Platelet Proteomics and Tissue Metabolomics Investigation for the Mechanism of Aspirin Eugenol Ester on Preventive Thrombosis Mechanism in a Rat Thrombosis Model.

Platelet activation is closely related to thrombosis. Aspirin eugenol ester (AEE) is a novel medicinal compound synthesized by esterifying aspirin with eugenol using the pro-drug principle. Pharmacological and pharmacodynamic experiments showed that AEE has excellent anti-inflammatory, antioxidant, and inhibitory platelet activation effects, preventing thrombosis. However, the regulatory network and action target of AEE in inhibiting platelet activation remain unknown. This study aimed to investigate the effects of AEE on platelets of thrombosed rats to reveal its regulatory mechanism via a multi-omics approach. The platelet proteomic results showed that 348 DEPs were identified in the AEE group compared with the model group, of which 87 were up- and 261 down-regulated. The pathways in this result were different from previous results, including mTOR signaling and ADP signaling at P2Y purinoceptor 12. The metabolomics of heart and abdominal aortic tissue results showed that the differential metabolites were mainly involved in steroid biosynthesis, the citric acid cycle, phenylalanine metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis, and glutathione metabolism. Molecular docking results showed that AEE had a better binding force to both the COX-1 and P2Y12 protein. AEE could effectively inhibit platelet activation by inhibiting COX-1 protein and P2Y12 protein activity, thereby inhibiting platelet aggregation. Therefore, AEE can have a positive effect on inhibiting platelet activation.

Isobavachalcone enhances sensitivity of colistin-resistant Klebsiella pneumoniae: In vitro and in vivo proof-of-concept studies.

OBJECTIVE: Antibiotic resistance poses a considerable worldwide concern, particularly in clinical environments where drug-resistant Gram-negative bacteria like Klebsiella pneumoniae (K. pneumoniae) present a major challenge. The objective of this research was to investigate the mechanisms by which isobavachalcone (IBC) restores the sensitivity of K. pneumoniae to colistin in vitro and to validate the synergistic therapeutic effect in vivo. RESULTS: The results indicate that the combined administration of colistin and IBC exhibits a potent antibacterial effect both in vitro and in vivo. The in vitro concurrent administration of colistin and IBC resulted in increased membrane permeability, compromised cell integrity, diminished membrane fluidity, and disrupted membrane homeostasis. Additionally, this combination reduced biofilm production, inhibited the synthesis of the autoinducer factor, altered membrane potential, and affected levels of reactive oxygen species and adenosine triphosphate synthesis, ultimately leading to bacterial death. In vivo experiments on Galleria mellonella and mice demonstrated that the co-administration of colistin and IBC increased the survival rate and significantly reduced pathological damage compared to colistin alone. CONCLUSION: These results suggested that IBC effectively restores the sensitivity of colistin by inducing physical disruption of bacterial membranes and oxidative stress. The combination therapy of colistin and IBC presents a viable and safe strategy to combat drug-resistant K. pneumoniae-associated infections.

Coulomb focusing in attosecond angular streaking.

Angular streaking technique employs a close-to-circularly polarized laser pulse to build a mapping between the instant of maximum ionization and the most probable emission angle in the photoelectron momentum distribution, thereby enabling the probe of laser-induced electron dynamics in atoms and molecules with attosecond temporal resolution. Here, through the jointed experimental observations and improved Coulomb-corrected strong-field approximation statistical simulations, we identify that electrons emitted at different initial ionization times converge to the most probable emission angle due to the previously-unexpected Coulomb focusing triggered by the nonadiabatic laser-induced electron tunneling. We reveal that the Coulomb focusing induces the observed nonintuitive energy-dependent trend in the angular streaking measurements on the nonadiabatic tunneling, and that tunneling dynamics under the classically forbidden barrier can leave fingerprints on the resulting signals. Our findings have significant implications for the decoding of the intricate tunneling dynamics with attosecond angular streaking.

Sub-cycle strong-field tunneling dynamics in solids.

Tunneling ionization is a crucial process in the interaction between strong laser fields and matter which initiates numerous nonlinear phenomena including high-order harmonic generation, photoelectron holography, etc. Both adiabatic and nonadiabatic tunneling ionization are well understood in atomic systems. However, the tunneling dynamics in solids, especially nonadiabatic tunneling, has not yet been fully understood. Here, we study the sub-cycle resolved strong-field tunneling dynamics in solids via a complex saddle-point method. We compare the instantaneous momentum at the moment of tunneling and the tunneling distances over a range of Keldysh parameters. Our results demonstrate that for nonadiabatic tunneling, tunneling ionization away from Γ point is possible. When this happens the electron has a nonzero initial velocity when it emerges in the conduction band. Moreover, consistent with atomic tunneling, a reduced tunneling distance as compared to the quasi-static case is found. Our results provide remarkable insight into the basic physics governing the sub-cycle electron tunneling dynamics with significant implications for understanding subsequent strong-field nonlinear phenomena in solids.

Fingolimod synergizes and reverses K. pneumoniae resistance to colistin.

Klebsiella pneumoniae (K. pneumoniae) infection and the rapid spread of multi-drug resistant (MDR) bacteria pose a serious threat to global healthcare. Polymyxin E (colistin), a group of cationic antimicrobial polypeptides, is currently one of the last resort treatment options against carbapenem-resistant Gram-negative pathogens. The effectiveness of colistin has been compromised due to its intensive use. This study found that fingolimod (FLD), a natural product derivative, exhibited a significant synergistic bactericidal effect on K. pneumoniae when combined with colistin, both in vitro and in vivo. The checkerboard method was employed to assess the in vitro synergistic effect of FLD with colistin. FLD enhanced the susceptibility of bacteria to colistin and lowered effectively minimum inhibitory concentrations (MIC) when compared to colistin MIC, and the fractional inhibitory concentrations (FIC) value was less than 0.3. The time-kill curve demonstrated that the combination treatment of FLD and colistin had significant bactericidal efficacy. The in vitro concurrent administration of colistin and FLD resulted in heightening membrane permeability, compromising cell integrity, diminishing membrane fluidity, and perturbing membrane homeostasis. They also induced alterations in membrane potential, levels of reactive oxygen species, and adenosine triphosphate synthesis, ultimately culminating in bacterial death. Moreover, the combination of FLD with colistin significantly influenced fatty acid metabolism. In the mouse infection model, the survival rate of mice injected with K. pneumoniae was significantly improved to 67% and pathological damage was significantly relieved with combination treatment of FLD and colistin when compared with colistin treatment. This study highlights the potential of FLD in combining with colistin for treating infections caused by MDR isolates of K. pneumoniae.

A combined transcriptomics and proteomics approach to reveal the mechanism of AEE relieving hyperlipidemia in ApoE-/- mice.

Hyperlipidemia caused by abnormal lipid metabolism has reached epidemic proportions. This phenomenon is also common in companion animals. Previous studies showed that AEE significantly improves abnormal blood lipids in hyperlipidemia rats and mice, but its mechanism is still not clear enough. In this study, the mechanism and potential key pathways of AEE on improving hyperlipidemia in mice were investigated through the transcriptome and proteome study of ApoE-/- mice liver and the verification study on high-fat HepG2 cells. The results showed that AEE significantly decreased the serum TC and LDL-C levels of hyperlipidemia ApoE-/- mice, and significantly increased the enzyme activity of CYP7A1. After AEE intervention, the results of mice liver transcriptome and proteome showed that differential genes and proteins were enriched in lipid metabolism-related pathways. The results of RT-qPCR showed that AEE significantly regulated the expression of genes related to lipid metabolism in mice liver tissue. AEE significantly upregulated the protein expression of CYP7A1 in hyperlipidemia ApoE-/- mice liver tissue. The results in vitro showed that AEE significantly decreased the levels of TC and TG, and improved lipid deposition in high-fat HepG2 cells. AEE significantly increased the expression of CYP7A1 protein in high-fat HepG2 cells. AEE regulates the expression of genes related to lipid metabolism in high-fat HepG2 cells, mainly by FXR-SHP-CYP7A1 and FGF19-TFEB-CYP7A1 pathways. To sum up, AEE can significantly improve the hyperlipidemia status of ApoE-/- mice and the lipid deposition of high-fat HepG2 cells, and its main pathway is probably the bile acid metabolism-related pathway centered on CYP7A1.

NAA10 gene related Ogden syndrome with obstructive hypertrophic cardiomyopathy: A rare case report.

RATIONALE: Ogden syndrome is an exceptionally rare X-linked disease caused by mutations in the NAA10 gene. Reported cases of this syndrome are approximately 20 children and are associated with facial dysmorphism, growth delay, developmental disorders, congenital heart disease, and arrhythmia. PATIENT CONCERNS: We present the clinical profile of a 3-year-old girl with Ogden syndrome carrying a de novo NAA10 variant [NM_003491:c.247C>T, p.(Arg83Cys)]. During infancy, she exhibited features such as left ventricular hypertrophy, protruding eyeballs, and facial deformities. DIAGNOSIS: Clinical diagnosis included Ogden syndrome, congenital heart disease (obstructive hypertrophic cardiomyopathy, left ventricular outflow tract obstruction, mitral valve disease, tricuspid valve regurgitation), tonsillar and adenoidal hypertrophy, and speech and language delay. INTERVENTIONS: The girl was considered to have hypertrophic cardiomyopathy (HCM) and received oral metoprolol as a treatment for HCM at our hospital. The drug treatment effect was not ideal, and her hypertrophy myocardial symptoms were aggravated and she had to be hospitalized for surgery. OUTCOMES: The girl underwent a modified Morrow procedure under cardiopulmonary bypass and experienced a favorable postoperative recovery. No pulmonary infections or significant complications were observed during this period. The patient's family expressed satisfaction with the treatment process. LESSONS: The case emphasizes the HCM of Odgen syndrome, and early surgery should be performed if drug treatment is ineffective.

MicroRNA in the Exosomes Mediated by Resveratrol to Activate Neuronal Cells.

Resveratrol (RSV), a polyphenol, is known to have a wide range of pharmacological properties in vitro. RSV may have therapeutic value for various neurodegenerative diseases via neuroprotective effects. However, it is not yet clear whether RSV can induce intestinal-brain interactions. It is assumed that the intestinal cells may secrete some factors after being stimulated by other substances. These secreted factors may activate nerve cells through gut-brain interaction, such as exosomes. In this study, it was discovered that Caco-2 cells treated with RSV secrete exosomes to activate SH-SY5Y neuronal cells. The results showed that secreted factors from RSV-treated Caco-2 cells activated SH-SY5Y. The exosomes of RSV-treated Caco-2 cells activated SH-SY5Y cells, which was manifested in the lengthening of the nerve filaments of SH-SY5Y cells. The exosomes were characterized using transmission electron microscopy and sequenced using the Illumina NovaSeq 6000 sequencer. The results showed that the miRNA expression profile of exosomes after RSV treatment changed, and twenty-six kinds of miRNAs were identified which expressed differentially between the control group and the RSV-treated group. Among them, three miRNAs were selected as candidate genes for inducing SH-SY5Y neural cell activation. Three miRNA mimics could activate SH-SY5Y neurons. These results suggested that the miRNA in intestinal exocrine cells treated with RSV may play an important role in the activation of SH-SY5Y neurons.

Fingolimod Inhibits Exopolysaccharide Production and Regulates Relevant Genes to Eliminate the Biofilm of K. pneumoniae.

Klebsiella pneumoniae (K. pneumoniae) exhibits the ability to form biofilms as a means of adapting to its adverse surroundings. K. pneumoniae in this biofilm state demonstrates remarkable resistance, evades immune system attacks, and poses challenges for complete eradication, thereby complicating clinical anti-infection efforts. Moreover, the precise mechanisms governing biofilm formation and disruption remain elusive. Recent studies have discovered that fingolimod (FLD) exhibits biofilm properties against Gram-positive bacteria. Therefore, the antibiofilm properties of FLD were evaluated against multidrug-resistant (MDR) K. pneumoniae in this study. The antibiofilm activity of FLD against K. pneumoniae was assessed utilizing the Alamar Blue assay along with confocal laser scanning microscopy (CLSM), scanning electron microscopy (SEM), and crystal violet (CV) staining. The results showed that FLD effectively reduced biofilm formation, exopolysaccharide (EPS), motility, and bacterial abundance within K. pneumoniae biofilms without impeding its growth and metabolic activity. Furthermore, the inhibitory impact of FLD on the production of autoinducer-2 (AI-2) signaling molecules was identified, thereby demonstrating its notable anti-quorum sensing (QS) properties. The results of qRT-PCR analysis demonstrated that FLD significantly decreased the expression of genes associated with the efflux pump gene (AcrB, kexD, ketM, kdeA, and kpnE), outer membrane (OM) porin proteins (OmpK35, OmpK36), the quorum-sensing (QS) system (luxS), lipopolysaccharide (LPS) production (wzm), and EPS production (pgaA). Simultaneously, FLD exhibited evident antibacterial synergism, leading to an increased survival rate of G. mellonella infected with MDR K. pneumoniae. These findings suggested that FLD has substantial antibiofilm properties and synergistic antibacterial potential for colistin in treating K. pneumoniae infections.

Multi-Omics Approaches for Liver Reveal the Thromboprophylaxis Mechanism of Aspirin Eugenol Ester in Rat Thrombosis Model.

Aspirin eugenol ester (AEE) is a novel medicinal compound synthesized by esterifying aspirin with eugenol using the pro-drug principle. Pharmacological and pharmacodynamic experiments showed that AEE had excellent thromboprophylaxis and inhibition of platelet aggregation. This study aimed to investigate the effect of AEE on the liver of thrombosed rats to reveal its mechanism of thromboprophylaxis. Therefore, a multi-omics approach was used to analyze the liver. Transcriptome results showed 132 differentially expressed genes (DEGs) in the AEE group compared to the model group. Proteome results showed that 159 differentially expressed proteins (DEPs) were identified in the AEE group compared to the model group. Six proteins including fibrinogen alpha chain (Fga), fibrinogen gamma chain (Fgg), fibrinogen beta chain (Fgb), orosomucoid 1 (Orm1), hemopexin (Hpx), and kininogen-2 (Kng2) were selected for parallel reaction monitoring (PRM) analysis. The results showed that the expression of all six proteins was upregulated in the model group compared with the control group. In turn, AEE reversed the upregulation trend of these proteins to some degree. Metabolome results showed that 17 metabolites were upregulated and 38 were downregulated in the model group compared to the control group. AEE could reverse the expression of these metabolites to some degree and make them back to normal levels. The metabolites were mainly involved in metabolic pathways, including linoleic acid metabolism, arachidonic acid metabolism, and the tricarboxylic acid (TCA) cycle. Comprehensive analyses showed that AEE could prevent thrombosis by inhibiting platelet activation, decreasing inflammation, and regulating amino acid and energy metabolism. In conclusion, AEE can have a positive effect on thrombosis-related diseases.

Tunnelling of electrons via the neighboring atom.

As compared to the intuitive process that the electron emits straight to the continuum from its parent ion, there is an alternative route that the electron may transfer to and be trapped by a neighboring ionic core before the eventual release. Here, we demonstrate that electron tunnelling via the neighboring atomic core is a pronounced process in light-induced tunnelling ionization of molecules by absorbing multiple near-infrared photons. We devised a site-resolved tunnelling experiment using an Ar-Kr+ ion as a prototype system to track the electron tunnelling dynamics from the Ar atom towards the neighboring Kr+ by monitoring its transverse momentum distribution, which is temporally captured into the resonant excited states of the Ar-Kr+ before its eventual releasing. The influence of the Coulomb potential of neighboring ionic cores promises new insights into the understanding and controlling of tunnelling dynamics in complex molecules or environment.

sTREM2 in the prognostic evaluation of acute lung injury after cardiac surgery in infants.

BACKGROUND: Previous studies have shown that TREM2 plays a protective role in acute lung injury (ALI). This prospective study aimed to investigate the role of sTREM2 as a forecasting factor for ALI in infants after pediatric cardiac surgery undergoing cardiopulmonary bypass (CPB). METHODS: Seventy-five consecutive patients younger than 1 year who underwent cardiac surgery were enrolled in this study. Sixty-one fulfilled the inclusion criteria and had been divided into ALI and non-ALI groups. Children's demographic characteristics and clinical data were collected. Perioperative sTREM2 levels were analyzed at five timepoints. RESULTS: In this study, children in the ALI group were younger, lighter, with higher RACHS-1 scores and underwent significantly longer CPB time. Post-CPB ALI had an impact on clinical outcomes, which contributed to a longer duration of mechanical ventilation, ICU and hospital stay than non-ALI group. Significant differences were manifested off-CPB, 1 h/6 h after CPB, and day 1 after surgery between the two groups. Binary logistic models revealed that off-CPB sTREM2 was significantly associated with the incidence of post-CPB ALI after adjustment. ROC analysis showed that the AUC of off-CPB sTREM2 level was 0.791, and the optimal cutoff value was 788.6 pg/ml. CONCLUSIONS: The off-CPB sTREM2 level was an independent prognostic factor for post-CPB ALI in infants. IMPACT: Plasma sTREM2 works together with downstream TREM2 to regulate inflammation response by binding the receptor to other cells. Previous studies have shown that TREM2 plays a protective role in ischemia-reperfusion and has anti-inflammatory effects on acute lung injury (ALI). This study analyzed the risk factors of post-cardiopulmonary bypass (CPB) ALI. We found that weight and off-CPB sTREM2 level were independent prognostic factors for post-CPB ALI. Plasma sTREM2 may serve as an early biomarker in the prognostic evaluation of acute lung injury after cardiac surgery in infants.

Synthesis and antibacterial activity of FST and its effects on inflammatory response and intestinal barrier function in mice infected with Escherichia coli O78.

Pathogenic Escherichia coli (E. coli) can cause intestinal diseases in humans and livestock, damage the intestinal barrier, increase systemic inflammation, and seriously threaten human health and the development of animal husbandry. In this study, we designed and synthesized a novel conjugate florfenicol sulfathiazole (FST) based on drug combination principles, and investigated its antibacterial activity in vitro and its protective effect on inflammatory response and intestinal barrier function in E. coli O78-infected mice in vivo. The results showed that FST had superior antibacterial properties and minimal cytotoxicity compared with its prodrugs as florfenicol and sulfathiazole. FST protected mice from lethal E. coli infection, reduced clinical signs of inflammation, reduced weight loss, alleviated intestinal structural damage. FST decreased the expression of inflammatory cytokines IL-1ß, IL-6, TNF-α, and increased the expression of claudin-1, Occludin, and ZO-1 in the jejunum, improved the intestinal barrier function, and promoted the absorption of nutrients. FST also inhibited the expression of TLR4, MyD88, p-p65, and p-p38 in the jejunum. The study may lay the foundation for the development of FST as new drugs for intestinal inflammation and injury in enteric pathogen infection.

Protective Effect and Mechanism of Aspirin Eugenol Ester on Lipopolysaccharide-Induced Intestinal Barrier Injury.

Intestinal inflammation is a complex and recurrent inflammatory disease. Pharmacological and pharmacodynamic experiments showed that aspirin eugenol ester (AEE) has good anti-inflammatory, antipyretic, and analgesic effects. However, the role of AEE in regulating intestinal inflammation has not been explored. This study aimed to investigate whether AEE could have a protective effect on LPS-induced intestinal inflammation and thus help to alleviate the damage to the intestinal barrier. This was assessed with an inflammation model in Caco-2 cells and in rats induced with LPS. The expression of inflammatory mediators, intestinal epithelial barrier-related proteins, and redox-related signals was analyzed using an enzyme-linked immunosorbent assay (ELISA), Western blotting, immunofluorescence staining, and RT-qPCR. Intestinal damage was assessed by histopathological examination. Changes in rat gut microbiota and their functions were detected by the gut microbial metagenome. AEE significantly reduced LPS-induced pro-inflammatory cytokine levels (p < 0.05) and oxidative stress levels in Caco-2 cells and rats. Compared with the LPS group, AEE could increase the relative expression of Occludin, Claudin-1, and zonula occludens-1 (ZO-1) and decrease the relative expression of kappa-B (NF-κB) and matrix metalloproteinase-9. AEE could significantly improve weight loss, diarrhea, reduced intestinal muscle thickness, and intestinal villi damage in rats. Metagenome results showed that AEE could regulate the homeostasis of the gut flora and alter the relative abundance of Firmicutes and Bacteroidetes. Flora enrichment analysis indicated that the regulation of gut flora with AEE may be related to the regulation of glucose metabolism and energy metabolism. AEE could have positive effects on intestinal inflammation-related diseases.

Anesthesia management experience for pediatric day-case PDA ligation under thoracoscopy assisted by a robot: a retrospective study.

BACKGROUND: To summarize the anesthesia management experience for pediatric day-case patent ductus arteriosus (PDA) ligation under robot-assisted thoracoscopy and explore the key points of anesthesia management for this procedure. METHODS: The clinical data of 72 pediatric patients who underwent robot-assisted thoracoscopic day-case PDA ligation at the Children's Hospital, Zhejiang University School of Medicine from April 2021 to February 2023 were retrospectively analyzed. 0.3% ropivacaine local infiltration combined with S-ketamine 0.2 mg/kg intravenous injection was used for postoperative analgesia The patient's basic information and intraoperative conditions were analyzed, which included gender, age, weight, surgery time, anesthesia time, extubation time, intraoperative blood loss, MAP before pneumothorax, PaCO2 before pneumothorax, etc. Postoperative conditions were also monitored, such as PACU stay time, agitation during the recovery period, pain, and the incidence of nausea and vomiting. After discharge, the recovery status was assessed. RESULTS: A total of 70 pediatric patients who met the criteria for day-case PDA ligation were included in this study. Before the occurrence of pneumothorax, the mean arterial pressure (MAP) of these 70 patients was 69.58 ± 12.52 mmHg, and during controlled hypotension, the MAP was 54.96 ± 11.23 mmHg. Before the occurrence of pneumothorax, the partial pressure of carbon dioxide (PaCO2) was 38.69 ± 3.38 mmHg, and during controlled hypotension, the PaCO2 was 51.42 ± 4.05 mmHg. Three cases experienced agitation during the recovery period, and four cases had mild pain, but there was no moderate or severe pain, nausea, or vomiting. Only 1 case of postoperative respiratory tract infection and 1 case of postoperative pneumothorax occurred. Within 30 days after discharge, the unplanned revisit rate, unplanned readmission rate, and surgical wound infection rate were all 0. The residual shunt rate detected by echocardiography was 0 after 1 month. CONCLUSIONS: The children under the robot-assisted thoracoscopic day case PDA surgeries in this study have limited trauma, little bleeding, and little postoperative pain, though still at a risk of respiratory infection and pneumothorax.

AEE alleviates ox-LDL-induced lipid accumulation and inflammation in macrophages.

Atherosclerosis is a chronic immune inflammatory disease. Aspirin eugenol ester (AEE) is a novel safe and non-toxic compound with many pharmacological effects such as anti-inflammatory, anti-hyperlipidemic and anti-thrombotic action. In order to investigate the effect of AEE on the inhibition of aortic lipid plaque formation and macrophage-derived foam cell formation induced by oxidized low density lipoprotein (ox-LDL), in vivo atherosclerosis model by feeding ApoE-/- mice with a high-fat diet and foam cells formation in vitro model by ox-LDL-induced RAW264.7 macrophages were established. It was found that AEE decreased the levels of TC and LDL-C in serum, and the plaque formation area and lipid accumulation in the aortic intima of ApoE-/- mice. In vitro studies showed that AEE could prevent the uptake of ox-LDL and reduce the contents of TC and FC in cells. AEE enhanced the cholesterol efflux by increasing the expression of ABCA1, ABCG1 and PPARγ, which effectively alleviated excess cholesterol accumulated in the cells. Meanwhile, AEE also reduced the secretion and expression of inflammatory factors in the cells. In addition, AEE could reverse the action of PPARγ inhibitor T0070907 and/or ox-LDL. Therefore, AEE may become an effective candidate drug for the prevention of atherosclerosis.

Aspirin eugenol ester ameliorates LPS-induced inflammatory responses in RAW264.7 cells and mice.

Introduction: Inflammation is a defensive response of the body and the pathological basis of many diseases. However, excessive inflammation and chronic inflammation impair the homeostasis of the organism. Arachidonic acid (AA) has a close relationship with inflammation and is the main mediator of the pro-inflammatory response. Based on the prodrug principle, the new pharmaceutical compound aspirin eugenol ester (AEE) was designed and synthesized. However, the effects of AEE on key enzymes, metabolites and inflammatory signaling pathways in the AA metabolic network have not been reported. Methods: In this study, the anti-inflammation effects of AEE were first investigated in mice and RAW264.7 cells in LPS induced inflammation model. Then, the changes of the key enzymes and AA metabolites were explored by RT-PCR and targeted metabolomics. Moreover, the regulatory effects on NF-kB and MAPKS signaling pathways were explored by Western Blotting. Results: Results indicated that AEE significantly reduced the number of leukocyte and increased the lymphocyte percentage. AEE decreased the expression levels of IL-1ß, IL-6, IL-8 and TNF-α both in vivo and in vitro. In the liver of mice, AEE downregulated the levels of AA, prostaglandin D2 (PGD2) and upregulated 12- hydroxyeicosatetraenoic acid (12-HETE). However, the changes of PGE2, PGF2α, 6-keto-prostaglandin F1α (6-KETO-PGF1α), 9-hydroxy-octadecenoic acid (9- HODE), 13-HODE, 15-HETE, docosahexaenoic acid (DHA) and thromboxane B2 (TXB2) were not significant. Additionally, it was found that AEE decreased the relative mRNA expression levels of p65 and p38 and the ratio of p-p65/p65. Discussion: It was concluded that AEE might inhibit the LPS-induced inflammatory response through the regulation of AA metabolism. This study provides the theoretical foundation for the development of AEE as a medicinal anti-inflammatory drug.

Multi-omics reveals aspirin eugenol ester alleviates neurological disease.

BACKGROUND: Exosomes play an essential role in maintaining normal brain function due to their ability to cross the blood-brain barrier. Aspirin eugenol ester (AEE) is a new medicinal compound synthesized by the esterification of aspirin with eugenol using the prodrug principle. Aspirin has been reported to have neuroprotective effects and may be effective against neurodegenerative diseases. PURPOSE: This study wanted to investigate how AEE affected neurological diseases in vivo and in vitro. EXPERIMENTAL APPROACH: A multi-omics approach was used to explore the effects of AEE on the nervous system. Gene and protein expression changes of BDNF and NEFM in SY5Y cells after AEE treatment were detected using RT-qPCR and Western Blot. KEY RESULTS: The multi-omics results showed that AEE could regulate neuronal synapses, neuronal axons, neuronal migration, and neuropeptide signaling by affecting transport, inflammatory response, and regulating apoptosis. Exosomes secreted by AEE-treated Caco-2 cells could promote the growth of neurofilaments in SY5Y cells and increased the expression of BDNF and NEFM proteins in SY5Y cells. miRNAs in the exosomes of AEE-treated Caco-2 cells may play an important role in the activation of SY5Y neuronal cells. CONCLUSIONS: In conclusion, AEE could play positive effects on neurological-related diseases.

Serum soluble triggering receptor levels expressed on myeloid cells2 identify early acute kidney injury in infants and young children after pediatric cardiopulmonary bypass.

Background: Acute kidney injury (AKI) is a potential complication after cardiopulmonary bypass (CPB) of pediatric cardiac surgery and contributes to a certain amount of perioperative mortality. Serum soluble triggering receptor expressed on myeloid cells2 (sTREM2) is an inflammation-associated cytokine in circulation. Alterations of sTREM2 level have been reported in Alzheimer's disease, sepsis, and some other pathologic conditions. This study aimed to investigate the role of sTREM2 as a forecasting factor for AKI in infants and young children and other factors associated with early renal injury after pediatric CPB. Methods: A prospective cohort study with consecutive infants and young children ≤ 3 years old undergoing CPB from September 2021 to August 2022 was conducted in an affiliated university children's hospital. These patients were divided into an AKI group (n = 10) and a non-AKI group (n = 60). Children's characteristics and clinical data were measured. Perioperative sTREM2 levels were analyzed with enzyme-linked immunosorbent assay (ELISA). Results: In children developing AKI, the sTREM2 levels significantly decreased at the beginning of CPB compared to the non-AKI group. Based on binary logistic regression analysis and multivariable regression analysis, risk-adjusted classification for congenital heart surgery (RACHS-1), operation time, and the s-TREM2 level at the beginning of CPB (AUC = 0.839, p = 0.001, optimal cut-off value: 716.0 pg/ml) had predictive value for post-CPB AKI. When combining the sTREM2 level at the beginning of CPB and other indicators together, the area under the ROC curve enlarged. Conclusions: Operation time, RACHS-1 score, and sTREM2 level at the beginning of CPB were independent prognosis factors of post-CPB AKI in infants and young children ≤ 3 years old. Decreased sTREM2 identified post-CPB AKI, and ultimately hampered the outcomes. Our findings indicated that sTREM2 may be a protective factor for AKI after CPB in infants and young children ≤ 3 years old.

The Transport and Uptake of Resveratrol Mediated via Glucose Transporter 1 and Its Antioxidant Effect in Caco-2 Cells.

Resveratrol has anti-inflammatory, anti-cancer, and anti-aging pharmacological activities. There is currently a gap in academic research regarding the uptake, transport, and reduction of H2O2-induced oxidative damage of resveratrol in the Caco-2 cell model. This study investigated the role of resveratrol in the uptake, transport, and alleviation of H2O2-induced oxidative damage in Caco-2 cells. In the Caco-2 cell transport model, it was observed that the uptake and transport of resveratrol (10, 20, 40, and 80 µM) were time dependent and concentration dependent. Different temperatures (37 °C vs. 4 °C) could significantly affect the uptake and transportation of resveratrol. The apical to basolateral transport of resveratrol was markedly reduced by STF-31, a GLUT1 inhibitor, and siRNA intervention. Furthermore, resveratrol pretreatment (80 µM) improves the viability of Caco-2 cells induced by H2O2. In a cellular metabolite analysis combined with ultra-high performance liquid chromatography-tandem mass spectrometry, 21 metabolites were identified as differentials. These differential metabolites belong to the urea cycle, arginine and proline metabolism, glycine and serine metabolism, ammonia recycling, aspartate metabolism, glutathione metabolism, and other metabolic pathways. The transport, uptake, and metabolism of resveratrol suggest that oral resveratrol could prevent intestinal diseases caused by oxidative stress.