Discovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is currently the leading cause of chronic liver disease worldwide. Metabolic Dysfunction-Associated Steatohepatitis (MASH), an advanced form of MASLD, can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Based on recent findings by our team that liver 5HT2A knockout male mice suppressed steatosis and reduced fibrosis-related gene expression, we developed a peripheral 5HT2A antagonist, compound 11c for MASH. It shows good in vitro activity, stability, and in vivo pharmacokinetics (PK) in rats and dogs. Compound 11c also shows good in vivo efficacy in a diet-induced obesity (DIO) male mice model and in a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) male mice model, effectively improving histologic features of MASH and fibrosis. According to the tissue distribution study using [14C]-labeled 11c, the compound was determined to be a peripheral 5HT2A antagonist. Collectively, first-in-class compound 11c shows promise as a therapeutic agent for the treatment of MASLD and MASH.

Inhibition of pyruvate dehydrogenase kinase 4 ameliorates kidney ischemia-reperfusion injury by reducing succinate accumulation during ischemia and preserving mitochondrial function during reperfusion.

Ischemia-reperfusion (IR) injury, a leading cause of acute kidney injury (AKI), is still without effective therapies. Succinate accumulation during ischemia followed by its oxidation during reperfusion leads to excessive reactive oxygen species (ROS) and severe kidney damage. Consequently, the targeting of succinate accumulation may represent a rational approach to the prevention of IR-induced kidney injury. Since ROS are generated primarily in mitochondria, which are abundant in the proximal tubule of the kidney, we explored the role of pyruvate dehydrogenase kinase 4 (PDK4), a mitochondrial enzyme, in IR-induced kidney injury using proximal tubule cell-specific Pdk4 knockout (Pdk4ptKO) mice. Knockout or pharmacological inhibition of PDK4 ameliorated IR-induced kidney damage. Succinate accumulation during ischemia, which is responsible for mitochondrial ROS production during reperfusion, was reduced by PDK4 inhibition. PDK4 deficiency established conditions prior to ischemia resulting in less succinate accumulation, possibly because of a reduction in electron flow reversal in complex II, which provides electrons for the reduction of fumarate to succinate by succinate dehydrogenase during ischemia. The administration of dimethyl succinate, a cell-permeable form of succinate, attenuated the beneficial effects of PDK4 deficiency, suggesting that the kidney-protective effect is succinate-dependent. Finally, genetic or pharmacological inhibition of PDK4 prevented IR-induced mitochondrial damage in mice and normalized mitochondrial function in an in vitro model of IR injury. Thus, inhibition of PDK4 represents a novel means of preventing IR-induced kidney injury, and involves the inhibition of ROS-induced kidney toxicity through reduction in succinate accumulation and mitochondrial dysfunction.

Changes in the number and characteristics of patients with acute acquired concomitant esotropia over time: An 8-year retrospective study.

This study aimed to evaluate changes in the number and clinical characteristics of patients with acute acquired concomitant esotropia (AACE) over the course of 8 years. This retrospective study enrolled patients with AACE who visited our clinic between July 2014 and June 2022. The total study period was divided into 4 periods in chronological order. The number of patients who initially visited the clinic and underwent surgery was compared over time by dividing the time period into 8 quarters (quarters, 2 years). Clinical factors were analyzed between patients with and without surgery. Ninety-seven patients were enrolled (mean age, 29.5 years; 43 females). Among these, 65 patients (67.0%) underwent surgery. The number of patients with AACE increased steadily throughout the study period. The number of patients who underwent surgery was the highest during the 2020 Q3 to 2022 Q2. There was an increasing trend in patients with large ocular deviation (≥30 prism diopters) over time among patients with AACE who underwent surgical treatment (P = .037). Mean ocular deviation at the initial visit was greater in patients who underwent surgery than in those who did not (P < .001). The mean age of patients who underwent surgery was lower than that of patients who did not (P = .005). The number of patients with AACE has been increasing over time. Patients who underwent surgical treatment showed more ocular deviation and were younger at the initial visit than patients who did not.

Upregulation of the ERRγ-VDAC1 axis underlies the molecular pathogenesis of pancreatitis.

Emerging evidence suggest that transcription factors play multiple roles in the development of pancreatitis, a necroinflammatory condition lacking specific therapy. Estrogen-related receptor γ (ERRγ), a pleiotropic transcription factor, has been reported to play a vital role in pancreatic acinar cell (PAC) homeostasis. However, the role of ERRγ in PAC dysfunction remains hitherto unknown. Here, we demonstrated in both mice models and human cohorts that pancreatitis is associated with an increase in ERRγ gene expression via activation of STAT3. Acinar-specific ERRγ haploinsufficiency or pharmacological inhibition of ERRγ significantly impaired the progression of pancreatitis both in vitro and in vivo. Using systematic transcriptomic analysis, we identified that voltage-dependent anion channel 1 (VDAC1) acts as a molecular mediator of ERRγ. Mechanistically, we showed that induction of ERRγ in cultured acinar cells and mouse pancreata enhanced VDAC1 expression by directly binding to specific site of the Vdac1 gene promoter and resulted in VDAC1 oligomerization. Notably, VDAC1, whose expression and oligomerization were dependent on ERRγ, modulates mitochondrial Ca2+ and ROS levels. Inhibition of the ERRγ-VDAC1 axis could alleviate mitochondrial Ca2+ accumulation, ROS formation and inhibit progression of pancreatitis. Using two different mouse models of pancreatitis, we showed that pharmacological blockade of ERRγ-VDAC1 pathway has therapeutic benefits in mitigating progression of pancreatitis. Likewise, using PRSS1R122H-Tg mice to mimic human hereditary pancreatitis, we demonstrated that ERRγ inhibitor also alleviated pancreatitis. Our findings highlight the importance of ERRγ in pancreatitis progression and suggests its therapeutic intervention for prevention and treatment of pancreatitis.

CycloZ Improves Hyperglycemia and Lipid Metabolism by Modulating Lysine Acetylation in KK-Ay Mice.

BACKGRUOUND: CycloZ, a combination of cyclo-His-Pro and zinc, has anti-diabetic activity. However, its exact mode of action remains to be elucidated. METHODS: KK-Ay mice, a type 2 diabetes mellitus (T2DM) model, were administered CycloZ either as a preventive intervention, or as a therapy. Glycemic control was evaluated using the oral glucose tolerance test (OGTT), and glycosylated hemoglobin (HbA1c) levels. Liver and visceral adipose tissues (VATs) were used for histological evaluation, gene expression analysis, and protein expression analysis. RESULTS: CycloZ administration improved glycemic control in KK-Ay mice in both prophylactic and therapeutic studies. Lysine acetylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, liver kinase B1, and nuclear factor-κB p65 was decreased in the liver and VATs in CycloZ-treated mice. In addition, CycloZ treatment improved mitochondrial function, lipid oxidation, and inflammation in the liver and VATs of mice. CycloZ treatment also increased the level of ß-nicotinamide adenine dinucleotide (NAD+), which affected the activity of deacetylases, such as sirtuin 1 (Sirt1). CONCLUSION: Our findings suggest that the beneficial effects of CycloZ on diabetes and obesity occur through increased NAD+ synthesis, which modulates Sirt1 deacetylase activity in the liver and VATs. Given that the mode of action of an NAD+ booster or Sirt1 deacetylase activator is different from that of traditional T2DM drugs, CycloZ would be considered a novel therapeutic option for the treatment of T2DM.

Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease.

Ca2+ overload-induced mitochondrial dysfunction is considered as a major contributing factor in the pathogenesis of alcohol-associated liver disease (ALD). However, the initiating factors that drive mitochondrial Ca2+ accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in hepatic GRP75-mediated mitochondria-associated ER membrane (MAM) Ca2+-channeling (MCC) complex formation promotes mitochondrial dysfunction in vitro and in male mouse model of ALD. Unbiased transcriptomic analysis reveals PDK4 as a prominently inducible MAM kinase in ALD. Analysis of human ALD cohorts further corroborate these findings. Additional mass spectrometry analysis unveils GRP75 as a downstream phosphorylation target of PDK4. Conversely, non-phosphorylatable GRP75 mutation or genetic ablation of PDK4 prevents alcohol-induced MCC complex formation and subsequent mitochondrial Ca2+ accumulation and dysfunction. Finally, ectopic induction of MAM formation reverses the protective effect of PDK4 deficiency in alcohol-induced liver injury. Together, our study defines a mediatory role of PDK4 in promoting mitochondrial dysfunction in ALD.

Effect of Spine-Pelvis Relationship in Total Hip Arthroplasty.

When spine-pelvic motion is normally coordinated, the pelvis may tilt posteriorly and acetabular anteversion may increase as the patient's position changes from standing to sitting; this scenario allows for improved clearance of the femoral head and neck during hip flexion. However, changes in the mobility of the spine and pelvis may result in impingement after total hip arthroplasty (THA), with the most obvious complication being dislocation. Understanding the spinal-pelvic relationship in the sagittal plane is essential for planning THA in patients with spinal fusion or a known spine disease. Careful attention should be payed to the cup position when performing THA on patients with an increased risk of dynamic impingement.

Effect of ramosetron on QTc interval: a randomised controlled trial in patients undergoing off-pump coronary artery bypass surgery.

BACKGROUND: Ramosetron is a relatively new 5-hydroxytryptamine three receptor antagonist with higher binding affinity and more prolonged duration of action compared to ondansetron. The present study was performed to evaluate the effects of ramosetron on QTc interval and possible cardiovascular adverse effects in patients undergoing cardiac surgery. METHOD: A total of 114 patients who underwent off-pump coronary artery bypass surgery were enrolled in this randomised placebo-controlled trial. Patients were allocated into two groups that received intravenous injection of 0.3 mg ramosetron or normal saline during induction of anaesthesia. QTc intervals were measured before the operation, intraoperatively (0, 1, 2, 3, 5, 10, 15, 30, 45, 60, 90, 120, and 240 min after injection of ramosetron or normal saline), at the end of the operation, and on postoperative day 1. RESULTS: There were no differences in mean QTc interval between groups at every time point. However, maximal change in QTc interval during surgery was higher in the ramosetron group than the placebo group (25.1 ± 22.0 vs. 17.5 ± 14.5 ms, 95 % CI 0.34-14.78, P = 0.040). Also, there were more patients with a QTc interval increase of > 60 ms in the ramosetron group (5 vs. 0, 95 % CI 1.6-18.0, P = 0.021). There were no significant differences in cardiovascular complications. CONCLUSIONS: Ramosetron administered during induction of anaesthesia may affect maximal change in QTc interval during off-pump coronary artery bypass surgery. Ramosetron should be used with caution in high risk patients for developing Torsades de Pointes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02139241. Registered November 12, 2013.

Reliability of 3-Dimensional Computed Tomography for Application of the Bernard Quadrant Method in Femoral Tunnel Position Evaluation After Anatomic Anterior Cruciate Ligament Reconstruction.

PURPOSE: To validate whether the Bernard quadrant method, which was developed for application on simple lateral radiography, can be used with 3-dimensional computed tomography (3D CT) to localize the femoral insertion of the reconstructed anterior cruciate ligament (ACL). METHODS: We analyzed 32 knees with ACL tears that were reconstructed using a metal interference screw for fixation at the femoral tunnel between March 2012 and May 2013. Postoperative lateral radiographs and 3D CT images were obtained 7 days after the operation. By use of the Bernard quadrant method, the location of the femoral tunnel was measured by 2 orthopaedic surgeons by locating the position of the metal interference screw using 3D CT imaging and simple lateral knee radiography. The correlation between the femoral tunnels on the 2 radiographic images was compared using the MedCalc statistical analysis program. RESULTS: On the 3D CT image, the position of the femoral insertion of the ACL as measured by the position of the metal screw head was 36.3% ± 6.0% in the x-coordinate and 39.6% ± 9.1% in the y-coordinate compared with 37.6% ± 5.8% and 41.0% ± 11.6%, respectively, on the simple radiograph. The Pearson correlation coefficients between 3D CT and simple radiography were 0.840 for the x-coordinate and 0.858 for the y-coordinate. Intraobserver reliability and interobserver reliability for both coordinates were greater than 0.9 on 3D CT. CONCLUSIONS: Application of the Bernard quadrant method on 3D CT showed high correlation to the originally described method using lateral radiographs and can be used reliably for localizing the reconstructed ACL. LEVEL OF EVIDENCE: Level III, diagnostic study.

The effect of Doppler ultrasound on early vascular interventions and clinical outcomes after liver transplantation.

BACKGROUND: During the immediate postoperative period after liver transplantation (LT), postoperative bleeding and vascular complications (stenosis, thrombosis) are the two most common complications that require therapeutic decisions. Doppler ultrasound (DUS) is the established method for screening vascular patency after LT during the immediate postoperative period. The objective of our study was to evaluate the impact of DUS performed on postoperative days (POD) 1 and 2 on early vascular interventions. METHODS: We studied 200 patients who had undergone living donor or deceased donor liver transplantation between January 2011 and March 2012. Postoperative liver DUS findings of up to POD 14, including patency of hepatic artery, portal vein, and hepatic vein, were retrieved. Patients with normal DUS findings on POD 1 and POD 2 were classified as the normal early DUS group. Patients with abnormal DUS findings at POD1 or POD2 were classified as the abnormal early DUS group. Frequency of vascular interventions was compared between the two groups. Risk factors that predict vascular interventions also were assessed. RESULTS: On POD 1 and 2, 81.5 % (163/200) had normal DUS findings and management was not altered by subsequent DUS findings. Two patients in the normal group were found to have hepatic artery dissection and hepatic vein thrombosis on routine CT on POD 7 and received vascular intervention. DUS results in the two patients were normal until POD 6, but DUS performed after the CT on POD 7 were consistent with the CT findings. Of the 37 recipients who showed abnormal DUS findings on POD 1 or 2, the DUS findings were normalized or unchanged thereafter in 33 patients and no vascular interventions were performed. Two patients underwent hepatic artery thrombectomy on POD 2, one patient required a portal vein thrombectomy on POD 1, and one patient died on POD 3 due to bleeding. The overall incidence of vascular complication requiring vascular interventions was 2.5 %. Logistic regression identified abnormal DUS findings on POD 1 or 2 as an independent risk factor of vascular complications requiring intervention. CONCLUSIONS: In LT recipients who demonstrate normal DUS findings in the first 2 postoperative days, additional DUS screening may have value only when clinically indicated.