Neuroprotection effects of kynurenic acid-loaded micelles for the Parkinson's disease models.

Anti-glutamatergic agents may have neuroprotective effects against excitotoxicity that is known to be involved in the pathogenesis of Parkinson's disease (PD). One of these agents is kynurenic acid (KYNA), a tryptophan metabolite, which is an endogenous N-methyl-D-aspartic acid (NMDA) receptor antagonist. However, its pharmacological properties of poor water solubility and limited blood-brain barrier (BBB) permeability rules out its systemic administration in disorders affecting the central nervous system. Our aim in the present study was to investigate the neuroprotective effects of KYNA-loaded micelles (KYNA-MICs) against PD in vitro and in vivo. Lipid-based micelles (MICs) in conjunction with KYNA drug delivery have the potential to enhance the penetration of therapeutic drugs into a diseased brain without BBB obstacles. KYNA-MICs were characterized by particle size (105.8 ± 12.1 nm), loading efficiency (78.3 ± 4.23%), and in vitro drug release (approximately 30% at 24 h). The in vitro experiments showed that KYNA-MICs effectively reduced 2-fold protein aggregation. The in vivo studies revealed that KYNA was successfully delivered by 5-fold increase in neurotoxin-induced PD brains. The results showed significant enhancement of KYNA delivery into brain. We also found that the KYNA-MICs exhibited several therapeutic effects. The KYNA-MICs reduced protein aggregation of an in vitro PD model, ameliorated motor functions, and prevented loss of the striatal neurons in a PD animal model. The beneficial effects of KYNA-MICs are probably explained by the anti-excitotoxic activity of the treatment's complex. As the KYNA-MICs did not induce any appreciable side-effects at the protective dose applied to a chronic PD mouse model, our results demonstrate that KYNA provides neuroprotection and attenuates PD pathology.

Multiple cancer cell types release LIF and Gal3 to hijack neural signals.

Neural signals can significantly influence cancer prognosis. However, how cancer cells may proactively modulate the nervous system to benefit their own survival is incompletely understood. In this study, we report an overlapping pattern of brain responses, including that in the paraventricular nucleus of the hypothalamus, in multiple mouse models of peripheral cancers. A multi-omic screening then identifies leukemia inhibitory factor (LIF) and galectin-3 (Gal3) as the key cytokines released by these cancer cell types to trigger brain activation. Importantly, increased plasma levels of these two cytokines are observed in patients with different cancers. We further demonstrate that pharmacologic or genetic blockage of cancer cell-derived LIF or Gal3 signaling abolishes the brain responses and strongly inhibits tumor growth. In addition, ablation of peripheral sympathetic actions can similarly restore antitumor immunity. These results have elucidated a novel, shared mechanism of multiple cancer cell types hijacking the nervous system to promote tumor progression.

Prognostic variations between 'primary' and 'progressive' muscle-invasive bladder cancer following radical cystectomy: a novel propensity score-based multicenter cohort study.

OBJECTIVE: To assess prognostic differences between primary and progressive muscle-invasive bladder cancer (MIBC) following radical cystectomy. MATERIAL AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to abstract MIBC data following radical cystectomy from 2000 to 2019. Patients were classified as either 'Primary' MIBC (defined as the presentation of muscle-invasive disease at initial diagnosis) or 'Progressive' MIBC (defined as a non-muscle invasive disease that later progressed to MIBC). Baseline characteristics for the two groups were balanced using a propensity score overlap weight (PSOW) technique. Survival differences between the two groups were analyzed using Kaplan-Meier's plots and log-rank tests. Cox's proportional hazard regression was used to assess risk factors associated with overall survival (OS) and cancer-specific survival (CSS). RESULTS: Six thousand six hundred thirty-two MIBC patients were identified in the SEER database. Among them, 83.3% ( n =5658) were considered primary MIBC patients, and 16.7% ( n =974) were categorized as progressive MIBC patients. Distribution of baseline covariates, including age, sex, race, T stage, N stage, tumour grade, marital status, and chemotherapy, were well-balanced after PSOWs were applied. After stable PSOW adjustments, Kaplan-Meier survival analysis showed that the CSS for progressive MIBC [hazard ratio (HR)=1.25, 95% confidence interval (CI): 1.12-1.38, P <0.001) was poorer than the primary MIBC group. However, the difference in OS (HR=1.08, 95% CI: 0.99-1.18) was not significant ( P =0.073). Multivariate analysis also suggested that patients with progressive MIBC have significantly poorer CSS (HR=1.24, 95% CI: 1.19-1.38, P <0.001) but not OS (HR=1.08, 95% CI: 0.99-1.18, P =0.089). CONCLUSION: CSS for progressive MIBC patients appears worse than for those with primary MIBC. This highlights the need to direct more resources for this patient population and particularly for high-risk cases of non-MIBC, where timely radical surgery will improve patients prognoses.

Developing a prototype system of computer-aided appointment scheduling: A radiology department case study.

BACKGROUND: Scheduling patient appointments in hospitals is complicated due to various types of patient examinations, different departments and physicians accessed, and different body parts affected. OBJECTIVE: This study focuses on the radiology scheduling problem, which involves multiple radiological technologists in multiple examination rooms, and then proposes a prototype system of computer-aided appointment scheduling based on information such as the examining radiological technologists, examination departments, the patient's body parts being examined, the patient's gender, and the patient's age. METHODS: The system incorporated a stepwise multiple regression analysis (SMRA) model to predict the number of examination images and then used the K-Means clustering with a decision tree classification model to classify the patient's examination time within an appropriate time interval. RESULTS: The constructed prototype creates a feasible patient appointment schedule by classifying patient examination times into different categories for different patients according to the four types of body parts, eight hospital departments, and 10 radiological technologists. CONCLUSION: The proposed patient appointment scheduling system can schedule appointment times for different types of patients according to the type of visit, thereby addressing the challenges associated with diversity and uncertainty in radiological examination services. It can also improve the quality of medical treatment.

Effect of subsequent bladder cancer on survival in upper tract urothelial carcinoma patients post-radical nephroureterectomy: a systematic review and meta-analysis.

BACKGROUND: Radical nephroureterectomy (RNU) is the primary treatment strategy for upper tract urothelial carcinoma (UTUC). However, the intravesical recurrence occurs in 20-50% of all patients. The specific effect of subsequent bladder cancer (SBCa) on survival remains unclear. Therefore, we investigated the effect of SBCa following RNU in patients with UTUC. METHODS: PubMed, EMBASE, and Cochrane Library were exhaustively searched for studies comparing oncological outcomes between SBCa and without SBCa. Standard cumulative analyses using hazard ratios (HR) with 95% confidence intervals (CI) were performed using Review Manager (version 5.3). RESULTS: Five studies involving 2057 patients were selected according to the predefined eligibility criteria. Meta-analysis of cancer-specific survival (CSS) and overall survival (OS) revealed no significant differences between the SBCa and non-SBCa groups. However, subgroup analysis of pT0-3N0M0 patients suggested that people with SBCa had worse CSS (HR = 5.13, 95%CI 2.39-10.98, p < 0.0001) and OS (HR = 4.00, 95%CI 2.19-7.31, p < 0.00001). CONCLUSIONS: SBCa appears to be associated with worse OS in patients with early stage UTUC. However, caution must be taken before recommendations are made because this interpretation is based on very few clinical studies and a small sample size. Research sharing more detailed surgical site descriptions, as well as enhanced outcome data collection and improved reporting, is required to further investigate these nuances.

Allium ureteral stent for the treatment of malignant ureteral obstruction: A median term study.

This study aimed to assess the safety and efficacy of Allium ureteral stents for the maintenance therapy of malignant ureteral obstruction (MUO). Clinical data of 25 patients (27 sides) with ureteral obstruction caused by a malignant tumor from December 2018 to December 2021 were retrospectively analyzed. Preoperative ultrasonography and computed tomography urography indicated hydronephrosis and MUO. Allium ureteral stents were placed using a retrograde or antegrade approach. Therapeutic effects and complications were recorded. The Wilcoxon signed-rank test was used to compare continuous variables between the preoperative and the last follow-up. A total of 25 patients (27 sides) were included in this study. After a follow-up time of 18 (11-29) months, the width of hydronephrosis [1.6 (1.0-2.2) cm vs 2.6 (1.2-3.3) cm, P = .000], glomerular filtration rate [83.8 (58.1-86.4) mL/minutes/1.73 m2 vs 74.5 (56.8-79.1) mL/minutes/1.73 m2, P = .001] and score of ureteral stent symptoms questionnaire [77 (76-79) vs 100 (98-103), P = .000] was significantly improved. Stent migration occurred in 3 of the 25 patients within 3 months after surgery. All patients with complications were followed up for at least 6 months after stent adjustment or exchange, and no other complications were found. Two patients died because of malignant complications. The stent patency rate was 88.9% (24/27) after the first operation, and 100% (27/27) after complications were treated. The Allium ureteral stent is safe and effective for the maintenance therapy of MUO, which can dramatically relieve the symptoms of patients. Stent migration is a major complication that can be resolved by endoscopic adjustment.

Long-term maintenance treatment of recurrent ureteropelvic junction obstruction with covered metallic ureteral stent.

Whether or not the covered metallic ureteral stent can be used as maintenance treatment for recurrent ureteropelvic junction obstruction (UPJO) after pyeloplasty is unknown. Therefore, this study aims to analyze its feasibility. We retrospectively analyzed the records of 20 patients with recurrent UPJO who were treated with the covered metallic ureteral stents from March 2019 to June 2021 at our institution. Then, we assessed their renal function, stent patency and stent-related quality of life by the blood creatinine, renal ultrasound (or computed tomography), and the Chinese version of the ureteral symptom score questionnaire (USSQ). The last follow-up mean blood creatinine dropped from 0.98 ± 0.22 to 0.91 ± 0.21 mg/dL (P = .04), and the median renal pelvic width was reduced from 3.25 (3.10) to 2.00 (1.67) cm (P = .03) compared with the preoperative conditions. Meanwhile, the last follow-up mean USSQ total score of the covered metallic ureteral stent among the 16 patients with preoperative indwelling double-J ureteral stent was 78.56 ± 14.75, significantly lower than the preoperative USSQ total score, which was 102.25 ± 5.57 (P < .001). During the median duration of follow-up of 27.00 (18.00) months, 85% (17/20) of patients maintained unobstructed drainage from the renal pelvis to the ureter. Stent-related complications occurred in 7 patients, 3 of which failed because of complications, including stent migration (1 patient), stent encrustation (1 patient), and stent-related infection (1 patient). The covered metallic ureteral stent is feasible for the long-term maintenance treatment of recurrent UPJO after pyeloplasty.

Applying Simulation Optimization to Minimize Drug Inventory Costs: A Study of a Case Outpatient Pharmacy.

Drug inventory management is an important part of hospital management. The large amounts of drug data in hospitals bring challenges to optimizing the setting values for the safety stock and the maximum inventory of each drug. This study combined a two-stage clustering method with an inventory policy (s, S) and established a simulation optimization model for the case hospital's outpatient pharmacy. This research used the simulation optimization software Arena OptQuest, developed by Rockwell Automation Inc (Rockwell Automation, Coraopolis, PA, USA), in order to determine the minimum and maximum values (s, S) of the best stock amounts for each drug under the considerations of cost and related inventory constraints. The research results showed that the minimum and maximum inventory settings for each drug in the simulation model were better than those set by the case outpatient pharmacy system. The average inventory cost was reduced by 55%, while the average inventory volume was reduced by 68%. The proposed method can improve management efficiency and inventory costs of hospital pharmacies without affecting patient services and increasing the inventory turnover rate of the drugs.

Increased expression of POLR3G predicts poor prognosis in transitional cell carcinoma.

BACKGROUND: Previous studies have shown that RNA Polymerase III Subunit G (POLR3G) has oncogenic effects in cultured cells and mice. However, the role of POLR3G in transitional cell carcinoma (TCC) has not been reported. This study explores the potential of POLR3G as a novel molecular marker for TCC. METHODS: The RNA sequencing data and clinical information of patients with TCC were downloaded from The Cancer Genome Atlas official website. Transcriptome analysis was performed as implemented in the edgeR package to explore whether POLR3G was up-regulated in TCC tissues compared to normal bladder tissues. The expression of POLR3G in bladder cancer cell line T24 and human uroepithelial cell line SV-HUC-1 were detected via quantitative real time polymerase chain reaction (qRT-PCR). Correlations between POLR3G expression and clinicopathological characteristics were analyzed using Mann-Whitney U test or Kruskal-Wallis H test. Clinicopathological characteristics associated with overall survival were explored using the Kaplan-Meier method and Cox regression analyses. Gene set enrichment analysis (GSEA) was performed to explore the associated gene sets enriched in different POLR3G expression phenotypes and the online tool Tumor IMmune Estimation Resource (TIMER) was used to explore the correlation between POLR3G expression and tumor immune infiltration in TCC. RESULTS: Transcriptome analysis showed that POLR3G was significantly up-regulated in TCC tissues compared to normal bladder tissues. Furthermore, qRT-PCR revealed high expression of POLR3G in T24 cells compared to SV-HUC-1 cells. Overall, POLR3G expression was associated with race, tumor status, tumor subtype, T classification, and pathological stage. Kaplan-Meier survival analysis revealed that higher POLR3G expression was associated with lower overall survival. The univariate Cox regression model revealed that age at diagnosis, pathological stage, and POLR3G expression were associated with prognosis of TCC patients. Further multivariate analyses identified these three clinicopathological characteristics as independent prognostic factors for overall survival. GSEA analysis showed that several gene sets associated with tumor development and metastasis, including TGF-ß signaling, PI3K-AKT-mTOR signaling, and IL6-JAK-STAT3 signaling, were significantly enriched in POLR3G high expression phenotype. Immune infiltration analysis revealed that the expression of POLR3G was significantly correlated with infiltrating levels of immune cells, including CD8+ T cells, neutrophils, and dendritic cells; and the expression of POLR3G was also significantly correlated with the expression of immune checkpoint molecules, such as PD1, PD-L1, PD-L2, CTLA4, LAG3, HAVCR2, and TIGIT. CONCLUSIONS: POLR3G was up-regulated in TCC and high POLR3G expression correlated with poor prognosis. POLR3G can potentially be used as a prognostic marker for TCC and might be of great value in predicting the response to immunotherapy.

DEPDC1B is a tumor promotor in development of bladder cancer through targeting SHC1.

Bladder cancer is one of the most commonly diagnosed malignant tumors in the urinary system and causes a massive cancer-related death. DEPDC1B is a DEP domain-containing protein that has been found to be associated with a variety of human cancers. This study aimed to explore the role and mechanism of DEPDC1B in the development of bladder cancer. The analysis of clinical specimens revealed the upregulated expression of DEPDC1B in bladder cancer, which was positively related to tumor grade. In vitro and in vivo studies showed that DEPDC1B knockdown could inhibit the growth of bladder cancer cells or xenografts in mice. The suppression of bladder cancer by DEPDC1B was executed through inhibiting cell proliferation, cell migration, and promoting cell apoptosis. Moreover, a mechanistic study found that SHC1 may be an important route through which DEPDC1B regulates the development of bladder cancer. Knockdown of SHC1 in DEPDC1B-overexpressed cancer cells could abolish the promotion effects induced by DEPDC1B. In conclusion, DEPDC1B was identified as a key regulator in the development of bladder cancer, which may be used as a potential therapeutic target in the treatment of bladder cancer.

Pretreatment with the ALDH2 activator Alda­1 protects rat livers from ischemia/reperfusion injury by inducing autophagy.

Hepatic ischemia/reperfusion injury (HIRI) is a complex pathophysiological process that often leads to poor clinical prognosis. Clinically, the effective means to alleviate HIRI are limited. The aim of the present study was to investigate whether Alda­1, an activator of mitochondrial aldehyde dehydrogenase 2 (ALDH2), had a protective effect on HIRI and to investigate the mechanisms underlying this protective effect. Sprague­Dawley rats were treated with Alda­1 or Daidzin, an ALDH2 inhibitor, 30 min before partial (70%) warm liver ischemia to induce HIRI. The 48 rats were randomly divided into four groups: Sham, ischemia injury (IR), IR­Alda­1, and IR­Daidzin. After 6 and 24 h of reperfusion, serum and liver tissue samples were collected and stored for further experiments. Alanine aminotransferase, aspartate aminotransferase and hematoxylin & eosin staining was used to evaluate the liver damage. Western blotting and reverse transcription­quantitative PCR were used to detect the expression of related proteins and mRNA. TUNEL staining was used to observe the apoptosis of liver cells. Transmission electron microscopy was used to detect the mitochondrial injuries. Alda­1 pretreatment ameliorated the HIRI­induced damage to the liver function and reduced histological lesions. Alda­1 also increased ALDH2 activity after HIRI. Moreover, the pretreatment with Alda­1 reduced the accumulation of toxic aldehyde 4­hydroxy­2­nonenal, decreased the production of reactive oxygen species and malondialdehyde, reversed the damage to the liver mitochondria, attenuated hepatocyte apoptosis and inhibited the HIRI­induced inflammatory response, including high­mobility group box 1/toll­like receptor 4 signaling. Alda­1 also induced autophagy by upregulating autophagy­related 7 and Rab7 increasing the microtubule associated protein 1 light chain 3 αII/I ratio and inhibiting p62 expression. ALDH2­induced autophagy was dependent on the activation of the AKT/mammalian target of rapamycin (mTOR) and AMP­activated protein kinase (AMPK) signaling pathways. In conclusion, the findings of the present study suggested that Alda­1 may protect the liver against HIRI­induced damage, including hepatic enzyme injury, acetaldehyde accumulation, oxidative stress, hepatocyte apoptosis and inflammation. Alda­1 may confer this protection by inducing autophagy through the AKT/mTOR and AMPK signaling pathways. Therefore, ALDH2 could represent a potential pharmacological target in the clinical treatment of HIRI.

TAK242 suppresses the TLR4 signaling pathway and ameliorates DCD liver IRI in rats.

Ischemia­reperfusion injury (IRI) is a notable cause of tissue damage during surgical procedures and a major risk factor in graft dysfunction in liver transplantation. Livers obtained from donors after circulatory death (DCD) are prone to IRI and toll­like receptor 4 (TLR4) serves a prominent role in the inflammatory response associated with DCD liver IRI. The present study was designed to investigate whether TAK242, a specific TLR4 inhibitor, improves hepatic IRI following a DCD graft and to investigate its underlying protective mechanisms. Male Sprague­Dawley rats were randomized into 4 groups: Control, TAK242, DCD and DCD+TAK242 groups. Rats were pretreated with TAK242 or its vehicle for 30 min, then the livers were harvested without warm ischemia (control group and TAK242 group) or with warm ischemia in situ for 30 min. The livers were stored in cold University of Wisconsin solution for 24 h and subsequently perfused for 60 min with an isolated perfused rat liver system. Rat liver injury was evaluated thereafter. When compared with the DCD group, DCD livers with TAK242 pretreatment displayed significantly improved hepatic tissue injury and less tissue necrosis (P<0.05). Compared with DCD livers, mechanistic experiments revealed that TAK242 pretreatment alleviated mitochondrial dysfunction, reduced reactive oxygen species and malondialdehyde levels and inhibited apoptosis. Additionally, TAK242 significantly inhibited the IRI­associated inflammatory response, indicated by the decreased expression of TLR4, interleukin (IL)­1ß, IL­6 and cyclooxygenase 2 at the mRNA and protein levels (P<0.05). TAK242 ameliorates DCD liver IRI via suppressing the TLR4 signaling pathway in rats. The results of the present study have revealed that TAK242 pretreatment harbors a potential benefit for liver transplantation.

Simvastatin ameliorates total liver ischemia/reperfusion injury via KLF2-mediated mechanism in rats.

OBJECTIVE: The total hepatic ischemia/reperfusion injury (IRI) involves the fact that both liver and gut are subjected to warm ischemia, which is a complex unavoidable process encountered during liver transplantation and a serious threat to graft outcome. The ways to improve hepatic IRI are currently limited. The aim of the present study was to explore the protective effect of simvastatin on total hepatic IRI and examine the underlying mechanisms. METHODS: Male Sprague Dawley rats were subjected to total (100%) hepatic warm ischemia to induce hepatic IRI. Thirty-six male rats (250-300 g) were randomly divided into three groups: sham, IRI control and simvastatin (1 mg/kg) pretreatment 0.5 h before surgery. Serum samples and liver tissues were collected after reperfusion at 6 and 24 h for further studies. RESULTS: Simvastatin pretreatment significantly decreased the values of the transaminases alanine aminotransferase and aspartate aminotransferase and improved histological alterations according to improved Suzuki's Score (P < 0.05). Moreover, simvastatin upregulated the expression of Kruppel-like factor 2 (KLF2), phosphorylated endothelial nitric oxide synthase and thrombomodulin (P < 0.05). Furthermore, simvastatin pretreatment affected superoxide dismutase and malondialdehyde activities (P < 0.05) to reduce oxidative stress, and inhibited levels of high-mobility group box-1, CD68, toll-like receptor 4, tumor necrosis factor α, interleukin-1ß and interleukin-6 (P < 0.05) to suppress inflammatory response. CONCLUSION: Simvastatin pretreatment ameliorates total hepatic IRI via a KLF2-mediated protective mechanism. Simvastatin may be used as a potential prophylactic treatment strategy for clinical trials against hepatic IRI.

Donor Treatment With a Hypoxia-Inducible Factor-1 Agonist Prevents Donation After Cardiac Death Liver Graft Injury in a Rat Isolated Perfusion Model.

The protective role of hypoxia-inducible factor-1 (HIF-1) against liver ischemia-reperfusion injury has been well proved. However its role in liver donation and preservation from donation after cardiac death (DCD) is still unknown. The objective of this study was to test the hypothesis that pharmaceutical stabilization of HIF-1 in DCD donors would result in a better graft liver condition. Male SD rats (6 animals per group) were randomly given the synthetic prolyl hydroxylase domain inhibitor FG-4592 (Selleck, 6 mg/kg of body weight) or its vehicle (dimethylsulfoxide). Six hours later, cardiac arrest was induced by bilateral pneumothorax. Rat livers were retrieved 30 min after cardiac arrest, and subsequently cold stored in University of Wisconsin solution for 24 h. They were reperfused for 60 min with Krebs-Henseleit bicarbonate buffer in an isolated perfused liver model, after which the perfusate and liver tissues were investigated. Pretreatment with FG-4592 in DCD donors significantly improved graft function with increased bile production and synthesis of adenosine triphosphate, decreased perfusate liver enzyme release, histology injury scores and oxidative stress-induced cell injury and apoptosis after reperfusion with the isolated perfused liver model. The beneficial effects of FG-4592 is attributed in part to the accumulation of HIF-1 and ultimately increased PDK1 production. Pretreatment with FG-4592 in DCD donors resulted in activation of the HIF-1 pathway and subsequently protected liver grafts from warm ischemia and cold-stored injury. These data suggest that the pharmacological HIF-1 induction may provide a clinically applicable therapeutic intervention to prevent injury to DCD allografts.

Management of displaced inferior patellar pole fractures with modified tension band technique combined with cable cerclage using Cable Grip System.

INTRODUCTION: We present a modified tension band technique combined with cable cerclage using Cable Grip System for the treatment of displaced inferior patellar pole fractures and report the knee functional outcome. PATIENTS AND METHODS: The patients who had had operative treatment of a displaced inferior patellar pole fracture (AO/OTA 34-A1) between December 2013 and December 2015 were studied retrospectively. Eleven consecutive patients had had open reduction and internal fixation with the modified technique using Cable Grip System, of whom, five males and six females with an average age of 60.9 years (range, 29-81 years). All fractures occurred from direct fall onto the knee. The average time from injury to surgery was 6.1days (range, 2-12days). The range of motion (ROM) was measured in degrees by goniometry at postoperative intervals of 1, 2, 4, 12, and 48 weeks; Knee function was evaluated using the Rasmussen scores at final follow-up. RESULTS: No patients had nonunion, loss of reduction, migration of wire, irritation from the implant and fixation breakage during the follow-up period. Recovery of ROM was achieved at 12 weeks, with the average ROM at 1 week was 72° (range, 65°-78°), 86.4° (range, 78°-92°) at 2 weeks, 115.5° (range, 103°-122°) at 4 weeks, 129.6° (range, 122°-133°) at 12 weeks, 134.5° (range, 129°-139°) at 48 weeks after the operation. Concerning the knee function outcome assessment, all patients showed excellent results at final follow-up. The average Rasmussen scores was 27.9 out of 30 (range, 27-29). CONCLUSIONS: The modified tension band technique combined with cable cerclage using Cable Grip System for displaced inferior patellar pole fractures can provide stable fixation with excellent results in knee function, allows for immediate mobilization and early weight-bearing, which is a simple and valuable technique in routine clinical practice.

Pretreatment Donors after Circulatory Death with Simvastatin Alleviates Liver Ischemia Reperfusion Injury through a KLF2-Dependent Mechanism in Rat.

OBJECTIVE: Severe hepatic ischemia reperfusion injury (IRI) can result in poor short- and long-term graft outcome after transplantation. The way to improve the viability of livers from donors after circulatory death (DCD) is currently limited. The aim of the present study was to explore the protective effect of simvastatin on DCD livers and investigate the underlying mechanism. METHODS: 24 male rats randomly received simvastatin or its vehicle. 30 min later, rat livers were exposed to warm ischemia in situ for 30 min. Livers were removed and cold-stored in UW solution for 24 h, subsequently reperfused for 60 min with an isolated perfused rat liver system. Liver injury was evaluated during and after warm reperfusion. RESULTS: Pretreatment of DCD donors with simvastatin significantly decreased IRI liver enzyme release, increased bile output and ATP, and ameliorated hepatic pathological changes. Simvastatin maintained the expression of KLF2 and its protective target genes (eNOS, TM, and HO-1), reduced oxidative stress, inhibited innate immune responses and inflammation, and increased the expression of Bcl-2/Bax to suppress hepatocyte apoptosis compared to DCD control group. CONCLUSION: Pretreatment of DCD donors with simvastatin improves DCD livers' functional recovery probably through a KLF2-dependent mechanism. These data suggest that simvastatin may provide a potential benefit for clinical DCD liver transplantation.