The Bibliometric and Visualized Analysis of Research for Hospital Medication Management Based on the Web of Science Database.

Objective: Identify the collaborations between authors, countries, and institutions, respectively, and explore the hot issues and prospects for research on hospital medication management. Materials and Methods: Publications on hospital medication management were retrieved from the Web of Science Core Collection. Bibliometric analyses were performed using CiteSpace 6.1.R3, HistCite 2.1, and VOSviewer 1.6.16. The network maps were created between authors, countries institutions, and keywords. Results: A total of 18,723 articles related to hospital medication management studies were identified. Rapid growth in the number of publications since 2017. The high papers were published in AM J HEALTH-SYST PH, while JAMA-J AM MED ASSOC was the most co-cited journal. Manias E and WHO ranked first in the author and cited author. There were active collaborations among the top authors. Bates DW was the key author in this field. The authors have active collaborations in adverse drug events, acute coronary syndrome, in-hospital major bleeding, and so on. The US was the leading contributor in this field. The UK, Australia, and China are also very active. Active cooperation between countries and between institutions was observed. The main hot topics included matters related to outcome indicators, hospital pharmacy service behaviors, and medication use in pain management. More recent keywords focus on chronic disease medication management and clinical medication management. Conclusion: Hospital medication management studies have significantly increased after 2017. There was active cooperation between authors, countries, and institutions. The application of hospital medication management in the emergency department and the relationship between medication management and medication adherence are current research hotspots. In addition, with the continuous progress of society, chronic diseases have become an important factor affecting people's health, and medication management is becoming more and more subdivided, so the direction of chronic disease medication management as well as precise medication may become the development direction of future research.

Ischemia and reperfusion-injured liver-derived exosomes elicit acute lung injury through miR-122-5p regulated alveolar macrophage polarization.

Acute lung injury (ALI) is a common postoperative complication, particularly in pediatric patients after liver transplantation. Hepatic ischemia-reperfusion (HIR) increases the release of exosomes (IR-Exos) in peripheral circulation. However, the role of IR-Exos in the pathogenesis of ALI induced by HIR remains unclear. Here, we explored the role of exosomes derived from the HIR-injured liver in ALI development. Intravenous injection of IR-Exos caused lung inflammation in naive rats, whereas pretreatment with an inhibitor of exosomal secretion (GW4869) attenuated HIR-related lung injury. In vivo and in vitro results show that IR-Exos promoted proinflammatory responses and M1 macrophage polarization. Furthermore, miRNA profiling of serum identified miR-122-5p as the exosomal miRNA with the highest increase in young rats with HIR compared with controls. Additionally, IR-Exos transferred miR-122-5p to macrophages and promoted proinflammatory responses and M1 phenotype polarization by targeting suppressor of cytokine signaling protein 1(SOCS-1)/nuclear factor (NF)-κB. Importantly, the pathological role of exosomal miR-122-5p in initiating lung inflammation was reversed by inhibition of miR-122-5p. Clinically, high levels of miR-122-5p were found in serum and correlated to the severity of lung injury in pediatric living-donor liver transplant recipients with ALI. Taken together, our findings reveal that IR-Exos transfer liver-specific miR-122-5p to alveolar macrophages and elicit ALI by inducing M1 macrophage polarization via the SOCS-1/NF-κB signaling pathway.

Intraoperative management during liver transplantation in the child with mitochondrial depletion syndrome: A case report.

INTRODUCTION: Mitochondrial DNA depletion syndrome (MDS) is a kind of autosomal recessive genetic disorder associated with a reduction in mitochondrial DNA (mtDNA) copy number caused by mutations in nuclear genes during nucleotide synthesis, which affects the energy production of tissues and organs. Changes in hemodynamics during liver transplantation may lead to high energy-demanding organs and tissues being vulnerable. This report described the intraoperative management during liver transplantation in a child with MDS. Ultimately, the child was discharged smoothly without any complications. PRESENTATION OF THE CASE: A five-year-old boy was diagnosed with mitochondrial depletion syndrome preoperatively and scheduled for living donor liver transplantation. The incidence of postreperfusion syndrome (PRS) could not be avoided for 30 min after opening, despite our best efforts to aggressively prevent it before opening. While ensuring hemodynamic stability, we actively prevented and adopted high-energy-demand organ protection strategies to reduce the incidence of postoperative complications. Finally, the child was discharged 28 days after the operation, and no other complications were found. DISCUSSION: Liver transplantation can be performed for liver failure in this disease to improve the quality of life and prolong the life of patients. As this child has mitochondrial DNA depletion syndrome, the disruption of cellular energy generation caused by mitochondrial malfunction puts high-energy-demanding organs and tissues at risk during surgery. It motivates us to pay closer attention to the prevention and treatment of PRS in anesthetic management to minimize damage to the child's organs and tissues with high energy demands. CONCLUSIONS: This report describes the intraoperative management during liver transplantation in a child with mitochondrial depletion syndrome. To increase the safety of perioperative anesthesia and reduce mortality in patients with mitochondrial disease, for such patients, maintaining an acid-base balance and a stable internal environment is essential. We should also pay attention to protecting body temperature, using vasoactive drugs beforehand to lessen the incidence of PRS, and protecting high-energy-demanding organs afterward.

Risk factors for myocardial injury during living donor liver transplantation in pediatric patients with biliary atresia.

BACKGROUND: Cold ischemia-reperfusion of the liver is an inevitable occurrence in liver transplantation that may also cause damage to the heart. Perioperative myocardial injury during liver transplantation can increase the incidence of postoperative mortality, but there is little research on the incidence of myocardial injury in children who undergo living donor liver transplantation (LDLT). Therefore, this study mainly explores the independent risk factors for myocardial injury in children who undergo LDLT. AIM: To analyze the data of children who underwent LDLT to determine the risk factors for intraoperative myocardial injury. METHODS: We retrospectively analyzed the inpatient records of pediatric patients who underwent LDLT in Tianjin First Central Hospital from January 1, 2020, to January 31, 2022. Recipient-related data and donor-related data were collected. The patients were divided into a myocardial injury group and a nonmyocardial injury group according to the value of the serum cardiac troponin I at the end of surgery for analysis. Univariate analysis and multivariate logistic regression were used to evaluate the risk factors for myocardial injury during LDLT in pediatric patients. RESULTS: A total of 302 patients met the inclusion criteria. The myocardial injury group had 142 individuals (47%), and the nonmyocardial injury group included 160 patients (53%). Age, height, and weight were significantly lower in the myocardial injury group (P < 0.001). The pediatric end-stage liver disease (PELD) score, total bilirubin, and international standardized ratio were significantly higher in the myocardial injury group (P < 0.001). The mean arterial pressure, lactate, hemoglobin before reperfusion, duration of the anhepatic phase, cold ischemic time, incidence of postreperfusion syndrome (PRS), and fresh frozen plasma transfusion were significantly different between the two groups (P < 0.05). The postoperative intensive care unit stay and peak total bilirubin values in the first 5 d after LDLT were significantly higher in the myocardial injury group (P < 0.05). The pediatric patients with biliary atresia in the nonmyocardial injury group who underwent LDLT had a considerably higher one-year survival rate than those in the myocardial injury group (P = 0.015). Multivariate logistic regression revealed the following independent risk factors for myocardial injury: a high PELD score [odds ratio (OR) = 1.065, 95% confidence interval (CI): 1.013-1.121; P = 0.014], a long duration of the anhepatic phase (OR = 1.021, 95%CI: 1.003-1.040; P = 0.025), and the occurrence of intraoperative PRS (OR = 1.966, 95%CI: 1.111-3.480; P = 0.020). CONCLUSION: A high PELD score, a long anhepatic phase duration, and the occurrence of intraoperative PRS were independent risk factors for myocardial injury during LDLT in pediatric patients with biliary atresia.

The macrophage STING-YAP axis controls hepatic steatosis by promoting the autophagic degradation of lipid droplets.

BACKGROUND AND AIMS: The hallmark of NAFLD or hepatic steatosis is characterized by lipid droplet (LD) accumulation in hepatocytes. Autophagy may have profound effects on lipid metabolism and innate immune response. However, how innate immune activation may regulate the autophagic degradation of intracellular LDs remains elusive. APPROACH AND RESULTS: A mouse model of a high-fat diet-induced NASH was used in the myeloid-specific stimulator of interferon genes (STING) knockout or STING/yes-associated protein (YAP) double knockout mice. Liver injury, lipid accumulation, lipid droplet proteins, autophagic genes, chromatin immunoprecipitation coupled with massively parallel sequencing, and RNA-Seq were assessed in vivo and in vitro . We found that high-fat diet-induced oxidative stress activates STING and YAP pathways in hepatic macrophages. The acrophage STING deficiency (myeloid-specific STING knockout) enhances nuclear YAP activity, reduces lipid accumulation, and increases autophagy-related proteins ATG5, ATG7, and light chain 3B but diminishes LD protein perilipin 2 expression. However, disruption of STING and YAP (myeloid STING and YAP double knockout) increases serum alanine aminotransferase and triglyceride levels and reduces ß-fatty acid oxidation gene expression but augments perilipin 2 levels, exacerbating high-fat diet-induced lipid deposition. Chromatin immunoprecipitation coupled with massively parallel sequencing reveals that macrophage YAP targets transmembrane protein 205 and activates AMP-activated protein kinase α, which interacts with hepatocyte mitofusin 2 and induces protein disulfide isomerase activation. Protein disulfide isomerase activates hypoxia-inducible factor-1α signaling, increases autophagosome colocalization with LDs, and promotes the degradation of perilipin 2 by interacting with chaperone-mediated autophagy chaperone HSC70. CONCLUSIONS: The macrophage STING-YAP axis controls hepatic steatosis by reprogramming lipid metabolism in a transmembrane protein 205/mitofusin 2/protein disulfide isomerase-dependent pathway. These findings highlight the regulatory mechanism of the macrophage STING-driven YAP activity on lipid control.

Caspase 6 promotes innate immune activation by functional crosstalk between RIPK1-IκBα axis in liver inflammation.

BACKGROUND: Caspase 6 is an essential regulator in innate immunity, inflammasome activation and host defense. We aimed to characterize the causal mechanism of Caspase 6 in liver sterile inflammatory injury. METHODS: Human liver tissues were harvested from patients undergoing ischemia-related hepatectomy to evaluate Caspase 6 expression. Subsequently, we created Caspase 6-knockout (Caspase 6KO) mice to analyze roles and molecular mechanisms of macrophage Caspase 6 in murine models of liver ischemia/reperfusion (IR) injury. RESULTS: In human liver biopsies, Caspase 6 expression was positively correlated with more severe histopathological injury and higher serum ALT/AST level at one day postoperatively. Moreover, Caspase 6 was mainly elevated in macrophages but not hepatocytes in ischemic livers. Unlike in controls, the Caspase 6-deficient livers were protected against IR injury, as evidenced by inhibition of inflammation, oxidative stress and iron overload. Disruption of macrophage NF-κB essential modulator (NEMO) in Caspase 6-deficient livers deteriorated liver inflammation and ferroptosis. Mechanistically, Caspase 6 deficiency spurred NEMO-mediated IκBα phosphorylation in macrophage. Then phosphorylated-inhibitor of NF-κBα (p-IκBα) co-localized with receptor-interacting serine/ threonine-protein kinase 1 (RIPK1) in the cytoplasm to degradate RIPK1 under inflammatory conditions. The disruption of RIPK1-IκBα interaction preserved RIPK1 degradation, triggering downstream apoptosis signal-regulating kinase 1 (ASK1) phosphorylation and inciting NIMA-related kinase 7/NOD-like receptor family pyrin domain containing 3 (NEK7/NLRP3) activation in macrophages. Moreover, ablation of macrophage RIPK1 or ASK1 diminished NEK7/NLRP3-driven inflammatory response and dampened hepatocyte ferroptosis by reducing HMGB1 release from macrophages. CONCLUSIONS: Our findings underscore a novel mechanism of Caspase 6 mediated RIPK1-IκBα interaction in regulating macrophage NEK7/NLRP3 function and hepatocytes ferroptosis, which provides therapeutic targets for clinical liver IR injury. Video Abstract.

Single-cell analysis reveals the immune heterogeneity and interactions in lungs undergoing hepatic ischemia-reperfusion.

Hepatic ischemia-reperfusion IR (HIR) is an unavoidable pathophysiological process during liver transplantation, resulting in systematic sterile inflammation and remote organ injury. Acute lung injury (ALI) is a serious complication after liver transplantation with high postoperative morbidity and mortality. However, the underlying mechanism is still unclear. To assess the phenotype and plasticity of various cell types in the lung tissue microenvironment after HIR at the single-cell level, single-cell RNA sequencing (scRNA-seq) was performed using the lungs from HIR-induced mice. In our results, we identified 23 cell types in the lungs after HIR and found that this highly complex ecosystem was formed by subpopulations of bone marrow-derived cells that signaled each other and mediated inflammatory responses in different states and different intervals. We described the unique transcriptional profiles of lung cell clusters and discovered two novel cell subtypes (Tspo+Endothelial cells and Vcan+ monocytes), as well as the endothelial cell-immune cell and immune cell-T cell clusters interactome. In addition, we found that S100 calcium binding protein (S100a8/a9), specifically and highly expressed in immune cell clusters of lung tissues and exhibited detrimental effects. Finally, the cellular landscape of the lung tissues after HIR was established, highlighting the heterogeneity and cellular interactions between major immune cells in HIR-induced lungs. Our findings provided new insights into the mechanisms of HIR-induced ALI and offered potential therapeutic target to prevent ALI after liver transplantation.

Impact of patent foramen ovale on short-term outcomes in children with biliary atresia undergoing living donor liver transplantation: a retrospective cohort study.

OBJECTIVE: To investigate the impact of patent foramen ovale (PFO) on the short-term outcomes of living donor liver transplantation (LDLT) in children with biliary atresia. METHODS: With the approval of the hospital ethics committee, 304 children with biliary atresia who underwent LDLT in our center from January 2020 to December 2021 were enrolled. According to the results of echocardiography before the operation, the subjects were divided into the PFO group (n = 73) and the NoPFO group (n = 231). The baseline characteristics; intraoperative recipient-related data and donor-related data; incidence of postreperfusion syndrome (PRS); postoperative mechanical ventilation time; ICU stay duration; postoperative hospital stay duration; liver function index; incidences of postoperative complications including acute renal injury (AKI), graft dysfunction, hepatic artery thrombosis (HAT) and portal vein thrombosis (PVT); and one-year survival rate were compared between the two groups. RESULTS: The median age in the PFO group was 6 months and that in the NoPFO group was 9 months (P < 0.001), and the median height (65 cm) and weight (6.5 kg) in the PFO group were significantly lower than those in the NoPFO group (68 cm, 8.0 kg) (P < 0.001). The preoperative total bilirubin level (247 vs. 202 umol/L, P = 0.007) and pediatric end-stage liver disease (PELD) score (21 vs. 16, P = 0.001) in the PFO group were higher than those in the NoPFO group. There were no significant differences in the intraoperative PRS incidence (46.6% vs. 42.4%, P = 0.533 ), postoperative mechanical ventilation time (184 vs. 220 min, P = 0.533), ICU stay duration (3.0 vs. 2.5 d, P = 0.267), postoperative hospital stay duration (22 vs. 21 d, P = 0.138), AKI incidence (19.2% vs. 24.7%, P = 0.333), graft dysfunction incidence (11.0% vs. 12.6%, P = 0.716), HAT incidence (5.5% vs. 4.8%, P = 0.762), PVT incidence (2.7% vs. 2.2%, P = 0.675) or one-year survival rate (94.5% vs. 95.7%, P = 0.929) between the two groups. CONCLUSION: The presence of PFO has no negative impact on short-term outcomes in children with biliary atresia after LDLT.

Risk factors for postreperfusion syndrome during living donor liver transplantation in paediatric patients with biliary atresia: a retrospective analysis.

BACKGROUND: Living donor liver transplantation (LT) is the main treatment for paediatric biliary atresia (BA) in Asia. During LT, a series of haemodynamic changes often occur during LT reperfusion, which is called postreperfusion syndrome (PRS), and PRS is related to a prolonged postoperative hospital stay, delayed recovery of graft function and increased mortality. To reduce adverse reactions after paediatric living donor LT (LDLT), our study's objectives were to ascertain the incidence of PRS and analyse possible risk factors for PRS. METHODS: With the approval of the Ethics Committee of our hospital, the clinical data of 304 paediatric patients who underwent LDLT from January 2020 to December 2021 were analysed retrospectively. According to the presence or absence of PRS, the paediatric patients were divided into the non-PRS group and the PRS group. Independent risk factors of PRS were analysed using logistic regression analysis. RESULTS: PRS occurred in 132 recipients (43.4%). The peak values of AST (816 (507-1625) vs 678 (449-1107), p=0.016) and ALT (675 (415-1402) vs 545 (389-885), p=0.015) during the first 5 days after LDLT in paediatric patients with PRS were significantly higher than those in the non-PRS group. Meanwhile, the paediatric patients in the PRS group had longer intensive care unit stays and hospital stays, as well as lower 1-year survival rates. Graft cold ischaemic time (CIT) ≥90 min (OR (95% CI)=5.205 (3.094 to 8.754)) and a temperature <36°C immediately before reperfusion (OR (95% CI)=2.973 (1.669 to 5.295)) are independent risk factors for PRS. CONCLUSIONS: The occurrence of hypothermia (<36.0℃) in children immediately before reperfusion and graft CIT≥90 min are independent risk factors for PRS. PRS was closely related to the postoperative adverse outcomes of paediatric patients.

Circulating Exosomes Mediate Neurodegeneration Following Hepatic Ischemia-reperfusion Through Inducing Microglial Pyroptosis in the Developing Hippocampus.

BACKGROUND: Poor neurodevelopmental outcomes after pediatric liver transplantation seriously affect the long-term quality of life of recipients, in whom hepatic ischemia reperfusion (HIR) is considered to play a pivotal role. However, the link between HIR and brain injury remains unclear. Because circulating exosomes are considered as the key mediators of information transmission over long distances, we aimed to assess the role of circulating exosomes in HIR-induced hippocampal injury in young rats. METHODS: We administered exosomes extracted from the sera of HIR model rats to normal young rats via the tail vein. Western blotting, enzyme-linked immunosorbent assay, histological examination, and real-time quantitative polymerase chain reaction were used to evaluate the role of exosomes in neuronal injury and activation of microglial pyroptosis in the developing hippocampus. Primary microglial cells were cocultured with exosomes to further assess the effect of exosomes on microglia. To further explore the potential mechanism, GW4869 or MCC950 was used to block exosome biogenesis or nod-like receptor family protein 3, respectively. RESULTS: Serum-derived exosomes played a crucial role in linking HIR with neuronal degeneration in the developing hippocampus. Microglia were found to be the target cells of ischemia-reperfusion derived exosomes (I/R-exosomes). I/R-exosomes were taken up by microglia and promoted the occurrence of microglial pyroptosis in vivo and in vitro. Moreover, the exosome-induced neuronal injury was alleviated by suppressing the occurrence of pyroptosis in the developing hippocampus. CONCLUSIONS: Microglial pyroptosis induced by circulating exosomes plays a vital role in developing hippocampal neuron injury during HIR in young rats.

The protective effect of lncRNA NEAT1/miR-122-5p/Wnt1 axis on hippocampal damage in hepatic ischemic reperfusion young mice.

Hepatic ischemic reperfusion (HIR) is a common pathophysiological process in many surgical procedures such as liver transplantation (LT) and hepatectomy. And it is also an important factor leading to perioperative distant organ damage. Children undergoing major liver surgery are more susceptible to various pathophysiological processes, including HIR, since their brains are still developing and the physiological functions are still incomplete, which can lead to brain damage and postoperative cognitive impairment, thus seriously affecting the long-term prognosis of the children. However, the present treatments of mitigating HIR-induced hippocampal damage are not proven to be effective. The important role of microRNAs (miRNAs) in the pathophysiological processes of many diseases and in the normal development of the body has been confirmed in several studies. The current study explored the role of miR-122-5p in HIR-induced hippocampal damage progression. HIR-induced hippocampal damage mouse model was induced by clamping the left and middle lobe vessels of the liver of young mice for 1 h, removing the vessel clamps and re-perfusing them for 6 h. The changes in the level of miR-122-5p in the hippocampal tissues were measured, and its influences on the activity as well as apoptotic rate of neuronal cells were investigated. Short interfering RNA modified with 2'-O-methoxy substitution targeting long-stranded non-coding RNA (lncRNA) nuclear enriched transcript 1 (NEAT1) as well as miR-122-5p antagomir were used to further clarify the role played by the corresponding molecules in hippocampal injury in young mice with HIR. The result obtained in our study was that the expression of miR-122-5p in the hippocampal tissue of young mice receiving HIR is reduced. Upregulated expression of miR-122-5p reduces the viability of neuronal cells and promotes the development of apoptosis, thereby aggravating the damage of hippocampal tissue in HIR young mice. Additionally, in the hippocampal tissue of young mice receiving HIR, lncRNA NEAT1 exerts some anti-apoptotic effects by binding to miR-122-5p, promoting the expression of Wnt1 pathway. An essential observation of this study was the binding of lncRNA NEAT1 to miR-122-5p, which upregulates Wnt1 and inhibits HIR-induced hippocampal damage in young mice.

Association between serum HMGB1 elevation and early pediatric acute respiratory distress syndrome: a retrospective study of pediatric living donor liver transplant recipients with biliary atresia in China.

BACKGROUND: High mobility group box 1 (HMGB1) protein is one of the main risk factors for pediatric acute respiratory distress syndrome (PARDS) after living donor liver transplantation (LDLT). However, studies of the relationship between HMGB1 and PARDS are lacking. We evaluated the link between anomalies of intraoperative serum HMGB1 and PARDS in pediatric LDLT recipients with biliary atresia during the first week after transplant. METHODS: Data for 210 pediatric patients with biliary atresia who underwent LDLT between January 2018 and December 2021 were reviewed retrospectively. The main measure was serum HMGB1 levels 30 min after reperfusion, while the outcome was early PARDS after LDLT. Data including pretransplant conditions, laboratory indexes, variables of intraoperation, clinical complications, and outcomes after LDLT were analyzed for each patient. Univariate analysis of PARDS and multivariate logistic regression analyses of serum HMGB1 levels at 30 min in the neohepatic phase in the presence of PARDS were conducted to examine the potential associations. Subgroup interaction analyses and linear relationships between intraoperative serum HMGB1 levels and PARDS were also performed. RESULTS: Among the participants, 55 had PARDS during 7 days after LDLT, including four in the first HMGB1 tertile (4.3-8.1 pg/mL), 18 in the second tertile (8.2-10.6 pg/mL), and 33 in the third tertile (10.6-18.8 pg/mL). The nonadjusted association between intraoperative HMGB1 levels and PARDS was positive (odds ratio 1.41, 95% confidence intervals 1.24-1.61, P < 0.0001). The association remained unchanged after adjustment for age, weight, pretransplant total bilirubin, albumin, graft cold ischemia time, and intraoperative blood loss volume (odds ratio 1.28, 95% confidence interval 1.10-1.49, P = 0.0017). After controlling for potential confounders, the association between intraoperative HMGB1 levels and PARDS remained positive, as well as in the subgroup analyses. CONCLUSIONS: Serum HMGB1 levels at 30 min after reperfusion were positively associated with early PARDS among pediatric patients with biliary atresia who had undergone LDLT. Identifying such patients early may increase the efficacy of perioperative respiratory management.

Caspase 6/NR4A1/SOX9 signaling axis regulates hepatic inflammation and pyroptosis in ischemia-stressed fatty liver.

The mechanism of nonalcoholic fatty liver susceptibility to ischemia/reperfusion (IR) injury has not been fully clarified. Caspase 6 is a critical regulator in innate immunity and host defense. We aimed to characterize the specific role of Caspase 6 in IR-induced inflammatory responses in fatty livers. Human fatty liver samples were harvested from patients undergoing ischemia-related hepatectomy to evaluate Caspase 6 expression. in mice model, we generated Caspase 6-knockout (Caspase 6KO) mice to investigate cellular and molecular mechanisms of macrophage Caspase 6 in IR-stimulated fatty livers. In human liver biopsies, Caspase 6 expression was upregulated combined with enhanced serum ALT level and severe histopathological injury in ischemic fatty livers. Moreover, Caspase 6 was mainly accumulated in macrophages but not hepatocytes. Unlike in controls, the Caspase 6-deficiency attenuated liver damage and inflammation activation. Activation of macrophage NR4A1 or SOX9 in Caspase 6-deficient livers aggravated liver inflammation. Mechanistically, macrophage NR4A1 co-localized with SOX9 in the nuclear under inflammatory conditions. Specifically, SOX9 acts as a coactivator of NR4A1 to directly target S100A9 transcription. Furthermore, macrophage S100A9 ablation dampened NEK7/NLRP3-driven inflammatory response and pyroptosis in macrophages. In conclusion, our findings identify a novel role of Caspase 6 in regulating NR4A1/SOX9 interaction in response to IR-stimulated fatty liver inflammation, and provide potential therapeutic targets for the prevention of fatty liver IR injury.

Protective effects of cordycepin pretreatment against liver ischemia/reperfusion injury in mice.

INTRODUCTION: Cordycepin has been reported to exhibit hepatic protective and anti-inflammatory properties. Here, we investigated the role of cordycepin in ischemia/reperfusion (IR)-induced liver injury in a mouse model. METHODS: Mice were pretreated with cordycepin by gavage for 3 weeks, followed by the establishment of the IR modeling. Liver injury, Suzuki's histological grading, hepatic apoptosis, and inflammatory responses were evaluated by biochemical and pathological analysis. RESULTS: It was found that Cordycepin pretreatment at 50 mg/kg for 3 weeks attenuated IR-induced liver injury, as reflected by the significant decrease of the levels of aspartate aminotransferase, alanine transaminase, lactate dehydrogenase, and low-density lipoprotein. Cordycepin pretreatment also reduced histopathological changes, attenuated hepatocyte apoptosis, inflammatory responses in the livers of IR mice. Mechanically, toll-like receptor 4/nuclear factor kappa-B signaling in liver tissues was inhibited by Cordycepin pretreatment. CONCLUSIONS: In conclusion, Cordycepin pretreatment protects IR-induced liver injury, which demonstrates its potential for the treatment of IR in the liver.

Novel role of macrophage TXNIP-mediated CYLD-NRF2-OASL1 axis in stress-induced liver inflammation and cell death.

Background & Aims: The stimulator of interferon genes (STING)/TANK-binding kinase 1 (TBK1) pathway is vital in mediating innate immune and inflammatory responses during oxidative/endoplasmic reticulum (ER) stress. However, it remains unknown whether macrophage thioredoxin-interacting protein (TXNIP) may regulate TBK1 function and cell death pathways during oxidative/ER stress. Methods: A mouse model of hepatic ischaemia/reperfusion injury (IRI), the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific TXNIP knockout (TXNIPM-KO) and TXNIP-proficient (TXNIPFL/FL) mice. Results: The TXNIPM-KO mice were resistant to ischaemia/reperfusion (IR) stress-induced liver damage with reduced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the TXNIPFL/FL controls. IR stress increased TXNIP, p-STING, and p-TBK1 expression in ischaemic livers. However, TXNIPM-KO inhibited STING, TBK1, interferon regulatory factor 3 (IRF3), and NF-κB activation with interferon-ß (IFN-ß) expression. Interestingly, TXNIPM-KO augmented nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity, increased antioxidant gene expression, and reduced macrophage reactive oxygen species (ROS) production and hepatic apoptosis/necroptosis in IR-stressed livers. Mechanistically, macrophage TXNIP deficiency promoted cylindromatosis (CYLD), which colocalised and interacted with NADPH oxidase 4 (NOX4) to enhance NRF2 activity by deubiquitinating NOX4. Disruption of macrophage NRF2 or its target gene 2',5' oligoadenylate synthetase-like 1 (OASL1) enhanced Ras GTPase-activating protein-binding protein 1 (G3BP1) and TBK1-mediated inflammatory response. Notably, macrophage OASL1 deficiency induced hepatocyte apoptotic peptidase activating factor 1 (APAF1), cytochrome c, and caspase-9 activation, leading to increased caspase-3-initiated apoptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated necroptosis. Conclusions: Macrophage TXNIP deficiency enhances CYLD activity and activates the NRF2-OASL1 signalling, controlling IR stress-induced liver injury. The target gene OASL1 regulated by NRF2 is crucial for modulating STING-mediated TBK1 activation and Apaf1/cytochrome c/caspase-9-triggered apoptotic/necroptotic cell death pathway. Our findings underscore a novel role of macrophage TXNIP-mediated CYLD-NRF2-OASL1 axis in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases. Lay summary: Liver inflammation and injury induced by ischaemia and reperfusion (the absence of blood flow to the liver tissue followed by the resupply of blood) is a significant cause of hepatic dysfunction and failure following liver transplantation, resection, and haemorrhagic shock. Herein, we uncover an underlying mechanism that contributes to liver inflammation and cell death in this setting and could be a therapeutic target in stress-induced liver inflammatory injury.

Corrigendum to "Dexmedetomidine Ameliorates Hippocampus Injury and Cognitive Dysfunction Induced by Hepatic Ischemia/Reperfusion by Activating SIRT3-Mediated Mitophagy and Inhibiting Activation of the NLRP3 Inflammasome in Young Rats".

[This corrects the article DOI: 10.1155/2020/7385458.].

Comparison of clinical efficacy and safety between dexmedetomidine and propofol among patients undergoing gastrointestinal endoscopy: a meta-analysis.

OBJECTIVE: To compare the clinical efficacy and safety of dexmedetomidine and propofol in patients who underwent gastrointestinal endoscopy. METHODS: Relevant studies comparing dexmedetomidine and propofol among patients who underwent gastrointestinal endoscopy were retrieved from databases such as PubMed, Embase, and Cochrane Library. RESULTS: Seven relevant studies (dexmedetomidine group, n = 238; propofol group, n = 239) met the inclusion criteria. There were no significant differences in the induction time (weighted mean difference [WMD] = 3.46, 95% confidence interval [CI] = -0.95-7.88, I2 = 99%) and recovery time (WMD = 2.74, 95% CI = -2.72-8.19, I2 = 98%). Subgroup analysis revealed no significant differences in the risks of hypotension (risk ratio [RR] = 0.56, 95% CI = 0.25-1.22) and nausea and vomiting (RR = 1.00, 95% CI = 0.46-2.22) between the drugs, whereas dexmedetomidine carried a lower risk of hypoxia (RR = 0.26, 95% CI = 0.11-0.63) and higher risk of bradycardia (RR = 3.01, 95% CI = 1.38-6.54). CONCLUSIONS: Dexmedetomidine had similar efficacy and safety profiles as propofol in patients undergoing gastrointestinal endoscopy.

CD47-Mediated Hedgehog/SMO/GLI1 Signaling Promotes Mesenchymal Stem Cell Immunomodulation in Mouse Liver Inflammation.

BACKGROUND AND AIMS: The cluster of differentiation 47 (CD47)-signal regulatory protein alpha (SIRPα) signaling pathway plays important roles in immune homeostasis and tissue inflammatory response. Activation of the Hedgehog/smoothened (SMO)/GLI family zinc finger 1 (Gli1) pathway regulates cell growth, differentiation, and immune function. However, it remains unknown whether and how the CD47-SIRPα interaction may regulate Hedgehog/SMO/Gli1 signaling in mesenchymal stem cell (MSC)-mediated immune regulation during sterile inflammatory liver injury. APPROACH AND RESULTS: In a mouse model of ischemia/reperfusion (IR)-induced sterile inflammatory liver injury, we found that adoptive transfer of MSCs increased CD47 expression and ameliorated liver IR injury. However, deletion of CD47 in MSCs exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators. MSC treatment augmented SIRPα, Hedgehog/SMO/Gli1, and Notch1 intracellular domain (NICD), whereas CD47-deficient MSC treatment reduced these gene expressions in IR-stressed livers. Moreover, disruption of myeloid SMO or Notch1 increased IR-triggered liver inflammation with diminished Gli1 and NICD, but enhanced NIMA related kinase 7 (NEK7) and NLR family pyrin domain containing 3 (NLRP3) activation in MSC-transferred mice. Using a MSC/macrophage co-culture system, we found that MSC CD47 and macrophage SIRPα expression were increased after LPS stimulation. The CD47-SIRPα interaction increased macrophage Gli1 and NICD nuclear translocation, whereby NICD interacted with Gli1 and regulated its target gene Dvl2 (dishevelled segment polarity protein 2), which in turn inhibited NEK7/NLRP3 activity. CONCLUSIONS: The CD47-SIRPα signaling activates the Hedgehog/SMO/Gli1 pathway, which controls NEK7/NLRP3 activity through a direct interaction between Gli1 and NICD. NICD is a coactivator of Gli1, and the target gene Dvl2 regulated by the NICD-Gli1 complex is crucial for the modulation of NLRP3-driven inflammatory response in MSC-mediated immune regulation. Our findings provide potential therapeutic targets in MSC-mediated immunotherapy of sterile inflammatory liver injury.

Functional crosstalk between myeloid Foxo1-ß-catenin axis and Hedgehog/Gli1 signaling in oxidative stress response.

Foxo1 transcription factor is an evolutionarily conserved regulator of cell metabolism, oxidative stress, inflammation, and apoptosis. Activation of Hedgehog/Gli signaling is known to regulate cell growth, differentiation, and immune function. However, the molecular mechanisms by which interactive cell signaling networks restrain oxidative stress response and necroptosis are still poorly understood. Here, we report that myeloid-specific Foxo1 knockout (Foxo1M-KO) mice were resistant to oxidative stress-induced hepatocellular damage with reduced macrophage/neutrophil infiltration, and proinflammatory mediators in liver ischemia/reperfusion injury (IRI). Foxo1M-KO enhanced ß-catenin-mediated Gli1/Snail activity, and reduced receptor-interacting protein kinase 3 (RIPK3) and NIMA-related kinase 7 (NEK7)/NLRP3 expression in IR-stressed livers. Disruption of Gli1 in Foxo1M-KO livers deteriorated liver function, diminished Snail, and augmented RIPK3 and NEK7/NLRP3. Mechanistically, macrophage Foxo1 and ß-catenin colocalized in the nucleus, whereby the Foxo1 competed with T-cell factor (TCF) for interaction with ß-catenin under inflammatory conditions. Disruption of the Foxo1-ß-catenin axis by Foxo1 deletion enhanced ß-catenin/TCF binding, activated Gli1/Snail signaling, leading to inhibited RIPK3 and NEK7/NLRP3. Furthermore, macrophage Gli1 or Snail knockout activated RIPK3 and increased hepatocyte necroptosis, while macrophage RIPK3 ablation diminished NEK7/NLRP3-driven inflammatory response. Our findings underscore a novel molecular mechanism of the myeloid Foxo1-ß-catenin axis in regulating Hedgehog/Gli1 function that is key in oxidative stress-induced liver inflammation and necroptosis.

Dexmedetomidine Ameliorates Hippocampus Injury and Cognitive Dysfunction Induced by Hepatic Ischemia/Reperfusion by Activating SIRT3-Mediated Mitophagy and Inhibiting Activation of the NLRP3 Inflammasome in Young Rats.

Hepatic ischemia-reperfusion (HIR) has been proven to trigger oxidative stress and pyroptosis in the hippocampus. Sirtuin 3 (SIRT3) is an essential mitochondrial protein deacetylase regulating oxidative stress and mitophagy. Dexmedetomidine (Dex) has been demonstrated to confer neuroprotection in different brain injury models. However, whether the protective effects of Dex following HIR are orchestrated by activation of SIRT3-mediated mitophagy and inhibition of NOD-like receptor protein 3 (NLRP3) inflammasome activation remains unknown. Herein, two-week-old rats were treated with Dex or a selective SIRT3 inhibitor (3-TYP)/autophagy inhibitor (3-MA) and then subjected to HIR. The results revealed that Dex treatment effectively attenuated neuroinflammation and cognitive deficits via upregulating SIRT3 expression and activity. Furthermore, Dex treatment inhibited the activation of NLRP3 inflammasome, while 3-TYP and 3-MA eliminated the protective effects of Dex, suggesting that SIRT3-mediated mitophagy executes the protective effects of Dex. Moreover, 3-TYP treatment downregulated the expression level of SIRT3 downstream proteins: forkhead-box-protein 3α (FOXO3α), superoxide dismutase 2 (SOD2), peroxiredoxin 3 (PRDX3), and cyclophilin D (CYP-D), which were barely influenced by 3-MA treatment. Notably, both 3-TYP and 3-MA were able to offset the antioxidative and antiapoptosis effects of Dex, indicating that SIRT3-mediated mitophagy may be the last step and the major pathway executing the neuroprotective effects of Dex. In conclusion, Dex inhibits HIR-induced NLRP3 inflammasome activation mainly by triggering SIRT3-mediated mitophagy.