Long noncoding RNA and messenger RNA profiling in epicardial adipose tissue of patients with new-onset postoperative atrial fibrillation after coronary artery bypass grafting.

BACKGROUND: Postoperative atrial fibrillation (POAF) constitutes a significant complication following coronary artery bypass graft surgery (CABG), potentially linked to epicardial adipose tissue (EAT). This investigation seeks to elucidate the association between POAF and EAT at the genetic level. METHODS: EAT and clinical data from patients undergoing CABG were systematically acquired, adhering to established inclusion and exclusion criteria. Patients were categorized into POAF and Non-POAF groups based on the presence or absence of POAF. High-throughput sequencing data of EAT were subjected to differential expression analysis and gene function assessment. A random selection of long noncoding RNAs (lncRNAs) underwent quantitative real-time polymerase chain reaction (qRT-PCR) for validation of the high-throughput sequencing findings. Coexpression analysis was employed to elucidate the interactions between lncRNAs and messenger RNAs (mRNAs). RESULTS: RNA sequencing yielded a total of 69,685 transcripts (37,740 coding and 31,945 noncoding sequences), representing 16,920 genes. Within this dataset, 38 mRNAs and 12 lncRNAs exhibited differential expression between the POAF and Non-POAF groups (P < 0.05, fold change > 1.5). The qRT-PCR results for lncRNAs corroborated the sequencing findings (P < 0.01). Functional enrichment analysis of genes and the coexpression network indicated that these differentially expressed RNAs were primarily implicated in processes such as cell growth, differentiation, signal transduction, as well as influencing tissue fibrosis and ion transmembrane transport. CONCLUSIONS: This study unveils a potential association between myocardial fibrosis and ion channels co-regulated by mRNAs and lncRNAs, closely linked to the emergence of new-onset POAF, after accounting for clinical risk factors. This discovery holds promise for further advances in clinical and fundamental research.

Associations of ApoE Polymorphisms with Postoperative Atrial Fibrillation and Cardiac Injury in Patients with Coronary Artery Bypass Graft Surgery.

Genetic factors may be involved in postoperative atrial fibrillation (PoAF) development and cardiac injury. However, the associations of the apolipoprotein E (ApoE) gene polymorphisms with PoAF and cardiac injury after coronary artery bypass graft surgery (CABG) remain unclear.We recruited 150 patients with CABG, comprising 92 and 58 cases for the ApoE4 and ApoE3 groups, respectively, and analyzed PoAF incidence and the levels of cardiac biomarkers, including N-terminal prohormone of brain natriuretic peptide, cardiac troponin T (cTnT), and cardiac troponin I (cTnI). The linear regression model or logistic regression analysis was applied to investigate the associations of ApoE gene polymorphisms with PoAF and biomarkers for cardiac injury.A total of 58 (38.7%) patients with CABG developed PoAF, with 40 and 18 cases in the ApoE4 and ApoE3 groups (43.5% versus 31.0%, P < 0.05), respectively. Logistic regression analysis revealed that the ApoE4 allele was an independent risk factor for PoAF (OR = 3.340, P = 0.001), while the ApoE3 allele was a protective factor for the PoAF (OR = 0.841, P = 0.043). Patients carrying the ApoE4 allele had higher levels of cTnT and cTnI than those carrying the ApoE3 allele. ApoE3 was a protective factor for cardiac injury (ß = -0.220, P = 0.001), whereas ApoE4 was a risk factor for cTnI (ß = 0.335, P = 0.015).Our study reveals that the ApoE allele contributes to the occurrence of PoAF and severity of cardiac injury in an allele-dependent manner, with the ApoE4 allele increasing the risk and the ApoE3 allele reducing the risk.

The role of epigenetic modification in postoperative cognitive dysfunction.

With the ageing of the population, the health problems of elderly individuals have become particularly important. Through a large number of clinical studies and trials, it has been confirmed that elderly patients can experience postoperative cognitive dysfunction after general anesthesia/surgery. However, the mechanism of postoperative cognitive dysfunction is still unknown. In recent years, the role of epigenetics in postoperative cognitive dysfunction has been widely studied and reported. Epigenetics includes the genetic structure and biochemical changes of chromatin not involving changes in the DNA sequence. This article summarizes the epigenetic mechanism of cognitive impairment after general anesthesia/surgery and analyses the broad prospects of epigenetics as a therapeutic target for postoperative cognitive dysfunction.

Hematopoietic Somatic Mosaicism Is Associated With an Increased Risk of Postoperative Atrial Fibrillation.

BACKGROUND: On-pump cardiac surgery triggers sterile inflammation and postoperative complications such as postoperative atrial fibrillation (POAF). Hematopoietic somatic mosaicism (HSM) is a recently identified risk factor for cardiovascular diseases and results in a shift toward a chronic proinflammatory monocyte transcriptome and phenotype. OBJECTIVES: The aim of this study was to assess the prevalence, characteristics, and impact of HSM on preoperative blood and myocardial myeloid cells as well as on outcomes after cardiac surgery. METHODS: Blood DNA from 104 patients referred for surgical aortic valve replacement (AVR) was genotyped using the HemePACT panel (576 genes). Four screening methods were applied to assess HSM, and postoperative outcomes were explored. In-depth blood and myocardial leukocyte phenotyping was performed in selected patients using mass cytometry and preoperative and postoperative RNA sequencing analysis of classical monocytes. RESULTS: The prevalence of HSM in the patient cohort ranged from 29%, when considering the conventional HSM panel (97 genes) with variant allelic frequencies ≥2%, to 60% when considering the full HemePACT panel and variant allelic frequencies ≥1%. Three of 4 explored HSM definitions were significantly associated with higher risk for POAF. On the basis of the most inclusive definition, HSM carriers exhibited a 3.5-fold higher risk for POAF (age-adjusted OR: 3.5; 95% CI: 1.52-8.03; P = 0.003) and an exaggerated inflammatory response following AVR. HSM carriers presented higher levels of activated CD64+CD14+CD16- circulating monocytes and inflammatory monocyte-derived macrophages in presurgery myocardium. CONCLUSIONS: HSM is frequent in candidates for AVR, is associated with an enrichment of proinflammatory cardiac monocyte-derived macrophages, and predisposes to a higher incidence of POAF. HSM assessment may be useful in the personalized management of patients in the perioperative period. (Post-Operative Myocardial Incident & Atrial Fibrillation [POMI-AF]; NCT03376165).

Longitudinal profiling in patients undergoing cardiac surgery reveals postoperative changes in DNA methylation.

BACKGROUND: Cardiac surgery and cardiopulmonary bypass induce a substantial immune and inflammatory response, the overactivation of which is associated with significant pulmonary, cardiovascular, and neurologic complications. Commensurate with the immune and inflammatory response are changes in the heart and vasculature itself, which together drive postoperative complications through mechanisms that are poorly understood. Longitudinal DNA methylation profiling has the potential to identify changes in gene regulatory mechanisms that are secondary to surgery and to identify molecular processes that predict and/or cause postoperative complications. In this study, we measure DNA methylation in preoperative and postoperative whole blood samples from 96 patients undergoing cardiac surgery on cardiopulmonary bypass. RESULTS: While the vast majority of DNA methylation is unchanged by surgery after accounting for changes in cell-type composition, we identify several loci with statistically significant postoperative changes in methylation. Additionally, two of these loci are associated with new-onset postoperative atrial fibrillation, a significant complication after cardiac surgery. Paired statistical analysis, use of FACS data to support sufficient control of cell-type heterogeneity, and measurement of IL6 levels in a subset of patients add rigor to this analysis, allowing us to distinguish cell-type variability from actual changes in methylation. CONCLUSIONS: This study identifies significant changes in DNA methylation that occur immediately after cardiac surgery and demonstrates that these acute alterations in DNA methylation have the granularity to identify processes associated with major postoperative complications. This research also establishes methods for controlling for cell-type variability in a large human cohort that may be useful to deploy in other longitudinal studies of epigenetic marks in the setting of acute and chronic disease.

Increased Expression of SERPINB10 Associated with Postoperative Recurrence in Chronic Rhinosinusitis with Nasal Polyps.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common upper airway inflammatory disorder with a high rate of postoperative recurrence. SERPINB10 is a proinflammatory cytokine expressed on epithelial cells, but its role in CRSwNP has not been described. This study is aimed at exploring the SERPINB10 expression in CRSwNP and its relationship with postoperative recidivation. Methods: We recruited 140 individuals, consisting of 60 patients with CRSwNP, 40 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), and 40 healthy controls (HCs). Tissue specimens were collected during the surgery, and SERPINB10 expression was determined by reverse transcription-polymerase chain reaction, western blotting, and immunofluorescence. We determined the tissue SERPINB10 expression levels in CRSwNP and examined its clinical value in predicting postoperative recurrence. Results: We determined that tissue SERPINB10 mRNA and protein levels were increased in the CRSwNP group, especially in the recurrent CRSwNP group, compared with the CRSsNP and HC groups (p < 0.05), and SERPINB10 mRNA levels were correlated with peripheral and tissue eosinophil counts and percentages (p < 0.05). Binary logistic regression analysis and receiver operating characteristic (ROC) curves suggested that the expressions of tissue SERPINB10 mRNA were significantly linked to postoperative recurrence in CRSwNP patients (AUC = 0.741, p < 0.001). Conclusion: Elevated local SERPINB10 levels in patients with CRSwNP were related to tissue eosinophilic inflammation and disease recurrence. These data suggested that SERPINB10 might contribute to the eosinophilic inflammation in CRSwNP and appeared to be a potential biomarker for the prediction of relapse after surgery.

Limited clinical utility for GWAS or polygenic risk score for postoperative acute kidney injury in non-cardiac surgery in European-ancestry patients.

BACKGROUND: Prior studies support a genetic basis for postoperative acute kidney injury (AKI). We conducted a genome-wide association study (GWAS), assessed the clinical utility of a polygenic risk score (PRS), and estimated the heritable component of AKI in patients who underwent noncardiac surgery. METHODS: We performed a retrospective large-scale genome-wide association study followed by a meta-analysis of patients who underwent noncardiac surgery at the Vanderbilt University Medical Center ("Vanderbilt" cohort) or Michigan Medicine, the academic medical center of the University of Michigan ("Michigan" cohort). In the Vanderbilt cohort, the relationship between polygenic risk score for estimated glomerular filtration rate and postoperative AKI was also tested to explore the predictive power of aggregating multiple common genetic variants associated with AKI risk. Similarly, in the Vanderbilt cohort genome-wide complex trait analysis was used to estimate the heritable component of AKI due to common genetic variants. RESULTS: The study population included 8248 adults in the Vanderbilt cohort (mean [SD] 58.05 [15.23] years, 50.2% men) and 5998 adults in Michigan cohort (56.24 [14.76] years, 49% men). Incident postoperative AKI events occurred in 959 patients (11.6%) and in 277 patients (4.6%), respectively. No loci met genome-wide significance in the GWAS and meta-analysis. PRS for estimated glomerular filtration rate explained a very small percentage of variance in rates of postoperative AKI and was not significantly associated with AKI (odds ratio 1.050 per 1 SD increase in polygenic risk score [95% CI, 0.971-1.134]). The estimated heritability among common variants for AKI was 4.5% (SE = 4.5%) suggesting low heritability. CONCLUSION: The findings of this study indicate that common genetic variation minimally contributes to postoperative AKI after noncardiac surgery, and likely has little clinical utility for identifying high-risk patients.

Association between nitric oxide synthase 3 genetic variant and acute kidney injury following pediatric cardiac surgery.

BACKGROUND: Acute kidney injury (AKI) complicates 30% to 50% of cardiac surgeries in pediatric patients. Genetic variants that affect renal blood flow and inflammation have been associated with AKI after cardiac surgery in diverse populations of adults but have not been studied in children. The objective of this study is to test the hypothesis that common candidate genetic variants are associated with AKI following pediatric cardiac surgery. METHODS: This is a retrospective cohort study at a single tertiary referral children's hospital of 2,062 individual patients undergoing surgery for congenital heart disease from September 2007 to July 2020. Pre-specified variants in candidate genes (AGTR1, APOE, IL6, NOS3, and TNF) were chosen. AKI was defined using Kidney Disease: Improving Global Outcomes serum creatinine criteria in the first week following surgery. Outcomes were analyzed by univariate and multivariable analysis of demographic, clinical, and genetic factors. RESULTS: The study population had median age of 6 (interquartile range [IQR], 1-53) months, 759 (37%) of whom met criteria for postoperative AKI. In unadjusted analyses of each genetic variant, only NOS3 (rs2070744) was associated with lower risk for AKI (OR 0.75, 95% CI 0.62-0.9, P = .002). In logistic regression analyses adjusting for body surface area, previously identified genetic syndrome, Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) score, cardiopulmonary bypass time, and nephrotoxic medication exposure, the NOS3 variant remained protective against AKI (OR 0.7, 95% CI 0.58-0.85, P<.001). CONCLUSIONS: A common variant in NOS3 is associated with decreased incidence of AKI in children undergoing cardiac surgery. Further analysis of the genetic contributions to postoperative AKI may help identify individual risk in the pediatric population.

It is not NOD2 - genetic and clinical risk factors for postoperative complications following ileocolic resection in Crohn's disease.

PURPOSE: To evaluate the role of the nucleotide oligomerization domain 2 (NOD2) mutation status and other risk factors for the incidence of postoperative complications after ileocolic resection for Crohn's disease (CD). METHODS: Data of 138 patients consecutively undergoing ileocolic resection for CD at a tertiary academic referral center were retrospectively analyzed including single nucleotide polymorphism (SNP) data of the NOD2 gene. Uni- and multivariate regression analysis was performed to identify factors associated with increased risk of severe postoperative complications. RESULTS: From 114 patients (83%), the NOD2 mutation status was available. Of these, 60 (53%) had a NOD2 wildtype, whereas eleven (10%) were homozygous for the high risk p.Leu1007fsX1008 (rs2066847) variant. Major postoperative complications occurred in 28 patients (20%). Twenty-seven of these (96%) were intraabdominal septic complications such as anastomotic leakage or abscess. Male gender (P = 0.029; OR 3.052, the duration of CD (time [months] from initial diagnosis of CD to surgery; P = 0.001; OR 1.009), previous abdominal surgery for CD (P = 0.017; OR 3.49), and the presence of enteric fistulas (P = 0.023; OR 3.21) were identified as independent risk factors for major postoperative complications. Homozygosity for the NOD2 high-risk variant p.Leu1007fsX1008 did not show increased postoperative morbidity in the short and long-term outcome. CONCLUSIONS: We could detect independent risk factors for major postoperative complications after ileocolic resection for Crohn's disease. However, patients with the high-risk variant p.Leu1007fsX1008 of the NOD2 gene did not show increased postoperative morbidity.

Genetic variability in exon 1 of the glucocorticoid receptor gene NR3C1 is associated with postoperative complications.

Patients undergoing major surgery experience postoperative inflammation, which may contribute to postoperative morbidity. Endogenous glucocorticoids (GCs) are an essential part of the stress response, but this response varies between individuals, which may in turn affect clinical outcome and specifically postoperative inflammation. Exon 1 of the NR3C1 gene, encoding the GC receptor (GR), contains an established region of differential regulation. DNA methylation patterns in this region have been found to differ between individuals. The present study investigated the methylation status and genotype in the cytosine­phosphate­guanine (CpG) island in exon 1 of NR3C1 in 24 patients [Median age 65.5 (range 42­81) years, 11 male, 13 female] who underwent major abdominal (12 pancreatic, 12 hepatic) surgery and explored its association with postoperative complications. DNA was extracted from peripheral blood leukocytes and underwent targeted bisulfite sequencing of the CpG island. Complications were graded according to the Clavien­Dindo classification and 14 out of 24 patients had postoperative complications. Multifactorial and partial least square analyses were used to analyse the data. A homogenous demethylated pattern was observed in all patients and no single CpG methylation was associated with postoperative complications. Four SNPs were significantly associated with higher Clavien­Dindo scores. Genetic variability in the chromosome 5:143,402,505­143,405,805 region of exon 1 of the GR gene NR3C1, but not DNA methylation, was associated with more severe postoperative complications in patients having major abdominal surgery. These results indicated that the patients' response to GCs may be of clinical importance for inflammatory conditions.

Correlation between microRNA-320 and postoperative delirium in patients undergoing tibial fracture internal fixation surgery.

BACKGROUND: Although the incidence of postoperative delirium (POD) in the elderly after surgery are rising as individuals are living longer, the pathogenesis of POD remains poorly understood. It has been suggested that miRNA-320 may play a role in POD based on animal study and human study. METHODS: We first carried out an animal study, and designed and conducted a human study based on the result of animal study. The aged rats were randomly assigned to five groups: the control (C), anesthesia and surgery (AS), saline (NS), agomir-320 (AG), and antagomir-320 (AT) groups. Postoperative spatial learning and memory in rats were analyzed by the Morris water maze and the open field tests. The plasma levels of insulin-like growth factor-1 (IGF-1), amyloid precursor protein (APP) proteins, miRNA320 and IGF-1mRNA were measured by ELISA and qRT-PCR, respectively. A total of 240 Chinese Han patients over 65 years who underwent tibial fracture internal fixation were included in the PNDABLE study. POD cases and non-POD controls (1:1 matched) were selected by an anesthesiologist using Confusion Assessment Method. RESULTS: For Group AS, the escape latency was significantly longer and the ratio of time spent in the target quadrant was significantly reduced, APP and miR-320 were upregulated and IGF-1mRNA was downregulated compared with Group C. For Group AG, the escape latency was significantly longer and the ratio of time spent in the target quadrant was significantly reduced, APP and miR-320 were upregulated and IGF-1mRNA was downregulated compared with Group AS. For Group AT, the escape latency was significantly reduced and the ratio of time spent in the target quadrant was significantly longer, APP and miR-320 were downregulated and IGF-1mRNAwas upregulated compared with Group AS. Compared with NPOD patients, the expressions of plasma miR-320 and APP protein were increased and the expression of plasma IGF-1 mRNA was decreased in POD patients after surgery. CONCLUSIONS: MiRNA-320 might play a role in up-regulating the levels of IGF-1mRNA and APP protein, which offered a new target for POD treatment. TRIAL REGISTRATION: Correlation of perioperative neurocognitive disorders with lifestyle and biomarkers. ChiCTR2000033439 . Registered 1 June 2020.

Genetic Predisposition of Postoperative Adhesions Varies in Substrains of BALB/c Mice.

Postoperative adhesions are a major clinical problem because of the associated infertility, chronic pain, bowel obstruction, and the associated costs. Variability in adhesion formation was suggested by clinical observations that apparently similar interventions can cause little to severe adhesions. This is supported by the presence of polymorphisms and genetic predisposition to develop adhesions in animal models and humans. We previously demonstrated differences in postoperative adhesions between different mouse strains. In this study, we aimed to investigate the variability in adhesion formation in inbred substrains of BALB/c mice. Since genetic differences in inbred substrains are minimal, they might be an opportunity to tackle the genetics of adhesion formation.

Combining Breast and Ovarian Operations Increases Complications.

BACKGROUND: Breast cancer resulting from a genetic mutations, such as BRCA1 or BRCA2, is seen in 5 to 10 percent of patients. More widespread genetic testing has increased the number of affected women undergoing prophylactic mastectomy and oophorectomy. Recent studies have yielded mixed results regarding complication rates after combined breast and ovarian operations. The authors compared surgical outcomes of breast operations performed in combination with salpingo-oophorectomies or as separate procedures. METHODS: The authors retrospectively analyzed surgical complications and length of hospital stay in 145 female patients, from which 87 had undergone combined breast surgery and salpingo-oophorectomy, and 58 had undergone these procedures separately. Multivariate logistic regression models were used to calculate odds ratios and 95 percent confidence intervals. RESULTS: Patients undergoing combined breast and ovarian operations experienced higher rates of overall complications (46.5 percent versus 19 percent; p < 0.001), infections (22.2 percent versus 8.6 percent; p < 0.05), and delayed wound healing (13.2 percent versus 0 percent; p < 0.05) related to the breast surgery, when compared with patients undergoing separate procedures. Multivariate logistic regression analysis confirmed a significant association between combined surgery and overall postoperative complications (OR, 5.87; 95 percent CI, 2.03 to 16.91; p = 0.02). Patients undergoing tissue expander-based breast reconstruction combined with ovarian surgery had significantly longer hospital stays compared to patients undergoing separate procedures (3.5 days versus 1.8 days; p < 0.001). CONCLUSIONS: The authors' data indicate that combining breast and ovarian operations is associated with a higher risk of postoperative complications related to the breast procedure and increases the duration of hospital stay in patients with tissue expander-based reconstructions. The authors' study provides valuable information for preoperative counseling of patients considering both breast and ovarian surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Longitudinal monitoring of mRNA levels of regulatory T cell biomarkers by using non-invasive strategies to predict outcome in renal transplantation.

BACKGROUND: Acute T-cell mediated rejection (aTCMR) is still an issue in kidney transplantation, for it is associated with chronic rejection, graft loss, and overall worse outcomes. For these reasons, a standard non-invasive molecular tool to detect is desirable to offer a simpler monitoring of kidney transplant recipients (KTRs). The purpose of our study was to examine, in peripheral blood before and after transplantation, the expression patterns of regulatory T cell (Treg)-related genes: the forkhead box P3 (FOXP3) and the two CTLA-4 isoforms (full-length and soluble) to predict acute rejection onset, de novo donor-specific antibodies (DSA) development and renal dysfunction 1 year after transplantation. METHODS: We profiled by using a relative quantification analysis (qRT-PCR) circulating mRNA levels of these biomarkers in peripheral blood of 89 KTRs within the first post-transplant year (at baseline and 15, 60 and 365 days, and when possible at the acute rejection) and compared also the results with 24 healthy controls. RESULTS: The three mRNA levels drastically reduced 15 days after transplantation and gradually recovered at 1 year in comparison with baseline, with very low levels at the time of aTCMR for FOXP3 (RQ = 0.445, IQR = 0.086-1.264, p = 0.040), maybe for the pro-apoptotic role of FOXP3 during inflammation. A multivariate Cox regression analysis evidenced a significant relation between aTCMR onset and thymoglobuline induction (HR = 6.749 p = 0.041), everolimus use (HR = 7.017, p = 0.007) and an increased risk from the solCTLA-4 expression at 15 days, mainly considering recipients treated with Mycophelolic acid (HR = 13.94 p = 0.038, 95%CI:1.157-167.87). Besides, solCTLA-4 also predisposed to graft dysfunction (eGFR< 60 mL/min/1.73m2) at 1 year (AOR = 3.683, 95%CI = 1.145-11.845, p = 0.029). On the other hand, pre-transplant solCTLA-4 levels showed a protective association with de novo DSAs development (HR = 0.189, 95%CI = 0.078-0.459, p < 0.001). CONCLUSIONS: mRNA levels of Treg-associated genes, mainly for solCTLA-4, in peripheral blood could put forward as candidate non-invasive biomarkers of cellular and humoral alloreactivity in clinical transplantation and might help shape immunosuppression, tailor monitoring and achieve better long-term outcomes of kidney transplantation in the wake of "precision medicine".

Propofol ameliorates acute postoperative fatigue and promotes glucagon-regulated hepatic gluconeogenesis by activating CREB/PGC-1α and accelerating fatty acids beta-oxidation.

Postoperative fatigue (POF) is the most common and long-lasting complication after surgery, which brings heavy burden to individuals and society. Recently, hastening postoperative recovery receives increasing attention, but unfortunately, the mechanisms underlying POF remain unclear. Propofol is a wildly used general anesthetic in clinic, and inspired by the rapid antidepressant effects induced by ketamine at non-anesthetic dose, the present study was undertaken to investigate the anti-fatigue effects and underlying mechanisms of propofol at a non-anesthetic dose in 70% hepatectomy induced POF model in rats. We first showed here that single administration of propofol at 0.1 mg/kg ameliorated acute POF in hepatectomy induced POF rats. Based on metabonomics analysis, we hypothesized that propofol exerted anti-fatigue activity in POF rats by facilitating free fatty acid (FFA) oxidation and gluconeogenesis. We further confirmed that propofol restored the deficit in FFA oxidation and gluconeogenesis in POF rats, as evidenced by the elevated FFA utilization, acetyl coenzyme A content, pyruvic acid content, phosphoenolpyruvic acid content, hepatic glucose output and glycogen storage. Moreover, propofol stimulated glucagon secretion and up-regulated expression of cAMP-response element binding protein (CREB), phosphorylated CREB, peroxlsome prolifeator-activated receptor-γ coactivator-1α (PGC-1α), phosphoenolpyruvate carboxykinade1 and carnitine palmitoltransferase 1A. In summary, our study suggests for the first time that propofol ameliorates acute POF by promoting glucagon-regulated gluconeogenesis via CREB/PGC-1α signaling and accelerating FFA beta-oxidation.

Transcriptome sequencing analysis of primary fibroblasts: a new insight into postoperative abdominal adhesion.

PURPOSE: The specific genes or pathways in fibroblasts responsible for the pathogenesis of postoperative abdominal adhesion (PAA) remain to be elucidated. We aim to provide a new insight into disease mechanisms at the transcriptome level. METHODS: Male Sprague-Dawley rats were used to establish a PAA model. Primary fibroblasts were separated from normal peritoneal tissue (NF) and postoperative adhesion tissue (PF). RNA sequencing was used to analyze the transcriptome in NF and PF. RESULTS: One thousand two hundred thirty-five upregulated and 625 downregulated DEGs were identified through RNA-Seq. A pathway enrichment analysis identified distinct enriched biological processes, among which the most prominent was related to immune and inflammatory response and fibrosis. HE staining and Masson's trichrome staining histologically validated the RNA-Seq results. Six hub genes, ITGAM, IL-1ß, TNF, IGF1, CSF1R and EGFR were further verified by RT-PCR. CONCLUSIONS: Our study revealed the roles of the immune and inflammatory responses and fibrosis in the process of PAA. We also found six hub genes that may be potential therapeutic targets for PPA.

Deletion of Calponin 2 Reduces the Formation of Postoperative Peritoneal Adhesions.

Aim of the study: Postoperative peritoneal adhesions are a common cause of morbidity after surgery, resulting in multiple complications. Macrophage-mediated inflammation and myofibroblast differentiation after tissue injury play central roles in the pathogenesis and progression of adhesion formation. Calponin 2 is an actin cytoskeleton regulatory protein in endothelial cells, macrophages and fibroblasts that are key players in the development of fibrosis. Deletion of calponin 2 has been shown to attenuate inflammatory arthritis, atherosclerosis and fibrocalcification of the aortic valves. The present study investigated the effect of calponin 2 deletion on attenuating the formation of peritoneal adhesions in a mouse model for potential use as a new therapeutic target.Materials and methods: Sterile surgical procedures under general anesthesia were used on paired wild type (WT) and calponin 2 knockout (KO) mice to generate mild injury on the cecal and abdominal wall peritonea. Three and seven days post-operation, the mice were compared postmortem for the formation of peritoneal adhesions. Tissues at the adhesion sites were examined with histology and immunofluorescent studies for macrophage and myofibroblast activations.Results: Quantitative scoring demonstrated that calponin 2 KO mice developed significantly less postoperative peritoneal adhesions than that in WT mice. Calponin 2 deletion resulted in less infiltration of F4/80+ macrophages at the adhesion sites with less myofibroblast differentiation and collagen deposition than WT controls.Conclusions: The data show that deletion of calponin 2 effectively reduces postoperative peritoneal adhesion, presenting a novel molecular target for clinical prevention.

Electrospun tube reduces adhesion in rabbit Achilles tendon 12 weeks post-surgery without PAR-2 overexpression.

One great challenge in surgical tendon repair is the minimization of peritendinous adhesions. An electrospun tube can serve as a physical barrier around a conventionally sutured tendon. Six New Zealand White rabbits had one Achilles tendon fully transsected and sutured by a 4-strand suture. Another six rabbits had the same treatment, but with the additional electrospun DegraPol tube set around the sutured tendon. The adhesion formation to the surrounding tissue was investigated 12 weeks post-operation. Moreover, inflammation-related protease-activated receptor-2 (PAR-2) protein expression was assessed. Finally, rabbit Achilles tenocyte cultures were exposed to platelet-derived growth factor-BB (PDGF-BB), which mimicks the tendon healing environment, where PAR-2 gene expression was assessed as well as immunofluorescent staining intensity for F-actin and α-tubulin, respectively. At 12 weeks post-operation, the partially degraded DegraPol tube exhibited significantly lower adhesion formation (- 20%). PAR-2 protein expression was similar for time points 3 and 6 weeks, but increased at 12 weeks post-operation. In vitro cell culture experiments showed a significantly higher PAR-2 gene expression on day 3 after exposure to PDGF-BB, but not on day 7. The cytoskeleton of the tenocytes changed upon PDGF-BB stimulation, with signs of reorganization, and significantly decreased F-actin intensity. An electrospun DegraPol tube significantly reduces adhesion up to twelve weeks post-operation. At this time point, the tube is partially degraded, and a slight PAR-2 increase was detected in the DP treated tendons, which might however arise from particles of degrading DegraPol that were stained dark brown. PAR-2 gene expression in rabbit tenocytes reveals sensitivity at around day 10 after injury.

Utility of total cell-free DNA levels for surgical damage evaluation in patients with urological surgeries.

The evaluation of surgical damage is challenging because of the lack of specific biomarkers. Total cell-free DNA (cfDNA) levels have been reported to increase with external trauma and may be a biomarker for tissue damage. To investigate the utility of perioperative total cfDNA levels in evaluating surgical damage in urological surgeries. This multicenter, prospective, observational study included 196 patients scheduled for urological surgeries between September 2020 and July 2021. The primary outcome was the change in total cfDNA levels before and after urological surgery. The secondary outcome was the effect of surgical type on total cfDNA ratio before and after urological surgery. The postoperative median total cfDNA level of the 196 patients was significantly increased 2.5-fold compared to the preoperative level (185.2 ng/mL vs. 406.7 ng/mL, P < 0.001). The median total cfDNA before/after ratio was greater than four-fold for kidney transplantation, open cystectomy, and open adrenalectomy. The ratio was less than two-fold for laparoscopic adrenalectomy and robot-assisted radical prostatectomy. Major surgery showed a significant postoperative increase in total cfDNA levels, while minor surgery did not. Total cfDNA levels increased 2.5-fold after urological surgery and it can be used as an acute-phase biomarker for surgical damage.

A novel miRNA-762/NFIX pathway modulates LPS-induced acute lung injury.

Severe acute lung injury (ALI) cause significant morbidity and mortality worldwide. MicroRNAs (miRNAs) are possible biomarkers and therapeutic targets for ALI. We aimed to explore the role of miR-762, a known oncogenic factor, in the pathogenesis of ALI. Levels of miR-762 in lung tissues of LPS-treated ALI mice and blood cells of patients with lung injury were measured. Injury of human lung epithelial cell line A549 was induced by LPS stimulation. A downstream target of miR-762, NFIX, was predicted using online tools. Their interactions were validated by luciferase reporter assay. Effects of targeted regulation of the miR-762/NFIX axis on cell proliferation, apoptosis, and inflammatory responses were tested in vitro in A549 cells in vivo with an ALI mouse model. We found that upregulation of miR-762 expression and downregulation of NFIX expression were associated with lung injury. Either miR-762 inhibition or NFIX overexpression in A549 lung cells significantly attenuated LPS-mediated impairment of cell proliferation and viability. Notably, increasing expressions of miR-762 inhibitor or NFIX in vivo via airway lentivirus infection alleviated the LPS-induced ALI in mice. Further, targeted downregulation of miR-762 expression or upregulation of NFIX expression in A549 cells markedly down-regulates NF-κB/IRF3 activation, and substantially reduces the production of inflammatory factors, including TNF-α, IL-6, and IL-8. This study reveals a novel role for the miR-762/NFIX pathway in ALI pathogenesis and sheds new light on targeting this pathway for diagnosis, prevention, and therapy.