p21-activated kinase 4 counteracts PKA-dependent lipolysis by phosphorylating FABP4 and HSL.

Adipose tissue lipolysis is mediated by cAMP-protein kinase A (PKA)-dependent intracellular signalling. Here, we show that PKA targets p21-activated kinase 4 (PAK4), leading to its protein degradation. Adipose tissue-specific overexpression of PAK4 in mice attenuates lipolysis and exacerbates diet-induced obesity. Conversely, adipose tissue-specific knockout of Pak4 or the administration of a PAK4 inhibitor in mice ameliorates diet-induced obesity and insulin resistance while enhancing lipolysis. Pak4 knockout also increases energy expenditure and adipose tissue browning activity. Mechanistically, PAK4 directly phosphorylates fatty acid-binding protein 4 (FABP4) at T126 and hormone-sensitive lipase (HSL) at S565, impairing their interaction and thereby inhibiting lipolysis. Levels of PAK4 and the phosphorylation of FABP4-T126 and HSL-S565 are enhanced in the visceral fat of individuals with obesity compared to their lean counterparts. In summary, we have uncovered an important role for FABP4 phosphorylation in regulating adipose tissue lipolysis, and PAK4 inhibition may offer a therapeutic strategy for the treatment of obesity.

Dual outflow upper arm arteriovenous fistula: An effective technique to prevent cephalic arch stenosis.

Cephalic arch stenosis (CAS) is critical point to maintain functional arteriovenous fistula (AVF) in patients undergoing hemodialysis with brachio-cephalic AVFs. In this study, we aimed to determine the effectiveness of dual outflow (cephalic and basilic veins) as a surgical method to prevent CAS. Between July 2016 and December 2019, 369 patients underwent upper arm AVF creation. Among them the 251 patients were enrolled in this retrospective study. Two hundred seven underwent brachio-cephalic arteriovenous fistula (BCAVF) and 44 underwent brachio-cephalicbasilic arteriovenous fistula (BCBAVF). From the 251 patients, diabetes mellitus (66.7% vs 36.4%, P < .001) and hypertension (91.3% vs 75%, P = .002) were more common in the patient group who underwent BCAVF surgery; however, the difference in volume flow to the fistula did not differ between the 2 groups. CAS (30.4% vs 9.1%, P = .004) and fistula occlusion (15.9% vs 4.5%, P = .048) were likely to occur in the BCAVF group. The primary patency rates at 12 months were 74.3% and 86.4% for the BCAVFs and BCBAVFs, respectively (P = .075). The primary-assisted patency rates at 12 months were 87.0% for BCAVFs and 93.2% for BCBAVFs, respectively (P = .145). Secondary patency rates at 12 months were 92.2% for BCAVFs and 93.2% for BCBAVFs, respectively (P = .023). Compared to BCAVF, traditional upper arm AVF, upper arm AVF with cephalic and basilic vein dual drainage can be optimal surgical method to preventing CAS.

Estimation of right lobe graft weight for living donor liver transplantation using deep learning-based fully automatic computed tomographic volumetry.

This study aimed at developing a fully automatic technique for right lobe graft weight estimation using deep learning algorithms. The proposed method consists of segmentation of the full liver region from computed tomography (CT) images, classification of the entire liver region into the right and left lobes, and estimation of the right lobe graft weight from the CT-measured right lobe graft volume using a volume-to-weight conversion formula. The first two steps were performed with a transformer-based deep learning model. To train and evaluate the model, a total of 248 CT datasets (188 for training, 40 for validation, and 20 for testing and clinical evaluation) were used. The Dice similarity coefficient (DSC), mean surface distance (MSD), and the 95th percentile Hausdorff distance (HD95) were used for evaluating the segmentation accuracy of the full liver region and the right liver lobe. The correlation coefficient (CC), percentage error (PE), and percentage absolute error (PAE) were used for the clinical evaluation of the estimated right lobe graft weight. The proposed method achieved high accuracy in segmentation for DSC, MSD, and HD95 (95.9% ± 1.0%, 1.2 ± 0.4 mm, and 5.2 ± 1.9 mm for the entire liver region; 92.4% ± 2.7%, 2.0 ± 0.7 mm, and 8.8 ± 2.9 mm for the right lobe) and in clinical evaluation for CC, PE, and PAE (0.859, - 1.8% ± 9.6%, and 8.6% ± 4.7%). For the right lobe graft weight estimation, the present study underestimated the graft weight by - 1.8% on average. A mean difference of - 21.3 g (95% confidence interval: - 55.7 to 13.1, p = 0.211) between the estimated graft weight and the actual graft weight was achieved in this study. The proposed method is effective for clinical application.

A new formula for estimation of standard liver volume using liver height and thoracic width.

Purpose: Precise estimation of the standard liver volume (SLV) is crucial in decision making regarding major hepatectomy and living donor liver transplantation. This study aimed to propose an accurate and efficient formula for estimating the SLV in the Korean population. Methods: We created a regression model for SLV estimation using a data set of 230 Korean patients with healthy livers. The proposed model was cross validated using a different data set of 37 patients with healthy livers. The total liver volume (TLV), except for the volume of liver blood vessels, was measured through computed tomography volumetry as the dependent variable. Various anthropometric variables, liver height (LH), thoracic width (TW), age, and sex (0, female and 1, male) were considered as candidates for independent variables. We conducted stepwise regression analysis to identify variables to be included in the proposed model. Results: A new formula was established; SLV = -1,275 + 9.85 × body weight (BW, kg) + 19.95 × TW (cm) + 7.401 × LH (mm). The proposed formula showed the best performance among existing formulas over the cross-validation data set. Conclusion: The proposed formula derived using BW, TW, and LH estimated the TLV in the cross-validation data set more accurately than existing formulas.

p21-activated kinase 4 inhibition protects against liver ischemia/reperfusion injury: Role of nuclear factor erythroid 2-related factor 2 phosphorylation.

BACKGROUND AND AIMS: p21-activated kinase 4 (PAK4), an oncogenic protein, has emerged as a promising target for anticancer drug development. Its role in oxidative stress conditions, however, remains elusive. We investigated the effects of PAK4 signaling on hepatic ischemia/reperfusion (I/R) injury. APPROACH AND RESULTS: Hepatocyte- and myeloid-specific Pak4 knockout (KO) mice and their littermate controls were subjected to a partial hepatic I/R (HIR) injury. We manipulated the catalytic activity of PAK4, either through genetic engineering (gene knockout, overexpression of wild-type [WT] or dominant-negative kinase) or pharmacological inhibitor, coupled with a readout of nuclear factor erythroid 2-related factor 2 (Nrf2) activity, to test the potential function of PAK4 on HIR injury. PAK4 expression was markedly up-regulated in liver during HIR injury in mice and humans. Deletion of PAK4 in hepatocytes, but not in myeloid cells, ameliorated liver damages, as demonstrated in the decrease in hepatocellular necrosis and inflammatory responses. Conversely, the forced expression of WT PAK4 aggravated the pathological changes. PAK4 directly phosphorylated Nrf2 at T369, and it led to its nuclear export and proteasomal degradation, all of which impaired antioxidant responses in hepatocytes. Nrf2 silencing in liver abolished the protective effects of PAK4 deficiency. A PAK4 inhibitor protected mice from HIR injury. CONCLUSIONS: PAK4 phosphorylates Nrf2 and suppresses its transcriptional activity. Genetic or pharmacological suppression of PAK4 alleviates HIR injury. Thus, PAK4 inhibition may represent a promising intervention against I/R-induced liver injury.

Delayed pseudoaneurysm formation of the carotid artery following the oral cavity injury in a child: A case report.

BACKGROUND: An impalement injury of the oral cavity is a common traumatic injury in children. In most cases, it is not accompanied by sequelae, but if foreign body residues are not found due to a minor injury, they may result in inflammatory responses and delayed vascular injuries in the surrounding tissues. Without early diagnosis and appropriate initial management, residual foreign bodies can cause serious complications and even mortality in some cases. CASE SUMMARY: A 9-year-old boy suffered an intra-oral injury by a wooden chopstick, and the patient was discharged from the hospital after receiving conservative treatment for the injury. However, the patient was readmitted to the hospital due to intra-oral bleeding, and since neck hematoma and right internal carotid artery pseudoaneurysm formation were detected on computed tomography, emergency surgery was performed. A remnant fragment of a wooden chopstick was found during the operation, and a delayed rupture of the internal carotid artery caused by the foreign body was also found. CONCLUSION: The failure of early detection and diagnosis of a residual foreign body may result in delayed vascular rupture.

Laparoscopic lumbar artery ligation of type II endoleaks following endovascular aneurysm repair: A case report.

INTRODUCTION: Although the clinical significance of type II endoleaks remain controversial, management strategies continue to expand. The laparoscopic approach is a minimally invasive method for persistent type II endoleak repair after endovascular aneurysm repair. PATIENT CONCERNS: A 70 - year - old male patient with a history of endovascular aneurysm repair with left internal iliac artery embolization presented with persistent type II endoleak from the lumbar arteries 2 years ago. The aneurysm sac size had increased more than 10 mm during follow up period. DIAGNOSIS: Persistent type II endoleak after endovascular aneurysm repair. INTERVENTIONS: Transarterial embolization was attempted and failed. A minimally invasive laparoscopic lumbar artery ligation was then utilized. OUTCOMES: The patient was discharged without any complications after surgery. Follow-up computed tomography angiography has shown the complete disappearance of the type II endoleaks. CONCLUSIONS: Laparoscopic lumbar artery ligation may be a safe and effective alternative treatment for type II endoleaks, especially in high resource settings.

Ixeris dentata decreases ER stress and hepatic lipid accumulation through regulation of ApoB secretion.

Nonalcoholic fatty liver disease (NAFLD) is caused by the hepatic accumulation of saturated fatty acids involving the ER stress mechanism. Secretion of apo lipid carrier proteins and their binding to hepatic TG and cholesterol are affected by ER stress. This study was designed to identify ER stress regulators with potential effects against hepatic lipid accumulation. Ixeris dentata (IXD) is a traditional herbal remedy for indigestion, hepatitis, and diabetes used in Korea, Japan, and China. To examine the regulatory effects of IXD against hepatic lipid accumulation and elucidate its suggested mechanism of ER stress, HepG2 hepatocytes were treated with IXD extract in the presence of palmitate. While palmitate induced an ER stress response in hepatocytes, as indicated by the upregulation of PERK, increased eukaryotic initiation factor 2α (eIF2α) phosphorylation, enhanced expression of GADD153/C/EBP homologous protein (CHOP), and reduced secretion of apoB resulting in hepatic cellular accumulation of triglycerides (TG) and cholesterol, IXD extract significantly inhibited the lipid accumulation and PERK/eIF2α/CHOP-axis of the ER stress response. The inhibition of the PERK/eIF2α/CHOP signaling pathway by IXD in palmitate-treated cells suggests that IXD regulates hepatic dyslipidemia through the regulation of ER stress.

Eucommia ulmoides cortex, geniposide and aucubin regulate lipotoxicity through the inhibition of lysosomal BAX.

In this study we examined the inhibition of hepatic dyslipidemia by Eucommia ulmoides extract (EUE). Using a screening assay for BAX inhibition we determined that EUE regulates BAX-induced cell death. Among various cell death stimuli tested EUE regulated palmitate-induced cell death, which involves lysosomal BAX translocation. EUE rescued palmitate-induced inhibition of lysosomal V-ATPase, α-galactosidase, α-mannosidase, and acid phosphatase, and this effect was reversed by bafilomycin, a lysosomal V-ATPase inhibitor. The active components of EUE, aucubin and geniposide, showed similar inhibition of palmitate-induced cell death to that of EUE through enhancement of lysosome activity. Consistent with these in vitro findings, EUE inhibited the dyslipidemic condition in a high-fat diet animal model by regulating the lysosomal localization of BAX. This study demonstrates that EUE regulates lipotoxicity through a novel mechanism of enhanced lysosomal activity leading to the regulation of lysosomal BAX activation and cell death. Our findings further indicate that geniposide and aucubin, active components of EUE, may be therapeutic candidates for non-alcoholic fatty liver disease.

Eucommia ulmoides Oliver extract, aucubin, and geniposide enhance lysosomal activity to regulate ER stress and hepatic lipid accumulation.

Eucommia ulmoides Oliver is a natural product widely used as a dietary supplement and medicinal plant. Here, we examined the potential regulatory effects of Eucommia ulmoides Oliver extracts (EUE) on hepatic dyslipidemia and its related mechanisms by in vitro and in vivo studies. EUE and its two active constituents, aucubin and geniposide, inhibited palmitate-induced endoplasmic reticulum (ER) stress, reducing hepatic lipid accumulation through secretion of apolipoprotein B and associated triglycerides and cholesterol in human HepG2 hepatocytes. To determine how EUE diminishes the ER stress response, lysosomal and proteasomal protein degradation activities were analyzed. Although proteasomal activity was not affected, lysosomal enzyme activities including V-ATPase were significantly increased by EUE as well as aucubin and geniposide in HepG2 cells. Treatment with the V-ATPase inhibitor, bafilomycin, reversed the inhibition of ER stress, secretion of apolipoprotein B, and hepatic lipid accumulation induced by EUE or its component, aucubin or geniposide. In addition, EUE was determined to regulate hepatic dyslipidemia by enhancing lysosomal activity and to regulate ER stress in rats fed a high-fat diet. Together, these results suggest that EUE and its active components enhance lysosomal activity, resulting in decreased ER stress and hepatic dyslipidemia.

The protective role of Bax inhibitor-1 against chronic mild stress through the inhibition of monoamine oxidase A.

The anti-apoptotic protein Bax inhibitor-1 (BI-1) is a regulator of apoptosis linked to endoplasmic reticulum (ER) stress. It has been hypothesized that BI-1 protects against neuron degenerative diseases. In this study, BI-1⁻/⁻ mice showed increased vulnerability to chronic mild stress accompanied by alterations in the size and morphology of the hippocampi, enhanced ROS accumulation and an ER stress response compared with BI-1⁺/⁺ mice. BI-1⁻/⁻ mice exposed to chronic mild stress showed significant activation of monoamine oxidase A (MAO-A), but not MAO-B, compared with BI-1⁺/⁺ mice. To examine the involvement of BI-1 in the Ca²âº-sensitive MAO activity, thapsigargin-induced Ca²âº release and MAO activity were analyzed in neuronal cells overexpressing BI-1. The in vitro study showed that BI-1 regulates Ca²âº release and related MAO-A activity. This study indicates an endogenous protective role of BI-1 under conditions of chronic mild stress that is primarily mediated through Ca²âº-associated MAO-A regulation.

Determination of phenylbutyric acid and its metabolite phenylacetic acid in different tissues of mouse by liquid chromatography with tandem mass spectrometry and its application in drug tissue distribution.

Endoplasmic reticulum (ER) stress is associated with various human diseases. Phenylbutyric acid (PBA) is a well-known chemical chaperone that regulates ER stress. The main objective of this study was to develop a simple, rapid, and sensitive method for the simultaneous determination of phenylbutyric acid and its metabolite, phenylacetic acid (PAA). A LC-MS/MS analysis using negative electrospray ionization was used. Samples were analyzed by multiple reaction monitoring (MRM) in 15 min of total run time, using d11-PBA and d7-PAA as internal standards. The limit of quantification was 1 µg/g for tissue and 0.8 µg/mL for plasma. Recoveries for plasma and tissues were higher than 81% for both PBA and PAA. The inter-day and intra-day accuracy and precision were within ±15%. We then further successfully validated this method by applying it to determine the tissue distribution of PBA and its metabolite PAA after i.p. injection of PBA at a dose of 500 mg/kg in mice. The maximum concentrations of PBA and PAA in plasma and tissues were seen at 15 min and 45 min, respectively. The PBA plasma concentration was 15-fold higher than the concentration in the kidney, whereas the PAA plasma concentration was 6-fold higher than the concentration in the liver. The area under the curve decreased in the order of plasma > kidney > liver > heart > muscle > lung for PBA and plasma > liver > kidney > heart > muscle > lung for PAA. The tissue to plasma ratio ranged from 0.007 to 0.063 for PBA and 0.016 to 0.109 for PAA. In summary, the LC-ESI-MS method developed in this study is simple, sensitive and reliable.