Obeticholic acid attenuates the intestinal barrier disruption in a rat model of short bowel syndrome.

BACKGROUND: Short bowel syndrome (SBS) features nutrients malabsorption and impaired intestinal barrier. Patients with SBS are prone to sepsis, intestinal flora dysbiosis and intestinal failure associated liver disease. Protecting intestinal barrier and preventing complications are potential strategies for SBS treatment. This study aims to investigate the effects of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), have on intestinal barrier and ecological environment in SBS. METHODS AND RESULTS: Through testing the small intestine and serum samples of patients with SBS, impaired intestinal barrier was verified, as evidenced by reduced expressions of intestinal tight junction proteins (TJPs), increased levels of apoptosis and epithelial cell damage. The intestinal expressions of FXR and related downstream molecules were decreased in SBS patients. Then, global FXR activator OCA was used to further dissect the potential role of the FXR in a rat model of SBS. Low expressions of FXR-related molecules were observed on the small intestine of SBS rats, along with increased proinflammatory factors and damaged barrier function. Furthermore, SBS rats possessed significantly decreased body weight and elevated death rate. Supplementation with OCA mitigated the damaged intestinal barrier and increased proinflammatory factors in SBS rats, accompanied by activated FXR-related molecules. Using 16S rDNA sequencing, the regulatory role of OCA on gut microbiota in SBS rats was witnessed. LPS stimulation to Caco-2 cells induced apoptosis and overexpression of proinflammatory factors in vitro. OCA incubation of LPS-pretreated Caco-2 cells activated FXR-related molecules, increased the expressions of TJPs, ameliorated apoptosis and inhibited overexpression of proinflammatory factors. CONCLUSIONS: OCA supplementation could effectively ameliorate the intestinal barrier disruption and inhibit overexpression of proinflammatory factors in a rat model of SBS and LPS-pretreated Caco-2 cells. As a selective activator of FXR, OCA might realize its protective function through FXR activation.

Prenatal maternal inactivated COVID-19 vaccination: the maternal and neonatal outcomes, a retrospective cohort study.

Background: Despite the widespread adoption of COVID-19 vaccination, a comprehensive understanding of potential vaccine-induced adverse effects, particularly in the context of pregnancy, remains a critical area of investigation. Elevated concerns surround the maternal and neonatal outcomes subsequent to prenatal maternal COVID-19 vaccination. While existing studies have provided insights into the safety profile of COVID-19 mRNA vaccines, the extrapolation of these conclusions to inactivated COVID-19 vaccines poses uncertainties. Notably, limited data are available regarding the maternal and neonatal effects associated with inactivated COVID-19 vaccines. Objective: To evaluate the prenatal maternal inactivated COVID-19 vaccination and the impact on maternal and neonatal outcomes. Methods: This was a retrospective cohort study of women who delivered between January and June 2022 at a single university-affiliated hospital. Those who have completed at least one dose of inactivated vaccine before or during pregnancy were included in "vaccinated group," and those who were not vaccinated were included in "unvaccinated group," the maternal, pregnancy and neonatal outcomes were evaluated. Propensity score matching (PSM) was performed to balance the baseline parameters of the two groups. Results: A total of 1926 women were enrolled in this study, 827 (42.94%) women were prenatally vaccinated, and 1099 (57.06%) unvaccinated. The gestational week of delivery were slightly lower in the vaccinated group, 38.61 ± 1.89 weeks in the vaccinated group and 38.93 ± 1.49 weeks in the unvaccinated group. There was a higher rate of overall preterm delivery in the vaccinated group (aOR 1.61, 95% CI 1.07-2.42; p = 0.02), however, the probability of delivery before 34 weeks and before 32 weeks (early preterm delivery) were similar (p > 0.05). A total of 2009 infants were born, 851 in the vaccinated group and 1158 in the unvaccinated group. There were similar neonatal outcomes in the two groups. Conclusion: Although we found a slightly lower gestational week of delivery and a possible increased rate of late preterm birth in the vaccination group, there was no difference in mean neonatal weight, incidence of low birth weight infants and other neonatal adverse complications. Meanwhile, there was no difference in pregnancy and maternal outcomes between the two groups.

Ultrasound-guided anterior quadratus lumborum block at the L2 level for postsurgical analgesia in patients undergoing laparoscopic gynaecological surgery: a single-centre, randomised, double-blinded trial at a university-affiliated hospital in China.

OBJECTIVE: This study aimed to investigate the analgesic effect of an ultrasound-guided anterior quadratus lumborum block (QLB) at the L2 level on postoperative pain after laparoscopic gynaecological surgery. DESIGN: Prospective single-centre randomised double-blind trial. SETTING: University-affiliated hospital. PARTICIPANTS: Sixty patients aged between 18 and 65 years scheduled for laparoscopic gynaecological surgery. INTERVENTIONS: Before surgery, bilateral anterior QLB was performed with 20 mL of 0.375% ropivacaine injected on each side in the QLB group, whereas equal amount of saline was administered in the placebo group. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was the cumulative morphine dose in the first 24 hours, and the secondary endpoints were morphine consumption at each time interval, area under the curve (AUC) of the numeric rating scale (NRS) for pain, maximum pain intensity, incidence of moderate-to-severe pain (NRS>3), sedation score, adverse events, and time to home-readiness. RESULTS: Cumulative morphine consumption in the first 24 hours after surgery was significantly lower in the QLB group than in the placebo group (mean difference, 14.2; 95% CI 6.3 to 22.1; p<0.001). The AUCs of NRS pain intensity scores, including visceral and incisional pain at rest and on movement, were significantly lower in the QLB group than in the placebo group (all p<0.001). The time to home-readiness was significantly shorter in the QLB group than in the placebo group (p<0.05). CONCLUSION: Ultrasound-guided anterior QLB at the L2 level significantly reduced morphine consumption and relieved visceral and incision pain intensity after laparoscopic gynaecological surgery, which was beneficial for enhanced recovery. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR-IOR-17011960).

Association between different insulin resistance surrogates and infertility in reproductive-aged females.

BACKGROUND: Obesity and metabolic syndrome are observed more frequently in infertile women, and insulin resistance (IR) is closely related to them. However, there are no studies that have examined the association between different IR surrogates and female infertility, hence we investigated the potential association between them in the general population. METHODS: This was a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES, 2013-2018). The association of different IR surrogates (HOMA-IR index, TyG index and TyG-BMI index) with female infertility was estimated by multivariable regression analysis. RESULTS: After adjusting for confounders, the HOMA-IR index and TyG index did not show an association with female infertility, while the TyG-BMI index was found to have a positive association with female infertility (OR = 1.01, 95% CI: 1.00, 1.01; P < 0.0001), and the OR of the TyG-BMI group T3 (≥ 255.55) was significantly different compared to the group T1 (< 185.31) (OR = 3.02, 95% CI: 1.62, 5.60). Similar results were seen in most of the subgroup participants by stratified analysis (P-interaction > 0.05). However, different IR surrogates did not show variability in their ability to predict infertility [TyG-BMI: 0.68 (95% CI: 0.62, 0.74) vs. TyG: 0.62 (95% CI: 0.57, 0.68) vs. HOMA-IR: 0.65 (95% CI: 0.60, 0.71)]. CONCLUSIONS: Our result suggests that high levels of TyG-BMI index were positively associated with female infertility in US reproductive-aged females.

A negative association between triglyceride glucose-body mass index and testosterone in adult males: a cross-sectional study.

Background and objectives: Insulin resistance (IR) is closely related to the decline or deficiency of testosterone in males. Triglyceride glucose-body mass (TyG-BMI) is considered to be a novel indicator of IR. We conducted this analysis to investigate the association between TyG-BMI and male testosterone, and to explore whether its ability to predict testosterone deficiency is superior to HOMA-IR and TyG. Methods: This was a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES, 2011-2016). The TyG-BMI index was calculated from serum triglyceride, fasting plasma glucose and BMI. The association of TyG-BMI with male testosterone was estimated by weighted multivariable regression. Results: We included 3394 participants for the final analysis. After adjusting for confounders, TyG-BMI was found to show an independent negative association with testosterone (ß=-1.12, 95%CI: -1.50, -0.75, P<0.0001). Multivariate-adjusted beta also showed testosterone levels were significantly lower in the two highest TyG-BMI group (Q3, Q4) compared to the lowest group (Q1). Similar results were seen in all of the subgroup populations by stratified analysis (all P-interaction >0.05). Furthermore, ROC curve analysis indicated that the area under the curve of TyG-BMI index (0.73, 95% CI: 0.71, 0.75) was larger than that of HOMA-IR index (0.71, 95% CI: 0.69, 0.73) and TyG index (0.66, 95% CI: 0.64, 0.68). Conclusion: Our result suggested a negative association between TyG-BMI index and testosterone in adult males. The predictability of the TyG-BMI index for testosterone deficiency is better than that of HOMA-IR index and TyG index.

Role of galectin-3 in vascular calcification.

Vascular calcification is an abnormal process in which bone specific hydroxyapatite crystals are actively deposited on the vascular wall mediated by phenotypic differentiated smooth muscle cells and other mesenchymal cells under various pathological conditions. It is one of the important characteristics in the occurrence and development of atherosclerosis, prevalent in patients with type 2 diabetes and advanced chronic kidney disease, especially those requiring maintenance hemodialysis, with severely threatening human health. Previous studies have shown that the early diagnosis and control of vascular calcification is of great significance for cardiovascular risk stratification, prevention of acute cardiovascular events, which can greatly improve the prognosis and quality of life of patients. Galectins are a family of lectin superfamily. It is widely distributed in various animals and plays an important role in many physiological and pathological processes, such as cell adhesion, apoptosis, inflammatory response, tumor metastasis and so on. Many biomarker-and association-related studies and Preclinical-mechanistic studies have suggested that galactose-specific lectin-3 (galectin-3) plays an important role in vascular calcification and vascular intimal calcification (VIC) calcification induced by Wnt/ßcatenin signaling pathway, NF-κB signaling pathway and ERK1/2 signaling pathway. This paper mainly expounds the role and mechanism of galectin-3 in vascular calcification under different pathological conditions including atherosclerosis, diabetes and chronic kidney disease.

The utility of a multi-orifice epidural catheter when using the "Spray-as-You-Go" technique for topical Airway Anesthesia during Flexible Bronchoscopy, a randomised trial.

BACKGROUND: Lidocaine administered through the working channel of a flexible bronchoscope can provide effective local anesthesia but cannot achieve good distribution in the airway. This study was undertaken to determine whether lidocaine delivered via a multi-orifice epidural catheter (three orifices/openings) is superior to conventional method and if a better distribution and decreased the cough reflex can be achieved. METHODS: The patients (N = 100; 50 in each group) were randomized to receive either topical airway anesthesia by the "spray-as-you-go" technique via conventional application (group C) through the working channel of the bronchoscope or via a triple-orifice epidural catheter (group E). The primary outcome measurement was the cough severity, which was documented using a 4-point scale. Bronchoscopists and nurses assessed the coughing. The visual analogue scale (VAS) score for cough, total consumption of propofol and lidocaine, requirement frequency of propofol and topical anesthesia, PACU retention time, and adverse events were also compared. RESULTS: There was a significant difference in the median cough severity scores between the two groups (group C: 3 vs. group E: 2, P = 0.004). The median visual analogue scale (VAS) scores for the cough, were significantly higher in group C than those in group E (bronchoscopist: 3 vs. 2 P = 0.002; nurse: 3 vs. 2, P < 0.001). The incidence of cough was significantly higher in group C in the trachea, left and right bronchi. The highest respiratory rate was higher in group C than in group E (P < 0.01). Eight patients in group C and two patients in group E had an oxygen saturation below 90% during flexible bronchoscopy(FB) (P = 0.046). More patients in group C required extra topical anesthesia than in group E (P < 0.001). The total lidocaine consumption was also higher in group C than that in group E (P < 0.001). CONCLUSIONS: Endotracheal topical anesthesia via the multi-orifice epidural catheter (three holes/openings) during flexible bronchoscopy using the "spray-as-you-go" technique was appeared to be superior to the conventional method.

Dose-response association between 24-hour total movement activity and testosterone deficiency in adult males.

Background and objectives: Previous studies on the relationship between physical activity and testosterone are limited and controversial. Hence we investigated whether high level of physical activity is associated with a low risk of testosterone deficiency (TD). Methods: This cross-sectional analysis was conducted in a representative sample of US adult males who participated in the 2011-2014 cycle of the National Health and Nutrition Examination Survey (NHANES). We used the monitor independent movement summary (MIMS) to assess activity intensity, a novel physical activity metrics developed using raw data collected by accelerometers. Multivariable regression and smooth curve fitting was used to describe the relationships between physical activity and TD, and segmented regression model were used to analyze the threshold effect between them. Sensitivity analysis was conducted using interaction and stratified analysis. Results: A U-shaped relationship between daily MIMS units and risk of TD was observed. The optimal value of daily MIMS units for the lowest risk of TD was 14.77 (×103), the risk of TD decreased by 5% in patients per unit increase of daily MIMS units when daily MIMS units <14.77 (×103) (adjusted OR = 0.95, 95%CI: 0.91, 0.99), but increased by 12% per unit increase of daily MIMS units when daily MIMS units ≥14.77 (×103) (adjusted OR = 1.12, 95%CI: 1.01, 1.23). In sensitivity analyses, the threshold effect was also similar according to baseline characteristics (P-interaction >0.05). Conclusion: In a nationally representative sample of US adult males, light to moderate intensity physical activity is associated with a lower odds of TD, while high-intensity physical activity is associated with a higher risk of TD.

The Relationship between Perceived Social Support and Life Satisfaction: The Chain Mediating Effect of Resilience and Depression among Chinese Medical Staff.

Medical staff are direct providers of medical services and a key element in the development of health services, and their life satisfaction is important to both their work satisfaction and their patients' satisfaction, subsequently influencing the quality of medical care in general. This cross-sectional study aimed to explore the mechanisms underlying the influence of perceived social support on medical staff's life satisfaction. Convenience sampling was used to recruit participants from two non-tertiary hospitals in Shaoguan City, Guandong Province, China. A total of 533 medical staff completed the Multidimensional Scale of Perceived Social Support, the Satisfaction with Life Scale, the Connor and Davidson Resilience Scale, and the depression subscale of the Depression, Anxiety, and Stress Scales (DASS-21). The results showed that perceived social support could influence medical staff's life satisfaction not only through the separate effects of resilience and depression, but also through the chain mediation effect of resilience and depression. This study suggests that reducing the depressive symptoms of medical staff and improving their perceived social support as well as resilience could help to enhance their life satisfaction.

Anterior Quadratus Lumborum block area comparison in the three different volumes of Ropivacaine: a double-blind, randomized controlled trial in healthy volunteers.

BACKGROUND: In abdominal surgery, ultrasound-guided anterior quadratus lumborum blocks (QLB) are performed to induce analgesia. However, no study reported suitable volumes of the anterior QLB for the different postoperative analgesia regions. Therefore, this prospective randomized controlled study assessed the dermatomal spread and analgesic effects of the three different volumes of a local anesthetic for anterior QLB. METHODS: Ultrasound-guided anterior QLB was performed at the L2 level on 30 healthy volunteers. The volunteers were randomized to receive 20 ml (n = 10), 30 ml (n = 10), and 40 mL (n = 10) of 0.375% ropivacaine. The cutaneous sensory blocked area (CSBA), the number of block dermatomes, and the block duration time were measured by determining the extent of the cold sensation. RESULTS: The CSBA was significantly larger in the 40 ml group than in the 30 (P = 0.001; 1350.6 ± 234.4 vs. 1009.5 ± 151.6 cm2) and 20 ml groups (P < 0.001; 1350.6 ± 234.4 vs. 808.1 ± 120.5 cm2). Similarly, the number of blocked dermatomes was significantly higher in the 40 ml group than in the 30- and 20-ml groups. However, no significant difference was observed in block duration among the groups. CONCLUSIONS: No difference was observed in block duration with the various volumes of 0.375% ropivacaine. However, the larger volume for anterior QLB contributed to a larger area of cutaneous sensory blockade. Appropriate volumes in anterior QLB can create suitable postoperative analgesia levels for the different operative sites. TRIAL REGISTRATION: The study was registered in the Chinese Clinical Trial Registration Center on www.chictr.org.cn on 27th April 2018 (registration number: ChiCTR-IOR-17010853).

The difference of gut microbiome in different biliary diseases in infant before operation and the changes after operation.

BACKGROUND: Evidence supports an association between cholestatic liver disease and changes in microbiome composition. Nevertheless, the identification of this special type of biliary atresia from non-biliary atresia cholestasis is still a major clinical difficulty. The purpose of this study is to compare the differences in the composition of gut microbiome between infants with biliary atresia and infant with non-biliary atrestic cholestasis, to find new ways to identify and diagnose these two diseases early, to understand the influence of the presence or absence of bile on the composition of the gut microbiome in infants with cholestasis. METHODS: Using 16S rDNA gene sequencing technology to analyze the intestinal flora of the participants. RESULTS: In terms of diversity, there is an obvious structural separation in the intestinal microbiota of the BA group and the CD group, and this structural separation also exists in the comparison between the two groups before surgery. Taxonomic analysis demonstrated that the two groups showed an increase in Proteobacteria and Firmicutes before surgery, and the relative abundance of potential pathogens such as Shigella, Streptococcus, Klebsiella, etc. increased, potential probiotics such as Bifidobacteria and Lactobacillus decreased, but the relative abundance of each genus was different between groups. It was found that Enterococcus, Ralstonia, Nitriliruptoraceae, etc. were differentially enriched in the BA group, the CD group are mainly enriched in Veillonella, Clostridium_sensu_stricto_1 and Lactobacillus. Functional analysis of the groups showed that the BA group mainly focused on the processes of energy release processes, and the CD group mainly focused on the biosynthesis of amino-acids to consume energy. CONCLUSIONS: The composition of intestinal flora is different between biliary atresia and non-biliary atretic cholestasis. Enterococcus, Ralstonia, etc. may become biomarkers for the identification and diagnosis of both.

Effects of Intestinal FXR-Related Molecules on Intestinal Mucosal Barriers in Biliary Tract Obstruction.

Background: The farnesoid X receptor (FXR) is a key factor regulating hepatic bile acid synthesis and enterohepatic circulation. Repression of bile acid synthesis by the FXR is a potential strategy for treating cholestatic liver disease. However, the role of intestinal FXR on the intestinal barrier and intestinal microbiota needs further investigation. Materials: Intestinal tissues were collected from patients with biliary atresia or without hepatobiliary disease. Then, intestinal mRNA levels of FXR-related molecules were determined. To investigate the effect of FXR activation, bile-duct-ligation rats were treated with obeticholic acid [OCA (5 mg/kg/day)] or vehicle (0.5% methyl cellulose) per oral gavage for 14 days. The mRNA levels of intestinal FXR, SHP, TNF-α, FGF15 and bile acid transporter levels were determined. In addition, the intestinal permeability, morphologic changes, and composition of the intestinal microbiota were evaluated. Gut Microbiome was determined by 16S rDNA MiSeq sequencing, and functional profiling of microbial communities was predicted with BugBase and PICRUSt2. Finally, the role of OCA in injured intestinal epithelial cell apoptosis and proliferation was examined by pretreatment with lipopolysaccharide (LPS) in Caco-2 cells. Results: The downstream of the FXR in ileum tissues was inhibited in biliary obstruction. Activation of the FXR signaling pathway by OCA significantly reduced liver fibrosis and intestinal inflammation, improved intestinal microbiota, and protected intestinal mucosa in BDL rats. OCA also altered the functional capacities of ileum microbiota in BDL rats. Significant differences existed between the controls and BDL rats, which were attenuated by OCA in the alpha diversity analysis. Principal coordinates analysis showed that microbial communities in BDL rats clustered separately from controls, and OCA treatment attenuated the distinction. Bugbase and PICRUSt2 analysis showed that OCA changed the composition and structure of the intestinal microbiota and improved the metabolic function of the intestinal microbiota by increasing the relative abundance of beneficial bacteria and reducing the relative abundance of harmful bacteria. Moreover, OCA reduced the apoptosis induced by LPS in Caco-2 cells. Conclusion: The FXR agonist, OCA, activates the intestinal FXR signaling pathway and improves the composition and structure of the intestinal microbiota and intestinal barrier in BDL rats.

KGF-2 Protects against Lung Ischemia-Reperfusion Injury by Inhibiting Inflammation-Induced Damage to Endothelial Barrier Function.

Lung ischemia-reperfusion injury (LIRI), which has a mortality rate of approximately 50%, is a popular topic in critical care research. Keratinocyte growth factor-2 (KGF-2) is secreted by mesenchymal cells, and it is effective in promoting the proliferation, migration, and differentiation of various epithelial cells. To date, however, only a few reports on KGF-2-related regulators in LIRI have been published. In the current study, an LIRI rat model is constructed, and the upregulation of the fibroblast growth factor receptor 2 (FGFR2) is observed in the LIRI rat model. In addition, LIRI induces NLRP1 inflammasome activation in vivo and in vitro, and KGF-2 inhibits LIRI-induced damage to pulmonary microvascular endothelial cells. Mechanistically, KGF-2 inhibits NLRP1 inflammasome and NF-κB activity. KGF-2 inhibition attenuates LIRI injury-induced damage to endothelial integrity. In conclusion, KGF-2 protects against LIRI by inhibiting inflammation-induced endothelial barrier damage.

Polyphyllin I alleviates inflammatory injury in mice with gestational diabetes through AMPK pathway.

Our study aimed to detect the effects of polyphyllin I (PPI) on relieving gestational diabetes mellitus (GDM), and the possible mechanism. A mouse model of GDM was constructed. The effects of PPI on GDM mice were evaluated by detecting blood glucose, insulin level, glucose tolerance test, and insulin tolerance test. The inflammation response in GDM and GDM+PPI group were evaluated by enzyme-linked immunosorbent assay (ELISA). The effect of PPI on the offspring of GDM mice was analyzed. In addition, immunoblot assays were performed to investigate the effects of PPI on the AMPK pathway. We found that PPI improved diabetes-related symptoms and decreased serum inflammatory response in GDM mice. In addition, we also found that PPI reduced the tissue damage of GDM mice. We noticed that PPI alleviated inflammatory injury in GDM mice through targeting AMPK pathway. Our findings showed that PPI has the potential to be explored as the drug for GDM treatment.

Generation of an induced pluripotent stem cell line from a patient with Angelman syndrome carrying UBE3A mutation.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by abnormal expression or function defects of the UBE3A gene in the maternal chromosome region 15q11-13. In order to study the pathogenesis of Angelman syndrome and further search for its effective treatment, we established a human induced pluripotent stem cells (iPSCs) from an AS patient carrying the mutation p.Asp563Gly of UBE3A gene at maternal 15q11.2-q13. The established patient-derived iPSC showed normal karyotype, expressed pluripotency markers, and had the capacity to differentiate into three germ layers.

Apelin-13 Reverses Bupivacaine-Induced Cardiotoxicity via the Adenosine Monophosphate-Activated Protein Kinase Pathway.

BACKGROUND: Cardiotoxicity can be induced by the commonly used amide local anesthetic, bupivacaine. Bupivacaine can inhibit protein kinase B (AKT) phosphorylation and activated adenosine monophosphate-activated protein kinase alpha (AMPKα). It can decouple mitochondrial oxidative phosphorylation and enhance reactive oxygen species (ROS) production. Apelin enhances the phosphatidylinositol 3-kinase (PI3K)/AKT and AMPK/acetyl-CoA carboxylase (ACC) pathways, promotes the complete fatty acid oxidation in the heart, and reduces the release of ROS. In this study, we examined whether exogenous (Pyr1) apelin-13 could reverse bupivacaine-induced cardiotoxicity. METHODS: We used the bupivacaine-induced inhibition model in adult male Sprague Dawley (SD) rats (n = 48) and H9c2 cardiomyocyte cell cultures to explore the role of apelin-13 in the reversal of bupivacaine cardiotoxicity, and its possible mechanism of action. AMPKα, ACC, carnitine palmitoyl transferase (CPT), PI3K, AKT, superoxide dismutase 1 (SOD1), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p47-phox) were quantified. Changes in mitochondrial ultrastructure were examined, and mitochondrial DNA, cell viability, ROS release, oxygen consumption rate (OCR) were determined. RESULTS: Apelin-13 reduced bupivacaine-induced mitochondrial DNA lesions in SD rats (P < .001), while increasing the expression of AMPKα (P = .007) and PI3K (P = .002). Furthermore, apelin-13 blocked bupivacaine-induced depolarization of the mitochondrial membrane potential (P = .019) and the bupivacaine-induced increases in ROS (P = .001). Also, the AMPK pathway was activated by bupivacaine as well as apelin-13 (P = .002) in H9c2 cardiomyocytes. Additionally, the reduction in the PI3K expression by bupivacaine was mitigated by apelin-13 in H9c2 cardiomyocytes (P = .001). While the aforementioned changes induced by bupivacaine were not abated by apelin-13 after pretreatment with AMPK inhibitor compound C; the bupivacaine-induced changes were still mitigated by apelin-13, even when pretreated with PI3K inhibitor-LY294002. CONCLUSIONS: Apelin-13 treatment reduced bupivacaine-induced oxidative stress, attenuated mitochondrial morphological changes and mitochondrial DNA damage, enhanced mitochondrial energy metabolism, and ultimately reversed bupivacaine-induced cardiotoxicity. Our results suggest a role for the AMPK in apelin-13 reversal of bupivacaine-induced cardiotoxicity.

Dexmedetomidine preconditioning ameliorates lung injury induced by pulmonary ischemia/reperfusion by upregulating promoter histone H3K4me3 modification of KGF-2.

Keratinocyte growth factor (KGF)-2 has been highlighted to play a significant role in maintaining the endothelial barrier integrity in lung injury induced by ischemia-reperfusion (I/R). However, the underlying mechanism remains largely unknown. The aims of this study were to determine whether dexmedetomidine preconditioning (DexP) modulates pulmonary I/R-induced lung injury through the alteration in KGF-2 expression. In our I/R-modeled mice, DexP significantly inhibited pathological injury, inflammatory response, and inflammatory cell infiltration, while promoted endothelial barrier integrity and KGF-2 promoter activity in lung tissues. Bioinformatics prediction and ChIP-seq revealed that I/R significantly diminished the level of H3K4me3 modification in the KGF-2 promoter, which was significantly reversed by DexP. Moreover, DexP inhibited the expression of histone demethylase JMJD3, which in turn promoted the expression of KGF-2. In addition, overexpression of JMJD3 weakened the protective effect of DexP on lung injury in mice with I/R. Collectively, the present results demonstrated that DexP ameliorates endothelial barrier dysfunction via the JMJD3/KGF-2 axis.

Dexmedetomidine may decrease the bupivacaine toxicity to heart.

OBJECTIVE: The purpose of our study was to explore the effect of dexmedetomidine on cardiac tolerance to bupivacaine. METHOD: Human coronary endothelial cells were used to establish in vitro model. They were randomly divided into control (Con) group, dexmedetomidine (Dex) group, bupivacaine (Bupi) group, dexmedetomidine + bupivacaine group (DB group), and dexmedetomidine + bupivacaine + PI3K inhibitor (DB-inhibitor) group. Cell activity was measured by Cell counting kit-8 (CCK-8). Transwell was used to detect cell permeability. Western blotting was used to detect the protein expression of related factors. RESULTS: There were no notable differences in cell activity among the five groups (P > 0.05). Dexmedetomidine significantly reduced the permeability of endothelial cells to bupivacaine and increased the protein expression of Zonulaoeeludens-1 (ZO-1) (P < 0.01). However, the aforementioned effects of dexmedetomidine were disappeared after the addition of PI3K inhibitors. Furthermore, Dex and DB markedly increased the protein expression of PI3K, p-Akt, and p-PTEN in comparison with Con group (P < 0.001), but there was no significant difference in p-PTEN among DB-inhibitor, Con, and Bupi groups (P > 0.05). CONCLUSION: Dex reduced Bupi-induced vasopermeability through protein expression of ZO-1 and PI3K/Akt pathway, which may lead to the decrease of Bupi-induced cardiotoxicity.

Role of NFAT in the Progression of Diabetic Atherosclerosis.

Nuclear factor of activated T cells (NFAT) is a transcription factor with a multidirectional regulatory function, that is widely expressed in immune cells, including cells in the cardiovascular system, and non-immune cells. A large number of studies have confirmed that calcineurin/NFAT signal transduction is very important in the development of vascular system and cardiovascular system during embryonic development, and plays some role in the occurrence of vascular diseases such as atherosclerosis, vascular calcification, and hypertension. Recent in vitro and in vivo studies have shown that NFAT proteins and their activation in the nucleus and binding to DNA-related sites can easily ɨnduce the expression of downstream target genes that participate in the proliferation, migration, angiogenesis, and vascular inflammation of vascular wall related cells in various pathophysiological states. NFAT expression is regulated by various signaling pathways, including CD137-CD137L, and OX40-OX40L pathways. As a functionally diverse transcription factor, NFAT interacts with a large number of signaling molecules to modulate intracellular and extracellular signaling pathways. These NFAT-centered signaling pathways play important regulatory roles in the progression of atherosclerosis, such as in vascular smooth muscle cell phenotypic transition and migration, endothelial cell injury, macrophage-derived foam cell formation, and plaque calcification. NFAT and related signaling pathways provide new therapeutic targets for vascular diseases such as atherosclerosis. Hence, further studies of the mechanism of NFAT in the occurrence and evolution of atherosclerosis remain crucial.

Single and Repeated Intrapleural Ropivacaine Administration: A Plasma Concentration and Pharmacodynamics Study.

BACKGROUND: Intrapleural analgesia has been increasingly recommended for postoperative analgesia after thoracic surgery. However, the analgesic effect provided by a single intrapleural administration is time limited. This study reports the efficacy and safety of repeated intrapleural 0.75% ropivacaine administration after thoracoscopic surgery. METHODS: Twenty patients were randomly divided into two groups: a single administration group receiving a single intrapleural injection of 0.75% ropivacaine 15 mL (single administration group, SA group), and a repeated administration group with an intrapleural injection of 0.75% ropivacaine 15 mL every 4h for 4 doses (repeated administration group, RA group). The primary outcomes of this study were the peak plasma concentration of ropivacaine and 24h morphine consumption. The secondary outcomes were pain score, patient satisfaction, extubation time, hospital length of stay, and adverse reactions. RESULTS: In SA group, the highest plasma concentration after intrapleural administration of 0.75% ropivacaine 15 mL was 1345±364 µg/L. The highest plasma concentration in RA group after the fourth administration was 1864±492 µg/L. The 24h morphine consumption in RA group was significantly less than that in SA group (9.0±5.66 vs 15.9±3.48 mg, P=0.004). The NRS scores at rest and while coughing of patients in RA group were significantly lower than those in SA group at 5, 9, 13, 17 and 24h after operation. The patients in RA group had higher satisfaction than those in SA group. There was no significant difference in postoperative adverse events, drainage tube placement days and hospital length of stay between the two groups. CONCLUSION: Repeated intrapleural administration with 0.75% ropivacaine, 15 mL every 4h for 4 doses after video-assisted thoracoscopic lobectomies, can provide a more durable and more effective analgesic effect than single intrapleural administration. Repeated intrapleural administration of ropivacaine is an effective postoperative method of analgesia resulting in higher patient satisfaction. Moreover, it was also able to keep the plasma concentration of ropivacaine within a possible safe range. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-IOR-17010560.