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Seung Hwan Han,1 Gyu Chul Oh,2 Hyuck Moon Kwon,3 Chang Gyu Park,4 In Jai Kim,5 Gyo-Seung Hwang,6 Byung Su Yoo,7 Seong Hoon Park,8 Kwang Je Lee,9 Hyo-soo Kim21Division of Cardiology, Department of Internal Medicine, Gachon University College of Medicine, Gil Hospital, Incheon, Republic of Korea; 2Division of Cardiology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; 3Cardiology Division, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 4Division of Cardiology, Cardiovascular Center, Korea University Guro Hospital, Seoul, Republic of Korea; 5Department of Cardiology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; 6Department of Cardiology, Ajou University School of Medicine, Suwon, Republic of Korea; 7Division of Cardiology, Department of Internal Medicine, Wonju Severance Christian Hospital, Wonju, Republic of Korea; 8Division of Cardiology, Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Republic of Korea; 9Division of Cardiology, Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Republic of Korea Purpose: This study aimed to compare the efficacy and safety of generic and branded irbesartan for 8 weeks in patients with mild-to-moderate essential hypertension.Patients and methods: We screened 221 patients with mild-to-moderate hypertension. After exclusion per study criteria, 177 subjects were randomized to receive 150 mg generic irbesartan (n=91) or branded irbesartan (n=86) as the intention to treat set. The primary efficacy endpoint of this study was the change in mean sitting diastolic blood pressure (SiDBP) from baseline to 8 weeks between the generic and branded irbesartan groups. The secondary efficacy endpoints were the change in mean SiDBP at Week 4 from baseline and the change in mean sitting systolic blood pressure (SiSBP) at Weeks 4 and 8 from baseline in both groups. All safety issues were evaluated.Results: At Week 8, the generic and branded irbesartan groups showed significantly reduced SiDBP (−10.3±8.0, −10.7±7.7 mmHg, all P

The protective effects of an extract from bitter melon (. Momordica charantia, Cucurbitaceae) against oxidative stress was previously reported and found that protocatechuic acid (PCA) was one of the major phenolic constituents in the extract. The renoprotective effect of PCA from bitter melon was investigated in the present study. In the LLC-PK1 cellular model, the decline in cells viabilities induced by oxidative stress, such as that induced by sodium nitroprusside, pyrogallol, and SIN-1, was significantly and dose-dependently inhibited by PCA. In the in vivo model, the cisplatin-treated rats showed increased plasma levels of creatinine, decreased creatinine clearance, and increased urine protein levels. However, these parameters related to renal dysfunction were markedly attenuated by PCA treatment. Administration of PCA resulted in remarkable improvement in the histological appearance and reduction in tubular cell damage in the cisplatin-treated rat kidneys. Moreover, the elevated levels of pro-caspase-3 induced by cisplatin in rat kidneys were down-regulated by PCA co-treatment. These results suggest that PCA has protective activity against anticancer drug-induced oxidative nephrotoxicity.

Background: Ileostomy reversals are commonly performed procedures after colon and rectal operations. Laparoscopic ileostomy reversal (LIR) with lysis of adhesions has potential benefits over conventional open surgery. The aim of this study was to compare outcomes of laparoscopic and open ileostomy reversal. Methods: 133 consecutive patients undergoing ileostomy reversal at our institution between June 2009 and August 2013 were analyzed using a retrospective database. The group comprised 53 laparoscopic cases and 80 open cases, performed by four surgeons at a single center. The data were analyzed for patient demographics, operative characteristics, postoperative outcomes, and 30-day morbidity and mortality. Results: The two groups had comparable mean age, gender distribution, ASA scores, and BMI. The laparoscopic group had a significantly longer duration of surgery compared to the open reversal group (109 versus 93 min, p < 0.05). However, this group underwent more lysis of adhesions (60.4 % versus 26.3 %, p < 0.01) as well as concurrent stoma site mesh reinforcement (32.1 % versus 6.3 %, p < 0.01). In the laparoscopy group, 20.7 % of patients underwent intra-corporeal ileo-ileal anastomosis. There were no significant differences between the laparoscopic and open groups with regard to estimated blood loss (31 versus 40 ml, respectively) or mean length of stay (5.3 vs. 5.7 days, respectively). The rates of overall 30-day morbidity (16.9 % for laparoscopic vs. 21.3 % for open) as well as rates of specific complications were equivalent between groups. 30-day mortalities were not noted in either group. Conclusion: LIR is safe and effective with low perioperative morbidity and mortality. The use of laparoscopy as an option in terms of concomitant hernia repair and lysis of adhesions may be considered in selected patients.

Background We sought to investigate morbidity and infectious complications following pelvic exenteration (PEx) and compare infectious complications of patients undergoing PEx and conventional rectal resections. Methods The NSQIP database was utilized to examine the clinical data of patients undergoing elective rectal resections during 2005-2013. Multivariate regression analysis was used to compare postoperative complications of patients who underwent PEx and proctectomy procedure. Results We sampled a total of 7,950 patients who underwent rectal resection. Of these, 303 (3.8%) patients underwent pelvic exenteration. Mortality, morbidity, and infectious complications of patients who underwent pelvic exenteration were 1.7%, 65.7%, and 42.6%, respectively. Patients who underwent PEx had a significantly higher rate of morbidity (AOR: 2.01, P < 0.01), overall infectious complications (AOR: 1.49, P < 0.01), hemorrhagic complications (AOR: 3.36, P < 0.01), and surgical site infections (SSI) (AOR: 1.23, P = 0.04) compared to patients who underwent proctectomy. Return to operation room (AOR: 4.99, P < 0.01), obesity (AOR: 1.43, P < 0.01), disseminated cancer (AOR: 1.30, P = 0.01) were significantly associated with SSI complications. Conclusion Postoperative morbidity and infectious complication are significantly higher after PEx procedure. Return to operation room, obesity, and disseminated cancer are strongly associated with surgical site infections complications in rectal surgery. Specific consideration to infectious complications is recommended for these patients.

Development of parastomal hernias (PH) is very common after stoma formation and carries a risk of subsequent bowel incarceration, obstruction and strangulation. The management of PH remains a challenge for the colorectal surgeon, and there are currently no standardized guidelines for the treatment of PH. Even more difficult is the management of complex parastomal hernias (CPH). We conducted a review of the literature to identify recent developments in the treatment of CPH, including analysis of the use of synthetic and biologic mesh prostheses, method of mesh placement and surgical approach.

We investigated the abilities of pulse pressure variation (PPV) and stroke volume variation (SVV) to predict fluid responsiveness during robot-assisted laparoscopic prostatectomy, requiring pneumoperitoneum and the Trendelenburg position. In 42 patients without cardiopulmonary disease, PPV and SVV were measured before and after administration of 500 ml colloid under pneumoperitoneum combined with the steep Trendelenburg position (35°). Fluid responsiveness was defined as a ≥15% increase in stroke volume after the fluid loading measured using transoesophageal echocardiography. Of the 42 included patients, 22 were responders and 20 were non-responders. A PPV of ≥9.5% identified responders with a sensitivity of 77.3% and a specificity of 90.0%, and a SVV of ≥9.5% also identified responders with a sensitivity of 77.3% and a specificity of 75.0%. The area under receiver operating characteristic curves for PPV and SVV were 0.87 (P <0.001) and 0.81 (P=0.001), respectively. The findings suggest that both PPV and SVV could be useful predictors of fluid responsiveness in patients without cardiopulmonary disease undergoing robotic laparoscopic surgery with pneumoperitoneum in the Trendelenberg position. [ABSTRACT FROM AUTHOR]

Background: There is limited data on the diagnostic utility of the transmitral to mitral annular velocity (E/E') by tissue Doppler imaging (TDI) in the presence of regional wall motion abnormalities (RWMA). We aimed to investigate whether the E/E' is reliable in estimating left ventricular filling pressure (LVFP) despite RWMA.Methods: One hundred thirty consecutive patients with myocardial infarction (MI) and subsequent RWMA referred for cardiac catheterization and echocardiography to measure LV pre-A pressure (LVP(PRE-A)) and Doppler signals from the mitral inflow with tissue Doppler imaging (TDI) of the mitral annulus. All patients were classified into three groups according to RWMA of the segment adjacent to the E'-measuring point using TDI: 83 patients with normal wall motions of the basal septal and basal lateral segments (group A); 28 patients with RWMA of the basal septum (group B); and 19 patients with RWMA of the basal lateral segment (group C).Results: Septal E/E' correlated with LVP(PRE-A) in groups A and C (r = 0.383, P < 0.001; r = 0.482, P = 0.037, respectively). Lateral E/E' and LVP(PRE-A) showed good correlation in groups A, B and C (r = 0.470, P < 0.001; r = 0.416, P = 0.028; r = 0.727, P < 0.001, respectively). The largest area under the receiver operating curve was obtained by the lateral E/E' for the prediction of a high LVFP, irrespective of the location of RWMA.Conclusions: In selected patients with abnormal wall motion of the basal septum, E/E' measured at the septum was not representative for LVFP. Lateral E/E' is reliable for the prediction of high LVFP, regardless of the site of RWMA. [ABSTRACT FROM AUTHOR]

The effect of Haeamtang (HAT) on the colon cancer HT-29 cells was investigated in this study. A water extract of HAT significantly decreased the number of HT-29 cells in a dose-and time-dependent manner as determined by a MTT assay. Flow cytometry results revealed a dose- and time-dependent increase of dead cells in HT-29 cells treated with HAT extract. The anticancer activity of the H AT extract is attributed to apoptosis induced in HT-29 cells, which was demonstrated by increased caspase-3 activity and poly-ADP-ribose polymerase fragmentation. A selective caspase inhibitor, z-VAD-fmk, inhibited the HAT-induced cell death. Taken together, these results demonstrate that HAT extract induces apoptosis in HT-29 cells. [ABSTRACT FROM AUTHOR]

Objective: To study the relationship of echocardiographic epicardial adipose tissue (EAT) with coronary artery disease (CAD) risk factors and the extent of coronary atherosclerosis. Methods: EAT thickness was measured in 527 patients undergoing their first coronary angiography. EAT was defined as an echo-lucent area on the free wall of the right ventricle on the still image of the two-dimensional echocardiogram at end diastole in the parasternal long-axis and parasternal short-axis views. A CT scan at the umbilicus was acquired to measure abdominal visceral adipose tissue (VAT) from a random sample of 30 patients. The extent of coronary atherosclerosis was assessed using a coronary atherosclerosis score based on the quantitative coronary angiography results. Results: EAT thickness was correlated with abdominal VAT (r(s) = 0.626, p<0.001), age (r(s) = 0.480, p<0.001), waist circumference (r(s) = 0.309, p<0.001), body mass index (r(s) = 0.233, p<0.001), C reactive protein (r(s) = 0.224, p<0.001), and the homoeostasis model assessment score (r(s) = 0.249, p<0.001). EAT was thicker in subjects with CAD than in those without CAD (4.0 vs 1.5 mm, p<0.001). Patients with unstable angina had thicker EAT than those with stable angina or atypical chest pain (4.0, 3.0, and 1.5 mm, respectively, p<0.001). EAT (> or =3.0 mm) was an independent factor of CAD on multiple logistic analysis (odds ratio = 3.357; 95% CI 2.177 to 5.175, p<0.001). Conclusions: These results suggest that EAT may reflect the amount of visceral fat, which is associated with insulin resistance and inflammation. The echocardiographic measurement of EAT may provide additional information for assessing CAD risk and predicting the extent and activity of CAD. [ABSTRACT FROM AUTHOR]

Although immune checkpoint inhibitors (ICIs) have revolutionized immuno-oncology with effective clinical responses, only 30 to 40 % of patients respond to ICIs, highlighting the need for reliable biomarkers to predict and enhance therapeutic outcomes. This study investigated how amino acid, glycolysis, and bile acid metabolism affect ICI efficacy in non-small cell lung cancer (NSCLC) patients. Through targeted metabolomic profiling and machine learning analysis, we identified amino acid metabolism as a key factor, with histidine (His) linked to favorable outcomes and homocysteine (HCys), phenylalanine (Phe), and sarcosine (Sar) linked to poor outcomes. Importantly, the His/HCys+Phe+Sar ratio emerges as a robust biomarker. Furthermore, we emphasize the role of glycolysis-related metabolites, particularly lactate. Elevated lactate levels post-immunotherapy treatment correlate with poorer outcomes, underscoring lactate as a potential indicator of treatment efficacy. Moreover, specific bile acids, glycochenodeoxycholic acid (GCDCA) and taurolithocholic acid (TLCA), are associated with better survival and therapeutic response. Particularly, TLCA enhances T cell activation and anti-tumor immunity, suggesting its utility as a predictive biomarker and therapeutic agent. We also suggest a connection between gut microbiota and TLCA levels, with the Eubacterium genus modulating this relationship. Therefore, modulating specific metabolic pathways-particularly amino acid, glycolysis, and bile acid metabolism-could predict and enhance the efficacy of ICI therapy in NSCLC patients, with potential implications for personalized treatment strategies in immuno-oncology. ONE SENTENCE SUMMARY: Our study identifies metabolic biomarkers and pathways that could predict and enhance the outcomes of immune checkpoint inhibitor therapy in NSCLC patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Acute kidney injury (AKI) is one of the most common complications after liver transplantation (LT) and can significantly impact outcomes. The presence of hepatitis C virus (HCV) infection increases the risk of AKI development. However, the impact of HCV on AKI after LT has not been evaluated. The aim of this study was to assess the effect of HCV on AKI development in patients who underwent LT., Methods: Between January 2008 and April 2023, 2183 patients who underwent living donor LT (LDLT) were included. Patients were divided into 2 groups based on the presence of chronic HCV infection. We compared LT recipients using the propensity score matching (PSM) method. Factors associated with AKI development were evaluated using multiple logistic regression analysis. In addition, 1-year mortality and graft failure were assessed using a Cox proportional regression model., Results: Among 2183 patients, the incidence of AKI was 59.2%. After PSM, the patients with HCV showed a more frequent development of AKI (71.9% vs 63.9%, P = .026). In multivariate analysis after PSM, HCV was associated with AKI development (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.06-2.20, P = .022), 1-year mortality (Hazard ratio [HR], 1.98; 95% CI, 1.12-3.52, P = .019), and graft failure (HR, 2.12; 95% CI, 1.22-3.69, P = .008)., Conclusions: The presence of HCV was associated with increased risk for the development of AKI, 1-year mortality, and graft failure after LT., Competing Interests: Conflicts of Interest, Funding: Please see DISCLOSURES at the end of this article., (Copyright © 2024 International Anesthesia Research Society.)

Competing Interests: Disclosures The authors have no conflicts of interest to disclose.

Background: With the rise of metabolic diseases and aging in liver transplant (LT) candidates, mitral annular calcification (MAC) is more recognizable. Despite cardiovascular risk becoming a leading cause of mortality in LT recipients, the influence of MAC remains unexamined. This study investigates the prevalence, related factors, and impact of MAC on LT outcomes., Methods: We explored 4148 consecutive LT patients who underwent routine pretransplant echocardiography from 2008 to 2019. Multivariate logistic analysis and the tree-based Shapley additive explanation scores in machine learning were used to evaluate the significant and important related factors. The primary outcome was 30-d major adverse cardiac events (MACE), and the secondary outcome was a median of 5-y cumulative all-cause mortality., Results: MAC was found in 123 (3.0%) patients. Significant and important related factors included age, alcoholic liver disease, chronic kidney disease, hyperuricemia, hypertension, and coronary artery disease. The MACE rate was higher in patients with MAC compared with those without MAC at 30 d ( P  < 0.001, adjusted hazard ratio 1.67; 95% confidence interval, 1.08-2.57). Patients with MAC had poorer cumulative overall survival probability compared with those without MAC ( P  = 0.0016; adjusted hazard ratio 1.47; 95% confidence interval, 1.01-2.15). Specifically, women with MAC had a poorer survival probability compared with men without MAC (65.0% versus 80.7%, P  < 0.001) >10 y post-LT., Conclusions: The presence of MAC before LT was linked to increased 30-d MACE and lower long-term survival rates, especially in women. Identification and management of MAC and potential risk factors are crucial for improving post-LT survival., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

We evaluated the liver transplantation (LT) criteria in acute-on-chronic liver failure (ACLF), incorporating an urgent living-donor LT (LDLT) program. Critically ill patients with a Chronic Liver Failure Consortium (CLIF-C) ACLF score (CLIF-C&#95;ACLF&#95;score) ≥65, previously considered unsuitable for LT, were included to explore the excess mortality threshold of the CLIF-C&#95;ACLF&#95;score (CLIF-C&#95;ACLF&#95;score&#95;threshold). We followed 854 consecutive patients with ACLF (276 ACLF grade 2 and 215 ACLF grade 3) over 10 years among 4432 LT recipients between 2008 and 2019. For advanced ACLF patients without immediate deceased-donor (DD) allocation, an urgent LDLT program was expedited. The CLIF-C&#95;ACLF&#95;score&#95;threshold was determined by the metrics of transplant survival benefit: >60% 1-year and >50% 5-year survival rate. In predicting post-LT mortality, the CLIF-C&#95;ACLF&#95;score outperformed the (model for end-stage liver disease-sodium) MELD-Na and (model for end-stage liver disease) MELD-3.0 scores but was comparable to the Sundaram ACLF-LT-mortality score. A CLIF-C&#95;ACLF&#95;score ≥65 (n = 54) demonstrated posttransplant survival benefits, with 1-year and 5-year survival rates of 66.7% and 50.4% (P < .001), respectively. Novel CLIF-C&#95;ACLF&#95;score&#95;threshold for 1-year and 5-year mortalities was 70 and 69, respectively. A CLIF-C&#95;ACLF&#95;score-based nomogram for predicting survival probabilities, integrating cardiovascular disease, diabetes, and donor type (LDLT vs DDLT), was generated. This study suggests reconsidering the criteria for unsuitable LT with a CLIF-C&#95;ACLF&#95;score ≥65. Implementing a timely salvage LT strategy, and incorporating urgent LDLT, can enhance survival rates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

TFE3-rearranged renal cell cancer (tRCC) is a rare form of RCC that involves chromosomal translocation of the Xp11.2 TFE3 gene. Despite its early onset and poor prognosis, the molecular mechanisms of the pathogenesis of tRCC remain elusive. This study aimed to identify novel therapeutic targets for patients with primary and recurrent tRCC. We collected 19 TFE3-positive RCC tissues that were diagnosed by immunohistochemistry and subjected them to genetic characterization to examine their genomic and transcriptomic features. Tumor-specific signatures were extracted using whole exome sequencing (WES) and RNA sequencing (RNA-seq) data, and the functional consequences were analyzed in a cell line with TFE3 translocation. Both a low burden of somatic single nucleotide variants (SNVs) and a positive correlation between the number of somatic variants and age of onset were observed. Transcriptome analysis revealed that four samples (21.1%) lacked the expected fusion event and clustered with the genomic profiles of clear cell RCC (ccRCC) tissues. The fusion event also demonstrated an enrichment of upregulated genes associated with mitochondrial respiration compared with ccRCC expression profiles. Comparison of the RNA expression profile with the TFE3 ChIP-seq pattern data indicated that PPARGC1A is a metabolic regulator of the oncogenic process. Cell proliferation was reduced when PPARGC1A and its related metabolic pathways were repressed by its inhibitor SR-18292. In conclusion, we demonstrate that PPARGC1A-mediated mitochondrial respiration can be considered a potential therapeutic target in tRCC. This study identifies an uncharacterized genetic profile of an RCC subtype with unique clinical features and provides therapeutic options specific to tRCC., (© 2024. The Author(s).)

Background and Aims: Hepatic lipogenesis is elevated in nutrient abundant conditions to convert the excess carbohydrate into triacylglycerol (TAG). Fatty acyl moiety of TAG is eventually transported into adipose tissues by very low density lipoprotein, leading to the accumulation of TAG as a preferred storage form of excess energy. Disruption of the balance between TAG clearance and synthesis leads to the accumulation of lipids in the liver, leading to the progression of non-alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis. Protein arginine methyltransferase (PRMT) 6 has been linked to the various metabolic processes including hepatic gluconeogenesis, muscle atrophy and lipodystrophy in mouse models. However, the role of PRMT6 in the control of hepatic lipogenesis has not been elucidated to date., Methods: We assessed the interaction between PRMT6 and LXR alpha by using co-immunoprecipitation assay. The specific arginine residue of LXR alpha that is methylated by PRMT6 was assessed by LC-MS/MS assay and the functional consequences of LXR alpha methylation was explored by mSREBP-1c luciferase assay. The effect of PRMT6 on hepatic lipogenesis was assessed by adenovirus-mediated ectopic expression of PRMT6 or knockdown of PRMT6 via shRNA in hepatocytes. Finally, the role of PRMT6 in hepatic lipid metabolism in vivo was explored by either ectopic expression of LXR alpha mutant that is defective in PRMT6-mediated arginine methylation or knockdown of PRMT6 in liver., Results: We found that promoter activity of sterol regulatory element binding protein (SREBP) 1c is robustly activated by PRMT6. Interestingly, we demonstrated that PRMT6 binds to LXR alpha, a transcription factor for SREBP-1c, via its LXXLL motif, leading to the asymmetric dimethylation of an arginine residue and activation of this protein. Indeed, ectopic expression of PRMT6 in hepatocytes led to the enhanced expression of LXR alpha target genes in the lipogenic pathway. Conversely, genetic or pharmacological inhibition of PRMT6 diminished expression of lipogenic genes and the lipid accumulation in primary hepatocytes. Mechanistically, we found that asymmetric dimethylation of LXR alpha led to the dissociation of small heterodimer partner (SHP), a transcriptional co-inhibitor of this factor, resulting in the activation of LXR alpha-mediated transcriptional process. Finally, we showed that disruption of asymmetric dimethylation of LXR alpha in the liver led to the diminished expression of genes in the lipogenesis, resulting in the reduced hepatic lipid accumulation in high fat diet-fed mice in vivo., Conclusions: We showed that PRMT6 modulates LXR alpha activity by conferring asymmetric dimethylation of arginine 253, thus blocking SHP-mediated inhibition and promoting hepatic lipid accumulation. These results suggest that PRMT6 is critical in the control of lipid homeostasis by regulation of LXR alpha-mediated lipogenesis in the liver., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction and Objectives: Acute kidney injury (AKI) is prevalent and has deleterious effects on postoperative outcomes following liver transplantation (LT). The impact of nonselective beta-blockers (NSBBs) in patients with liver cirrhosis remains controversial. This study investigated the association between preoperative NSBB use and AKI after living donor LT (LDLT)., Patients and Methods: We evaluated 2,972 adult LDLT recipients between January 2012 and July 2022. The patients were divided into two groups based on the preoperative NSBB use. Propensity score matched (PSM) and inverse probability of treatment weighting (IPTW) analyses were performed to evaluate the association between preoperative NSBB use and postoperative AKI. Multiple logistic regression analyses were also used to identify the risk factors for AKI., Results: The overall incidence of AKI was 1,721 (57.9%) cases. The NSBB group showed a higher incidence of AKI than the non-NSBB group (62.4% vs. 56.7%; P = 0.011). After PSM and IPTW analyses, no significant difference in the incidence of AKI was found between the two groups (Odds ratio, OR 1.13, 95% confidence interval, CI 0.93-1.37, P = 0.230, PSM analysis; OR 1.20, 95% CI 0.99-1.44, P = 0.059, IPTW analysis). In addition, preoperative NSBB use was not associated with AKI after multivariate logistic regression analysis (OR 1.16, 95% CI 0.96-1.40, P = 0.118)., Conclusions: Preoperative NSBB use was not associated with AKI after LDLT. Further studies are needed to validate our results., Competing Interests: Conflicts of interest None., (Copyright © 2024 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Acute kidney injury (AKI) is one of the most common complications after living-donor liver transplantation (LDLT) that has great impact on recipient and graft outcomes. Dexmedetomidine is reported to decrease the incidence of AKI. In the current study, the authors investigated whether intraoperative dexmedetomidine infusion would reduce the AKI following LDLT., Material and Methods: In total, 205 adult patients undergoing elective LDLT were randomly assigned to the dexmedetomidine group ( n =103) or the control group ( n =102). Dexmedetomidine group received continuous dexmedetomidine infusion at a rate of 0.4 mcg/kg/h after the anesthesia induction until 2 h after graft reperfusion. The primary outcome was to compare the incidence of AKI. Secondary outcomes included serial lactate levels during surgery, chronic kidney disease, major adverse cardiovascular events, early allograft dysfunction, graft failure, overall mortality, duration of mechanical ventilation, intensive care unit, and hospital length of stay. Intraoperative hemodynamic parameters were also collected., Results: Of 205 recipients, 42.4% ( n =87) developed AKI. The incidence of AKI was lower in the dexmedetomidine group (35.0%, n =36/103) compared with the control (50.0%, n =51/102) ( P =0.042). There were significantly lower lactate levels in the dexmedetomidine group after reperfusion [4.39 (3.99-4.8) vs 5.02 (4.62-5.42), P =0.031] until the end of surgery [4.23 (3.73-4.74) vs 5.35 (4.84-5.85), P =0.002]. There were no significant differences in the other secondary outcomes besides lactate. Also, intraoperative mean blood pressure, cardiac output, and systemic vascular resistance did not show any difference., Conclusion: Our study suggests that intraoperative dexmedetomidine administration was associated with significantly decreased AKI incidence and lower intraoperative serum lactate levels in LDLT recipients, without untoward hemodynamic effects., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Myopenia is a condition marked by progressive decline of muscle mass and strength and is associated with aging or obesity. It poses the risk of falling, with potential bone fractures, thereby also increasing the burden on family and society. Skeletal muscle wasting is characterized by a reduced number of myoblasts, impaired muscle regeneration and increased muscle atrophy markers (Atrogin-1, MuRF-1). Endothelin-1 (ET-1) is a potent vasoconstrictor peptide. Increased circulating levels of ET-1 is noted with aging and is associated with muscular fibrosis and decline of strength. However, the regulatory mechanism controlling its effect on myogenesis and atrophy remains unknown. In the present study, the effects of ET-1 on myoblast proliferation, differentiation and development were investigated in C2C12 cells and in ET-1-infused mice. The results show that ET-1, acting via ETB receptors, reduced insulin-stimulated cell proliferation, and also reduced MyoD, MyoG and MyHC expression in the differentiation processes of C2C12 myoblasts. ET-1 inhibited myoblast differentiation through ETB receptors and the p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Additionally, ET-1 decreased MyHC expression in differentiated myotubes. Inhibition of proteasome activity by MG132 ameliorated the ET-1-stimulated protein degradation in differentiated C2C12 myotubes. Furthermore, chronic ET-1 infusion caused skeletal muscle atrophy and impaired exercise performance in mice. In conclusion, ET-1 inhibits insulin-induced cell proliferation, impairs myogenesis and induces muscle atrophy via ETB receptors and the p38 MAPK-dependent pathway., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Intestinal microbiota and their metabolites affect systemic inflammation and kidney disease outcomes. Here, we investigated the key metabolites associated with the acute kidney injury (AKI)-to chronic kidney disease (CKD) transition and the effect of antibiotic-induced microbiota depletion (AIMD) on this transition. In 61 patients with AKI, 59 plasma metabolites were assessed to determine the risk of AKI-to-CKD transition. An AKI-to-CKD transition murine model was established four weeks after unilateral ischemia-reperfusion injury (IRI) to determine the effects of AIMD on the gut microbiome, metabolites, and pathological responses related to CKD transition. Human proximal tubular epithelial cells were challenged with CKD transition-related metabolites, and inhibitory effects of NADPH oxidase 2 (NOX2) signals were tested. Based on clinical metabolomics, plasma trimethylamine N-oxide (TMAO) was associated with a significantly increased risk for AKI-to-CKD transition [adjusted odds ratio 4.389 (95% confidence interval 1.106-17.416)]. In vivo, AIMD inhibited a unilateral IRI-induced increase in TMAO, along with a decrease in apoptosis, inflammation, and fibrosis. The expression of NOX2 and oxidative stress decreased after AIMD. In vitro, TMAO induced fibrosis with NOX2 activation and oxidative stress. NOX2 inhibition successfully attenuated apoptosis, inflammation, and fibrosis with suppression of G2/M arrest. NOX2 inhibition (in vivo) showed improvement in pathological changes with a decrease in oxidative stress without changes in TMAO levels. Thus, TMAO is a key metabolite associated with the AKI-to-CKD transition, and NOX2 activation was identified as a key regulator of TMAO-related AKI-to-CKD transition both in vivo and in vitro., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Transcriptional coactivator with a PDZ-binding motif (TAZ) plays a key role in normal tissue homeostasis and tumorigenesis through interaction with several transcription factors. In particular, TAZ deficiency causes abnormal alveolarization and emphysema, and persistent TAZ overexpression contributes to lung cancer and pulmonary fibrosis, suggesting the possibility of a complex mechanism of TAZ function. Recent studies suggest that nuclear factor erythroid 2-related factor 2 (NRF2), an antioxidant defense system, induces TAZ expression during tumorigenesis and that TAZ also activates the NRF2-mediated antioxidant pathway. We thus thought to elucidate the cross-regulation of TAZ and NRF2 and the underlying molecular mechanisms and functions. TAZ directly interacted with NRF2 through the N-terminal domain and suppressed the transcriptional activity of NRF2 by preventing NRF2 from binding to DNA. In addition, the return of NRF2 to basal levels after signaling was inhibited in TAZ deficiency, resulting in sustained nuclear NRF2 levels and aberrantly increased expression of NRF2 targets. TAZ deficiency failed to modulate optimal NRF2 signaling and concomitantly impaired lysosomal acidification and lysosomal enzyme function, accumulating the abnormal autophagy vesicles and reactive oxygen species and causing protein oxidation and cellular damage in the lungs. TAZ restoration to TAZ deficiency normalized dysregulated NRF2 signaling and aberrant lysosomal function and triggered the normal autophagy-lysosomal pathway. Therefore, TAZ is indispensable for the optimal regulation of NRF2-mediated autophagy-lysosomal pathways and for preventing pulmonary damage caused by oxidative stress and oxidized proteins., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Although the esophageal stethoscope is used for continuous auscultation during general anesthesia, few studies have investigated phonocardiographic data as a continuous hemodynamic index. In this study, we aimed to induce hemodynamic variations and clarify the relationship between the heart sounds and hemodynamic variables through an experimental animal study. Changes in the cardiac contractility and vascular resistance were induced in anesthetized pigs by administering dobutamine, esmolol, phenylephrine, and nicardipine. In addition, a decrease in cardiac output was induced by restricting the venous return by clamping the inferior vena cava (IVC). The relationship between the hemodynamic changes and changes in the heart sound indices was analyzed. Experimental data from eight pigs were analyzed. The mean values of the correlation coefficients of changes in S1 amplitude (ΔS1amp) with systolic blood pressure (ΔSBP), pulse pressure (ΔPP), and ΔdP/dt during dobutamine administration were 0.94, 0.96, and 0.96, respectively. The mean values of the correlation coefficients of ΔS1amp with ΔSBP, ΔPP, and ΔdP/dt during esmolol administration were 0.80, 0.82, and 0.86, respectively. The hemodynamic changes caused by the administration of phenylephrine and nicardipine did not correlate significantly with changes in the heart rate. The S1 amplitude of the heart sound was significantly correlated with the hemodynamic changes caused by the changes in cardiac contractility but not with the variations in the vascular resistance. Heart sounds can potentially provide a non-invasive monitoring method to differentiate the cause of hemodynamic variations., (© 2024. The Author(s).)

The performance of lithium-ion batteries largely depends on the stability of the solid electrolyte interphase (SEI) layer formed on the anode surface. Strategies to improve SEI robustness often rely on optimizing its composition through electrolytic additives. Recently, the amalgamation of fluorinated cosolvents with nitride sources as additives has been shown to enable the construction of sustainable fluorinated-nitrided SEI layers (FN-SEI). Furthermore, the presence of lithiophilic nitrides embedded in lithium fluoride (LiF) was found to contribute toward stability of a beneficial amorphous phase for interfacial passivation. However, there is a lack of understanding on how key indicators of mechanical longevity, like plasticity and fracture resistance, may evolve in such multiphase SEI building blocks. Herein, in conjunction with first-principles calculations, a reactive force field (ReaxFF) has been developed for deriving new mechanistic insights into the intriguing FN-SEI. Our studies demonstrate that owing to a significant elasticity mismatch, the hard nitride phases have a propensity to affect the native deformation modes when embedded in a soft amorphous LiF-rich matrix. Impact of the volume fraction and distribution of the nitride (Li 3 N) phases are discussed from the perspective of how they interfere with the propagation of shear bands. Interestingly, brittle-ductile-brittle regimes are recognized along the nitride infusion window, providing a glimpse into the effect of phase distribution on the structural toughness of the LiF-Li 3 N-enhanced SEI.

Although early life colonization of commensal microbes contributes to long-lasting immune imprinting in host tissues, little is known regarding the pathophysiological consequences of postnatal microbial tuning of cutaneous immunity. Here, we show that postnatal exposure to specific skin commensal Staphylococcus lentus (S. lentus) promotes the extent of atopic dermatitis (AD)-like inflammation in adults through priming of group 2 innate lymphoid cells (ILC2s). Early postnatal skin is dynamically populated by discrete subset of primed ILC2s driven by microbiota-dependent induction of thymic stromal lymphopoietin (TSLP) in keratinocytes. Specifically, the indole-3-aldehyde-producing tryptophan metabolic pathway, shared across Staphylococcus species, is involved in TSLP-mediated ILC2 priming. Furthermore, we demonstrate a critical contribution of the early postnatal S. lentus-TSLP-ILC2 priming axis in facilitating AD-like inflammation that is not replicated by later microbial exposure. Thus, our findings highlight the fundamental role of time-dependent neonatal microbial-skin crosstalk in shaping the threshold of innate type 2 immunity co-opted in adulthood., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The safety and cycle life of lithium-ion batteries (LIBs) are largely determined by the solid electrolyte interphase (SEI) formed on the surface of the anode. However, there is still a lack of understanding regarding the structure and properties of the individual SEI components. Among others, lithium oxide (Li 2 O), lithium carbonate (Li 2 CO 3 ), and lithium fluoride (LiF) are known to be the main components of the inorganic SEI layer in conventional LIBs, but their intrinsic protective roles remain controversial. Herein, we present the transformational effects of their amorphous phase on the mechanical and transport characteristics, based on first-principles calculations. Our studies clearly demonstrate that their amorphous phases exhibit significantly improved Li-ion conductivity when compared to the crystalline structures. Additionally, among them, amorphous LiF emerges as a frontrunner for fast Li + ion transportation, reversing the conventionally understood hierarchy. Under ambient conditions, the amorphous phases of LiF, Li 2 O, and Li 2 CO 3 are thermodynamically unstable and tend to undergo recrystallization. However, this work highlights that exceptionally ductile and resilient amorphous phases can form if SEI formation and growth would involve some admixing of lithiophilic impurities like nitrogen (N) within the host matrices.

(1) Background: Liver transplantation (LT) is associated with significant hemorrhage and massive transfusions. Fibrinogen replacement has a key role in treating massive bleeding during LT and hypofibrinogenemia is treated by fibrinogen concentrate or cryoprecipitate. However, these two products are known to be associated with major thromboembolism events (MTEs). We aimed to compare the effect of fibrinogen concentrate and cryoprecipitate on MTEs in living donor LT (LDLT) recipients. (2) Methods: We analyzed 206 patients who underwent LDLT between January 2021 and March 2022. The patients were divided into two groups according to fibrinogen concentrate or cryoprecipitate use. We compared the incidence of MTEs between the two groups. In addition, we performed multiple logistic regression analyses to identify the risk factors for MTEs. (3) Results: There was no significant difference in the incidence of MTEs (16 [14.7%] vs. 14 [14.4%], p = 1.000) between the cryoprecipitate group and fibrinogen concentrate group. In the multivariate analysis, cryoprecipitate (OR 2.09, 95%CI 0.85-5.11, p = 0.107) and fibrinogen concentrate (OR 2.05, 95%CI 0.82-5.12, p = 0.126) were not significantly associated with MTEs. (4) Conclusions: there was no significant difference in the incidence of MTEs between cryoprecipitate and fibrinogen concentrate in LDLT recipients.

Background: Excessive visceral obesity in recipients of living donor liver transplantation (LDLT) is associated with mortality, and a recent study reported the correlation between visceral adiposity of male LDLT recipients and hepatocellular carcinoma (HCC) recurrence. However, there is no study on the relationship between the donor's visceral adiposity and surgical outcomes in LDLT recipients. We investigated the association of the visceral-to-subcutaneous fat area ratio (VSR) in donors and recipients with HCC recurrence and mortality in LDLT., Methods: We analyzed 1386 sets of donors and recipients who underwent LDLT between January 2008 and January 2018. The maximal chi-square method was used to determine the optimal cutoff values for VSR for predicting overall HCC recurrence and mortality. Cox regression analyses were performed to evaluate the association of donor VSR and recipient VSR with overall HCC recurrence and mortality in recipients., Results: The cutoff values of VSR was determined as 0.73 in males and 0.31 in females. High donor VSR was significantly associated with overall HCC recurrence (adjusted hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.06-1.93, p = 0.019) and mortality (HR: 1.35, 95% CI: 1.03-1.76, p = 0.030). High recipient VSR was significantly associated with overall HCC recurrence (HR: 1.40, 95% CI: 1.04-1.88, p = 0.027) and mortality (HR: 1.50, 95% CI: 1.14-1.96, p = 0.003)., Conclusions: Both recipient VSR and donor VSR were significant risk factors for HCC recurrence and mortality in LDLT recipients. Preoperative donor VSR and recipient VSR may be strong predictors of the surgical outcomes of LDLT recipients with HCC., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

This study investigated chronic and repeated sleep deprivation (RSD)-induced neuronal changes in hexosamine biosynthetic pathway/O-linked N-acetylglucosamine (HBP/O-GlcNAc) cycling of glucose metabolism and further explored the role of altered O-GlcNAc cycling in promoting neurodegeneration using an adult zebrafish model. RSD-triggered degenerative changes in the brain led to impairment of memory, neuroinflammation and amyloid beta (Aβ) accumulation. Metabolite profiling of RSD zebrafish brain revealed a significant decrease in glucose, indicating a potential association between RSD-induced neurodegeneration and dysregulated glucose metabolism. While RSD had no impact on overall O-GlcNAcylation levels in the hippocampus region, changes were observed in two O-GlcNAcylation-regulating enzymes, specifically, a decrease in O-GlcNAc transferase (OGT) and an increase in O-GlcNAcase (OGA). Glucosamine (GlcN) treatment induced an increase in O-GlcNAcylation and recovery of the OGT level that was decreased in the RSD group. In addition, GlcN reversed cognitive impairment by RSD. GlcN reduced neuroinflammation and attenuated Aβ accumulation induced by RSD. Repeated treatment of zebrafish with diazo-5-oxo-l-norleucine (DON), an inhibitor of HBP metabolism, resulted in cognitive dysfunction, neuroinflammation and Aβ accumulation, similar to the effects of RSD. The pathological changes induced by DON were restored to normal upon treatment with GlcN. Both the SD and DON-treated groups exhibited a common decrease in glutamate and γ-aminobutyric acid compared to the control group. Overexpression of OGT in zebrafish brain rescued RSD-induced neuronal dysfunction and neurodegeneration. RSD induced a decrease in O-GlcNAcylation of amyloid precursor protein and increase in β-secretase activity, which were reversed by GlcN treatment. Based on the collective findings, we propose that dysregulation of HBP and O-GlcNAc cycling in brain plays a crucial role in RSD-mediated progression of neurodegeneration and Alzheimer's disease pathogenesis. Targeting of this pathway may, therefore, offer an effective regulatory approach for treatment of sleep-associated neurodegenerative disorders., (© 2023. The Author(s).)

Aims: Idiopathic ventricular fibrillation (IVF) is a disease in which the cause of ventricular fibrillation cannot be identified despite comprehensive clinical evaluation. This study aimed to investigate the clinical yield and implications of genetic testing for IVF., Methods and Results: This study was based on the multi-centre inherited arrhythmia syndrome registry in South Korea from 2014 to 2017. Next-generation sequencing-based genetic testing was performed that included 174 genes previously linked to cardiovascular disease. A total of 96 patients were clinically diagnosed with IVF. The mean age of the onset was 41.2 ± 12.7 years, and 79 patients were males (82.3%). Of these, 74 underwent genetic testing and four (5.4%) of the IVF probands had pathogenic or likely pathogenic variants (each having one of MYBPC3, MYH7, DSP, and TNNI3). All pathogenic or likely pathogenic variants were located in genes with definite evidence of a cardiomyopathy phenotype, either hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy., Conclusion: Next-generation sequencing-based genetic testing identified pathogenic or likely pathogenic variants in 5.4% of patients initially diagnosed with IVF, suggesting that genetic testing with definite evidence genes of cardiomyopathy may enable molecular diagnosis in a minority of patients with IVF. Further clinical evaluation and follow-up of patients with IVF with positive genotypes are needed to unveil concealed phenotypes, such as the pre-clinical phase of cardiomyopathy., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

An intermittent fasting (IF) regimen has been shown to protect against metabolic dysfunction-associated steatohepatitis (MASH). However, the precise mechanism remains unclear. Here, we explored how IF reduced hepatic lipid accumulation, inflammation, and fibrosis in mice with MASH. The mice were fed a high-fat diet (HFD) for 30 weeks and either continued on the HFD or were subjected to IF for the final 22 weeks. IF reduced body weight, insulin resistance, and hepatic lipid accumulation in HFD-fed mice. Lipidome analysis revealed that IF modified HFD-induced hepatic lipid composition. In particular, HFD-induced impaired autophagic flux was reversed by IF. The decreased hepatic lysosome-associated membrane protein 1 level in HFD-fed mice was upregulated in HFD+IF-fed mice. However, increased hepatic lysosomal acid lipase protein levels in HFD-fed mice were reduced by IF. IF attenuated HFD-induced hepatic inflammation and galectin-3-positive Kupffer cells. In addition to the increases in hepatic hydroxyproline and lumican levels, lipocalin-2-mediated signaling was reversed in HFD-fed mice by IF. Taken together, our findings indicate that the enhancement of the autophagy-lysosomal pathway may be a critical mechanism of MASH reduction by IF.

Background and Objectives: Inherited arrhythmia (IA) is a more common cause of sudden cardiac death in Asian population, but little is known about the genetic background of Asian IA probands. We aimed to investigate the clinical characteristics and analyze the genetic underpinnings of IA in a Korean cohort., Methods: This study was conducted in a multicenter cohort of the Korean IA Registry from 2014 to 2017. Genetic testing was performed using a next-generation sequencing panel including 174 causative genes of cardiovascular disease., Results: Among the 265 IA probands, idiopathic ventricular fibrillation (IVF) and Brugada Syndrome (BrS) was the most prevalent diseases (96 and 95 cases respectively), followed by long QT syndrome (LQTS, n=54). Two-hundred-sixteen probands underwent genetic testing, and 69 probands (31.9%) were detected with genetic variant, with yield of pathogenic or likely pathogenic variant as 6.4%. Left ventricular ejection fraction was significantly lower in genotype positive probands (54.7±11.3 vs. 59.3±9.2%, p=0.005). IVF probands showed highest yield of positive genotype (54.0%), followed by LQTS (23.8%), and BrS (19.5%)., Conclusions: There were significant differences in clinical characteristics and genetic yields among BrS, LQTS, and IVF. Genetic testing did not provide better yield for BrS and LQTS. On the other hand, in IVF, genetic testing using multiple gene panel might enable the molecular diagnosis of concealed genotype, which may alter future clinical diagnosis and management strategies., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2023. The Korean Society of Cardiology.)

Background: Acute-on-chronic liver failure (ACLF) is a life-threatening disease that requires urgent liver transplantation (LT). Accurate identification of high-risk patients is essential for predicting post-LT survival. The chronic liver failure consortium ACLF score is a widely accepted risk-stratification score that includes total white blood cell (WBC) counts as a component. This study aimed to evaluate the predictive value of total and differential WBC counts for short-term mortality following LT in patients with ACLF., Methods: A total of 685 patients with ACLF who underwent LT between January 2008 and February 2019 were analyzed. Total and differential WBC counts were examined as a function of the model for end-stage liver disease for sodium (MELD-Na) score. The association between total and differential WBC counts and 90-day post-LT mortality was assessed using multivariable Cox proportional hazards regression analysis., Results: The total WBC counts and neutrophil ratio were higher in patients with ACLF than in those without ACLF. The neutrophil ratio was significantly associated with 90-day post-LT mortality after adjustment (hazard ratio [HR], 1.04; P = 0.001), whereas total WBC counts were not significantly associated with 90-day post-LT mortality in either univariate or multivariate Cox analyses. The neutrophil ratio demonstrated a relatively linear trend with an increasing MELD-Na score and HR for 90-day post-LT mortality, whereas the total WBC counts exhibited a plateaued pattern., Conclusions: Neutrophilia, rather than total WBC counts, is a better prognostic indicator for short-term post-LT mortality in patients with ACLF.

Our previous study demonstrated that beneficial effect of β-blockers on clinical outcomes in patients with ST elevation myocardial infarction (STEMI). In clinical practice, β-blocker treatment is occasionally discontinued due to their side effect. The purpose of this study is to assess the impact of discontinuation of β-blockers on long-term clinical outcomes in patients with STEMI. We analyzed the data and clinical outcomes of 901 patients (716 males, 58 ± 13-year-old) STEMI patients who underwent successful primary percutaneous coronary intervention. At discharge of index STEMI, 598 patients were treated with β-blockers (491 males, 56 ± 12-year-old). After more than 1-month β-blocker treatment, β-blockers were stopped in 188 patients for any reason. We classified patients into continuation of β-blockers (410 patients, 56 ± 12-year-old) and discontinuation of β-blockers groups (188 patients, 57 ± 11-year-old) according to discontinuation of β-blockers. Occurrence of major adverse cardiovascular events (MACEs; death, recurrent MI and target vessel revascularization) during up to 10 years of follow-up was evaluated. Mean follow-up month was 56 ± 28 month. In 132 patients (22%), MACEs were occurred. The MACE-free survival rates in the 2 groups were not statistically different (log-rank P = .461). Adjusted hazard ratio (HR) of discontinuation of β-blockers for MACEs was 1.006 (95% confidence interval (CI) 0.701-1.445, P = .973; all cause of death, HR = 0.942, 95% CI = 0.547-1.622, P = .828; recurrent MI, HR = 0.476, 95% CI = 0.179-1.262, P = .136; target vessel revascularization, HR = 1.417, 95% CI = 0.865-2.321, P = .166). The MACE-free survival and survival rates of the non β-blockers treatment group was significantly worse than the discontinuation of β-blockers group (log-rank P = .003 and < 0.001, respectively). This study demonstrated that discontinuation of β-blockers was not associated with adverse cardiovascular outcomes after STEMI. The beneficial effect of β-blockers on clinical outcomes may persist in patients with initial β-blockers treatment at index STEMI., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Arachidonic and adrenic acids in the membrane play key roles in ferroptosis. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen reveals that darapladib, an inhibitor of Lp-PLA2, synergistically induces ferroptosis in the presence of GPX4 inhibitors. We show that darapladib is able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, we find that Lp-PLA2 is located in the membrane and cytoplasm and suppresses ferroptosis, suggesting a critical role for intracellular Lp-PLA2. Lipidomic analyses show that darapladib treatment or deletion of PLA2G7, which encodes Lp-PLA2, generally enriches phosphatidylethanolamine species and reduces lysophosphatidylethanolamine species. Moreover, combination treatment of darapladib with the GPX4 inhibitor PACMA31 efficiently inhibits tumour growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment., (© 2023. Springer Nature Limited.)

Developing soft robots that can control their own life cycle and degrade on-demand while maintaining hyperelasticity is a notable research challenge. On-demand degradable soft robots, which conserve their original functionality during operation and rapidly degrade under specific external stimulation, present the opportunity to self-direct the disappearance of temporary robots. This study proposes soft robots and materials that exhibit excellent mechanical stretchability and can degrade under ultraviolet light by mixing a fluoride-generating diphenyliodonium hexafluorophosphate with a silicone resin. Spectroscopic analysis revealed the mechanism of Si─O─Si backbone cleavage using fluoride ion (F - ) and thermal analysis indicated accelerated decomposition at elevated temperatures. In addition, we demonstrated a robotics application by fabricating electronics integrated gaiting robot and a fully closed-loop trigger disintegration robot for autonomous, application-oriented functionalities. This study provides a simple yet novel strategy for designing life cycle mimicking soft robotics that can be applied to reduce soft robotics waste, explore hazardous areas, and ensure hardware security with on-demand destructive material platforms.

Background: Diastolic dysfunction is regarded as an important predictor of outcome after liver transplantation (LT). We investigated the influence of liver disease severity on left ventricular diastolic properties using end-diastolic pressure-volume relationship (EDPVR) analysis in patients with end-stage liver disease (ESLD). Association between alterations of the EDPVR and mortality after LT was evaluated., Methods: In this observational retrospective cohort study, 3,211 patients who underwent LT for ESLD were included in analysis. Variables derived from single-beat EDPVR (diastolic stiffness-coefficient [β] and end-diastolic volume at an end-diastolic pressure of 20 mmHg [EDVI 20 ] indicating ventricular capacitance) were estimated using preoperative echocardiographic data. Alterations in EDPVR with increased stiffness (β > 6.16) were categorized into 3 groups; leftward-shifted (EDVI 20 <51 mL/m 2 ), rightward-shifted (EDVI 20 > 69.7 mL/m 2 ), and intermediate (EDVI 20 51-69.7 mL/m 2 )., Results: As the model for ESLD score increases, both EDVI 20 and β gradually increased, which indicated ventricular remodeling with larger capacitance and higher diastolic stiffness. Among patients with increased stiffness (β > 6.16, n = 1,090), survival rates after LT were lower in leftward-shifted EDPVR than in rightward-shifted EDPVR (73.7% vs 82.9%; log-rank P = 0.002). In the adjusted Cox proportional hazard model, risk of cumulative all-cause mortality at 11 years was the highest in leftward-shifted EDPVR (hazard ratio [HR]: 1.93; 95% confidence interval [CI]: 1.27-2.92), followed by intermediate EDPVR (HR: 1.55; 95% CI: 1.12-2.26), compared with rightward-shifted EDPVR. The SHapley Additive exPlanation model revealed that the variables associated with leftward-shifted EDPVR were diabetes, female sex, old age, and hypertension., Conclusions: As ESLD advances, diastolic ventricular properties are characterized by increased EDVI 20 and β on rightward-shifted EDPVR, indicating larger capacitance and higher stiffness. However, leftward-shifted EDPVR with left ventricle remodeling failure is associated with poor post-LT survival., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Adipose tissues are central in controlling metabolic homeostasis and failure in their preservation is associated with age-related metabolic disorders. The exact role of mature adipocytes in this phenomenon remains elusive. Here we describe the role of adipose branched-chain amino acid (BCAA) catabolism in this process. We found that adipocyte-specific Crtc2 knockout protected mice from age-associated metabolic decline. Multiomics analysis revealed that BCAA catabolism was impaired in aged visceral adipose tissues, leading to the activation of mechanistic target of rapamycin complex (mTORC1) signaling and the resultant cellular senescence, which was restored by Crtc2 knockout in adipocytes. Using single-cell RNA sequencing analysis, we found that age-associated decline in adipogenic potential of visceral adipose tissues was reinstated by Crtc2 knockout, via the reduction of BCAA-mTORC1 senescence-associated secretory phenotype axis. Collectively, we propose that perturbation of BCAA catabolism by CRTC2 is critical in instigating age-associated remodeling of adipose tissue and the resultant metabolic decline in vivo., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)