Cell type-specific DNA methylome signatures reveal epigenetic mechanisms for neuronal diversity and neurodevelopmental disorder.

DNA methylation plays a critical function in establishing and maintaining cell identity in brain. Disruption of DNA methylation-related processes leads to diverse neurological disorders. However, the role of DNA methylation characteristics in neuronal diversity remains underexplored. Here, we report detailed context-specific DNA methylation maps for GABAergic, glutamatergic (Glu) and Purkinje neurons, together with matched transcriptome profiles. Genome-wide mCH levels are distinguishable, while the mCG levels are similar among the three cell types. Substantial CG-differentially methylated regions (DMRs) are also seen, with Glu neurons experiencing substantial hypomethylation events. The relationship between mCG levels and gene expression displays cell type-specific patterns, while genic CH methylation exhibits a negative effect on transcriptional abundance. We found that cell type-specific CG-DMRs are informative in terms of represented neuronal function. Furthermore, we observed that the identified Glu-specific hypo-DMRs have a high level of consistency with the chromatin accessibility of excitatory neurons and the regions enriched for histone modifications (H3K27ac and H3K4me1) of active enhancers, suggesting their regulatory potential. Hypomethylation regions specific to each cell type are predicted to bind neuron type-specific transcription factors. Finally, we show that the DNA methylation changes in a mouse model of Rett syndrome, a neurodevelopmental disorder caused by the de novo mutations in MECP2, are cell type- and brain region-specific. Our results suggest that cell type-specific DNA methylation signatures are associated with the functional characteristics of the neuronal subtypes. The presented results emphasize the importance of DNA methylation-mediated epigenetic regulation in neuronal diversity and disease.

cypress: an R/Bioconductor package for cell-type-specific differential expression analysis power assessment.

SUMMARY: Recent methodology advances in computational signal deconvolution have enabled bulk transcriptome data analysis at a finer cell-type level. Through deconvolution, identifying cell-type-specific differentially expressed (csDE) genes is drawing increasing attention in clinical applications. However, researchers still face a number of difficulties in adopting csDE detection methods in practice, especially in their experimental design. Here we present cypress, the first experimental design and statistical power analysis tool in csDE identification. This tool can reliably model purified cell-type-specific (CTS) profiles, cell-type compositions, biological and technical variations, offering a high-fidelity simulator for bulk RNA-seq convolution and deconvolution. cypress conducts simulation and evaluates the impact of multiple influencing factors, by various biostatistical metrics, to help researchers optimize experimental design and conduct power analysis. AVAILABILITY AND IMPLEMENTATION: cypress is an open-source R/Bioconductor package at https://bioconductor.org/packages/cypress/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

LRcell: detecting the source of differential expression at the sub-cell-type level from bulk RNA-seq data.

Given most tissues are consist of abundant and diverse (sub-)cell types, an important yet unaddressed problem in bulk RNA-seq analysis is to identify at which (sub-)cell type(s) the differential expression occurs. Single-cell RNA-sequencing (scRNA-seq) technologies can answer the question, but they are often labor-intensive and cost-prohibitive. Here, we present LRcell, a computational method aiming to identify specific (sub-)cell type(s) that drives the changes observed in a bulk RNA-seq experiment. In addition, LRcell provides pre-embedded marker genes computed from putative scRNA-seq experiments as options to execute the analyses. We conduct a simulation study to demonstrate the effectiveness and reliability of LRcell. Using three different real datasets, we show that LRcell successfully identifies known cell types involved in psychiatric disorders. Applying LRcell to bulk RNA-seq results can produce a hypothesis on which (sub-)cell type(s) contributes to the differential expression. LRcell is complementary to cell type deconvolution methods.

Clinical value of prokineticin 2 in the diagnosis of neonatal necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is an inflammatory and necrotizing intestinal emergency that occurs in preterm infants and low birth weight newborns, however no specific serum markers for the diagnosis of NEC has been identified so far. Prokineticin 2 (PK2) is a newly identified immunomodulator in a variety of inflammatory diseases. METHODS: Serum samples were collected from healthy neonatal controls and patients with NEC newly admitted to the Children's Hospital of Chongqing Medical University from January 1, 2021 to January 1, 2022 (before clinical intervention and after surgical treatment). ELISA was used to measure serum PK2 levels, and values, including white blood cell count (WBC), neutrophil-lymphocyte ratio (NLR), procalcitonin (PCT), C-reactive protein (CRP) and platelet (PLT), were analysed; the efficiency of PK2 combined with the above biomarkers in the differential diagnosis of NEC was compared using receiver operating characteristic (ROC) curve analysis. RESULTS: Serum PK2 levels in the NEC group (n = 53) were significantly lower than those in the control group (n = 18), but increased to near-normal levels after the postoperative recovery period. The NLR value of NEC group was higher than that of control group (P < 0.05). There was no significant difference in WBC and PLT count between NEC group and control group (P > 0.05). Serum CRP and PCT levels in NEC group were significantly higher than those in control group (P < 0.001 for CRP and P < 0.05 for PCT, respectively). After surgery, serum CRP, NLR and PCT levels were lower than before surgery, while serum PK2 levels were higher than before surgery (P < 0.05). The areas under the ROC curve (AUC) of PK2, PCT and CRP for the diagnosis of NEC were 0.837, 0.662 and 0.552, respectively. The AUC of PK2 combined with PCT, PK2 combined with CRP, and PK2 combined with PCT and CRP were 0.908, 0.854, and 0.981, respectively. PK2 exhibited the highest diagnostic efficacy for NEC. CONCLUSION: PK2 has higher diagnostic efficacy than PCT and CRP in the diagnosis of NEC, the combination of PK2 and PCT or CRP can significantly improve its diagnostic efficiency, especially when the three are combined at the same time.

Synthesis and antihepatoma activity of guaianolide dimers derived from lavandiolide I.

Guaianolide dimers represent a unique class of natural products with anticancer activities, but their low content in plants has limited in-depth pharmacological studies. Lavandiolide I is a guaianolide dimer isolated from Artemisia species, and had been synthesized on a ten-gram scale in four steps with 60 % overall yield, which showed potent antihepatoma activity on the HepG2, Huh7, and SK-Hep-1 cell lines with IC50 values of 12.1, 18.4, and 17.6 µM, respectively. To explore more active dimers, 33 lavandiolide I derivatives were designed, synthesized, and evaluated for their inhibitory activity on human hepatoma cell lines. Among them, 10 derivatives were more active than lavandiolide I and sorafenib on the three cell lines. The primary structure-activity relationship concluded that the introduction of aldehyde, ester, azide, amide, carbamate and urea functional groups at C-14' of the guaianolide dimer significantly enhanced the antihepatoma activity. Among these compounds, derivatives 25, 27, and 33 enhanced antihepatoma activity more than 1.2-5.8 folds than that of lavandiolide I, and demonstrated low toxicity to the human liver cell lines (THLE-2) and good safety profiles with selective index ranging from 1.3 to 3.4, while lavandiolide I was more toxic to THLE-2 cells. This work provides new insights into enhancing the antihepatoma efficacy and reducing the toxicity of sesquiterpenoid dimers.

Ferroptosis inducers: A new frontier in cancer therapy.

Ferroptosis represents a non-apoptotic form of programmed cell death characterized by iron-dependent lipid peroxidation. This cell death modality not only facilitates the direct elimination of cancer cells, but also enhances their susceptibility to other pharmacological anti-cancer agents. The burgeoning interest in ferroptosis has been driven by a growing body of evidence that underscores the efficiency and minimal toxicity of ferroptosis inducers. Traditional inducers, such as erastin and RSL3 have shown substantial promise in clinical applications due to their potent therapeutic effects. Their significant potential of these inducers has spurred the development of a variety of small molecule ferroptosis inducers. These novel inducers boast an enhanced structural variety, improved metabolic stability, the capability to initiate ferroptosis without triggering apoptosis, making them well-suited for in vivo use. Despite these advancements, challenges still remain, particularly concerning the drug delivery, tumor specificity, and circulation duration of these small molecules in vivo. Addressing these challenges, contemporary research has pivoted towards innovative delivery systems tailored for ferroptosis inducers to facilitate precise, targeted, and synegestic therapeutic delivery. This review scrutinizes the latest progress in small molecule ferroptosis inducers and nano drug delivery systems geared towards ferroptosis sensitization. Furthermore, it delineated the prospective therapeutic advantages and the existing hurdles in the development of ferroptosis inducers for malignant tumor treatment.

Structure-activity relationships of natural and synthetic lathyrane-based diterpenoids for suppression of NLRP3-driven inflammation and gouty arthritis.

Lathyrane-based diterpenoid is one of the critical bioactive elements of Euphorbia lathyris L., a widely used traditional Chinese medicine for the treatment of inflammation and infection. In this study, we introduced and evaluated seven synthetic or natural lathyrane-based diterpenoids with the same core structure but notable structural variations at specific positions, for their anti-inflammatory and gout-alleviating properties. There was no significant cytotoxicity below 10 µM among the initial test of the cell counting kit 8 of the seven candidate derivatives (compounds 13 to 19) in this work. Furthermore, maintaining the acyloxy group at 15-C position and the strongly hydrophobic aryl structure at 3-C and 5-C positions, compounds 15 (Euphorbia factor L3, EFL3) and 17 strikingly inhibited the production of IL-1ß related to the actuation of the inflammasome in our study. The ELISA assay indicated that the anti-inflammatory effects of EFL3 were better associated with MSU stimulation than other second-line pathways triggered by inflammasome. Further examinations on the acute paw gout model in C57BL/6 mice showed that EFL3 had a significantly inflammatory retarding effect by intraperitoneal injection. It decreased swelling volume as well as the cleavage and activation of local IL-1ß and casepas-1 in the paw. To conclude, our findings reveal several potential key structure-activity relationships that govern the anti-inflammatory effects of lathyrane-type diterpenoids, the dispensable acyl group at the 15-C position, the importance of maintaining the spatial structure of the B-ring, and the potential importance of hydrophobic substituents at the 3-C position. These insights may provide guidance for the structural design of lathyrane-type agents in the future; furthermore, we found that the lathyrane-based diterpenoid EFL3 is a potential agent for gout that is expected to provide a novel therapeutic strategy for inflammation intervention.

Investigation the mechanism of iron overload-induced colonic inflammation following ferric citrate exposure.

Iron overload occurs due to excessive iron intake compared to the body's demand, leading to iron deposition and impairment of multiple organ functions. Our previous study demonstrated that chronic oral administration of ferric citrate (FC) caused colonic inflammatory injury. However, the precise mechanism underlying this inflammatory response remains unclear. The current study aims to investigate the mechanism by which iron overload induced by FC exposure leads to colonic inflammation. To accomplish this, mice were orally exposed to three different concentrations of FC (71 mg/kg/bw (L), 143 mg/kg/bw (M) and 286 mg/kg/bw (H)) for continuous 16 weeks, with the control group receiving ultrapure water (C). Exposure to FC caused disturbances in the excretory system, altered colonic flora alpha diversity, and enriched pathogenic bacteria, such as Mucispirillum, Helicobacter, Desulfovibrio, and Shigella. These changes led to structural disorders of the colonic flora and an inflammatory response phenotype characterized by inflammatory cells infiltration, atrophy of intestinal glands, and irregular thickening of the intestinal wall. Mechanistic studies revealed that FC-exposure activated the NF-κB signaling pathway by up-regulating TLR4, MyD88, and NF-κB mRNA levels and protein expression. This activation resulted in increased production of pro-inflammatory cytokines, further contributing to the colonic inflammation. Additionally, in vitro experiments in SW480 cells confirmed the activation of NF-κB signaling pathway by FC exposure, consistent with the in vivo findings. The significance of this study lies in its elucidation of the mechanism by which iron overload caused by FC exposure leads to colonic inflammation. By identifying the role of pathogenic bacteria and the NF-κB signaling pathway, this study could potentially offer a crucial theoretical foundation for the research on iron overload, as well as provide valuable insights for clinical iron supplementation.

The value of contrast-enhanced portal vein imaging at the hepatobiliary phase obtained with gadobenate dimeglumine for predicting decompensation and transplant-free survival in chronic liver disease.

OBJECTIVES: To investigate the value of contrast-enhanced portal vein imaging at the hepatobiliary phase obtained with gadobenate dimeglumine for predicting clinical outcomes in patients with chronic liver disease (CLD). METHODS: Three hundred and fourteen CLD patients who underwent gadobenate dimeglumine-enhanced hepatic magnetic resonance imaging were stratified into three groups: nonadvanced CLD (n = 116), compensated advanced CLD (n = 120), and decompensated advanced CLD (n = 78) groups. The liver-to-portal vein contrast ratio (LPC) and liver-spleen contrast ratio (LSC) at the hepatobiliary phase were measured. The value of LPC for predicting hepatic decompensation and transplant-free survival was assessed using Cox regression analysis and Kaplan-Meier analysis. RESULTS: The diagnostic performance of LPC was significantly better than LSC in evaluating the severity of CLD. During a median follow-up period of 53.0 months, the LPC was a significant predictor for hepatic decompensation (p < 0.001) in patients with compensated advanced CLD. The predictive performance of LPC was higher than that of the model for end-stage liver disease score (p = 0.006). With the optimal cut-off value, patients with LPC ≤ 0.98 had a higher cumulative incidence of hepatic decompensation than patients with LPC > 0.98 (p < 0.001). The LPC was also a significant predictive factor for transplant-free survival in patients with compensated advanced CLD (p = 0.007) and those with decompensated advanced CLD (p = 0.002). CONCLUSIONS: Contrast-enhanced portal vein imaging at the hepatobiliary phase obtained with gadobenate dimeglumine is a valuable imaging biomarker for predicting hepatic decompensation and transplant-free survival in CLD patients. KEY POINTS: • The liver-to-portal vein contrast ratio (LPC) significantly outperformed liver-spleen contrast ratio in evaluating the severity of chronic liver disease. • The LPC was a significant predictor for hepatic decompensation in patients with compensated advanced chronic liver disease. • The LPC was a significant predictor for transplant-free survival in patients with compensated and those with decompensated advanced chronic liver disease.

Rhodamine-based fluorescent sensors for the rapid and selective off-on detection of salicylic acid and their use in plant cell imaging.

Salicylic acid (SA) is a key hormone that regulates plant growth and immunity, and understanding the physiologic processes induced by SA enables the development of highly pathogen-resistant crops. Here, we report the synthesis of three new SA-sensors (R1-R3) from hydroxyphenol derivatives of a rhodamine-acylhydrazone scaffold and their characterization by NMR and HRMS. Spectroscopic analyses revealed that structural variations in R1-R3 resulted in sensors with different sensitivities for SA. Sensor R2 (with the 3-hydroxyphenyl modification) outperformed R1 (2-hydroxyphenyl) and R3 (4-hydroxyphenyl). The SA-detection limit of R2 is 0.9 µM with an ultra-fast response time (<60 s). In addition, their plant imaging indicated that designed sensor R2 is useful for the further study of SA biology and the discovery and development of new inducers of plant immunity.

Design, synthesis, and biological evaluation of artemyrianolide H derivatives as potential antihepatoma agents.

Artemyrianolide H (AH) is a germacrene-type sesquiterpenolid isolated from Artemisia myriantha, and showed potent cytotoxicity against three human hepatocellular carcinoma cell lines HepG2, Huh7, and SK-Hep-1 with IC50 values of 10.9, 7.2, and 11.9 µM, respectively. To reveal structure-activity relationship, 51 artemyrianolide H derivatives including 19 dimeric analogs were designed, synthesized, and assayed for their cytotoxicity against three human hepatoma cell lines. Among them, 34 compounds were more active than artemyrianolide H and sorafenib on the three cell lines. Especially, compound 25 exhibited the most promising activity with IC50 values of 0.7 (HepG2), 0.6 (Huh7), and 1.3 µM (SK-Hep-1), which were 15.5, 12.0, and 9.2-fold higher than that of AH and 16.4, 16.3 and 17.5-fold higher than that of sorafenib. Cytotoxicity evaluation on normal human liver cell lines (THLE-2) demonstrated good safety profile of compound 25 with SI of 1.9 (HepG2), 2.2 (Huh 7) and 1.0 (SK-Hep1). Further studies revealed that compound 25 dose-dependently arrested cells at G2/M phase which was correlated with the up-regulation of both cyclin B1 and p-CDK1, and induced apoptosis through the activation of mitochondrial pathways in HepG2 cells. In addition, the migratory and invasive abilities in HepG2 cells after treatment with 1.5 µM of compound 25 were decreased by 89% and 86% with the increase of E-cadherin expression accompanied by the decrease of N-cadherin, vimentin expression. Bioinformatics analysis based on machine learning predicted that PDGFRA and MAP2K2 might be acting targets of compound 25, and SPR assays demonstrated compound 25 were bound with PDGFRA and MAP2K2 with KD value of 0.168 nM, and 8.49 µM, respectively. This investigation proposed that compound 25 might be considered as a promising lead compound for the development of antihepatoma candidate.

Study on Chemical Components from Derris taiwaniana and Their Lung Epithelial Cell Protect Effects.

The ethanol extract of roots of Derris taiwaniana gave two undescribed compounds, 3,3'-dimethoxy-5'-hydroxystilbene-4-O-ß-apiofuranosyl-(1→6)-ß-D-glucopyranoside (1) and 4',5-dihydroxy-3'-methoxyisoflavone-7-O-ß-apiofuranosyl-(1→6)-ß-D-glucopyranoside (2), along with thirty known components. Among them, compounds 14, 16-17, 23, 26-32 were isolated from this genus for the first time. Their structures were established based on physico-chemical properties and spectroscopic data, the lung epithelial cell protective effects were evaluated using NNK-induced MLE-12 cells. Among them, 2α,3α-epoxy-5,7,3',4'-tetrahydroxyflavan-(4ß-8-catechin) (30) showed the best significant protective effect, speculated to be the key component of D. taiwaniana that plays a protective role in lung epithelial cells.

Optimization and multi-uncertainty analysis of best management practices at the watershed scale: A reliability-level based bayesian network approach.

Best management practices (BMPs) have been widely adopted to mitigate diffuse source pollutants, and the simulated processes of its pollutant reduction effectiveness suffer from manifold uncertainties, such as watershed model parameters and climate change. We presented a novel Bayesian modeling framework for BMPs planning, integrating process-based watershed modeling and Bayesian optimization algorithm to reveal the impact of multiple uncertainties. The proposed framework was applied to a BMPs planning case study in the Erhai watershed, the seventh-largest freshwater lake in China. Firstly, priority management areas (PMAs) were identified for BMPs siting using a simulation-optimization approach. Bayesian networks were subsequently embedded to reveal the multiple uncertainty sources in the optimal planning and the reliability level (RL) is introduced to represent the probability to meet the water quality target with BMPs implementation. The results suggest that ENS of discharge and nutrients concentration simulation by LSPC are both greater than 0.5, which displays satisfactory performance. The identified PMAs account for 0.8% of the total watershed areas while contribute to more than 15% of nutrient loadings reduction. The analysis of multiple uncertainty sources reveals that precipitation is the most influential source of uncertainties in BMP effectiveness. The construction of hedgerows plays an important role in the nutrient reduction. With the improvement of the reliability levels, the cost increases sharply, indicating that the implementation of BMPs has a marginal utility. The study addressed the urgent need for effective and efficient BMPs planning by identifying PMAs and addressing multi-source uncertainties.

High-fat diet causes mitochondrial damage and downregulation of mitofusin-2 and optic atrophy-1 in multiple organs.

High-fat consumption promotes the development of obesity, which is associated with various chronic illnesses. Mitochondria are the energy factories of eukaryotic cells, maintaining self-stability through a fine-tuned quality-control network. In the present study, we evaluated high-fat diet (HFD)-induced changes in mitochondrial ultrastructure and dynamics protein expression in multiple organs. C57BL/6J male mice were fed HFD or normal diet (ND) for 24 weeks. Compared with ND-fed mice, HFD-fed mice exhibited increased body weight, cardiomyocyte enlargement, pulmonary fibrosis, hepatic steatosis, renal and splenic structural abnormalities. The cellular apoptosis of the heart, liver, and kidney increased. Cellular lipid droplet deposition and mitochondrial deformations were observed. The proteins related to mitochondrial biogenesis (TFAM), fission (DRP1), autophagy (LC3 and LC3-II: LC3-I ratio), and mitophagy (PINK1) presented different changes in different organs. The mitochondrial fusion regulators mitofusin-2 (MFN2) and optic atrophy-1 (OPA1) were consistently downregulated in multiple organs, even the spleen. TOMM20 and ATP5A protein were enhanced in the heart, skeletal muscle, and spleen, and attenuated in the kidney. These results indicated that high-fat feeding caused pathological changes in multiple organs, accompanied by mitochondrial ultrastructural damage, and MFN2 and OPA1 downregulation. The mitochondrial fusion proteins may become promising targets and/or markers for treating metabolic disease.

Integrated Chemoenzymatic Approach to Streamline the Assembly of Complex Glycopeptides in the Liquid Phase.

Glycosylation of proteins is a complicated post-translational modification. Despite the significant progress in glycoproteomics, accurate functions of glycoproteins are still ambiguous owing to the difficulty in obtaining homogeneous glycopeptides or glycoproteins. Here, we describe a streamlined chemoenzymatic method to prepare complex glycopeptides by integrating hydrophobic tag-supported chemical synthesis and enzymatic glycosylations. The hydrophobic tag is utilized to facilitate peptide chain elongation in the liquid phase and expeditious product separation. After removal of the tag, a series of glycans are installed on the peptides via efficient glycosyltransferase-catalyzed reactions. The general applicability and robustness of this approach are exemplified by efficient preparation of 16 well-defined SARS-CoV-2 O-glycopeptides, 4 complex MUC1 glycopeptides, and a 31-mer glycosylated glucagon-like peptide-1. Our developed approach will open up a new range of easy access to various complex glycopeptides of biological importance.

The 14-3-3ζ-c-Src-integrin-ß3 complex is vital for platelet activation.

Several adaptor molecules bind to cytoplasmic tails of ß-integrins and facilitate bidirectional signaling, which is critical in thrombosis and hemostasis. Interfering with integrin-adaptor interactions spatially or temporally to inhibit thrombosis without affecting hemostasis is an attractive strategy for the development of safe antithrombotic drugs. We show for the first time that the 14-3-3ζ-c-Src-integrin-ß3 complex is formed during platelet activation. 14-3-3ζ-c-Src interaction is mediated by the -PIRLGLALNFSVFYYE- fragment (PE16) on the 14-3-3ζ and SH2-domain on c-Src, whereas the 14-3-3ζ-integrin-ß3 interaction is mediated by the -ESKVFYLKMKGDYYRYL- fragment (EL17) on the 14-3-3ζ and -KEATSTF- fragment (KF7) on the ß3-integrin cytoplasmic tail. The EL17-motif inhibitor, or KF7 peptide, interferes with the formation of the 14-3-3ζ-c-Src-integrin-ß3 complex and selectively inhibits ß3 outside-in signaling without affecting the integrin-fibrinogen interaction, which suppresses thrombosis without causing significant bleeding. This study characterized a previously unidentified 14-3-3ζ-c-Src-integrin-ß3 complex in platelets and provided a novel strategy for the development of safe and effective antithrombotic treatments.

Blow-Spun Nanofibrous Membrane for Simultaneous Treatment of Emulsified Oil/Water Mixtures, Dyes, and Bacteria.

Membrane separation is of great significance due to its unique performance in treating wastewater. However, the simultaneous treatment of oily emulsions and other complex pollutants in water remains challenging. Herein, we have proposed a simple strategy to prepare a multifunctional titanium dioxide/silver nanoparticles/polyacrylonitrile (TiO2/AgNPs/PAN) nanofibrous membrane. The experimental results showed that the combination of the hierarchical structure composed of PAN nanofibers and Ag/TiO2 nanoprotrusions contributed to the superhydrophilicity and superoleophobicity (UOCA = 153.3 ± 2.0°). Further, the nanofibrous membrane exhibited a rapid gravity-driven permeate flux (>1829.37 ± 83.51 L m-2 h-1) and an ultrahigh separation efficiency (>99.9%) for the surfactant-stabilized oil/water emulsions. Moreover, due to the synergistic effect between the PAN fibers and TiO2/Ag heterojunction, Rhodamine B dye in water can be removed quickly and efficiently (up to 97.67% in 90 min). More importantly, the obtained nanofibrous membrane exhibited ultrahigh stability in different harsh environments. The design of superoleophobic nanofiber membrane with a high separation efficiency and high photocatalytic activity has great potential for practical applications in the purification of oily wastewater.

Effect of Dexmedetomidine on Intestinal Barrier in Patients Undergoing Gastrointestinal Surgery-A Single-Center Randomized Clinical Trial.

INTRODUCTION: Gastrointestinal failure results in death in critically ill patients. This study aimed to explore the effect of dexmedetomidine (DEX) on intestinal barrier function and its mechanism in critically ill patients undergoing gastrointestinal surgery. METHODS: Patients undergoing gastrointestinal surgery were randomized into the DEX group (n = 21) or midazolam (MID) group (n = 21). Sufentanil was used for analgesia in both groups. In the DEX group, DEX was loaded (1 µg/kg) before sedation and infused (0.7 µg/kg/h) during sedation. In the MID group, MID was loaded (0.05 mg/kg) before sedation and infused (0.1 mg/kg/h) during sedation. The mean arterial pressure , heart rate , borborygmus resumption time , first defecation time, length of intensive care unit stay, and length of hospital stay were observed. The diamine oxidase (DAO), D-lactate , TNF-α, IL-6, and α7nAChR levels in plasma or hemocytes were detected before the start of sedation (0 h) and after sedation (24 h). RESULTS: No significant differences in age, sex, body mass index, Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were noted (P > 0.05). The mean arterial pressure between 0 h and 24 h showed no significant difference between the groups (P > 0.05), but the heart rate was significantly lower in the DEX group (P = 0.042). The borborygmus resumption time was significantly earlier in the DEX group (P = 0.034). The lengths of intensive care unit stay (P = 0.016) and hospital stay (P = 0.031) were significantly shorter in the DEX group. The TNF-α level in the DEX group was lower at 24 h than 0 h. The D-lactate level was significantly lower in the DEX group than the MID group at 24 h (P = 0.016). The expression of α7nAChR in the DEX group was significantly higher at 24 h than 0 h (P < 0.05). CONCLUSIONS: DEX maintained intestinal barrier integrity in patients undergoing gastrointestinal surgery through the cholinergic anti-inflammatory pathway.

Effect of individualized treatment strategy on postoperative nausea and vomiting in gynaecological laparoscopic surgery: a double-blind, randomized, controlled trial.

BACKGROUND: Postoperative nausea and vomiting (PONV) have always been a concern of clinicians and may increase medical costs for patients. Consensus guidelines recommend using multiple antiemetics with different mechanisms as prophylaxis in patients at high risk of PONV. Individualized risk scores for nausea and vomiting and individualized treatment strategies are feasible. This study evaluated the effect of individualized treatment strategies on postoperative nausea and vomiting after laparoscopic gynaecological operations. METHODS: This was a double-blind, randomized, controlled trial. A total of 119 adult patients who underwent gynaecological laparoscopic surgery under general anaesthesia were randomly divided into an individualized treatment group or a control group, with the individualized treatment group receiving individualized prevention according to a preoperative risk score of nausea and vomiting and the control group receiving no individualized prevention. Vomiting, retching, nausea, and use of rescue medication were all recorded for 24 h after the operation. The primary outcome variable was complete response, defined as no emesis or the use of rescue medication 24 h postoperatively. RESULTS: The complete response rate was higher in the individualized treatment group (56.7%) than in the control group (23.7%) (95% CI, 0.01-0.27; P < 0.001). The incidences of emesis (18.3% vs. 44.1%, P = 0.002) were significantly lower in the individualized treatment group than in the control group. There were no differences in any nausea (26.7% vs. 33.9%, P = 0.391) or rescue medication use (6.7% vs. 8.5%, P = 0.743). Adverse events and laboratory and electrocardiogram abnormalities occurred no more frequently in the individualized treatment group than in the control group. CONCLUSION: In conclusion, this single-centre, double-blind, randomized study suggests that an individualized PONV prophylactic treatment strategy based on the number of PONV risk factors could be a safe and effective regimen to reduce the incidence of PONV in adult patients undergoing laparoscopic gynaecological surgery.

iTRAQ-based identification of differentially expressed proteins in ED rat model induced by cold stress combined with environmental oestrogen.

We aim to identify serum biomarkers and key proteins of erectile dysfunction (ED) induced by cold stress combined with environmental oestrogen through iTRAQ combined with LC-MS/MS. ED rat model was established by using oestrogen-like feed and cold stimulation. Differentially expressed proteins in serum were screened and analysed with iTRAQ combined with LC-MS/MS and IPA bioanalysis platform. We found that 35 proteins were differentially expressed in the ED group, including 31 upregulated and four downregulated proteins. The molecular functions of differential proteins mainly involved the activation of endopeptidase inhibitor and regulator. The main pathways involved were the FXR/RXR activation signalling pathway and the acute phase response signalling pathway. Furthermore, three protein markers related to ED were obtained, namely C-reactive protein (CRP), T-kininogen 1 and apolipoprotein Protein H (APOH). ELISA results showed that compared with the control group, proteins of HPX, TTR, APOH, RBP4, CRP and ORM1 were significantly upregulated, but ANGPT1 protein was significantly downregulated in the serum of the ED group (p < 0.05). Conclusively, the candidate serum markers for ED induced by cold stress combined with environmental hormones were obtained. Our results indicate that inflammation and vascular endothelial function changes may play a key role in the occurrence and development of ED.