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Background: To assess the frequency of major complications after thermal ablation of liver tumours and to determine risk factors for adverse events.Methods: A retrospective study was conducted between January 2015 and January 2021. A total of 2084 thermal ablation sessions in 1592 patients with primary and metastatic liver tumours were evaluated. The frequency of major complications was evaluated according to the Society of Interventional Radiology Standards, and putative predictors of adverse events were analysed using simple and multivariate logistic regression.Results: Thermal ablation-related mortality was 0.1% (2/2084), with an overall major complication rate of 5.6% (117/2084). The most frequent major complication was symptomatic pleural effusion (51.3%, 60/117). Multivariate logistic regression analysis revealed that a total maximum diameter of lesions >3 cm, microwave ablation (MWA) and MWA combined with radiofrequency ablation, intrahepatic cholangiocarcinoma and postoperative systemic inflammatory response syndrome were independent prognostic factors for major complications. Conclusions: Thermal ablation of liver tumours is a safe procedure with an acceptable incidence of major complications. The risk factors identified in this study will help to stratify high-risk patients.

Activation of hepatic stellate cells (HSCs) is a central driver of liver fibrosis. Previous investigations have identified various altered epigenetic landscapes during the cellular progression of HSC activation. N6-methyladenosine (m

Background. Obesity and type 2 diabetes mellitus (DM) contribute to a higher mortality rate in patients with septic acute kidney injury (AKI) during sepsis. Reactive oxygen species (ROS) is the major injury factor for sepsis. This study was aimed at exploring the potential therapeutic drug for septic AKI targeting on ROS. Methods. A murine septic AKI model was established in both wild-type and high-fat diet-fed (HFD) mice. NADPH oxidase inhibitor Vas2870 was used in vivo to explore the role of NADPH oxidase in ROS release in septic AKI in diabetic mice. Ferrostatin-1 was administered to investigate the role of ferroptosis in ROS accumulation during NADPH oxidase activating in septic AKI in diabetic mice. Results. Compared to chow diet-fed mice, HFD diabetic mice which were subjected to LPS exhibited aggravated renal function (blood urea nitrogen, creatinine clearance, and serum cystatin C) and oxidative stress (malondialdehyde, 4-HNE, ROS, 8-OHdG, and NADPH oxidase), thus resulting in a higher mortality rate. Septic renal injury was significantly attenuated by the ferroptosis inhibitor Fer-1 in HFD-challenged mice. Furthermore, ferroptosis accumulation and related protein expression (ASCL4, FTH1, and GPX4) were altered by LPS stimulation in HFD-challenged mice and suppressed by NADPH oxidase inhibition via Vas2870 in vivo. In summary, NADPH inhibition restored septic renal function from injury by suppressing ferroptosis accumulation in HFD-challenged mice. Conclusion. These results suggest that targeting NADPH-mediated ROS release and ferroptosis accumulation is a novel therapeutic strategy to protect the kidney from septic injury in patients with obesity and type 2 DM.

Background Early prediction of acute kidney injury (AKI) after liver transplantation (LT) facilitates timely recognition and intervention. We aimed to build a risk predictor of post-LT AKI via supervised machine learning and visualize the mechanism driving within to assist clinical decision-making. Methods Data of 894 cases that underwent liver transplantation from January 2015 to September 2019 were collected, covering demographics, donor characteristics, etiology, peri-operative laboratory results, co-morbidities and medications. The primary outcome was new-onset AKI after LT according to Kidney Disease Improving Global Outcomes guidelines. Predicting performance of five classifiers including logistic regression, support vector machine, random forest, gradient boosting machine (GBM) and adaptive boosting were respectively evaluated by the area under the receiver-operating characteristic curve (AUC), accuracy, F1-score, sensitivity and specificity. Model with the best performance was validated in an independent dataset involving 195 adult LT cases from October 2019 to March 2021. SHapley Additive exPlanations (SHAP) method was applied to evaluate feature importance and explain the predictions made by ML algorithms. Results 430 AKI cases (55.1%) were diagnosed out of 780 included cases. The GBM model achieved the highest AUC (0.76, CI 0.70 to 0.82), F1-score (0.73, CI 0.66 to 0.79) and sensitivity (0.74, CI 0.66 to 0.8) in the internal validation set, and a comparable AUC (0.75, CI 0.67 to 0.81) in the external validation set. High preoperative indirect bilirubin, low intraoperative urine output, long anesthesia time, low preoperative platelets, and graft steatosis graded NASH CRN 1 and above were revealed by SHAP method the top 5 important variables contributing to the diagnosis of post-LT AKI made by GBM model. Conclusions Our GBM-based predictor of post-LT AKI provides a highly interoperable tool across institutions to assist decision-making after LT. Graphic abstract

This study aims to determine whether perioperative treatment with dexmedetomidine (DEX) during laparoscopic radical prostatectomy (LRP) can provide a reno-protective effect. This pilot study enrolled 89 patients between 60 and 79 years old, who underwent LRP. These patients were randomly allocated into two groups: group D (n = 44) and group C (n = 45). For patients in group D, 1 µg/kg of DEX was intravenously administered within 10 min, followed by 0.5 µg/kg/h of DEX infusion during the operation. This was stopped at 30 min before the end of surgery. For patients in group C, saline was administered at the same doses. The primary outcome was the incidence of acute kidney injury (AKI), and secondary outcomes included other postoperative variables. The incidence of AKI in group D and C was 4.5% and 13.3%, respectively (P > 0.05). Compared with group C, patients in group D had significantly lower urea nitrogen levels at 6 h after surgery, lower creatinine levels at 6 and 48 h after surgery, and significantly lower CysC levels at 48 h after surgery. A significant decrease in VAS scores for pain and postoperative nausea and vomiting (PONV) at the second and third day after surgery was observed in patients in group D when compared to patients in group C. Intraoperative DEX does not reduce the incidence of AKI, but provides a potential reno-protective effect, and alleviates postoperative pain and PONV in patients undergoing LRP.

Ischemia–reperfusion (I/R) injury is common during surgery and often results in organ dysfunction. The mechanisms of I/R injury are complex, diverse, and not well understood. RNA methylation is a novel epigenetic modification that is involved in the regulation of various biological processes, such as immunity, response to DNA damage, tumorigenesis, metastasis, stem cell renewal, fat differentiation, circadian rhythms, cell development and differentiation, and cell division. Research on RNA modifications, specifically N6-methyladenosine (m6A), have confirmed that they are involved in the regulation of organ I/R injury. In this review, we summarized current understanding of the regulatory roles and significance of m6A RNA methylation in I/R injury in different organs.

Background. Liver transplantation leads to liver ischemia/reperfusion (I/R) injury, resulting in early graft dysfunction and failure. Exacerbations of oxidative stress and inflammatory response are key processes in the development of liver I/R injury. Intravenous anesthetic propofol potent effects on free radical scavenging and protects livers against I/R injury. However, the role and mechanism of propofol-mediated hepatic protection in liver transplantation is poorly understood. The aim of this study was to evaluate the role of propofol postconditioning in the liver I/R injury after liver transplantation. Methods. Forty-eight rats were randomly divided into six groups: rats receiving either sham operation or orthotopic autologous liver transplantation (OALT) in the absence or presence of propofol (high dose and low dose) postconditioning or intralipid control or VAS2870 (Nox2 special inhibitor). Eight hours after OALT or sham operation, parameters of organ injury, oxidative stress, inflammation, and NADPH-associated proteins were assessed. Results. After OALT, severe liver pathological injury was observed that was associated with increases of serum AST and ALT, which were attenuated by propofol postconditioning. In addition, especially high dose of propofol postconditioning reduced TNF-α, IL-1β, IL-6, TLR4, and NF-κB inflammatory pathway, accompanied with decrease of neutrophil elastase activity, MPO activity, 8-isoprotane, p47phox and gp91phox protein expressions, and increase of SOD activity. Inhibition of Nox2 by VAS2870 conferred similar protective effects in liver transplantation. Conclusion. Liver transplantation leads to severe inflammation and oxidative stress with NADPH oxidase activation. Propofol postconditioning reduces liver I/R injury after liver transplantation partly via inhibiting NADPH oxidase Nox2 and the subsequent inflammation and oxidative stress.

To explore the effects of propofol post‐conditioning (PPC) on hepatic ischaemia/reperfusion injury (HIRI) and the potential mechanisms that might be involved in the interaction of Brahma‐related gene1(BRG1) and Nuclear‐related factor 2(Nrf2). Patients were randomized into PPC(n = 16) and non‐PPC(NPC)( n = 21) groups. Propofol(2 mg/kg) was infused within 10 min. of the onset of liver reperfusion during liver transplantation in the PPC group. Liver function tests, as well as Brg1, Nrf2, Heme oxygenase‐1(HO‐1) and NADPH:quinone oxidoreductase1(NQO1) expression levels were evaluated. CMV‐Brg1 mice were designed to investigate the role of Brg1 overexpression during HIRI. Brg1 and Nrf2 siRNA were used to examine the relationship between Brg1 and Nrf2/HO‐1 pathways in propofol‐mediated effects in a human hepatocyte(L02) hypoxia/reoxygenation(H/R) model. In patients, PPC attenuated both donor liver pathological and function injury, and reducing oxidative stress markers, compared to the NPC group, 24 hrs after surgery. PPC increased liver Brg1, Nrf2, HO‐1 and NQO1 expression. In mice, PPC reduced HIRI by decreasing liver oxidative stress and activating Nrf2/HO‐1 pathway, accompanied by up‐regulation of BRG1 expression. BRG1 overexpression activated Nrf2/HO‐1 transcription in CMV‐BRG1 mice during HIRI. In vitro, PPC significantly elevated expression of Nrf2, HO‐1 and NQO1, resulting in a reduction of cell DCFH‐DA and 8‐isoprostane levels and decreased lactate dehydrogenase levels, leading to an overall increase in cell viability. Moreover, the protective effects of propofol were partially abrogated in Nrf2‐knock‐down or BRG1‐knock‐down hepatocytes. Nrf2‐knock‐down drastically reduced protein expression of HO‐1 and NQO1, while Brg1‐knock‐down decreased HO‐1 expression. Propofol post‐conditioning alleviates HIRI through BRG1‐mediated Nrf2/HO‐1 transcriptional activation.

Aims: Perioperative acute kidney injury (AKI) resulting from renal ischemia reperfusion (IR) is not conducive to the postoperative surgical recovery. Our previous study demonstrated that reactive oxygen species (ROS) transmitted by gap junction (GJ) composed of connexin32 (Cx32) contributed to AKI. However, the precise underlying pathophysiologic mechanisms were largely unknown. This study focuses on the underlying mechanisms related to ROS transmitted by Cx32 responsible for AKI aggravation. Results: In a set of in vivo studies, renal IR was found to cause severe impairment in renal tissues with massive ROS generation, which occurred contemporaneously with activation of NF-κB/p53/p53 upregulated modulator of apoptosis (PUMA)-mediated mitochondrial apoptosis pathways. Cx32 deficiency alleviated renal IR-induced AKI, and simultaneously attenuated ROS generation and distribution in renal tissues, which further inhibited NF-κB/p53/PUMA-mediated mitochondrial apoptotic pathways. Correspondingly, in a set of in vitro studies, hypoxia reoxygenation (HR)-induced cellular injury, and cell apoptosis in both human kidney tubular epithelial cells (HK-2s) and rat kidney tubular epithelial cells (NRK52Es) were significantly attenuated by Cx32 inhibitors or Cx32 gene knockdown. More importantly, Cx32 inhibition not only decreased ROS generation and distribution in human or rat kidney tubular epithelial cells but also inhibited its downstream NF-κB/p53/PUMA-mediated mitochondrial apoptotic pathway activation. Innovation and Conclusion: This is the first identification of the underlying mechanisms of IR-induced renal injury integrally which demonstrates the critical role played by Cx32 in IR-induced AKI. Moreover, GJ composed of Cx32 manipulates ROS generation and distribution between neighboring cells, and alters activation of NF-κB/p53/PUMA-mediated mitochondrial apoptotic pathways. Both inhibiting Cx32 function and scavenging ROS effectively reduce mitochondrial apoptosis and subsequently attenuate AKI, providing effective strategies for kidney protection.

Sevoflurane (SEV) preconditioning plays a protective effect against liver ischemia reperfusion (IR) injury, while the role of autophagy in SEV-mediated hepatoprotection and the precise mechanism is unclear. In the current study, mice were pretreated with SEV or autophagy inhibitor before liver IR injury. In vitro, primary rat hepatocytes were pretreated with SEV and then exposed to hypoxia/reoxygenation (H/R). Liver function was measured by biochemical and histopathological examinations, and markers associated with inflammation, oxidation, apoptosis and autophagy were subsequently measured. We found that SEV preconditioning dramatically reduced hepatic damage, alleviated cell inflammatory response, oxidative stress and apoptosis in mice suffering hepatic IR injury, whereas these protective effects were abolished by the autophagy inhibitor 3-MA. In addition, pretreatment with SEV markedly activated HGF/Met signaling pathway regulation. Besides, pretreatment with an hepatocyte growth factor (HGF) inhibitor or knocking down HGF expression significantly downregulated phosphorylated met (p-met) and autophagy levels, and abolished the protective effects of SEV against hepatic IR or hepatocyte H/R injury. Conversely, HGF overexpression efficiently increased the p-met and autophagy levels and strengthened the protective effects of SEV. These results indicated that sevoflurane preconditioning ameliorates hepatic IR injury by activating HGF/Met-mediated autophagy.

Aims Lipopolysaccharide (LPS)-induced intestinal injury is a common clinical feature of sepsis. Aggravated inflammation and higher sensitivity to infection are associated with high-fat diet (HFD) in patients with type 2 diabetes and/or obesity. However, the mechanism by which HFD exacerbates LPS-induced intestinal injury has not been elucidated. This study aims to examine the effects of HFD on intestinal injury induced by LPS and the underlying mechanism. Main methods Mice were fed with HFD or regular chow for 12 weeks and were then challenged with LPS. Vas2870 was administered to mice that received HFD before the initiation of the diet. The levels of tight junction protein expression, oxidative stress, organ injury, and nicotinamide adenine dinucleotide phosphate (NADPH)-associated proteins were assessed periodically. Key findings LPS treatment resulted in severe intestinal pathological injury and increased oxidative stress, evidenced by significantly increased serum diamine oxidase, reactive oxygen species, malondialdehyde, and intestinal fatty acid binding protein contents. Additionally, a decrease in tight junction protein expression was observed, indicating a loss of tight junction integrity. LPS treatment induced the expression of Nox2 and Nox4. All the effects were more severe in HFD mice. Treatment with vas2870 conferred protection against LPS-induced intestinal injury in HFD-fed mice, partially reduced oxidative stress, and rescued the expression of tight junction proteins. Conclusion HFD aggravated LPS-induced intestine injury through exacerbating intestinal Nox-related oxidative stress, which led to a loss of the integrity of tight junctions and consequently increased intestinal permeability.

ObjectiveOur previous retrospective study demonstrated that perioperative dexmedetomidine (Dex) administration was associated with low systemic inflammatory response syndrome (SIRS) incidence. The present study was designed to investigate whether perioperative administration of Dex decreases the incidence of postpercutaneous nephrolithotomy lithotripsy (PCNL) SIRS in patients who undergo PCNL.DesignA randomised controlled trial was designed.ParticipantsA total of 190 patients were randomly assigned to receive Dex (DEX group, n=95) or saline control (CON group, n=95) and completed the study. In the DEX group, Dex was loaded (1 µg/kg) before anaesthesia induction and was infused (0.5 µg/kg/h) during surgery.OutcomesThe incidences of postoperative SIRS were recorded. Serum interleukin-6 (IL-6) and tumour necrosis factor α(TNF-α) were measured.ResultsThe incidence rates of SIRS were significantly lower in the DEX group than in the CON group (35.8% vs 50.5%, p=0.04). No patients developed sepsis in either group. These results might be attributed to inhibition of inflammatory responses and the resulting lower serum levels of IL-6 and TNF-α, caused by Dex administration. However, compared with the CON group, the lower incidence rate of SIRS in the DEX group did not result in better outcomes, such as shorter postoperative hospitalisation stays and lower costs.ConclusionThe present study showed that Dex administration during PCNL might be beneficial for decreasing the incidence of SIRS through inhibiting the release of inflammatory mediators, but not clinical consequences such as postoperative hospitalisation duration and costs. Further effects of Dex administration on SIRS in patients who are scheduled for PCNL should be explored in future studies.Trial registration numberChiCTR-ICR-15006167.

Intestinal motility and barriers are often impaired due to intestinal congestion during liver transplantation. Intestinal bacteria and enterogenous endotoxins enter into the blood stream or lymphatic system and translocate to other organs, which can result in postoperative multi-organ dysfunction (MODF) and systemic inflammatory reaction syndrome (SIRS) severely affecting patient survival. However, the mechanisms underlying liver transplantation-induced intestinal injury remain unclear and effective therapies are lacking. Thus, the present study investigated whether these effects were associated with endotoxin-mediated apoptosis. Rat autologous orthotopic liver transplantation (AOLT) models were established to observe dynamic intestinal injuries at different time-points following reperfusion. Changes in the levels of endotoxins and the primary receptor, toll-like receptor 4 (TLR4), as well as its downstream signaling molecule, nuclear factor-κB (NF-κB) were all determined. Finally, immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling assays were conducted to detect caspase-3 expression and intestinal cell apoptosis, respectively. AOLT resulted in significant pathological intestinal injury, with the most serious intestine damage apparent four or eight hours following reperfusion. Furthermore, the levels of endotoxins and inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, peaked during this time period and gradually decreased to the normal level. Notably, TLR4 and downstream NF-κB expression, as well as NF-κB-mediated caspase-3 activation and intestinal cell aapoptosis coincided with the intestinal pathological damage. Thus, the possible mechanism of post-liver transplantation intestinal injury was demonstrated to be associated with NF-κB activation-induced cell apoptosis.

Adhesion between circulating monocytes and vascular endothelial cells is a key initiator of atherosclerosis. In our previous studies, it was demonstrated that the expression of connexin (Cx)43 in monocytes modulates cell adhesion, however, the effects of the expression of Cx43 in endothelial cells remains to be elucidated. Therefore, the present study investigated the role of the expression of Cx43 in endothelial cells in the process of cell adhesion. A total of four different methods with distinct mechanisms were used to change the function and expression of Cx43 channels in human umbilical vein endothelial cells: Cx43 channel inhibitor (oleamide), enhancer (retinoic acid), overexpression of Cx43 by transfection with pcDNA‑Cx43 and knock‑down of the expression of Cx43 by small interfering RNA against Cx43. The results indicated that the upregulation of the expression of Cx43 enhanced monocyte‑endothelial adhesion and this was markedly decreased by downregulation of Cx43. This mechanism was associated with Cx43‑induced expression of vascular cell adhesion molecule‑1 and intercellular cell adhesion molecule‑1. The effects of Cx43 in endothelial cells was independent of Cx37 or Cx40. These experiments suggested that local regulation of endothelial Cx43 expression within the vasculature regulates monocyte‑endothelial adhesion, a critical event in the development of atherosclerosis and other inflammatory pathologies, with baseline adhesion set by the expression of Cx43. This balance may be crucial in controlling leukocyte involvement in inflammatory cascades.

Background Nuclear factor-E2–related factor 2 (Nrf2)–mediated antioxidant response is the main protective system of graft-liver against ischemia–reperfusion injury after liver transplantation. Propofol is considered to confer protective effects on different organs; thus, we explored the possibility that whether propofol could attenuate graft-liver injury in a rat autologous orthotopic liver transplantation (AOLT) model and mechanisms were associated with activation of Nrf2 pathway. Methods Sprague–Dawley rats were randomly divided into four groups: sham-operated group, saline-treated AOLT group, low-dose propofol intervention group, and high-dose propofol intervention group. Liver injury was determined, and concentration of hydroxyl free radical (•OH), superoxide anion (O 2 •− ), and malondialdehyde in the liver tissue were detected. The expression of Keap1, Nrf2, HO-1, and NQO1 were explored by Western blotting, and also the change of Nrf2 and keap1 was assessed by immunofluorescence. Results Compared with sham group, pathologic damage of graft-livers was in a time-dependent manner, accompanied with the increased level of oxidative stress in the AOLT group, and nuclear Nrf2 expression and its downstream antioxidant enzyme, HO-1 and NQO1, were also increased in this group. However, in propofol pretreatment groups especially in the high-dose group, the pathologic score was significantly decreased, accompanied with a lower level of •OH, O 2 •− , and malondialdehyde than that of the AOLT group. The change of oxidative stress might be related to the Nrf2 pathway, evidenced as the elevation of protein expression level of NQO1, HO-1, and nuclear Nrf2. Conclusions Protective effects of propofol against liver transplantation–induced graft-liver injury may be related with Keap1-Nrf2 signal pathway activation.

Acute lung injury (ALI) is a severe complication of orthotopic liver transplantation (OLT) with unclear underline mechanism. Toll-like receptor 4 (TLR4) has been identified as a key receptor mediating inflammation. We hypothesized that TLR4-mediated pulmonary inflammation may contribute to development of ALI during OLT. Patients with or without ALI were observed for serum cytokines and expression of TLR4 on peripheral blood polymorphonuclear leukocytes (PMNs). Next, rats which underwent orthotopic autologous liver transplantation (OALT) were divided into sham and model groups. Pulmonary function and the level of TLR4 expression and cytokines were analyzed. Furthermore, the role of TLR4 in OALT-mediated ALI was assessed in rats treated with TLR4-siRNA before OALT. The PMNs TLR4 expression and the serum TNF-αand IL-βlevel were higher in patients with ALI than those with non-ALI. Interestingly, lung TLR4 expression was significantly increased after 8 hours of OALT with increased levels of TNF-αand IL-β, which lead to lung pathological damage and an increase of lung myeloperoxidase content. Moreover, knockdown of TLR4 reduced lung cytokines release and reversed the above pathologic changes after OALT and finally improved rats’ survival rate. In conclusion, TLR4 overexpression, potentially by stimulating proinflammatory cytokine overproduction, contributes to the development of ALI after OLT.

Aim. To investigate whether overexpression of Brahma-related gene-1 (Brg1) can alleviate lung injury induced by hepatic ischemia/reperfusion (HIR) and its precise mechanism.Methods. Cytomegalovirus-transgenic Brg1-overexpressing (CMV-Brg1) mice and wild-type (WT) C57BL/6 mice underwent HIR. Lung histology, oxidative injury markers, and antioxidant enzyme concentrations in the lung were assessed. The protein expression levels of Brg1, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H:quinone oxidoreductase 1 (NQO1) in the lung were analyzed by Western blotting.Results. In the WT group, histopathological analysis revealed that lung damage peaked at 6 h after HIR. Meanwhile, the lung reactive oxygen species (ROS) and 8-isoprostane levels were significantly increased. The protein expression of Brg1 in lung tissue decreased to a minimum at 6 h. Overexpression of Brg1 alleviated lung injury and decreased the amounts of oxidative products, including the levels of 8-isoprostane and ROS, as well as the percentage of positive cells for 4-hydroxynonenal (4-HNE) and 8-oxo-2′-deoxyguanosine (8-OHdG). Brg1 overexpression increased the expression and nuclear translocation of Nrf2 as well as activated the antioxidases. In addition, it decreased the expression of inflammatory factors.Conclusion. Overexpression of Brg1 alleviates oxidative lung injury induced by HIR, likely through the Nrf2 pathway.

Objective: We examined the value of inflammatory and oxidative biomarkers in predicting acute kidney injury (AKI) following orthotopic liver transplantation (OLT).Methods: Urinary excretion of tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8), interleukin-10 (IL-10), superoxide dismutase (SOD), malondialdehyde (MDA), 6-keto prostaglandin F1α (6-keto-PGF1α), hydrogen peroxide (H2O2), and 8-keto prostaglandin F2α (8-iso-PGF2α), serum creatinine (SCr), blood urea nitrogen (BUN), urinary N-acetyl-beta-D-glucosaminidase (NAG), β2-microglobulin (β2-MG) and γ-glutamyl-transferase (γ-GT), were measured before surgery (baseline), at 2 h after graft reperfusion and 24 h after OLT in 28 liver transplantation patients.Results: The levels of TNF-α, IL-8, IL-10, SOD, MDA, 6-keto-PGF1α, H2O2 and 8-iso-PGF2α in urine were all significantly higher in patients who had AKI than in those who did not at 2 h after graft reperfusion and 24 h after OLT (p

Stabilizing mast cells (MCs) can either inhibit or augment inflammation; however, how improved therapeutic benefits against small intestinal ischemia-reperfusion injury (IIRI) can be achieved by stabilizing MCs remains to be elucidated. The present study was designed to evaluate different treatments with cromolyn sodium (CS, an MC stabilizer), which was administrated either prior to ischemia or after reperfusion. Kunming mice were randomized into a sham-operated group (SH), a sole IIR group (M), in which mice were subjected to 30 min superior mesenteric artery occlusion followed by 3 day or 3 h reperfusion, or IIR, treated with CS 15 min prior to ischemia or 15 min after reperfusion in the PreCr and PostCr groups. The survival rate and Chiu's scores were evaluated. The levels of ET-1, histamine, TNF-α and IL-6, and expression of MC protease 7 (MCP7), MC counts and myeloperoxidase (MPO) activity were quantified. IIR resulted in severe injury as demonstrated by significant increases in mortality and injury score. IIR also led to substantial elevations in the levels of ET-1, histamine, TNF-α and IL-6, expression of MCP7, MC counts and MPO activities (P0.05, M vs. SH groups). All biochemical changes were markedly reduced in the PostCr group (P0.05, PostCr vs. M groups), whereas pretreatment of IIR mice with CS prior to ischemia exhibited no changes of ET-1 levels, injury score and inflammation (P0.05, PreCr vs. M groups). In conclusion, administration of CS after reperfusion, but not prior to ischemia, attenuates IIRI by downregulating ET-1 and suppressing sustained MC activation.

Findings of previous studies have revealed that intestinal mucosal mast cells (IMMCs) are involved in small intestinal ischemia‑reperfusion injury (IIRI). However, time-course changes of mast cell counts and mast cell function in this process remain unclear. The present study aimed to observe the number of IMMCs and to investigate the correlation between their activation and small intestine injury at various time points during the period of small intestinal ischemia reperfusion (IIR). Healthy male Kunming mice were randomly divided into five groups, and were subjected to occlusion of the superior mesenteric artery (SMA) for 30 min and followed by reperfusion for 1, 3, 6 and 12 h. By contrast, the SMA was isolated but not clamped in the baseline group. Chiu's scores were assessed by light microscopy, tryptase protein and MCP7 protein expression in the intestine were quantified, and mast cell counts and levels of histamine and TNF-α in the intestine were measured. The results showed that IIR induced severe intestine injury within 12 h as demonstrated by Chiu's scores that was greatly increased as compared to the baseline group, accompanied by increased mast cell counts, histamine and TNF-α levels. However, the Chiu's scores were reduced in the IIR 12 h group compared with the IIR 1 h, IIR 3 h and IIR 6 h groups, with concomitant decreased mast cell counts, histamine and TNF-α levels. The tryptase and MCP7 protein expression was markedly increased in the IIR 1 h and IIR 3 h groups as compared with the baseline group, whereas this expression was gradually decreased at 6 and 12 h after reperfusion. The results of the present study suggest that IIR results in severe mucosal destruction within 6 h after reperfusion, associated with mast cell activation and substantial increases in the mast cell counts.

Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling plays a dominant role in the pathogenesis of liver ischemia-reperfusion (IR) injury. Dexmedetomidine (Dex) protects the liver against IR injury via α2-adrenoceptor activation, but the contribution of TLR4 signaling remains unknown. The authors aimed to examine whether pretreatment with Dex produces hepatic protection and investigate the influence of Dex on TLR4/NF-κB signaling. Dex was given via intraperitoneal injection 30 min prior to orthotopic autologous liver transplantation (OALT) in rats, and three α2-adrenoceptor antagonists including atipamezole (a nonselective α2 receptor blocker), ARC-239 (a specific α2B/C blocker) and BRL-44408 (a specific α2A blocker) were injected intraperitoneally 10 min before Dex administration. Histopathologic evaluation of the liver and the measurement of serum alanine aminotransferase activity, TLR4/NF-κB expression in the liver, and pro-inflammatory factors (serum tumor necrosis factor-α, interleukin-1β and hepatic myeloperoxidase) concentrations were performed 8 h after OALT. Dex ameliorated liver injury after OALT probably by suppressing the TLR4/NF-κB pathway and decreasing inflammatory mediator levels. The protective effects of Dex were reversed by atipamezole and BRL-44408, but not by ARC-239, suggesting that these effects were mediated in part by the α2A subtype. In conclusion, Dex attenuates liver injury partly via the α2A-adrenoceptor subtype, and the mechanism is due to the suppression of the TLR4/NF-κB pathway.

Mast cell activation plays a key role in the process of small intestinal ischemia-reperfusion (IIR) injury; however, the precise role of tryptase released from mast cell on IIR injury remains poorly understood. The aim of this study was to determine the protective role against IIR injury by using tryptase inhibitor protamine after ischemia and to explore the underlying mechanism.Adult Sprague-Dawley rats were randomized into sham-operated group (S), sole IIR group (IIR) in which rats were subjected to 75-minute superior mesenteric artery occlusion followed by 4-hour reperfusion, or IIR being respectively treated with mast cell stabilizer cromolyn sodium (CS group), with the mast cell degranulator compound 48/80 (CP group), or with protamine (P group). The previously mentioned agents were, respectively, administered intravenously 5 minutes before reperfusion. The intestine tissue was obtained for histologic assessment and assays for protein expressions of tryptase and mast cell protease 7 and protease-activated receptor 2 (PAR-2). The intestine mast cell number and levels of tumor necrosis factor κ and interleukin 8 were quantified.IIR resulted in intestinal injury evidenced as significant increases in Chiu's scores, accompanied with concomitant increases of mast cell counts and intestinal tryptase and mast cell protease 7 protein expressions. IIR also increased intestinal PAR-2 expressions, tumor necrosis factor κ, and interleukin 8 levels. Cromolyn sodium and protamine significantly reduced the responses to IIR injury while compound 48/80 further aggravated the previously mentioned biochemical changes.Tryptase releasing from mast cell activation participates in IIR injury through PAR-2, and inhibiting tryptase after ischemia provides promising benefits in limiting IIR injury.

Cytoprotective gene heme oxygenase 1 (HO-1) could be induced by nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. The purpose of this study was to determine the role of Brahma-related gene 1 (Brg1), a catalytic subunit of SWI2/SNF2-like chromatin remodeling complexes, in Nrf2/HO-1 pathway activation during hepatic ischemia–reperfusion (HIR). Our results showed that hepatic Brg1 was inhibited during early HIR while Brg1 overexpression reduced oxidative injury in CMV-Brg1 mice subjected to HIR. Moreover, promoter-driven luciferase assay showed that overexpression of Brg1 by adenovirus transfection in AML12 cells selectively enhanced HO-1 gene expression after hypoxia/reoxygenation (H/R) treatment but did not affect the other Nrf2 target gene NQO1. Furthermore, inhibition of HO-1 by the selective HO-1 inhibitor zinc protoporphyria could partly reverse the hepatic protective effects of Brg1 overexpression while HO-1-Adv attenuated AML12 cells H/R damage. Further, chromatin immunoprecipitation analysis revealed that Brg1 overexpression, which could significantly increase the recruitment of Brg1 protein to HO-1 but not NQO1 promoter, was recruited by Nrf2 to the HO-1 regulatory regions in AML12 hepatocytes subjected to H/R. In conclusion, our results demonstrated that restoration of Brg1 during reperfusion could enhance Nrf2-mediated inducible expression of HO-1 during HIR to effectively increase antioxidant ability to combat against hepatocytes damage.

Nuclear factor erythroid 2‑related factor 2 (Nrf2) is a critical regulator of the cellular‑defense response in protection against oxidative injury. Several studies have demonstrated that propofol ameliorates ischemia/reperfusion injury in a number of organs. However, whether propofol exerts renal protection against liver transplantation via Nrf2 activation remains to be elucidated. The aim of the present study was to investigate the effects of orthotopic liver autotransplantation (OLAT) on renal Nrf2 expression and to determine whether propofol protects against kidney injury induced by OLAT via Nrf2 activation. A total of 24 male Sprague Dawley rats were randomly divided into four groups: sham surgery + normal saline (sham group); OLAT + normal saline (OLAT group); OLAT + propofol 50 mg/kg (L‑Prop group) and OLAT + propofol 100 mg/kg (H‑Prop group). Normal saline and propofol were administered for 3 consecutive days through an intraperitoneal injection prior to surgery. Kidney pathology, blood urea nitrogen (BUN), creatinine (Cr), superoxide anion (O2•‑), hydroxyl radical (·OH), maleic dialdehyde (MDA) and expression levels of Nrf2, Kelch‑like ECH‑associated protein 1 (Keap1), heme oxygenase‑1 (HO‑1) and NADP quinine oxidoreductase 1 (NQO1) were assessed 8 h after OLAT. It was demonstrated that OLAT induced remote kidney damage. Pretreatment with propofol significantly ameliorated renal pathology and abrogated the increase of the Cr and BUN concentrations, O2•‑ and ·OH activities, and MDA levels induced by OLAT. In the H‑Prop group, Keap1 expression in the cytoplasm was decreased and Nrf2 expression in the nucleus was upregulated, accompanied by an increase of HO‑1 and NQO1 expression. The present results suggest that propofol pretreatment exerted renal protection against OLAT, with the upregulation of nuclear Nrf2 expression as a potential mechanism.

To explore the effects of cromolyn sodium (CS) on intestinal ischemia-reperfusion (IIR) and its relationship with mast cell activation and protease-activated receptor 2 (PAR-2) expression.A total of 32 SD rats were randomly divided into 4 groups: sham-operated (S), intestinal ischemia reperfusion (IIR), CS (a mast cell stabilizer, CS, 25 mg/kg) and compound 48/80 (a mast cell degranulation, CP, 0.75 mg/kg) (n = 8 each). IIR was induced by clamping superior mesenteric artery for 75 min followed by reperfusion for 3 hours. The above agents were intravenously administrated at 5 min pre-reperfusion. Rats were then sacrificed and intestinal issues harvested for histological examinations. The tryptase expression and mast cell count were analyzed by immunohistochemistry. PAR-2 was analyzed by Western blot.The Chiu's score (0.75 ± 0.21), mast cell count (10 ± 3), tryptase expression (125 ± 15) and PAR-2 expression (109 ± 10) of group S were the least while those of group CP the most (all P0.05). The Chiu's score (2.14 ± 0.64), mast cell count (15 ± 4), tryptase expression (138 ± 17) and PAR-2 expression (124 ± 12) of group CS were less than those of groups IIR and CP (all P0.05).Cromolyn sodium may reduce IIR injury by stabilizing mast cell membrane and inhibiting the expressions of tryptase and PAR-2.

Background:To investigate the effects of intraoperative application of dexmedetomidine (Dex) on early gastrointestinal motility after laparoscopic resection of colorectal cancer.Methods:In this prospective, randomized double-blind investigation, 60 patients who underwent laparoscopic resecti

Aim Histamine released from mast cell degranulation participates in the pathogenesis of ischemia/reperfusion injury. The purpose of our study was to define the role of histamine in hypoxia/reoxygenation mediated liver cell injury and to elucidate the underlying mechanism in vitro. Methods Histamine alone or in combination with H1 receptor antagonist (pyrilamine), H2 receptor antagonist (cimetidine) or H3/4 receptor antagonist (thioperamide) at different concentrations before hypoxia was added to rat liver BRL-3A cell which was subjected to 24 h hypoxia followed by 4 h reoxygenation. Cell proliferation, apoptosis and the changes of ultrastructure were assessed, and MDA contents, SOD activities and ALT levels were quantified as well. Results Histamine (from 10−3 to 10−9 M) did not affect the growth of BRL-3A cells without hypoxia treatment. However, histamine 10−8 M significantly lowered the growth of BRL-3A cells challenged by hypoxia/reoxygenation, accompanied with concomitant elevations in MDA contents and decreases in SOD activities, all these changes were blocked by cimetidine, not by pyrilamine or thioperamide. However, histamine (above 10−6 M) did not show exacerbating effects in BRL-3A cell subjected to hypoxia/reoxygenation. Conclusion Histamine at low concentrations (10−7–10−9 M) aggravates hypoxia/reoxygenation mediated BRL-3A damage through histamine H2 receptor.

To observe the changes in systemic hemodynamics and their relations to the concentrations of nitric oxide, endothelin, prostacyclin, and thromboxane A2 after portal cavity clamping and opening in portal hypertensive canines.Twelve canines were randomly divided into control group and model group, and partial ligation of the portal vein was performed in the model group. Portal cavity clamping and opening was performed 12 weeks later in the two groups. The hemodynamic parameters including cardiac output index (CI), heart rate (HR), mean artery blood pressure (MABP), central venous pressure (CVP), pulmonary arteriole wedge pressure (PAWP), and systemic vascular resistance index (SVRI) were measured during the operation. Samples were obtained from the central vein at 3 time points during the operation for measuring NO, ET, PGI2, and TXA2.Portal vein ligation and portal cavity clamping produced obvious changes in the systemic circulation of the dogs, and the alteration was milder in the control group. After obstruction of the portal vein, the NO levels in systemic circulation in portal hypertensive dogs declined obviously, but gradually recovered the normal level after reperfusion.Systemic circulation undergoes significant alterations after portal vein obstruction, but its changes in portal hypertensive dogs are milder than those in the control group, the mechanism of which needs further investigation.

This paper proposes a self-adaptive algorithm for the projection-time of the cluster warhead, which is applicable to the realization of the engineering project with low cost. On the basis of keeping the simplified correction strategy that keeps the constant distance of the projection points and through detecting the deviation of the actual trajectory data at a specific time with respect to the pre-determined trajectory data, this algorithm adopts the simple functional relationship to calculate the correction of the projection time. It adopts Monte Carlo computer simulation method to verify. The circular probable error of the projection point, caused by this algorithm, at the horizontal distance is 8.2 meters. The working content and the flow procedures for the setter and the fuze projection-time self-adaptive controller, which adopts this algorithm, are finally concluded. While being free from influencing the precision, this algorithm can effectively simplify the design of the projection-time self-adaptive projection controller, can reduce the volume and the circuit power consumption, and is applicable to be used on the fuze.