The redox-dependent inhibition of thioredoxin (TRX) by thioredoxin-interacting protein (TXNIP) plays a pivotal role in various cancers and metabolic syndromes. However, the molecular mechanism of this regulation is largely unknown. Here, we present the crystal structure of the TRX–TXNIP complex and demonstrate that the inhibition of TRX by TXNIP is mediated by an intermolecular disulphide interaction resulting from a novel disulphide bond-switching mechanism. Upon binding to TRX, TXNIP undergoes a structural rearrangement that involves switching of a head-to-tail interprotomer Cys63-Cys247 disulphide between TXNIP molecules to an interdomain Cys63-Cys190 disulphide, and the formation of a de novo intermolecular TXNIP Cys247-TRX Cys32 disulphide. This disulphide-switching event unexpectedly results in a domain arrangement of TXNIP that is entirely different from those of other arrestin family proteins. We further show that the intermolecular disulphide bond between TRX and TXNIP dissociates in the presence of high concentrations of reactive oxygen species. This study provides insight into TRX and TXNIP-dependent cellular regulation.

To evaluate the feasibility of low-concentration contrast medium (CM) for vascular enhancement, image quality, and radiation dose on computed tomography aortography (CTA) using a combined low-tube-voltage and iterative reconstruction (IR) technique. Ninety subjects underwent dual-source CT (DSCT) operating in dual-source, high-pitch mode. DSCT scans were performed using both high-concentration CM (Group A, n = 50; Iomeprol 400) and low-concentration CM (Group B, n = 40; Iodixanol 270). Group A was scanned using a reference tube potential of 120 kVp and 120 reference mAs under automatic exposure control with IR. Group B was scanned using low-tube-voltage (80 or 100 kVp if body mass index ≥25 kg/m(2)) at a fixed current of 150 mAs, along with IR. Images of the two groups were compared regarding attenuation, image noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), iodine load, and radiation dose in various locations of the CTA. In comparison between Group A and Group B, the average mean attenuation (454.73 ± 86.66 vs. 515.96 ± 101.55 HU), SNR (25.28 ± 4.34 vs. 31.29 ± 4.58), and CNR (21.83 ± 4.20 vs. 27.55 ± 4.81) on CTA in Group B showed significantly greater values and significantly lower image noise values (18.76 ± 2.19 vs. 17.48 ± 3.34) than those in Group A (all Ps < 0.05). Homogeneous contrast enhancement from the ascending thoracic aorta to the infrarenal abdominal aorta was significantly superior in Group B (P < 0.05). Low-concentration CM and a low-tube-voltage combination technique using IR is a feasible method, showing sufficient contrast enhancement and image quality.

Background and ObjectivesVascular smooth muscle cell (VSMC) proliferation is responsible for the restenosis of previously inserted coronary stents. Angiotensin II (Ang II) is known to regulate VSMC proliferation. LKB1, a serine/threonine kinase, interacts with the p53 pathway and acts as a tumor suppressor.Materials and MethodsWe assessed the association of Ang II and the expression of LKB1 in primary cultured murine VSMCs and neointima of the Sprague Dawley rat carotid artery injury model. We created carotid balloon injuries and harvested the injured carotid arteries 14 days after the procedure.ResultsAng II increased LKB1 expression in a time-dependent manner and peaked at an Ang II concentration of 10-7 mole/L in VSMCs. In the animal experiment, neointima was markedly increased after balloon injury compared to the control group. Immunohistochemical studies showed that LKB1 expression increased according to neointima thickness. Ang II augmented LKB1 expression after the injury. Western blot analysis of LKB1 with carotid artery lysate revealed the same pattern as LKB1 immunohistochemistry. Increased LKB1 expression started at 5 days after the balloon injury, and peaked at 14 days after the injury. Although LKB1 expression was increased after the injury, LKB1 kinase activity was not increased. Ang II or balloon-injury increased the expression of LKB1 although the LKB1 activity was reduced.ConclusionAng II increased LKB1 expression in VSMCs and neointima. These findings were not kinase dependant.

Background Despite the benefit of culprit‐only percutaneous coronary intervention (PCI) in the CULPRIT‐SHOCK (Culprit Lesion Only PCI Versus Multi‐vessel PCI in Cardiogenic Shock) trial, the optimal revascularization strategy for refractory cardiogenic shock (CS) requiring mechanical circulatory support devices remains controversial. This study aimed to compare clinical outcomes between the culprit‐only and immediate multivessel PCI strategies in patients with acute myocardial infarction complicated by CS who underwent venoarterial‐extracorporeal membrane oxygenation before revascularization. Methods and Results This study included patient‐pooled data from the RESCUE (Retrospective and Prospective Observational Study to Investigate Clinical Outcomes and Efficacy of Left Ventricular Assist Devices for Korean Patients With Cardiogenic Shock) and SMC‐ECMO (Samsung Medical Center–Extracorporeal Membrane Oxygenation) registries. A total of 315 patients with acute myocardial infarction with multivessel disease who underwent venoarterial‐extracorporeal membrane oxygenation before revascularization attributable to refractory CS were included in this analysis. The study population was classified into culprit‐only versus immediate multivessel PCI according to nonculprit lesion treatment strategies. The primary end point was 30‐day mortality or renal‐replacement therapy, and the key secondary end point was 12‐month follow‐up mortality. Among the study population, 175 (55.6%) underwent culprit‐only PCI and 140 (44.4%) underwent immediate multivessel PCI. Compared with culprit‐only PCI, immediate multivessel PCI was associated with significantly lower risks of 30‐day mortality or renal‐replacement therapy (68.0% versus 54.3%; P =0.018) and all‐cause mortality during 12 months of follow‐up (59.5% versus 47.5%; hazard ratio [HR], 0.689 [95% CI, 0.506–0.939]; P =0.018) in patients with acute myocardial infarction and CS who underwent venoarterial‐extracorporeal membrane oxygenation before revascularization. These results were also consistent in the 99 pairs of propensity score–matched population (60.6% versus 43.6%; HR, 0.622 [95% CI, 0.420–0.922]; P =0.018). Conclusions Among patients with acute myocardial infarction with multivessel disease complicated by advanced CS requiring venoarterial‐extracorporeal membrane oxygenation before revascularization, immediate multivessel PCI was associated with lower incidences of 30‐day mortality or renal replacement therapy and 12‐month follow‐up mortality, compared with culprit‐only PCI. Registration Information clinicaltrials.gov . Identifier: NCT02985008.

In supraoptic nucleus (SON) magnocellular neurosecretory cells (MNCs), γ-GABA, via activation of GABAA receptors (GABAA Rs), mediates persistent tonic inhibitory currents (Itonic ), as well as conventional inhibitory postsynaptic currents (IPSCs, Iphasic ). In the present study, we examined the functional significance of Itonic in SON MNCs challenged by 24-h water deprivation (24WD). Although the main characteristics of spontaneous IPSCs were similar in 24WD compared to euhydrated (EU) rats, Itonic , measured by bicuculline (BIC)-induced Iholding shifts, was significantly smaller in 24WD compared to EU rats (P < 0.05). Propofol and diazepam prolonged IPSC decay time to a similar extent in both groups but induced less Itonic in 24WD compared to EU rats, suggesting a selective decrease in GABAA receptors mediating Itonic over Iphasic in 24WD rats. THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), a preferential δ subunit agonist, and L-655,708, a GABAA receptor α5 subunit selective imidazobenzodiazepine, caused a significantly smaller inward and outward shift in Iholding , respectively, in 24WD compared to EU rats (P < 0.05 in both cases), suggesting an overall decrease in the α5 subunit-containing GABAA Rs and the δ subunit-containing receptors mediating Itonic in 24WD animals. Consistent with a decrease in 24WD Itonic , bath application of GABA induced significantly less inhibition of the neuronal firing activity in 24WD compared to EU SON MNCs (P < 0.05). Taken together, the results of the present study indicate a selective decrease in GABAA Rs functions mediating Itonic as opposed to those mediating Iphasic in SON MNCs, demonstrating the functional significance of Itonic with respect to increasing neuronal excitability and hormone secretion in 24WD rats.