Mendelian randomization analysis reveals causal associations of serum metabolites with sepsis and 28-day mortality.

Metabolic disorder has been found to be an important factor in the pathogenesis and progression of sepsis. However, the causation of such an association between serum metabolites and sepsis has not been established. We conducted a two-sample Mendelian randomization (MR) study. A genome-wide association study of 486 human serum metabolites was used as the exposure, whereas sepsis and sepsis mortality within 28 days were set as the outcomes. In MR analysis, 6 serum metabolites were identified to be associated with an increased risk of sepsis, and 6 serum metabolites were found to be related to a reduced risk of sepsis. Furthermore, there were 9 metabolites positively associated with sepsis-related mortality, and 8 metabolites were negatively correlated with sepsis mortality. In addition, "glycolysis/gluconeogenesis" (p = 0.001), and "pyruvate metabolism" (p = 0.042) two metabolic pathways were associated with the incidence of sepsis. This MR study suggested that serum metabolites played significant roles in the pathogenesis of sepsis, which may provide helpful biomarkers for early disease diagnosis, therapeutic interventions, and prognostic assessments for sepsis.

Berberine alleviates neuroinflammation by downregulating NFκB/LCN2 pathway in sepsis-associated encephalopathy: network pharmacology, bioinformatics, and experimental validation.

BACKGROUND: Sepsis refers to a systemic inflammatory response caused by infection, involving multiple organs. Sepsis-associated encephalopathy (SAE), as one of the most common complications in patients with severe sepsis, refers to the diffuse brain dysfunction caused by sepsis without central nervous system infection. However, there is no clear diagnostic criteria and lack of specific diagnostic markers. METHODS: The main active ingredients of coptidis rhizoma(CR) were identified from TCMSP and SwissADME databases. SwissTargetPrediction and PharmMapper databases were used to obtain targets of CR. OMIM, DisGeNET and Genecards databases were used to explore targets of SAE. Limma differential analysis was used to identify the differential expressed genes(DEGs) in GSE167610 and GSE198861 datasets. WGCNA was used to identify feature module. GO and KEGG enrichment analysis were performed using Metascape, DAVID and STRING databases. The PPI network was constructed by STRING database and analyzed by Cytoscape software. AutoDock and PyMOL software were used for molecular docking and visualization. Cecal ligation and puncture(CLP) was used to construct a mouse model of SAE, and the core targets were verified in vivo experiments. RESULTS: 277 common targets were identified by taking the intersection of 4730 targets related to SAE and 509 targets of 9 main active ingredients of CR. 52 common DEGs were mined from GSE167610 and GSE198861 datasets. Among the 25,864 DEGs in GSE198861, LCN2 showed the most significant difference (logFC = 6.9). GO and KEGG enrichment analysis showed that these 52 DEGs were closely related to "inflammatory response" and "innate immunity". A network containing 38 genes was obtained by PPI analysis, among which LCN2 ranked the first in Degree value. Molecular docking results showed that berberine had a well binding affinity with LCN2. Animal experiments results showed that berberine could inhibit the high expression of LCN2,S100A9 and TGM2 induced by CLP in the hippocampus of mice, as well as the high expression of inflammatory factors (TNFα, IL-6 and IL-1ß). In addition, berberine might reduce inflammation and neuronal cell death by partially inhibiting NFκB/LCN2 pathway in the hippocampus of CLP models, thereby alleviating SAE. CONCLUSION: Overall, Berberine may exert anti-inflammatory effects through multi-ingredients, multi-targets and multi-pathways to partially rescue neuronal death and alleviate SAE.

Bispectral Index versus the University of Michigan Sedation Scale in assessing sedation depth during pediatric drug-induced sleep endoscopy.

BACKGROUND AND PURPOSE: Bispectral Index (BIS) and University of Michigan Sedation Scale (UMSS) were two commonly used methods of monitoring the sedation depth, but their correlation was not clear. The purpose of this study is to ascertain if BIS correlates with UMSS in determining the sedation level during pediatric drug-induced sleep endoscopy (DISE). METHODS: One-hundred children, aged 36-143 months, with ASA I~II grade, were enrolled. They were subject to general anesthesia for an elective adenotonsillectomy. Two drug regimens were used. After UMSS ≥ 3, the sites of airway obstructions were located by checking the supraglottic airway structures with a fibrous laryngoscope. UMSS scores, BIS values, electromyography (EMG), and signal quality indices (SQIs) were recorded at the pre-medication and pre-DISE baseline (T0), 5 min subsequent to medication administration but prior to DISE initiation (T1), 1 min after DISE was initiated (T2), 1 min after DISE was completed (T3), 1 min subsequent to tracheal intubation (T4), 1 min following extubation (T5), and 30 min past extubation (T6). RESULTS: There were strong correlations between BIS monitor readings and UMSS scores for total and two regimens. Kappa values revealed moderate agreement between BIS and UMSS for total and two regimens. The agreement rates were 67.47% for the total, 61.43% for Regimen 1, and 73.42% for Regimen 2, respectively. CONCLUSION: BIS correlates with UMSS in determining the sedation level during pediatric DISE for two regimens. BIS might serve as an appropriate indicator of sedation intensity when UMSS could not be used.

Developing the E. coli platform for efficient production of UMP-derived chemicals.

5-Methyluridine (5-MU) is a prominent intermediate for industrial synthesis of several antiviral-drugs, however, its availability over the past decades has overwhelmingly relied on chemical and enzymatic strategies. Here, we have realized efficient production of 5-MU in E. coli, for the first time, via a designer artificial pathway consisting of a two-enzyme cascade (UMP 5-methylase and phosphatase). More importantly, we have engineered the E. coli cell factory to boost 5-MU production by systematic evaluation of multiple strategies, and as a proof of concept, we have further developed an antibiotic-free fermentation strategy to realize 5-MU production (10.71 g/L) in E. coli MB229 (a ΔthyA strain). Remarkably, we have also established a versatile and robust platform with exploitation of the engineered E. coli for efficient production of diversified UMP-derived chemicals. This study paves the way for future engineering of E. coli as a synthetic biology platform for acceleratively accessing UMP-derived chemical diversities.

METTL4 mediated-N6-methyladenosine promotes acute lung injury by activating ferroptosis in alveolar epithelial cells.

Sepsis-induced acute lung injury has been deemed to be an life-threatening pulmonary dysfunction caused by a dysregulated host response to infection. The modification of N6-Methyladenosine (m6A) is implicated in several biological processes, including mitochondrial transcription and ferroptosis. Ferroptosis is an iron-dependent type of programed cell death, which plays a role in sepsis-induced acute lung injury (ALI). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial regulator of intracellular oxidative homeostasis, linked to ferroptosis resistance. This research aims to explore the effect of m6A in ferroptosis in sepsis-induced ALI. First, we found a time-dependent dynamic alteration on pulmonary methylation level during sepsis-induced ALI. We identified METTL4 as a differentially expressed gene in ALI mice using m6A sequencing and RNA-sequencing, and revealed the methylation of several ferroptosis related genes (Nrf2). Thus, we generated METTL4 deficiency mice and found that METTL4 knockdown alleviated ferroptosis, as evidenced by lipid ROS, MDA, Fe2+, as well as alterations in GPX4 and SLC7A11 protein expression. Consistently, we found that METTL4 silencing could decrease ferroptosis sensitivity in LPS-induced TC-1 cells. Furthermore, both the dual-luciferase reporter assay and rescue experiments indicated that METTL4 mediated the N6-methyladenosine of Nrf2 3'UTR, then YTHDF2 binded with the m6A site, promoting the degradation of Nrf2. In conclusion, we revealed that METTL4 promoted alveolar epithelial cells ferroptosis in sepsis-induced lung injury via N6-methyladenosine of Nrf2, which might provide a novel approach to therapeutic strategies for sepsis-induced ALI.

Erbin accelerates TFEB-mediated lysosome biogenesis and autophagy and alleviates sepsis-induced inflammatory responses and organ injuries.

Mounting attention has been focused on defects of the autophagy-lysosomal pathway in sepsis, however, the precise mechanisms governing the autophagy-lysosomal process in sepsis are poorly known. We have previously reported that Erbin deficiency aggravated the inflammatory response and organ injuries caused by sepsis. In the present study, we found that Erbin knockout impaired the autophagy process in both muramyl dipeptide (MDP)-induced bone marrow-derived macrophages (BMDMs) and sepsis mouse liver and lung, as detected by the accumulation of LC3-II and SQSTM1/p62, and autophagosomes. Pretreatment with autophagy inhibitor chloroquine (CQ) further aggravated inflammatory response and organ injuries in vivo and in vitro sepsis model. We also observed that the impaired lysosomal function mediated autophagic blockade, as detected by the decreased expression of ATP6V, cathepsin B (CTSB) and LAMP2 protein. Immunoprecipitation revealed that the C-terminal of Erbin (aa 391-964) interacts with the N-terminal of transcription factor EB (TFEB) (aa 1-247), and affects the stability of TFEB-14-3-3 and TFEB-PPP3CB complexes and the phosphorylation status of TFEB, thereby promote the nucleus translocation of TFEB and the TFEB target genes transcription. Thus, our study suggested that Erbin alleviated sepsis-induced inflammatory responses and organ injuries by rescuing dysfunction of the autophagy-lysosomal pathway through TFEB-14-3-3 and TFEB-PPP3CB pathway.

Knockout of Erbin promotes pyroptosis via regulating NLRP3/caspase-1/Gasdermin D pathway in sepsis-induced acute kidney injury.

BACKGROUND: This study aims to investigate the correlation between Erbin and sepsis, and the role of Erbin on the pyroptosis pathway in acute kidney injury caused by sepsis and NLRP3/caspase-1/Gasdermin D pathway. METHODS: In the study, lipopolysaccharide (LPS) treatment or cecal ligation and puncture (CLP) surgery on mice were used to stimulate the in vitro and in vivo sepsis-induced renal injury model. The male C57BL/6 of wild-type mice (WT) and Erbin-knockout mice (Erbin-/-, EKO) were randomly divided into four groups (WT + Sham, WT + CLP, EKO + Sham, EKO + CLP). Inflammatory cytokine, renal function, pyroptotic cell numbers and the levels of protein and mRNA expression of pyroptosis, including the NLRP3 (all P < 0.05), were analyzed and found increase in Erbin-/- mice with CLP and LPS-induced HK-2 cells. RESULTS: The inhibited of Erbin shows a renal damaged effect by promoting NLRP3 inflammasome-mediated pyroptosis in SI-AKI. CONCLUSION: This study demonstrated a novel mechanism by which Erbin regulates NLRP3 inflammasome-mediated pyroptosis in SI-AKI.

[Retracted] MicroRNA­18b acts as an oncogene in gastric cancer by directly targeting Kruppel­like factor 6.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the cell migration assay data shown in Fig. 2C were strikingly similar to data that had appeared in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 19: 1926­1934, 2019; DOI: 10.3892/mmr.2019.9830].

Update on therapeutic strategy for esophageal anastomotic leak: A systematic literature review.

Anastomotic leak is still a severe complication in esophageal surgery due to high mortality. This article reviews the updates on the treatment of anastomotic leak after esophagectomy in order to provide reference for clinical treatment and research. The relevant studies published in the Chinese Zhiwang, Wanfang, and MEDLINE databases to December 21, 2021 were retrieved, and esophageal carcinoma, esophagectomy, anastomotic leakage, and fistula selected as the keywords. A total of 78 studies were finally included. The treatments include traditional surgical drainage, new reverse drainage trans-fistula, stent plugging, endoscopic clamping, biological protein glue injection plugging, endoluminal vacuum therapy (EVT), and reoperation, etc. Early diagnosis, accurate classification and optimal treatment can promote the rapid healing of anastomotic leaks. EVT may be the most valuable approach, simultaneously with good commercial prospects. Reoperation should be considered in patients with complex fistula in which conservative treatment is insufficient or has failed.

Inhibition of ferroptosis protects sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a serious and common complication of sepsis. To study the ferroptosis in the pathogenesis of SAE and demonstrate the protection effect of ferroptosis resistance, cognitive function, neurological deficits, blood-brain barrier integrity and neuroinflammation were detected. SAE model was established by cecal ligation and puncture (CLP) in mice and an in vitro model was created by introducing LPS to HT22 cells. Ferroptosis inducer Fe-citrate (Fe) and ferroptosis inhibitor ferrostatin-1 (Fer-1) was post-treated in the models, respectively. SAE caused ferroptosis, as evidenced by an increase in reactive oxygen species (ROS), iron content and malondialdehyde (MDA) and a decrease in glutathione (GSH) level, as well as changes in the expression of ferroptosis-related proteins as acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), and cystine-glutamate antiporter (SLC7A11), and harmed mitochondrial function. In contrast, inhibiting ferroptosis with Fer-1 attenuated ferroptosis. Meanwhile, Fer-1 attenuated neurologic severity score, learning and memory impairment, Fluoro-Jade C (FJC) staining, and decreased Evans Blue (EB) extravasation, microglia activation and TNF-α and IL-1ß production following SAE. The benefit of Fer-1 was diminished by ferroptosis inducer Fe. In addition, Fer-1 up-regulated the nuclear factor erythroid-2-related factor 2 (Nrf2)/ heme oxygenase-1(HO-1) signaling axis both in vivo and in vitro. In conclusion, our study revealed that Fer-1 might inhibit feroptosis in neurons by triggering the Nrf2/OH-1 pathway, thereby providing a therapeutic solution for SAE.

IL-33 Alleviates Postoperative Cognitive Impairment by Inhibiting Hippocampal Inflammation and Upregulating Excitatory Synaptic Number in Aged Mice.

Delayed neurocognitive recovery (dNCR), a postoperative complication that occurs in elderly patients, still lacks effective treatment. Interleukin-33 (IL-33) has been proved to modulate neuroinflammation and synaptic plasticity, among other effects, but the role of IL-33 in dNCR is not clear. We established a dNCR model in aged mice by laparotomy under sevoflurane anesthesia. Cognition was evaluated by Morris water maze (MWM) and fear conditioning test (FCT). Immunofluorescence was used to detect the density of IL-33 and glial fibrillary acidic protein (GFAP) co-localization, ionized calcium-binding adapter molecule 1, vesicular glutamate transporter 1 (vGlut1) and postsynaptic density protein-95 (PSD95) co-localization in the hippocampus. IL-33, GFAP, vGlut1 and PSD95 were tested by Western blotting. Enzyme-linked immunosorbent assay was used to detect the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß) and IL-10. Surgery/anesthesia reduced the level of IL-33 in the hippocampus. Intraperitoneal injection of 200 ng IL-33 per mouse significantly decreased the latency to the platform and increased the number of platform crossings and the target quadrant dwell time in MWM, while increasing the freezing time in the context test of FCT. Furthermore, IL-33 inhibited microglial activation and the release of TNF-α and IL-1ß while upregulating the markers of excitatory synapses vGlut1 and PSD95. Our findings indicated that IL-33 improved cognition by inhibiting the hippocampal inflammatory response and upregulating the number of excitatory synapses. Therefore, IL-33 is a potential drug for the treatment of dNCR.

Erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via IRE1α/Xbp1s-Ca2+ axis.

BACKGROUND: Microglia pyroptosis-mediated neuroinflammation is thought to be the crucial pathogenesis of sepsis-associated encephalopathy (SAE). Erbin has been reported to be associated with various inflammatory diseases. However, the role of Erbin in SAE and the relationship between Erbin and microglia pyroptosis are unknown. In this study, we investigated the promising role and underlying molecular mechanism of Erbin in the regulation of microglia pyroptosis. METHODS: WT and Erbin knockout mice underwent cecum ligation perforation (CLP) to induce SAE. Primary mouse microglia and BV2 cells were treated with LPS/nigericin in vitro. Behavioral tests were performed to evaluate cognitive function. Nissl staining and transmission electron microscopy were used to assess histological and structural lesions. ELISA and qPCR were carried out to detect neuroinflammation. Western blot and immunofluorescence were used to analyze protein expression. Flow cytometry and confocal microscopy were utilized to observe the Ca2+ changes in the cytoplasm and endoplasmic reticulum (ER). To further explore the underlying mechanism, STF083010 was administered to block the IRE1α/Xbp1s pathway. RESULTS: Erbin deletion resulted in more pronounced neuronal damage and cognitive impairment in mice that underwent CLP. Erbin knockout promoted microglial pyroptosis and inflammatory cytokines secretion in vivo and in vitro, which was mediated by activation of the IRE1α/Xbp1s. Treatment with the selective inhibitor STF083010 significantly inhibited IRE1α/Xbp1s pathway activity, decreased intracytoplasmic Ca2+, attenuated microglial pyroptosis, reduced pro-inflammatory cytokine secretion, lessened neuronal damage, and improved cognitive function. CONCLUSIONS: In SAE, Erbin inhibits IRE1/Xbp1s pathway activity and reduces the ER Ca2+ influx to the cytoplasm, reducing microglial pyroptosis.

Publication trends of research on COVID-19 and host immune response: A bibliometric analysis.

Introduction: As the first bibliometric analysis of COVID-19 and immune responses, this study will provide a comprehensive overview of the latest research advances. We attempt to summarize the scientific productivity and cooperation across countries and institutions using the bibliometric methodology. Meanwhile, using clustering analysis of keywords, we revealed the evolution of research hotspots and predicted future research focuses, thereby providing valuable information for the follow-up studies. Methods: We selected publications on COVID-19 and immune response using our pre-designed search strategy. Web of Science was applied to screen the eligible publications for subsequent bibliometric analyses. GraphPad Prism 8.0, VOSviewer, and CiteSpace were applied to analyze the research trends and compared the contributions of countries, authors, institutions, and journals to the global publications in this field. Results: We identified 2,200 publications on COVID-19 and immune response published between December 1, 2019, and April 25, 2022, with a total of 3,154 citations. The United States (611), China (353), and Germany (209) ranked the top three in terms of the number of publications, accounting for 53.3% of the total articles. Among the top 15 institutions publishing articles in this area, four were from France, four were from the United States, and three were from China. The journal Frontiers in Immunology published the most articles (178) related to COVID-19 and immune response. Alessandro Sette (31 publications) from the United States were the most productive and influential scholar in this field, whose publications with the most citation frequency (3,633). Furthermore, the development and evaluation of vaccines might become a hotspot in relevant scope. Conclusions: The United States makes the most indispensable contribution in this field in terms of publication numbers, total citations, and H-index. Although publications from China also take the lead regarding quality and quantity, their international cooperation and preclinical research need to be further strengthened. Regarding the citation frequency and the total number of published articles, the latest research progress might be tracked in the top-ranking journals in this field. By analyzing the chronological order of the appearance of retrieved keywords, we speculated that vaccine-related research might be the novel focus in this field.

YAP1 alleviates sepsis-induced acute lung injury via inhibiting ferritinophagy-mediated ferroptosis.

Ferroptosis is a phospholipid peroxidation-mediated and iron-dependent cell death form, involved in sepsis-induced organ injury and other lung diseases. Yes-associated protein 1 (YAP1), a key regulator of the Hippo signaling pathway, could target multiple ferroptosis regulators. Herein, this study aimed to explore the involvement of ferroptosis in the etiopathogenesis of sepsis-induced acute lung injury (ALI) and demonstrate that YAP1 could disrupt ferritinophagy and moderate sepsis-induced ALI. Cecal ligation and puncture (CLP) models were constructed in wild-type (WT) and pulmonary epithelium-conditional knockout (YAP1f/f) mice to induce ALI, while MLE-12 cells with or without YAP1 overexpression were stimulated by lipopolysaccharide (LPS) in vitro. In-vivo modes showed that YAP1 knockout aggravated CLP-induced ALI and also accelerated pulmonary ferroptosis, as presented by the downregulated expression of GPX4, FTH1, and SLC7A11, along with the upregulated expression of SFXN1 and NCOA4. Transcriptome research identified these key genes and ferroptosis pathways involved in sepsis-induced ALI. In-vitro modes consistently verified that YAP1 deficiency boosted the ferrous iron accumulation and mitochondrial dysfunction in response to LPS. Furthermore, the co-IP assay revealed that YAP1 overexpression could prevent the degradation of ferritin to a mass of Fe2+ (ferritinophagy) via disrupting the NCOA4-FTH1 interaction, which blocked the transport of cytoplasmic Fe2+ into the mitochondria via the mitochondrial membrane protein (SFXN1), further reducing the generation of mitochondrial ROS. Therefore, these findings revealed that YAP1 could inhibit ferroptosis in a ferritinophagy-mediated manner, thus alleviating sepsis-induced ALI, which may provide a new approach to the therapeutic orientation for sepsis-induced ALI.

Integrated Analysis of Gene Co-Expression Network and Prediction Model Indicates Immune-Related Roles of the Identified Biomarkers in Sepsis and Sepsis-Induced Acute Respiratory Distress Syndrome.

Sepsis is a series of clinical syndromes caused by immunological response to severe infection. As the most important and common complication of sepsis, acute respiratory distress syndrome (ARDS) is associated with poor outcomes and high medical expenses. However, well-described studies of analysis-based researches, especially related bioinformatics analysis on revealing specific targets and underlying molecular mechanisms of sepsis and sepsis-induced ARDS (sepsis/se-ARDS), still remain limited and delayed despite the era of data-driven medicine. In this report, weight gene co-expression network based on data from a public database was constructed to identify the key modules and screen the hub genes. Functional annotation by enrichment analysis of the modular genes also demonstrated the key biological processes and signaling pathway; among which, extensive immune-involved enrichment was remarkably associated with sepsis/se-ARDS. Based on the differential expression analysis, least absolute shrink and selection operator, and multivariable logistic regression analysis of the screened hub genes, SIGLEC9, TSPO, CKS1B and PTTG3P were identified as the candidate biomarkers for the further analysis. Accordingly, a four-gene-based model for diagnostic prediction assessment was established and then developed by sepsis/se-ARDS risk nomogram, whose efficiency was verified by calibration curves and decision curve analyses. In addition, various machine learning algorithms were also applied to develop extra models based on the four genes. Receiver operating characteristic curve analysis proved the great diagnostic and predictive performance of these models, and the multivariable logistic regression of the model was still found to be the best as further verified again by the internal test, training, and external validation cohorts. During the development of sepsis/se-ARDS, the expressions of the identified biomarkers including SIGLEC9, TSPO, CKS1B and PTTG3P were all regulated remarkably and generally exhibited notable correlations with the stages of sepsis/se-ARDS. Moreover, the expression levels of these four genes were substantially correlated during sepsis/se-ARDS. Analysis of immune infiltration showed that multiple immune cells, neutrophils and monocytes in particular, might be closely involved in the process of sepsis/se-ARDS. Besides, SIGLEC9, TSPO, CKS1B and PTTG3P were considerably correlated with the infiltration of various immune cells including neutrophils and monocytes during sepsis/se-ARDS. The discovery of relevant gene co-expression network and immune signatures might provide novel insights into the pathophysiology of sepsis/se-ARDS.

Quercetin attenuates sepsis-induced acute lung injury via suppressing oxidative stress-mediated ER stress through activation of SIRT1/AMPK pathways.

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction play a pivotal role in the pathological process of sepsis-induced acute lung injury (ALI). Quercetin has been proved to exert anti-inflammation in ALI. This study aimed to explore the protection mechanism of quercetin against sepsis-induced ALI via suppressing ER stress and mitochondrial dysfunction. Cecal ligation and puncture (CLP) mouse model was established to mimic sepsis, and LPS was used to stimulate murine lung epithelial (MLE-12) cells. We observed that quercetin ameliorated pulmonary pathological lesion and oxidative damage in sepsis-induced mice. In LPS-stimulated MLE-12 cells, quercetin could inhibit the level of ER stress as evidenced by decreased mRNA expression of PDI, CHOP, GRP78, ATF6, PERK, IRE1α and improve mitochondrial function, as presented by increased MMP, SOD level and reduced production of ROS, MDA. Meanwhile, transcriptome analysis revealed that quercetin upregulated SIRT1/AMPK mRNA expression. Furthermore, we used siRNA to knockdown SIRT1 in MLE-12 cells, and we found that SIRT1 knockdown could abrogate the quercetin-elicited antioxidation in vitro. Therefore, quercetin could protect against sepsis-induced ALI by suppressing oxidative stress-mediated ER stress and mitochondrial dysfunction via induction of the SIRT1/AMPK pathways.

Cement-Based Repair Materials and the Interface with Concrete Substrates: Characterization, Evaluation and Improvement.

Surface damages usually occur in concrete structures. In order to restore the functions and prolong the service life of concrete structures, their surface damages should be repaired in time. This paper reviews the main requirements for repair materials for concrete structures and the most used inorganic repair materials, such as cement-based materials, alkali-activated materials and polymer modified inorganic repair materials. Moreover, techniques to characterize and even improve the interfaces between these repair materials and concrete substrate are summarized. Cement-based material has the advantages of good mechanical properties and consistency with concrete substrate while having the problems of high shrinkage and low flexibility. Polymer modified materials were found as having lower shrinkage and higher flexural strength. Increasing the roughness or humidity of the surface, adding fibers and applying interfacial agents can improve the bond strength between cement-based repair materials and concrete substrates. All of these repair materials and techniques can help to build a good interfacial bonding, and mechanisms of how they improve the interface are discussed in this article. These are of great importance in guaranteeing the effectiveness of the repair of the concrete surface and to guide the research and development of new repair materials.

PTPN18 promotes colorectal cancer progression by regulating the c-MYC-CDK4 axis.

Protein tyrosine phosphatase non-receptor type 18 (PTPN18) is often highly expressed in colorectal cancer (CRC), but its role in this disease remains unclear. We demonstrated that PTPN18 overexpression promotes growth and tumorigenesis in CRC cells and that PTPN18 deficiency yields the opposite results in vitro. Moreover, a xenograft assay showed that PTPN18 deficiency significantly inhibited tumorigenesis in vivo. PTPN18 activated the MYC signaling pathway and enhanced CDK4 expression, which is tightly associated with the cell cycle and proliferation in cancer cells. Finally, we found that MYC interacted with PTPN18 and increased the protein level of MYC. In conclusion, our results suggest that PTPN18 promotes CRC development by stabilizing the MYC protein level, which in turn activates the MYC-CDK4 axis. Thus, PTPN18 could be a novel therapeutic target in the future.

Tumor necrosis factor α­induced protein 8­like 2 contributes to penehyclidine hydrochloride pretreatment against lipopolysaccharide­induced acute lung injury in a mouse model.

The aim of the present study was to investigate the effect of penehyclidine hydrochloride (PHC) pretreatment on mice with lipopolysaccharide (LPS)­induced acute lung injury (ALI) and its possible underlying mechanisms. Mice were randomly separated into six groups: i) Sham group; ii) LPS group; iii) LPS + PHC group; iv) tumor necrosis factor a­induced protein 8­like protein 2 (TIPE2) group; v) LPS + TIPE2 group; and vi) LPS + TIPE2 + PHC group. The ALI model was induced using LPS through intratracheal injection. The mice received adenovirus gene to induce the overexpression of TIPE2. After mice were sacrificed, lung injury indices were assessed, and arterial blood, bronchoalveolar lavage fluid and lung tissues were collected for subsequent assays. Expression levels of related proteins were detected by using western blotting. It was found that compared with the sham group, the mice treated with LPS showed increased lung injury and dysfunctions of gas exchange. However, these trends were significantly ameliorated in the LPS + PHC group. Evaluation of protein expression in lung tissues showed that the increased expression of nuclear NF­κB p65 and p­c­Jun N­terminal kinase (JNK) induced by LPS were suppressed in the LPS + PHC group and the expression of TIPE2 was increased. The mice that received adenovirus gene to induce TIPE2 overexpression could also showed protective effects compared with the mice in the LPS group. However, the expression of TIPE2 decreased rather than increased in LPS group. In the mice pretreated with PHC, the expression of TIPE2 increased in mice with LPS­induced ALI. To conclude, PHC pretreatment could inhibit the occurrence of inflammation and apoptosis in LPS­induced ALI. This process may be related to the activation of TIPE2 and the inhibition of NF­κB and JNK signaling pathway in the lungs of mice.

Targeting MUC1-C reverses the cisplatin resistance of esophageal squamous cell carcinoma in vitro and in vivo.

BACKGROUND: The efficacy of chemotherapeutic treatment of esophageal squamous cell carcinoma (ESCC) is limited by drug resistance during. This severely compromises the long-term survival rate of patients. Therefore, reversing chemotherapy resistance in ESCC may improve the therapeutic outcome. Here, we investigated the molecular mechanism of MUC1-C, the C-terminal transmembrane subunit of MUC1 (a transmembrane heterodimer protein), and its role in the reversal of cisplatin sensitivity in ESCC cells. METHODS: We assessed the efficacy of GO-203, a cell-penetrating peptide, as a chemotherapeutic target of MUC1-C using cell proliferation, colony-forming, and transwell assays. Apoptosis was analyzed in GO-203-treated cells by flow cytometry. Tumor xenograft assay was performed in nude mice to corroborate our in vitro findings. RESULTS: GO-203 treatment inhibited cell proliferation and restrained the migration and invasion of cisplatin-resistant ESCC. Moreover, targeting MUC1 resulted in enhanced apoptosis in GO-203-treated cells. These in vitro pro-apoptotic and anti-proliferative effects of GO-203 in combination with cisplatin were validated by in vivo models. Significantly smaller tumor volumes were observed in ESCCs-xenografted nude mice treated with GO-203 in combination with cisplatin compared with mice treated with monotherapy or their control counterparts. We found that blocking MUC1-C with GO-203 significantly reversed the cisplatin resistance in ESCC via modulating Akt and ERK pathways. CONCLUSIONS: Our findings suggest that GO-203 may hold potential as an ancillary therapeutic molecule and a chemosensitizer to improve the outcomes of cisplatin-based chemotherapy especially in patients with cisplatin-resistant ESCC.