Publications by authors named "Xueyin Shi"

44 Publications

Fine-mapping and identification of a candidate gene controlling seed coat color in melon (Cucumis melo L. var. chinensis Pangalo).

Theor Appl Genet 2021 Nov 26. Epub 2021 Nov 26.

Key Laboratory of Biology and Genetic Improvement of Horticultural Crops of the Ministry of Agriculture and Rural Affairs, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, 100081, China.

Key Message: MELO3C019554 encoding a homeobox protein (PHD transcription factor) is a candidate gene that involved in the formation of seed coat color in melon. Seed coat color is related to flavonoid content which is closely related to seed dormancy. According to the genetic analysis of a six-generation population derived from two parents (IC2508 with a yellow seed coat and IC2518 with a brown seed coat), we discovered that the yellow seed coat trait in melon is controlled by a single dominant gene, named CmBS-1. Bulked segregant analysis sequencing (BSA-Seq) revealed that the gene is located at 11,860,000-15,890,000 bp (4.03 Mb) on Chr 6. The F population was genotyped using insertion-deletions (InDels), from which cleaved amplified polymorphic sequence (dCAPS) markers were derived to construct a genetic map. The gene was then fine-mapped to a 233.98 kb region containing 12 genes. Based on gene sequence analysis with two parents, we found that the MELO3C019554 gene encoding a homeobox protein (PHD transcription factor) had a nonsynonymous single nucleotide polymorphism (SNP) mutation in the coding sequence (CDS), and the SNP mutation resulted in the conversion of an amino acid (A → T) at residue 534. In addition, MELO3C019554 exhibited lower relative expression levels in the yellow seed coat than in the brown seed coat. Furthermore, we found that MELO3C019554 is related to 12 flavonoid metabolites. Thus, we predicted that MELO3C019554 is a candidate gene controlling seed coat color in melon. The study lays a foundation for further cloning projects and functional analysis of this gene, as well as marker-assisted selection breeding.
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http://dx.doi.org/10.1007/s00122-021-03999-5DOI Listing
November 2021

Exosomal miR-30d-5p of neutrophils induces M1 macrophage polarization and primes macrophage pyroptosis in sepsis-related acute lung injury.

Crit Care 2021 10 12;25(1):356. Epub 2021 Oct 12.

Department of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China.

Background: Polymorphonuclear neutrophils (PMNs) play an important role in sepsis-related acute lung injury (ALI). Accumulating evidence suggests PMN-derived exosomes as a new subcellular entity acting as a fundamental link between PMN-driven inflammation and tissue damage. However, the role of PMN-derived exosomes in sepsis-related ALI and the underlying mechanisms remains unclear.

Methods: Tumor necrosis factor-α (TNF-α), a key regulator of innate immunity in sepsis-related ALI, was used to stimulate PMNs from healthy C57BL/6J mice in vitro. Exosomes isolated from the supernatant were injected to C57BL/6J wild-type mice intraperitoneally (i.p.) and then examined for lung inflammation, macrophage (Mϕ) polarization and pyroptosis. In vitro co-culture system was applied where the mouse Raw264.7 macrophages or bone marrow-derived macrophages (BMDMs) were co-cultured with PMN-derived exosomes to further confirm the results of in vivo animal study and explore the potential mechanisms involved.

Results: Exosomes released by TNF-α-stimulated PMNs (TNF-Exo) promoted M1 macrophage activation after in vivo i.p. injection or in vitro co-culture. In addition, TNF-Exo primed macrophage for pyroptosis by upregulating NOD-like receptor 3 (NLRP3) inflammasome expression through nuclear factor κB (NF-κB) signaling pathway. Mechanistic studies demonstrated that miR-30d-5p mediated the function of TNF-Exo by targeting suppressor of cytokine signaling (SOCS-1) and sirtuin 1 (SIRT1) in macrophages. Furthermore, intravenous administration of miR-30d-5p inhibitors significantly decreased TNF-Exo or cecal ligation and puncture (CLP)-induced M1 macrophage activation and macrophage death in the lung, as well as the histological lesions.

Conclusions: The present study demonstrated that exosomal miR-30d-5p from PMNs contributed to sepsis-related ALI by inducing M1 macrophage polarization and priming macrophage pyroptosis through activating NF-κB signaling. These findings suggest a novel mechanism of PMN-Mϕ interaction in sepsis-related ALI, which may provide new therapeutic strategies in sepsis patients.
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http://dx.doi.org/10.1186/s13054-021-03775-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507252PMC
October 2021

G-Protein-Coupled Estrogen Receptor (GPER) in the Rostral Ventromedial Medulla Is Essential for Mobilizing Descending Inhibition of Itch.

J Neurosci 2021 09 4;41(37):7727-7741. Epub 2021 Aug 4.

Department of Anesthesiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China

Chronic itch is a troublesome condition and often difficult to cure. Emerging evidence suggests that the periaqueductal gray (PAG)-rostral ventromedial medulla (RVM) pathway may play an important role in the regulation of itch, but the cellular organization and molecular mechanisms remain incompletely understood. Here, we report that a group of RVM neurons distinctively express the G-protein-coupled estrogen receptor (GPER), which mediates descending inhibition of itch. We found that GPER neurons in the RVM were activated in chronic itch conditions in rats and mice. Selective ablation or chemogenetic suppression of RVM GPER neurons resulted in mechanical alloknesis and increased scratching in response to pruritogens, whereas chemogenetic activation of GPER neurons abrogated itch responses, indicating that GPER neurons are antipruritic. Moreover, GPER-deficient mice and rats of either sex exhibited hypersensitivity to mechanical and chemical itch, a phenotype reversible by the µ type opioid receptor (MOR) antagonism. Additionally, significant MOR phosphorylation in the RVM was detected in chronic itch models in wild-type but not in GPER rats. Therefore, GPER not only identifies a population of medullary antipruritic neurons but may also determine the descending antipruritic tone through regulating µ opioid signaling. Therapeutic options for itch are limited because of an as yet incomplete understanding of the mechanisms of itch processing. Our data have provided novel insights into the cellular organization and molecular mechanisms of descending regulation of itch in normal and pathologic conditions. GPER neurons (largely GABAergic) in the RVM are antipruritic neurons under tonic opioidergic inhibition, activation of GPER promotes phosphorylation of MOR and disinhibition of the antipruritic GPER neurons from inhibitory opioidergic inputs, and failure to mobilize GPER neurons may result in the exacerbation of itch. Our data also illuminate on some of the outstanding questions in the field, such as the mechanisms underlying sex bias in itch, pain, and opioid analgesia and the paradoxical effects of morphine on pain and itch.
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http://dx.doi.org/10.1523/JNEUROSCI.2592-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445050PMC
September 2021

Driving Pressure-Guided Individualized Positive End-Expiratory Pressure in Abdominal Surgery: A Randomized Controlled Trial.

Anesth Analg 2021 11;133(5):1197-1205

From the Department of Anesthesiology and Critical Care Medicine, Xinhua Hospital, affiliated with Shanghai Jiaotong University School of Medicine, Shanghai, China.

Background: The optimal positive end-expiratory pressure (PEEP) to prevent postoperative pulmonary complications (PPCs) remains unclear. Recent evidence showed that driving pressure was closely related to PPCs. In this study, we tested the hypothesis that an individualized PEEP guided by minimum driving pressure during abdominal surgery would reduce the incidence of PPCs.

Methods: This single-centered, randomized controlled trial included a total of 148 patients scheduled for open upper abdominal surgery. Patients were randomly assigned to receive an individualized PEEP guided by minimum driving pressure or an empiric fixed PEEP of 6 cm H2O. The primary outcome was the incidence of clinically significant PPCs within the first 7 days after surgery, using a χ2 test. Secondary outcomes were the severity of PPCs, the area of atelectasis, and pleural effusion. Other outcomes, such as the incidence of different types of PPCs (including hypoxemia, atelectasis, pleural effusion, dyspnea, pneumonia, pneumothorax, and acute respiratory distress syndrome), intensive care unit (ICU) admission rate, length of hospital stay, and 30-day mortality were also explored.

Results: The median value of PEEP in the individualized group was 10 cm H2O. The incidence of clinically significant PPCs was significantly lower in the individualized PEEP group compared with that in the fixed PEEP group (26 of 67 [38.8%] vs 42 of 67 [62.7%], relative risk = 0.619, 95% confidence intervals, 0.435-0.881; P = .006). The overall severity of PPCs and the area of atelectasis were also significantly diminished in the individualized PEEP group. Higher respiratory compliance during surgery and improved intra- and postoperative oxygenation was observed in the individualized group. No significant differences were found in other outcomes between the 2 groups, such as ICU admission rate or 30-day mortality.

Conclusions: The application of individualized PEEP based on minimum driving pressure may effectively decrease the severity of atelectasis, improve oxygenation, and reduce the incidence of clinically significant PPCs after open upper abdominal surgery.
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http://dx.doi.org/10.1213/ANE.0000000000005575DOI Listing
November 2021

Comprehensive Analysis of Transcriptome and Metabolome Reveals the Flavonoid Metabolic Pathway Is Associated with Fruit Peel Coloration of Melon.

Molecules 2021 May 10;26(9). Epub 2021 May 10.

Key Laboratory of Biology and Genetic Improvement of Horticultural Crops of the Ministry of Agriculture and Rural Affairs, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing 100081, China.

The peel color is an important external quality of melon fruit. To explore the mechanisms of melon peel color formation, we performed an integrated analysis of transcriptome and metabolome with three different fruit peel samples (grey-green 'W', dark-green 'B', and yellow 'H'). A total of 40 differentially expressed flavonoids were identified. Integrated transcriptomic and metabolomic analyses revealed that flavonoid biosynthesis was associated with the fruit peel coloration of melon. Twelve differentially expressed genes regulated flavonoids synthesis. Among them, nine (two , , three , , , and ) up-regulated genes were involved in the accumulation of flavones, flavanones, flavonols, and isoflavones, and three (2 and ) down-regulated genes were involved in the accumulation of anthocyanins. This study laid a foundation to understand the molecular mechanisms of melon peel coloration by exploring valuable genes and metabolites.
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http://dx.doi.org/10.3390/molecules26092830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126211PMC
May 2021

Comparative research on nucleocapsid and spike glycoprotein as the rapid immunodetection targets of COVID-19 and establishment of immunoassay strips.

Mol Immunol 2021 03 9;131:6-12. Epub 2021 Jan 9.

Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Shenzhen 518055 PR China; School of Life Science, Tsinghua University, Beijing 100084, PR China; Tsinghua-Berkeley Shenzhen Institute (TBSI), Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China; Shenzhen Bay Laboratory, Shenzhen, PR China. Electronic address:

The SARS-CoV-2 virus responsible for coronavirus 2019 (COVID-19) poses a significant challenge to healthcare systems worldwide. According to the World Health Organization (WHO), the outbreak of COVID-19 has been a pandemic that infected more than 25.32 million people and caused more than 848.25 thousand deaths worldwide at the time of 1st September 2020. Despite governmental initiatives aimed to contain the spread of the disease, several countries are experiencing unmanageable increases in medical equipment and larger testing capacity. The current diagnosis based on nuclear acid requires specialized instruments, time-consuming, and laborious, the low-cost and convenient technologies were still urgently needed. Both spike and nucleocapsid are key structural proteins of COVID-19 with good immunogenicity, can serve as primary targets for immunoassay. After comparative research, we certified nucleocapsid antigen-monoclonal antibody (mAbs) system was more suitable for the COVID-19 immunodetection. Subsequently, we designed a rapid test strip based on it that can be used in large-scale screening of COVID-19 in population and more suitable for some remote and special needs areas were restricted by a medical condition or for quick and large quantities of screenings.
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http://dx.doi.org/10.1016/j.molimm.2021.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833923PMC
March 2021

Oral Administration of Penicillin or Streptomycin May Alter Serum Serotonin Level and Intestinal Motility via Different Mechanisms.

Front Physiol 2020 23;11:605982. Epub 2020 Dec 23.

Department of Anesthesiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background/aims: Enterochromaffin cells (EC cells) constitute the largest population of enteroendocrine cells and release serotonin (5-HT) in response to mechanical and chemical cues of the gastrointestinal tract (GIT). How EC cells respond to altered microbiota such as due to antibiotic treatments remain poorly understood. We hypothesized that the pacemaker channel HCN2 might contribute to the regulation of EC cells functions and their responses to antibiotics-induced changes in intestinal flora.

Methods: Mice were given either penicillin or streptomycin or both in drinking water for 10 consecutive days. The changes in the profile of short chain fatty acids (SCFAs) in the cecum following penicillin or streptomycin treatments were tested by GC-MS. Serum 5-HT content, whole intestinal transit time, fecal water content, cecum weight and expression of HCN2 and TPH1 in cecal mucosa were measured. Ivabradine (a HCN channels blocker) was used to explore the role of HCN2 in penicillin-induced changes in 5-HT availability and intestinal motility.

Results: HCN2 immunofluorescence was detected on intestinal EC cells. Both penicillin and streptomycin caused significant reduction in total SCFAs in the cecum, with the penicillin-treated group showing greater reductions in butyrate, isobutyrate and isovalerate levels than the streptomycin group. The expression of HCN2 was increased in the mice treated with penicillin, whereas TPH1 expression was increased in the mice treated with streptomycin. Mice treated with antibiotics all had larger and heavier cecum, elevated serum 5-HT level and increased fecal water content. Besides, mice treated with penicillin had prolonged intestinal transit time. Intraperitoneal injection of Ivabradine attenuated the effect of penicillin on serum 5-HT level, cecum size and weight, intestinal motility, and fecal water content.

Conclusion: Disruptions of the intestinal flora structure due to oral administration of penicillin may significantly increase serum 5-HT level and inhibit intestinal motility, at least partially through up-regulating the expression of HCN2. Oral administration of streptomycin may alter 5-HT availability by up-regulating TPH1 expression thus increasing synthesis of 5-HT. Alterations of intestinal flora composition due to exposure to different antibiotics may regulate 5-HT availability and intestinal motility through different mechanisms.
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http://dx.doi.org/10.3389/fphys.2020.605982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785965PMC
December 2020

GPER-Deficient Rats Exhibit Lower Serum Corticosterone Level and Increased Anxiety-Like Behavior.

Neural Plast 2020 28;2020:8866187. Epub 2020 Aug 28.

Department of Anesthesiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Ample evidence suggests that estrogens have strong influences on the occurrence of stress-related mood disorders, but the underlying mechanisms remain poorly understood. Through multiple approaches, we demonstrate that the G protein-coupled estrogen receptor (GPER) is widely distributed along the HPA axis and in brain structures critically involved in mood control. Genetic ablation of GPER in the rat resulted in significantly lower basal serum corticosterone level but enhanced ACTH release in response to acute restraint stress, especially in the female. GPER rats of either sex displayed increased anxiety-like behaviors and deficits in learning and memory. Additionally, GPER deficiency led to aggravation of anxiety-like behaviors following single-prolonged stress (SPS). SPS caused significant decreases in serum corticosterone in WT but not in GPER-deficient rats. The results highlight an important role of GPER at multiple sites in regulation of the HPA axis and mood.
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http://dx.doi.org/10.1155/2020/8866187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474769PMC
August 2021

Platelet-derived exosomes promote neutrophil extracellular trap formation during septic shock.

Crit Care 2020 06 29;24(1):380. Epub 2020 Jun 29.

Department of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China.

Background: Platelets have been demonstrated to be potent activators of neutrophil extracellular trap (NET) formation during sepsis. However, the mediators and molecular pathways involved in human platelet-mediated NET generation remain poorly defined. Circulating plasma exosomes mostly originating from platelets may induce vascular apoptosis and myocardial dysfunction during sepsis; however, their role in NET formation remains unclear. This study aimed to detect whether platelet-derived exosomes could promote NET formation during septic shock and determine the potential mechanisms involved.

Methods: Polymorphonuclear neutrophils (PMNs) were cocultured with exosomes isolated from the plasma of healthy controls and septic shock patients or the supernatant of human platelets stimulated ex vivo with phosphate buffer saline (PBS) or lipopolysaccharide (LPS). A lethal cecal ligation and puncture (CLP) mouse model was used to mimic sepsis in vivo; then, NET formation and molecular pathways were detected.

Results: NET components (dsDNA and MPO-DNA complexes) were significantly increased in response to treatment with septic shock patient-derived exosomes and correlated positively with disease severity and outcome. In the animal CLP model, platelet depletion reduced plasma exosome concentration, NET formation, and lung injury. Mechanistic studies demonstrated that exosomal high-mobility group protein 1 (HMGB1) and/or miR-15b-5p and miR-378a-3p induced NET formation through the Akt/mTOR autophagy pathway. Furthermore, the results suggested that IκB kinase (IKK) controls platelet-derived exosome secretion in septic shock.

Conclusions: Platelet-derived exosomes promote excessive NET formation in sepsis and subsequent organ injury. This finding suggests a previously unidentified role of platelet-derived exosomes in sepsis and may lead to new therapeutic approaches.
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http://dx.doi.org/10.1186/s13054-020-03082-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322900PMC
June 2020

A Novel Anti-Coagulative Nanocomplex in Delivering miRNA-1 Inhibitor Against Microvascular Obstruction of Myocardial Infarction.

Adv Healthc Mater 2020 06 27;9(11):e1901783. Epub 2020 Apr 27.

Department of Anesthesiology and SICU, Xinhua Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, 200092, China.

Great progress has been made in miRNA nanodelivery for the treatment of myocardial infarction (MI). However, miRNA nanodelivery within the infarct is impeded by microvascular obstruction as a local circulatory disorder caused by microthrombus formation in microvessels. Knowing that low molecular weight heparin (LMWH) can effectively prevent microthrombus formation in microcirculation, it is hypothesized whether surface modification of the nanocarrier with LMWH can overcome microvascular obstruction in the infarct area for better miRNA delivery. Herein, a novel nanocomlex consisting of dendrigraft poly-l-lysine (DGL)-loaded miR-1 inhibitor as the core to decrease apoptosis of cardiomyocytes and LMWH as the shell to overcome microvascular obstruction of the infarct area is developed. The results show that this anti-coagulative nanocomlex is able to reduce microthrombus formation in microvessels and inhibit blood-coagulation factor Xa, thereby overcoming microvascular obstruction in the infarct area. In addition, it further enhances the uptake of miR-1 inhibitor within the infarct and decreases myocardiocyte apoptosis, thus improving the cardiac function and attenuating the myocardial fibrosis. In conclusion, modification of DGL-loaded miR-1 inhibitor with LMWH helps overcome microvascular obstruction in delivering the drug to the infarct area, thus providing a promising therapeutic strategy for achieving a better therapeutic outcome of MI.
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http://dx.doi.org/10.1002/adhm.201901783DOI Listing
June 2020

Activation of the G Protein-Coupled Estrogen Receptor Elicits Store Calcium Release and Phosphorylation of the Mu-Opioid Receptors in the Human Neuroblastoma SH-SY5Y Cells.

Front Neurosci 2019 17;13:1351. Epub 2019 Dec 17.

Department of Anesthesiology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Estrogens exert extensive influences on the nervous system besides their well-known roles in regulation of reproduction and metabolism. Estrogens act via the nuclear receptor ERα and ERβ to regulate gene transcription (classical genomic effects). In addition, estrogens are also known to cause rapid non-genomic effects on neuronal functions including inducing fast changes in cytosolic calcium level and rapidly desensitizing the μ type opioid receptor (MOR). The receptors responsible for the rapid actions of estrogens remain uncertain, but recent evidence points to the G protein-coupled estrogen receptor (GPER), which has been shown to be expressed widely in the nervous system. In the current study, we test the hypothesis that activation of GPER may mediate rapid calcium signaling, which may promote phosphorylation of MOR through the calcium-dependent protein kinases in neuronal cells. By qPCR and immunocytochemistry, we found that the human neuroblastoma SH-SY5Y cells endogenously express GPER and MOR. Activation of GPER by 17β-estradiol (E2) and G-1 (GPER selective agonist) evoked a rapid calcium rise in a concentration-dependent manner, which was due to store release rather than calcium entry. The GPER antagonist G15, the PLC inhibitor U73122 and the IP3 receptor inhibitor 2-APB each virtually abolished the calcium responses to E2 or G-1. Activation of GPER stimulated translocation of PKC isoforms (α and ε) to the plasma membrane, which led to MOR phosphorylation. Additionally, E2 and G-1 stimulated c-Fos expression in SH-SY5Y cells in a PLC/IP3-dependent manner. In conclusion, the present study has revealed a novel GPER-mediated estrogenic signaling in neuroblastoma cells in which activation of GPER is followed by rapid calcium mobilization, PKC activation and MOR phosphorylation. GPER-mediated rapid calcium signal may also be transmitted to the nucleus to impact on gene transcription. Such signaling cascade may play important roles in the regulation of opioid signaling in the brain.
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http://dx.doi.org/10.3389/fnins.2019.01351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928052PMC
December 2019

Nanoparticle reinforced bacterial outer-membrane vesicles effectively prevent fatal infection of carbapenem-resistant Klebsiella pneumoniae.

Nanomedicine 2020 02 27;24:102148. Epub 2019 Dec 27.

Department of Anesthesiology and SICU, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address:

Infection resulting from carbapenem-resistant Klebsiella pneumoniae (CRKP) is an intractable clinical problem. Outer membrane vesicles (OMVs) from CRKP are believed to be potential vaccine candidates. However, their immune response remains elusive due to low structural stability and poor size homogeneity. In this study, hollow OMVs were reinforced internally by size-controlled BSA nanoparticles to obtain uniform and stable vaccines through hydrophobic interaction. The result showed that the BSA-OMV nanoparticles (BN-OMVs) were homogenous with a size around 100 nm and exhibited a core-shell structure. Remarkably, subcutaneous BN-OMVs vaccination mediated significantly higher CRKP specific antibody titers. The survival rate of the mice infected with a lethal dose of CRKP was increased significantly after BN-OMV immunization. The adoptive transfer experiment demonstrated that the protective effect of BN-OMVs was dependent on humoral and cellular immunity. This study demonstrated that the structure optimization improved the immune efficacy of OMVs for vaccine development against CRKP.
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http://dx.doi.org/10.1016/j.nano.2019.102148DOI Listing
February 2020

Self-Albumin Camouflage of Carrier Protein Prevents Nontarget Antibody Production for Enhanced LDL-C Immunotherapy.

Adv Healthc Mater 2020 01 9;9(1):e1901203. Epub 2019 Dec 9.

Department of Anesthesiology and SICU, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China.

Elevated low-density lipoprotein cholesterol (LDL-C) increases the risk of atherosclerotic cardiovascular disease. Peptide-based PCSK9 vaccines have shown a promising prospect of reducing LDL-C. In peptide vaccine (pVax) design, the peptide antigens need to conjugate with carrier protein (CP). However, CP incorporation can induce undesirable anti-CP antibodies, which sterically mask peptide epitopes from being recognized by specific B cells and impair subsequent therapeutically antibody production. This epitopic suppression has posed a barrier in clinical translation of conjugate vaccines all along. A model CP (keyhole limpet hemocyanin, KLH) is herein camouflaged with serum albumin (SA) into hybrid nanocarriers ([email protected]), with PCSK9 peptide being anchored onto the surface to form nanovaccine ([email protected]). Such camouflage of KLH via high "self" SA coverage is able to inhibit KLH from extracellular immune recognition and prevent detectable anti-KLH antibody production. Furthermore, the nanovaccine around 70 nm stabilized by intermolecular disulfide network is ideal for internalization and biodegradation by antigen presenting cells as well as better retention in draining lymph nodes and spleen. As expected, the [email protected] efficiently primes higher anti-PCSK9 IgG antibody titer than PCSK9 pVax.
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http://dx.doi.org/10.1002/adhm.201901203DOI Listing
January 2020

PCSK9 Hapten Multicopy Displayed onto Carrier Protein Nanoparticle: An Antiatherosclerosis Vaccine.

ACS Biomater Sci Eng 2019 Sep 20;5(9):4263-4271. Epub 2019 Aug 20.

Department of Anesthesiology and SICU, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.

In recent years, various vaccination strategies have shed new light on the treatment of atherosclerosis. Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a hot target in the development of antiatherosclerosis vaccine. However, the efficacy of conventional PCSK9 is largely limited by poor immunogenicity and low hapten density. Therefore, we hypothesized whether a nanostructure synthesized by self-assembled carrier protein accompanied by multicopy hapten display could improve the efficacy of vaccine. In this study, bovine serum albumin (BSA) was self-assembled into sub-100 nm nanoparticles via an intermolecular disulfide network as the inner core. Then, sequences of PCSK9 were conjugated onto the surface of nanoparticles by "click" chemistry to consequently form an orderly structured of nanovaccine with repetitive hapten display. Compared with conventional PCSK9 peptide vaccine, our immunization study demonstrated that the PCSK9 multicopy display nanovaccine (PMCDN) was able to induce higher titers of PCSK9 antibody and more efficient lymph node drainage and improve endocytosis by antigen presenting cells.
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http://dx.doi.org/10.1021/acsbiomaterials.9b00434DOI Listing
September 2019

Developmental neurotoxicity in the context of multiple sevoflurane exposures: Potential role of histone deacetylase 6.

Neurotoxicol Teratol 2019 Jul - Aug;74:106813. Epub 2019 Jun 26.

Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China. Electronic address:

Animal studies have demonstrated that multiple exposures to sevoflurane during the postnatal period lead to impaired synaptogenesis and cognitive deficits in adulthood. However, the underlying mechanisms remain unclear. Histone deacetylase 6 (HDAC6), a unique isoform of class II histone deacetylases (HDACs), mediates diverse cellular processes such as cell survival, inflammation, intracellular trafficking and protein degradation. Varieties of literature suggest the importance of HDAC6 in memory formation and abnormal neurodegenerative diseases. The aim of this study was to investigate potential roles of HDAC6 in sevoflurane-induced developmental neurotoxicity. Postnatal day 7 (P7) rat pups were randomly assigned to control group and sevoflurane group (n = 6 for each group). They were exposed to 60% oxygen and 40% nitrogen with or without 3% sevoflurane for 2 h daily for three consecutive days (P7, P8 and P9). Immediately after the last exposure, both hippocampi were harvested for detection of HDAC6 expression and activity. Next, P7 rat pups were divided into control group, sevoflurane group, sevoflurane + Tubastatin A, and Tubastatin A groups (n = 6 for each group in molecular experiments; n = 16 for each group in behavioral testing). A dose of 25 mg/kg body weight of Tubastatin A (a selective HDAC6 inhibitor) were administrated intraperitoneally 30 min prior to each sevoflurane exposure. After treatments, expression levels of synaptophysin and postsynaptic density 95 protein (PSD95) were quantified using Western blot, and synaptic ultrastructure was evaluated by transmission electron microscopy. Additional pups were raised until P49 to measure cognitive performance using the Morris water maze test. Our results demonstrated that multiple sevoflurane exposures enhanced HDAC6 expression and activity in hippocampi of the developing brain. Tubastatin A ameliorated sevoflurane-induced decreases in synaptophysin and PSD95 expression during development, as well as synaptic ultrastructural damage and cognitive deficits in adulthood. In conclusion, HDAC6 is involved in the developmental neurotoxicity caused by multiple sevoflurane exposures and its inhibition may prevent related damage.
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http://dx.doi.org/10.1016/j.ntt.2019.106813DOI Listing
May 2020

Intraoperative monitoring of nociception for opioid administration: a meta-analysis of randomized controlled trials.

Minerva Anestesiol 2019 May 7;85(5):522-530. Epub 2019 Feb 7.

Department of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.

Introduction: Under-dosage or over-dosage of intraoperative analgesia can cause harm to patients. Many studies have demonstrated the clinical advantages of nociception monitoring tools, but with some conflicting results. To clarify the issue, this meta-analysis compared the effects of Analgesia Nociception Index (ANI), Surgical Pleth Index (SPI), and pupillometry monitoring methods with those of analgesia management practices of intraoperative opioid administration.

Evidence Acquisition: A comprehensive literature search was conducted to identify clinical trials that compared the effect of monitoring of nociception-antinociception balance (versus clinical signs) on intraoperative opioid administration. Meta-analysis was performed for intraoperative opioid administration, postoperative pain and rescue opioid consumption separately using fixed-effects model and random effects model. In addition, a subgroup analysis was also performed to determine the effects of age, study quality, anesthesia regimen, and nociception monitoring devices on intraoperative opioid administration.

Evidence Analysis: Ten studies that used ANI, SPI, or pupillometry for intraoperative opioid guidance were identified. As a principle finding, nociception measurement-guided analgesia reduced intraoperative opioid consumption compared with conventional analgesia. In adults, SPI-guided intraoperative opioid administration was lower than conventional analgesia, whereas the difference between ANI-guided analgesia and standard clinical care was not statistically significant. Furthermore, in adults, anesthetized with sevoflurane, nociception monitoring decreased intraoperative analgesia doses.

Conclusions: Nociception monitoring devices seem to have an advantage over standard clinical practice on intraoperative management of analgesia during general anesthesia. Future research should focus on identifying appropriate indicators to objectively assess the degree of pain in children and perform large-scale multicenter trials to prove clinical advantages of nociception measurements during propofol anesthesia.
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http://dx.doi.org/10.23736/S0375-9393.19.13151-3DOI Listing
May 2019

Delivery of microRNA-1 inhibitor by dendrimer-based nanovector: An early targeting therapy for myocardial infarction in mice.

Nanomedicine 2018 02 18;14(2):619-631. Epub 2017 Dec 18.

Institute for Biomedical Engineering &Nano Science, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address:

Myocardial infarction (MI), known to be rapidly progressed and fatal, necessitates a timely and effective intervention particularly within golden 24 h. The crux is to develop a therapeutic agent that can early target the infarct site with integrated therapeutic capacity. Finding the AT receptor being most over-expressed at 24 h after MI, we developed a nanovector (AT-PEG-DGL) anchored with AT targeting peptide, and simultaneously armed it with specific microRNA-1 inhibitor (AMO-1) to attenuate cardiomyocyte apoptosis. In vivo imaging after IV administration demonstrated that AT-PEG-DGL quickly accumulated in the MI heart during the desired early period, significantly outperforming the control group without AT targeting. Most importantly, a pronounced in-vivo anti-apoptosis effect was observed upon a single IV injection. Apoptotic cell death in the infarct border zone was significantly decreased and the myocardial infarct size was reduced by 64.1% as compared with that in MI control group, promising for early MI treatment.
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http://dx.doi.org/10.1016/j.nano.2017.12.004DOI Listing
February 2018

Aging-Impaired Filamentous Actin Polymerization Signaling Reduces Alveolar Macrophage Phagocytosis of Bacteria.

J Immunol 2017 11 25;199(9):3176-3186. Epub 2017 Sep 25.

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;

In elderly patients, bacterial infection often causes severe complications and sepsis. Compared to younger patients, older patients are more susceptible to sepsis caused by respiratory infection. Macrophage (Mϕ) phagocytosis of bacteria plays a critical role in the clearance of pathogens and the initiation of immune responses. It has been suggested that Mϕ exhibit age-related functional alterations, including reduced chemotaxis, phagocytosis, antibacterial defense, and the ability to generate reactive oxygen species. However, the mechanisms behind these changes remain unclear. The present study sought to determine changes in bacterial phagocytosis in aging alveolar Mϕ (AMϕ) and the underlying mechanisms. We show that bacteria initiate cytoskeleton remodeling in AMϕ through interaction with macrophage receptor with collagenous structure (MARCO), a bacterial scavenger receptor. This remodeling, in turn, promotes enhanced cell surface expression of MARCO and bacterial phagocytosis. We further demonstrate that Rac1-GTP mediates MARCO signaling and activates actin-related protein-2/3 complex, an F-actin nucleator, thereby inducing F-actin polymerization, filopodia formation, and increased cell surface expression of MARCO, all of which are essential for the execution of bacteria phagocytosis. However, AMϕ isolated from aging mice exhibit suppressed Rac1 mRNA and protein expression, which resulted in decreases in Rac1-GTP levels and actin-related protein-2/3 activation, as well as subsequent attenuation of F-actin polymerization, filopodia formation, and cell surface expression of MARCO. As a result, bacterial phagocytosis in aging AMϕ is decreased. This study highlights a previously unidentified mechanism by which aging impairs Mϕ phagocytosis of bacteria. Targeting these pathways may improve outcomes of bacterial infection in elderly patients.
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http://dx.doi.org/10.4049/jimmunol.1700140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679440PMC
November 2017

Alveolar Recruitment Strategies After Cardiac Surgery.

JAMA 2017 08;318(7):667

Department of Anesthesiology and Critical Care Medicine, Xinhua Hospital, Shanghai, China.

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http://dx.doi.org/10.1001/jama.2017.8689DOI Listing
August 2017

Frontline Science: Macrophage-derived exosomes promote neutrophil necroptosis following hemorrhagic shock.

J Leukoc Biol 2018 02 28;103(2):175-183. Epub 2017 Dec 28.

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Hemorrhagic shock (HS) renders patients susceptible to development of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) through mechanisms that are, as yet, unclear. Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that controls cell release of inflammatory mediators from innate immune cells, such as polymorphonuclear neutrophils (PMNs), and critically regulates the progress of inflammation. In this study, we investigated the mechanisms of alveolar macrophage (AMϕ) effects on PMN necroptosis following HS. With the use of in vivo and ex vivo HS models, we reveal a novel function of shock-activated AMϕ in promoting PMN necroptosis. We demonstrate that exosomes released from HS-activated AMϕ induce mainly NADPH oxidase-derived reactive oxygen species (ROS) production inside PMNs and subsequent promotion of necroptosis. These findings explore a previously unidentified pathway of AMϕ-PMN cross-talk, which causes enhanced PMN necroptosis and subsequent exaggerated post-HS lung inflammation. The targeting of this PMN death pathway may serve as a new therapeutic strategy for treatment of post-HS SIRS.
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http://dx.doi.org/10.1189/jlb.3HI0517-173RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346432PMC
February 2018

Role of notch signaling pathway in mechanical ventilation induced lung injury.

Int J Clin Exp Pathol 2017 1;10(8):8106-8118. Epub 2017 Aug 1.

Department of Anesthesiology and SICU, Xinhua Hospital, Shanghai Jiao Tong University Shanghai, China.

Objective: To investigate the expression of Notch signaling pathway after mechanical ventilation and its role in mechanical ventilation and lung injury.

Methods: VILI model was established by mechanical ventilation at high tidal volume (VT = 20 ml/kg) for 4 hours. Lung injury and inflammatory response were evaluated. Hes-1 and Hes-5 mRNA levels were measured after mechanical ventilation, and the levels of NICD, Hes-1, and Hes-5 protein were measured. Furthermore, the Notch signaling pathway inhibitor (DAPT 100 mg/kg) was administered intraperitoneally before mechanical ventilation to assess the role of Notch signaling in VILI.

Results: Compared with the control group, hypertonic mechanical ventilation induced VILI and increased the expression of inflammatory factors such as TNF-α, IL-6 and MIP-2 in the cell lavage fluid. The level of Hes-5 gene was significantly up-regulated in pulmonary macrophages with high tidal volume ventilation, and the protein levels of NICD and Hes-5 were up-regulated in pulmonary macrophages. The levels of TNF-α, IL-6, MIP-2 and other inflammatory cytokines in the alveolar lavage fluid decreased, and the levels of NICD and Hes-5 were also decreased, after DAPT pretreatment compared with the high tidal volume. The upregulation of p-IκBα and the degradation of IκBα protein in alveolar macrophages after mechanical ventilation was also observed.

Conclusion: The expression of Notch signaling pathway protein in alveolar macrophages is upregulated after high tidal volume mechanical ventilation, and is involved in the regulation of mechanical ventilation and lung injury. Our results suggested that NF-κB pathway is likely involved in Notch-mediated mechanisms that underlie mechanical ventilation induced lung injury.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965473PMC
August 2017

Effects of colloid pre-loading on thromboelastography during elective intracranial tumor surgery in pediatric patients: hydroxyethyl starch 130/0.4 versus 5% human albumin.

BMC Anesthesiol 2017 04 27;17(1):62. Epub 2017 Apr 27.

Department of Anesthesiology, Huashan Hospital, FuDan University, Shanghai, 200040, China.

Background: Volume replacement therapy with colloid is still worth studying in major pediatric surgery with potential risk of bleeding. This study assessed the effects of 6% hydroxyethyl starch (HES) 130/0.4 and 5% Human Albumin (HA) on coagulation tested by thromboelastography (TEG) during elective intracranial tumor surgery in pediatric patients.

Methods: In this randomized controlled trial, 60 patients undergoing intracranial tumor resection under general anesthesia were assigned to HES and HA groups (n = 30), and administered preloads of 20 mL · kg HES 130/0.4 and 5% HA, respectively, prior to dura opening. Primary outcomes were perioperative thromboelastography findings, and hemodynamic and hematological parameters. Blood transfusion, perioperative fluid balance, intracranial pressure, mortality, intensive care unit stay, and hospital stay were also assessed.

Results: TEG parameters did not differ after preloading compared to baseline values in either group, except for a decrease in maximum amplitude immediately after infusion (HES group, 57.6 ± 6.0 mm vs. 50.9 ± 9.2 mm; HA group, 60.1 ± 7.9 mm vs. 56.6 ± 7.1 mm; p < 0.01), which was restored to preoperative levels 1 h after fluid infusion. Total perioperative fluid balance, blood loss or transfusion, intracranial pressure, and hematological and hemodynamic variables were similar between both groups (p > 0.05). Mortality, length of hospital stay, and clinical complications were similar between both groups.

Conclusion: These findings suggest that HES and HA might have no significant differences regarding coagulation as assessed by TEG during pediatric intracranial tumor surgery with 20 ml/kg volume pre-loading, which can maintain stable hemodynamics and may represent a new avenue for volume therapy during brain tumor resection in pediatrics.

Trial Registration: ChiCTR-IPR- 16009333 , retrospectively registered October 8, 2016.
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http://dx.doi.org/10.1186/s12871-017-0353-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408379PMC
April 2017

Aging-related Atg5 defect impairs neutrophil extracellular traps formation.

Immunology 2017 08 16;151(4):417-432. Epub 2017 May 16.

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Formation of neutrophil extracellular traps (NETs) is an important function of the innate immune system against infections. It has been proven that aging dysregulates immunity and impairs neutrophil function. However, the influence of aging on the ability to produce NETs has yet to be fully addressed. In this study, we tested the hypothesis that a lower level of autophagy in neutrophils from aged mice was responsible for the decrease in NET formation. We demonstrated that a broad range of Toll-like receptor 2 (TLR2) ligands could efficiently induce reactive oxygen species (ROS) -dependent NET release in young mice, but not in aged ones. We further explored that the difference between young and aged mice in TLR2 ligand-induced NETosis is the result of an Atg5 defect and subsequent impaired autophagy. Furthermore, we found that lower autophagy capacity led to not only reduced NET formation, but also increased apoptosis. Our results suggest an important role of Atg5 and autophagy in maintaining the function of NETs formation in response to infection and in regulating neutrophil death. Targeting autophagy-promoted NETs may present a therapeutic strategy to improve infection defence in an aged population.
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http://dx.doi.org/10.1111/imm.12740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506403PMC
August 2017

Picroside II protects against sepsis via suppressing inflammation in mice.

Am J Transl Res 2016 15;8(12):5519-5531. Epub 2016 Dec 15.

Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical UniversityXuzhou, China; Department of Anesthesiology and SICU, Xinhua Hospital, School of Medicine, Shanghai Jiaotong UniversityShanghai, China; Department of Anesthesiology, Changzheng Hospital, Second Military Medical UniversityShanghai, China.

Picroside II, an iridoid compound extracted from Picrorhiza, exhibits anti-inflammatory and anti-apoptotic activities. We explored the protective effects and mechanisms of picroside II in a mouse model of sepsis induced by cecal ligation and puncture (CLP), using three groups of mice: Group A (sham), Group B (CLP+NS) and Group C (CLP+20 mg/kg picroside II). The mortality in mice with sepsis was decreased by the administration of picroside II, and lung injury was alleviated simultaneously. Picroside II treatment enhanced bacterial clearance in septic mice. Further, picroside II treatment alleviated the inflammatory response in sepsis and enhanced immune function by inhibiting the activation of NLRP3 inflammasome and NF-κB pathways. Picroside II may represent an anti-inflammatory drug candidate, providing novel insight into the treatment of sepsis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5209503PMC
December 2016

Propofol Inhibits Neurogenesis of Rat Neural Stem Cells by Upregulating MicroRNA-141-3p.

Stem Cells Dev 2017 02 27;26(3):189-196. Epub 2016 Oct 27.

1 Department of Anaesthesiology and Intensive Care Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, China .

Prolonged or high-dose exposure to anesthetics, such as propofol, can cause brain cell degeneration and subsequent long-term learning or memory deficits, particularly in the developing brain. However, the cellular and molecular mechanisms underlying the deleterious effects of propofol at certain stages of development remain unclear. In this study we found that propofol inhibited the proliferation, neuronal differentiation, and migration of neural stem cells (NSCs) while upregulating miR-141-3p. Silencing of miR-141-3p abrogated the effects of propofol on NSC neurogenesis. Propofol treatment downregulated IGF2BP2, a direct target of miR-141-3p, whereas overexpression of IGF2BP2 attenuated the effects of propofol and miR-141-3p on NSC neurogenesis. In short, propofol inhibits NSC neurogenesis through a mechanism involving the miR-141-3p/IGF2BP2 axis. Our results may provide a potential approach for preventing the neurodegenerative effects of propofol in the developing brain.
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http://dx.doi.org/10.1089/scd.2016.0257DOI Listing
February 2017

TLR4-Upregulated IL-1β and IL-1RI Promote Alveolar Macrophage Pyroptosis and Lung Inflammation through an Autocrine Mechanism.

Sci Rep 2016 08 16;6:31663. Epub 2016 Aug 16.

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome (MODS) following pulmonary infection. Alveolar macrophages (AM) are at the center of the pathogenesis of the development of ALI. Interleukin-1β (IL-1β) is one of the key pro-inflammatory mediators, and its maturation is tightly controlled by the formation and activation of the inflammasome. The biological effects of IL-1β are mediated through IL-1 receptor (IL-1R). In this study, we investigated the influence of LPS-induced IL-1β release and IL-1RI upregulation on the development of lung inflammation. We demonstrated that in AM, LPS-TLR4 signaling not only activates Nlrp3 inflammasome activation and subsequent release of IL-1β, but also up-regulates IL-1RI expression on AM surface through MyD88 and NF-κB dependent signaling. The upregulated IL-1RI, therefore, sensitizes AM to IL-1β and results in pyroptosome formation, which in turn leads to AM pyroptosis, a type of caspase-1-dependent inflammatory cell death. We further showed that AM pyroptosis exaggerates lung inflammation. The present study demonstrates a novel mechanism underlying LPS-induced innate immunity; that is, a secondary upregulation of IL-1β-IL-1RI signaling is responsible for AM pyroptosis and augmented lung injury in response to LPS.
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http://dx.doi.org/10.1038/srep31663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985817PMC
August 2016

Electrical Impedance Tomography-guided PEEP Titration in Patients Undergoing Laparoscopic Abdominal Surgery.

Medicine (Baltimore) 2016 Apr;95(14):e3306

From the Department of Anesthesiology (XH, JJ, YL, HX, SZ, XS, HY), Changzheng Hospital, the Second Military Medical University, Shanghai; The Seventh Hospital of People's Liberation Army (SY), Xichuan Linxia, Gansu; and Department of Anesthesiology (XS), Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

The aim of the study is to utilize electrical impedance tomography (EIT) to guide positive end-expiratory pressure (PEEP) and to optimize oxygenation in patients undergoing laparoscopic abdominal surgery.Fifty patients were randomly assigned to the control (C) group and the EIT (E) group (n = 25 each). We set the fraction of inspired oxygen (FiO2) at 0.30. The PEEP was titrated and increased in a 2-cm H2O stepwise manner, from 6 to 14 cm H2O. Hemodynamic variables, respiratory mechanics, EIT images, analysis of blood gas, and regional cerebral oxygen saturation were recorded. The postoperative pulmonary complications within the first 5 days were also observed.We chose 10 cm H2O and 8 cm H2O as the "ideal" PEEP for the C and the E groups, respectively. EIT-guided PEEP titration led to a more dorsal shift of ventilation. The PaO2/FiO2 ratio in the E group was superior to that in the C group in the pneumoperitoneum period, though the difference was not significant (330 ± 10 vs 305.56 ± 4 mm Hg; P = 0.09). The C group patients experienced 8.7% postoperative pulmonary complications versus 5.3% among the E group patients (relative risk 1.27, 95% confidence interval 0.31-5.3, P = 0.75).Electrical impedance tomography represents a new promising technique that could enable anesthesiologists to assess regional ventilation of the lungs and optimize global oxygenation for patients undergoing laparoscopic abdominal surgery.
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http://dx.doi.org/10.1097/MD.0000000000003306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998820PMC
April 2016

Syntaxin 1A mediates isoflurane but not hypoxia preconditioning-induced alleviation of hypoxia-reoxygenation injury in rat cardiomyocytes.

Am J Transl Res 2015 15;7(10):1883-95. Epub 2015 Oct 15.

Department of Anesthesiology, Changzheng Hospital Affiliated to Second Military Medical University Shanghai 200003, China ; Department of Anesthesiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine Shanghai 200092, China.

Preconditioning with ischemia/hypoxia (IPC/HPC) or clinically available volatile anesthetics such as isoflurane (Iso-PC) could activate cardioprotective signaling pathways, thereby reducing myocardial ischemia/reperfusion (IR) injury. However, their molecular targets remain elusive. We herein investigated the roles of syntaxin 1A (Stx-1A) in cardiomyocyte protection induced by HPC and Iso-PC. Both in vivo myocardial IR model and in vitro cardiomyocyte hypoxia/reoxygenation (HR) model were used to test the effects of IR/HR, IPC/HPC and Iso-PC on Stx-1A protein expression. Stx-1A knockdown and overexpression in cardiomyocytes were achieved by adenovirus infection to define the relationship between Stx-1A levels and IPC/Iso-PC-induced cardioprotection. Cardiac troponin T (cTnT), cell apoptosis rate, and cell viability were introduced as indicators for cardiomyocyte HR injury. Changes of cardioprotective signaling pathways activities including PI3K/AKT/GSK3β, ERK1/2, STAT3 and PKC were also detected using Western blot. Rat cardiomyocyte Stx-1A was upregulated 4 hours after IR or HR. IPC/HPC as well as Iso-PC further increased Stx-1A expression compared with IR/HR. Stx-1A knockdown was accompanied with more cell apoptosis and decreased cell viability while overexpression of Stx-1A seemed cardioprotective. Iso-PC induced decrease in cell apoptosis and increase in cell viability but not HPC-induced cardioprotection was reversed by Stx-1A shRNA transfection. No difference in cell apoptosis or cell viability was found before and after Stx-1A overexpression in each group. Moreover, Stx-1A knockdown were accompanied with increased PI3K/AKT/GSK3β activities irrespective of the treatments. Stx-1A is cardioprotective and a potential target of isoflurane induced cardioprotection. Further studies are needed to test whether stx-1A is regulated by AKT/GSK3β signaling.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4656765PMC
December 2015

Trigeminal neuralgia increases cerebral blood flow in a focal cerebral ischemic model in rats.

Int J Clin Exp Med 2015 15;8(4):6544-52. Epub 2015 Apr 15.

Department of Anesthesiology, Changzheng Hospital, Second Military Medical University 415 Fengyang Road, Shanghai 200003, P. R. China.

Objective: To investigate the influences of trigeminal neuropathic pain on the cerebral blood flow in a ET-1 focal cerebral ischemia model.

Methods: Male Sprague-Dawley (SD) rats (220-260 g) were randomly divided into a model group (trigeminal neuralgia, TN group) and a sham operation group (sham group). The TN group received bilateral infraorbital nerve chronic constriction surgery, and the sham group only underwent exposure of the infraorbital nerve. The mechanical pain threshold of the rats was continuously monitored for 30 days post surgery. On postoperative day 30, the animals were anesthetized, and 3 μL (120 pM/μL) ET-1 was injected into the surroundings of the middle cerebral artery (MCA) to establish a cerebral focal ischemia-reperfusion injury model in rats. The changes in cerebral blood flow of these two groups were monitored 30 min after the injection of ET-1.

Results: The mechanic pain threshold values between rats in the two groups were not significantly different (P>0.05). The threshold value in the TN group on postoperative day 9 significantly decreased compared with that before surgery (P<0.01). Between postoperative days 9 and 30, the pain threshold values in the TN group were significantly lower than those in the sham group (P<0.01). From postoperative day 10, the mean arterial pressure in the TN group significantly increased compared with that before surgery (P<0.05), and the blood pressure (BP) in the TN group was higher than that in the sham group between postoperative days 10 and 30 (P<0.05). After 75 min of ET-1 microinjection, the cerebral blood flow in the rat frontal cortex exhibited reperfusion, and the cerebral blood flow in the TN group was significantly higher than that in the sham group (P<0.05). In addition, the content of calcitonin gene-related peptide (CGRP) in the blood of rats in the TN group was significantly higher than that in the sham group (P<0.05).

Conclusions: Trigeminal neuropathic pain may increase the mean arterial pressure and the content of CGRP in the plasma of rats, thus increasing the cerebral blood flow in the frontal cortex of the ET-1 ischemia-reperfusion model.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483892PMC
July 2015

Neutrophils counteract autophagy-mediated anti-inflammatory mechanisms in alveolar macrophage: role in posthemorrhagic shock acute lung inflammation.

J Immunol 2014 Nov 29;193(9):4623-33. Epub 2014 Sep 29.

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219; and Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240

Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome after hemorrhagic shock (HS) resulting from major surgery and trauma. The increased susceptibility in HS patients to the development of ALI suggests not yet fully elucidated mechanisms that enhance proinflammatory responses and/or suppress anti-inflammatory responses in the lung. Alveolar macrophages (AMϕ) are at the center of the pathogenesis of ALI after HS. We have previously reported that HS-activated polymorphonuclear neutrophils (PMNs) interact with macrophages to influence inflammation progress. In this study, we explore a novel function of PMNs regulating AMϕ anti-inflammatory mechanisms involving autophagy. Using a mouse "two-hit" model of HS/resuscitation followed by intratracheal injection of muramyl dipeptide, we demonstrate that HS initiates high mobility group box 1/TLR4 signaling, which upregulates NOD2 expression in AMϕ and sensitizes them to subsequent NOD2 ligand muramyl dipeptide to augment lung inflammation. In addition, upregulated NOD2 signaling induces autophagy in AMϕ, which negatively regulates lung inflammation through feedback suppression of NOD2-RIP2 signaling and inflammasome activation. Importantly, we further demonstrate that HS-activated PMNs that migrate in alveoli counteract the anti-inflammatory effect of autophagy in AMϕ, possibly through NAD(P)H oxidase-mediated signaling to enhance I-κB kinase γ phosphorylation, NF-κB activation, and nucleotide-binding oligomerization domain protein 3 inflammasome activation, and therefore augment post-HS lung inflammation. These findings explore a previously unidentified complexity in the mechanisms of ALI, which involves cell-cell interaction and receptor cross talk.
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http://dx.doi.org/10.4049/jimmunol.1400899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201969PMC
November 2014
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