPase and the F1FO-ATP synthase with different nucleotide occupation within the catalytic sites and visualize critical elements for latent ATP hydrolysis and efficient ATP synthesis. Mutational studies reveal that the extended C-terminal domain (αCTD) of subunit α is the main element for the self-inhibition mechanism of ATP hydrolysis for TB and NTM bacteria. Rotational studies indicate that the transition between the inhibition state by the αCTD and the active state is a rapid process. We demonstrate that the unique mycobacterial γ-loop and subunit δ are critical elements required for ATP formation. The data underline that these mycobacterium-specific elements of α, γ, and δ are attractive targets, providing a platform for the discovery of species-specific inhibitors.

Direct observation of stepping rotation of V-ATPase reveals rigid component in coupling between Vo and V1 motors.

V-ATPases are rotary motor proteins that convert the chemical energy of ATP into the electrochemical potential of ions across cell membranes. V-ATPases consist of two rotary motors, Vo and V1, and Enterococcus hirae V-ATPase (EhVoV1) actively transports Na+ in Vo (EhVo) by using torque generated by ATP hydrolysis in V1 (EhV1). Here, we observed ATP-driven stepping rotation of detergent-solubilized EhVoV1 wild-type, aE634A, and BR350K mutants under various Na+ and ATP concentrations ([Na+] and [ATP], respectively) by using a 40-nm gold nanoparticle as a low-load probe. When [Na+] was low and [ATP] was high, under the condition that only Na+ binding to EhVo is rate limiting, wild-type and aE634A exhibited 10 pausing positions reflecting 10-fold symmetry of the EhVo rotor and almost no backward steps. Duration time before the forward steps was inversely proportional to [Na+], confirming that Na+ binding triggers the steps. When both [ATP] and [Na+] were low, under the condition that both Na+ and ATP bindings are rate limiting, aE634A exhibited 13 pausing positions reflecting 10- and 3-fold symmetries of EhVo and EhV1, respectively. The distribution of duration time before the forward step was fitted well by the sum of two exponential decay functions with distinct time constants. Furthermore, occasional backward steps smaller than 36° were observed. Small backward steps were also observed during three long ATP cleavage pauses of BR350K. These results indicate that EhVo and EhV1 do not share pausing positions, Na+ and ATP bindings occur at different angles, and the coupling between EhVo and EhV1 has a rigid component.

The leaflet-annulus index in canine myxomatous mitral valve disease.

Myxomatous mitral valve disease (MMVD) is the most common chronic heart valve disease, leading to the eccentric hypertrophy. Recently, the leaflet-annulus index (LAI), which focuses on the mitral valve apparatus, has been considered a prognostic factor for human mitral regurgitation (MR); however, it has not been reported in veterinary medicine. In the present study, we retrospectively evaluated the LAI in dogs with MMVD. Eight-three dogs with MMVD diagnosed using echocardiography were included in this study. The anteroposterior length, anterior and posterior cusp coaptation lengths, LAI, left ventricular end-diastolic internal diameter normalized to body weight (LVIDDN), and left atrium to aorta ratio (LA/Ao) were measured. A significant correlation between the LAI, LVIDDN, and LA/Ao of MR grading, and left ventricle dilation was observed. In conclusion, LAI could help determine annular widening, suggesting the decision of an appropriate for SVR in clinical settings.

Endovascular Treatment for Acute Ischemic Stroke After Video-Assisted Thoracoscopic Pulmonary Lobectomy in Patients With Lung Cancer: A Report of Four Cases and Literature Review.

BACKGROUND: Postoperative cerebral embolic stroke is a serious complication of pulmonary lobectomy, occurring in 1.1% of patients undergoing lobectomy through video-assisted thoracoscopic surgery (VATS). The mechanism of this complication is thought to be embolic stroke caused by thrombus formed due to stagnation in the pulmonary vein stump after VATS lobectomy. There have been few reports demonstrating the utility of endovascular treatment (EVT) for cerebral embolic stroke after VATS lobectomy. CASE DESCRIPTION: In our case series, cerebral embolic stroke occurred after VATS pulmonary lobectomy for lung cancer, including the left upper lobe in three cases and the right lobe in one. The median duration of ischemic stroke after VATS was 4.5 days (interquartile range, 2-9 days). The median time from stroke onset to puncture was 130 min. Successful recanalization was achieved in all cases, and two patients achieved favorable clinical outcomes (modified Rankin scale, 0-2). CONCLUSION: We report a case series of four patients who underwent EVT for acute embolic stroke after VATS lobectomy for lung cancer. EVT is considered a reasonable and feasible therapeutic option for this condition.

Successful Management of Pheochromocytoma Crisis with Cardiogenic Shock by Percutaneous Left Ventricular Assist Device.

Therapeutic strategy utilizing mechanical circulatory supports in patients with pheochromocytoma-related cardiogenic shock remains unestablished. We had a 51-year-old man with acute decompensated heart failure due to pheochromocytoma crisis. He received a percutaneous left ventricular assist device-supported alpha-blocker and intensive fluid infusion therapy, which ameliorated impaired end-organ dysfunction, maintaining hemodynamics and achieving cardiac recovery, followed by the successfully scheduled adrenalectomy. Early suspicion of pheochromocytoma and Impella-supported disease-specific medical management might be a promising bridge to surgery strategy.

Primary Cardiac Angiosarcoma Accompanying Cardiac Tamponade.

A de novo cardiac malignant tumor is rare and sometimes challenging to diagnose. We encountered a 67-year-old man without any medical history complaining of dyspnea on effort. On admission, his hemodynamics were deteriorated due to cardiac tamponade, which was improved by percutaneous drainage of 1,200 mL pericardial effusion, showing 11.0 g/dL of hemoglobin. We suspected primary cardiac malignancy following multidisciplinary tests, and a cardiac biopsy via sternotomy demonstrated the definitive diagnosis of primary malignant tumor (angiosarcoma) infiltrating the right atrial myocardium. We initiated weekly paclitaxel therapy. Further studies are warranted to establish the optimal diagnostic and therapeutic strategy for de novo cardiac malignancy.

Structure-based drug design of novel and highly potent pyruvate dehydrogenase kinase inhibitors.

Pyruvate dehydrogenase kinases (PDHKs) are fascinating drug targets for numerous diseases, including diabetes and cancers. In this report, we describe the result of our structure-based drug design from tricyclic lead compounds that led to the discovery of highly potent PDHK2 and PDHK4 dual inhibitors in enzymatic assay. The C3-position of the tricyclic core was explored, and the PDHK2 X-ray structure with a representative compound revealed a novel ATP lid conformation in which the phenyl ring of Phe326 mediated the interaction of the Arg258 sidechain and the compound. Compounds with amide linkers were designed to release the ATP lid by forming an intramolecular pi-pi interaction, and these compounds showed single-digit nM IC50 values in an enzymatic assay. We also explored the C4-position of the tricyclic core to reproduce the interaction observed with the C3-position substitution, and the pyrrolidine compound showed the same level of IC50 values. By optimizing an interaction with the Asn255 sidechain through a docking simulation, compounds with 2-carboxy pyrrole moiety also showed single-digit nM IC50 values without having a cation-pi interaction with the Arg258 sidechain.

Intestinal fatty acid-binding protein and osteoprotegerin in anthracycline-induced rabbit models of dilated cardiomyopathy.

Anthracyclines are used for chemotherapy in small animal cancer patients. However, cardiotoxic complications are very common with anthracycline use and induce multi-organ complications. The purpose of this study was to investigate the associations between multi-organ complications, focusing on the liver and intestine, and the serum concentrations of intestinal fatty acid-binding protein (I-FABP) and osteoprotegerin (OPG) in rabbits with daunorubicin-induced dilated cardiomyopathy (DCM). Sixteen New Zealand white male rabbits (16-20 weeks old), weighing 2.4-3.65 kg, were randomly divided into the control (n = 8) and daunorubicin-induced DCM (n = 8) groups. The concentration of serum I-FABP was significantly elevated in the DCM group (201.9 ± 16.6 pg/mL) compared to the control group (152.2 ± 19.9 g/mL). Additionally, the concentration of serum lactate was markedly increased in the DCM group (0.16 ± 0.01 mM) compared to that in the control group (0.02 ± 0.01 mmol/mL). In addition, the OPG concentration was significantly higher in the DCM group (2.44 ± 0.14 ng/mL) than in the control group (0.1 ± 0.08 ng/mL). Although the histopathology of the ileum did not significantly differ between groups, pathological changes were observed in the livers of the DCM group animals. In conclusion, multi-organ complications were recognized in DCM models and were accompanied by elevated serum I-FABP and OPG concentrations.