Publications by authors named "Xin Xu"

2,323 Publications

  • Page 1 of 1

Controller Medication Use and Exacerbations for Children and Adults With Asthma in High-Deductible Health Plans.

JAMA Pediatr 2021 May 10. Epub 2021 May 10.

Harvard Pilgrim Health Care Institute, Department of Population Medicine, Harvard Medical School, Boston, Massachusetts.

Importance: High-deductible health plans (HDHPs) are increasingly common and associated with decreased medication use in some adult populations. How children are affected is less certain.

Objective: To examine the association between HDHP enrollment and asthma controller medication use and exacerbations.

Design, Setting, And Participants: For this longitudinal cohort study with a difference-in-differences design, data were obtained from a large, national, commercial (and Medicare Advantage) administrative claims database between January 1, 2002, and December 31, 2014. Children aged 4 to 17 years and adults aged 18 to 64 years with persistent asthma who switched from traditional plans to HDHPs or remained in traditional plans (control group) by employer choice during a 24-month period were identified. A coarsened exact matching technique was used to balance the groups on characteristics including employer and enrollee propensity to have HDHPs. In most HDHPs, asthma medications were exempt from the deductible and subject to copayments. Statistical analyses were conducted from August 13, 2019, to January 19, 2021.

Exposure: Employer-mandated HDHP transition.

Main Outcomes And Measures: Thirty-day fill rates and adherence (based on proportion of days covered [PDC]) were measured for asthma controller medications (inhaled corticosteroid [ICS], leukotriene inhibitors, and ICS long-acting β-agonists [ICS-LABAs]). Asthma exacerbations were measured by rates of oral corticosteroid bursts and asthma-related emergency department visits among controller medication users.

Results: The HDHP group included 7275 children (mean [SD] age, 10.8 [3.3] years; 4402 boys [60.5%]; and 5172 non-Hispanic White children [71.1%]) and 17 614 adults (mean [SD] age, 41.1 [13.4] years; 10 464 women [59.4%]; and 12 548 non-Hispanic White adults [71.2%]). The matched control group included 45 549 children and 114 141 adults. Compared with controls, children switching to HDHPs experienced significant absolute decreases in annual 30-day fills only for ICS-LABA medications (absolute change, -0.04; 95% CI, -0.07 to -0.01). Adults switching to HDHPs did not have significant reductions in 30-day fills for any controllers. There were no statistically significant differences in PDC, oral steroid bursts, or asthma-related emergency department visits for children or adults. For the 9.9% of HDHP enrollees with health savings account-eligible HDHPs that subjected medications to the deductible, there was a significant absolute decrease in PDC for ICS-LABA compared with controls (-4.8%; 95% CI, -7.7% to -1.9%).

Conclusions And Relevance: This cohort study found that in a population where medications were exempt from the deductible for most enrollees, HDHP enrollment was associated with minimal or no reductions in controller medication use for children and adults and no change in asthma exacerbations. These findings suggest a potential benefit from exempting asthma medications from the deductible in HDHPs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamapediatrics.2021.0747DOI Listing
May 2021

Tubeless video-assisted thoracoscopic surgery in mediastinal tumor resection.

Gland Surg 2021 Apr;10(4):1387-1396

Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China.

Background: It has been reported that tubeless video-assisted thoracoscopic surgery (tubeless-VATS) is feasible and safe for thoracic diseases. Herein, we compared the early outcomes of mediastinal lesion resection between the tubeless and traditional VATS.

Methods: Clinical data of all patients who underwent thoracoscopic mediastinal tumor resection were retrospectively collected. The study involved two groups: tubeless and traditional VATS group. Propensity score matching (PSM) was applied to eliminate the population bias. Intraoperative and postoperative variables were compared among matched cohorts.

Results: In total, 43 patients in the tubeless group and 231 patients in the traditional VATS group were included. After 1:1 PSM, baseline characteristics were comparable. Anesthesia time (177.63 202.53 min; P=0.004) was shorter in tubeless group, while operation time (90.95 . 101.47 min; P=0.109) was similar. Overall, the total postoperative morbidity rate was similar in the two groups (15% . 12.5%; P=0.556). Specially, 4/43 patients in tubeless VATS group need to be re-put chest tubes postoperatively. A significant lower similar level of visual analogue scale score was observed in tubeless VATS group (1.73±0.48 . 3.41±0.87, P<0.001) in postoperative day 1. Meanwhile, the number of patients using postoperative opioid analgesia was also lower in tubeless VATS group (22.88% . 48.38%, P=0.016). Furthermore, hospital duration after surgery (2.58 . 5.47 days; P=0.002) was shorter in tubeless group.

Conclusions: Compared with traditional VATS, tubeless VATS for mediastinal tumor may shorten the anesthesia time, decrease postoperative pain and fasten postoperative recovery in carefully selected patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/gs-20-682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102226PMC
April 2021

A new species of from Myanmar and description of the actual male of Thorell, 1897 (Araneae, Mesothelae, Liphistiidae).

Zookeys 2021 14;1031:41-58. Epub 2021 Apr 14.

Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543, Singapore.

Five Schiödte, 1849 species of the primitively segmented spider family Liphistiidae are currently known from Myanmar. Here, we described a new species, (♂♀), which was collected from Pyin Oo Lwin, Mandalay Region, Myanmar, diagnosed based on its genital morphology. The specimens (2♂♂, 5♀♀) collected by Walter C. Sedgwick from Pyin Oo Lwin in 1982 were misidentified as Thorell, 1897 and are treated here as the newly described species. Accordingly, we described the males of for the first time, redescribed its female, using newly collected specimens from Yadò, Than Taung and Kalekho Atet townships, Kayin State. We also provided information on the variation in genital morphology of both species, and their relationships within the -group of species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3897/zookeys.1031.59102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060243PMC
April 2021

Effect of predictive trauma nursing on emergency traumatic fracture patients.

Minerva Surg 2021 May 4. Epub 2021 May 4.

Department of Emergency, Huzhou Central Hospital, Huzhou, China -

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.23736/S2724-5691.21.08893-6DOI Listing
May 2021

Leaf area index estimation model for UAV image hyperspectral data based on wavelength variable selection and machine learning methods.

Plant Methods 2021 May 3;17(1):49. Epub 2021 May 3.

Science College of Information and Management, Henan Agricultural University, #63 Nongye Road, Zhengzhou, 450002, Henan, China.

Background: To accurately estimate winter wheat leaf area index (LAI) using unmanned aerial vehicle (UAV) hyperspectral imagery is crucial for crop growth monitoring, fertilization management, and development of precision agriculture.

Methods: The UAV hyperspectral imaging data, Analytical Spectral Devices (ASD) data, and LAI were simultaneously obtained at main growth stages (jointing stage, booting stage, and filling stage) of various winter wheat varieties under various nitrogen fertilizer treatments. The characteristic bands related to LAI were extracted from UAV hyperspectral data with different algorithms including first derivative (FD), successive projections algorithm (SPA), competitive adaptive reweighed sampling (CARS), and competitive adaptive reweighed sampling combined with successive projections algorithm (CARS_SPA). Furthermore, three modeling machine learning methods including partial least squares regression (PLSR), support vector machine regression (SVR), and extreme gradient boosting (Xgboost) were used to build LAI estimation models.

Results: The results show that the correlation coefficient between UAV and ASD hyperspectral data is greater than 0.99, indicating the UAV data can be used for estimation of wheat growth information. The LAI bands selected by using different algorithms were slightly different among the 15 models built in this study. The Xgboost model using nine consecutive characteristic bands selected by CARS_SPA algorithm as input was proved to have the best performance. This model yielded identical results of coefficient of determination (0.89) for both calibration set and validation set, indicating a high accuracy of this model.

Conclusions: The Xgboost modeling method in combine with CARS_SPA algorithm can reduce input variables and improve the efficiency of model operation. The results provide reference and technical support for nondestructive and rapid estimation of winter wheat LAI by using UAV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13007-021-00750-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094481PMC
May 2021

A novel rat model of chronic subdural hematoma: Induction of inflammation and angiogenesis in the subdural space mimicking human-like features of progressively expanding hematoma.

Brain Res Bull 2021 Apr 28;172:108-119. Epub 2021 Apr 28.

Department of Neurosurgery, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, 154 Anshan Road, Tianjin, 300052, China. Electronic address:

Pathophysiological mechanisms of chronic subdural hematoma (CSDH) involve localized inflammation, angiogenesis, and dysregulated coagulation and fibrinolysis. The scarcity of reproducible and clinically relevant animal models of CSDH hinders further understanding the underlying pathophysiology and improving new treatment strategies. Here, we developed a novel rat model of CSDH using extracellular matrices (Matrigel) and brain microvascular endothelial cell line (bEnd.3 cells). One hundred-microliter of Matrigel-bEnd.3 cell (10 cells per milliliter) mixtures were injected into the virtual subdural space of elderly male Sprague-Dawley rats. This approach for the first time led to a spontaneous and expanding subdural hematoma, encapsulated by internal and external neomembranes, formed as early as 3 d, reached its peak at 7 d, and lasted for more than 14 d, mimicking the progressive hemorrhage observed in patients with CSDH. The external neomembrane and hematoma fluid involved numerous inflammatory cells, fibroblasts, and highly fragile neovessels. Furthermore, a localized pathophysiological process was validated as evidenced by the increased expressions of inflammatory and angiogenic mediators in external neomembrane and hematoma fluid rather than in peripheral blood. Notably, the specific expression profiles of these mediators were closely associated with the dynamic changes in hematoma volume and neurological outcome. In summary, the CSDH model described here replicated the characteristics of human CSDH, and might serve as an ideal translational platform for preclinical studies. Meanwhile, the crucial roles of angiogenesis and inflammation in CSDH formation were reaffirmed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainresbull.2021.04.024DOI Listing
April 2021

A salivary microbiome-based auxiliary diagnostic model for type 2 diabetes mellitus.

Arch Oral Biol 2021 Apr 8;126:105118. Epub 2021 Apr 8.

The State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; Clinical Research Center for Oral Diseases, Sichuan, China. Electronic address:

Objective: Studies have shown that oral microbiota composition is altered in type 2 diabetes mellitus, implying that it is a potential biomarker for diabetes. This study aimed at constructing a noninvasive auxiliary diagnostic model for diabetes based on differences in the salivary microbial community.

Design: Salivary microbiota from 24 treatment-naive type 2 diabetes mellitus patients and 21 healthy populations were detected through 16S rRNA gene sequencing, targeting the V3/V4 region using the MiSeq platform. Salivary microbiome diversity and composition were analyzed so as to establish a diagnostic model for type 2 diabetes.

Results: Salivary microbiome for treatment-naive type 2 diabetes mellitus patients was imbalanced with certain taxa, including Slackia, Mitsuokella, Abiotrophia, and Parascardovia that being significantly dominant, while the abundance of Moraxella was high in healthy controls. Diabetic patients exhibited varying levels of Prevotella nanceiensis and Prevotella melaninogenica which were negatively correlated with glycosylated hemoglobin and fasting blood glucose levels, as well as fasting blood glucose levels, respectively. Based on differences in salivary microbiome composition between diabetic and healthy groups, we developed a diagnostic model that can be used for the auxiliary diagnosis of type 2 diabetes mellitus with an accuracy of 80 %.

Conclusions: These findings elucidate on the differences in salivary microbiome compositions between type 2 diabetic and non-diabetic populations, and the diagnostic model provides a promising approach for the noninvasive auxiliary diagnosis of diabetes mellitus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.archoralbio.2021.105118DOI Listing
April 2021

Sesquiterpene lactone Bigelovin induces apoptosis of colon cancer cells through inducing IKK-β degradation and suppressing nuclear factor kappa B activation.

Anticancer Drugs 2021 Jun;32(6):664-673

Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences.

Bigelovin, a sesquiterpene lactone extracted from plant Inula helianthus aquatica, exhibited multiple interesting biological activities, including anti-inflammation, antiangiogenesis and cytotoxic action against cancer cells. In the present study, we found that Bigelovin reduced the viability of human colon cancer cells and induced their apoptosis in a time- and dose-dependent manner, with an IC50-5 μM. RNAseq and luciferase reporter analyses revealed that the nuclear factor kappa B (NF-κB) signaling was one of the most significantly inhibited pathways after Bigelovin treatment. Further systemic examination showed that exposure to Bigelovin resulted in ubiquitination and degradation of inhibitor of kappa-B kinase-beta (IKK-β) and decrease of IκB-α and p65 phosphorylation, which led to the downregulation of NF-κB-regulated genes expression. Moreover, enforced expression of exogenous IKK-β attenuated Bigelovin-induced NF-κB suppression and cell viability reduction. These results indicated that Bigelovin exerts a cytotoxic action against colon cancer cells through the induction of IKK-β degradation and consequently the inhibition of NF-κB signaling. Given the abnormal activation of NF-κB signaling in colorectal cancer (CRC) cells and the critical role of chronic inflammation in CRC development, it is conceivable that at least some colorectal cancer cells are addictive to NF-κB activation and targeting the pathway is an effective anti-CRC strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CAD.0000000000001073DOI Listing
June 2021

Pazopanib ameliorates acute lung injuries via inhibition of MAP3K2 and MAP3K3.

Sci Transl Med 2021 Apr;13(591)

Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.

Acute lung injury (ALI) causes high mortality and lacks any pharmacological intervention. Here, we found that pazopanib ameliorated ALI manifestations and reduced mortality in mouse ALI models and reduced edema in human lung transplantation recipients. Pazopanib inhibits mitogen-activated protein kinase kinase kinase 2 (MAP3K2)- and MAP3K3-mediated phosphorylation of NADPH oxidase 2 subunit p47 at Ser to increase reactive oxygen species (ROS) formation in myeloid cells. Genetic inactivation of MAP3K2 and MAP3K3 in myeloid cells or hematopoietic mutation of p47 Ser to alanine attenuated ALI manifestations and abrogates anti-ALI effects of pazopanib. This myeloid MAP3K2/MAP3K3-p47 pathway acted via paracrine HO to enhance pulmonary vasculature integrity and promote lung epithelial cell survival and proliferation, leading to increased pulmonary barrier function and resistance to ALI. Thus, pazopanib has the potential to be effective for treating ALI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.abc2499DOI Listing
April 2021

A target-agnostic screen identifies approved drugs to stabilize the endoplasmic reticulum-resident proteome.

Cell Rep 2021 Apr;35(4):109040

National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address:

Endoplasmic reticulum (ER) dysregulation is associated with pathologies including neurodegenerative, muscular, and diabetic conditions. Depletion of ER calcium can lead to the loss of resident proteins in a process termed exodosis. To identify compounds that attenuate the redistribution of ER proteins under pathological conditions, we performed a quantitative high-throughput screen using the Gaussia luciferase (GLuc)-secreted ER calcium modulated protein (SERCaMP) assay, which monitors secretion of ER-resident proteins triggered by calcium depletion. We identify several clinically used drugs, including bromocriptine, and further characterize them using assays to measure effects on ER calcium, ER stress, and ER exodosis. Bromocriptine elicits protective effects in cell-based models of exodosis as well as in vivo models of stroke and diabetes. Bromocriptine analogs with reduced dopamine receptor activity retain similar efficacy in stabilizing the ER proteome, indicating a non-canonical mechanism of action. This study describes a strategic approach to identify small-molecule drugs capable of improving ER proteostasis in human disease conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2021.109040DOI Listing
April 2021

Clinical features and outcomes after endovascular therapy for penetrating aortic ulcer and intramural hematoma.

Vascular 2021 Apr 28:17085381211012573. Epub 2021 Apr 28.

Department of Vascular Surgery, Institute of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.

Objectives: To identify the differences between clinical features and outcomes after endovascular therapy for penetrating aortic ulcer (PAU) and intramural hematoma (IMH).

Methods: From January 2009 to March 2020, patients who underwent endovascular therapy for PAU and IMH were enrolled. Information on patient demographics, presentation, PAU and IMH morphology, laboratory examination, and clinical follow-up information was collected and analyzed. Univariate analysis was performed to identify the differences between IMH and PAU, and Kaplan-Meier was used to calculate the cumulative survival rate and freedom from reintervention.

Results: A total of 114 patients were enrolled; 80 (70.2%) of them were diagnosed with PAU. Compared with PAU, patients with IMH were younger ( = 0.006), more likely to be admitted emergently ( = 0.001), had longer hospital stay ( = 0.028), and had higher levels of C-reactive protein ( = 0.030). Meanwhile, patients with IMH were more likely to be associated with hypertension ( = 0.020) and pleural effusion ( < 0.001) and less likely to have a history of acute coronary syndrome ( = 0.019) and prior cardiovascular intervention ( = 0.017). The five-year freedom from reintervention and cumulative survival rate were 94.2% (95% confidential interval, 88.9%-99.9%) and 87.8% (95% confidential interval, 79.5%-96.9%) in PAU patients and 89.6% (95% confidential interval, 75.8%-99.9%) and 85.1% (95% confidential interval, 68.0%-99.9%) in IMH patients, respectively. There was no significant difference in freedom from reintervention ( = 0.795) or cumulative survival rate ( = 0.817).

Conclusions: IMH appeared to occur in younger patients with hypertension and usually had an acute onset, while PAU was more likely to be found incidentally in older patients with atherosclerosis. Endovascular therapy was effective in both IMH and PAU patients with encouraging outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/17085381211012573DOI Listing
April 2021

Non-in Situ Technique of Heart-lung Transplantation: Case Series and Technique Description.

Ann Thorac Surg 2021 Apr 23. Epub 2021 Apr 23.

Department of Thoracic Surgery/Oncology, State Key Laboratory and National Clinical Research Center for Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. Electronic address:

Purpose: Heart-lung transplantation (HLTx) is a life-saving treatment option for patients with advanced cardiopulmonary failure. However, posterior mediastinal bleeding and phrenic nerve damage are still intraoperative challenges for the traditional surgical method. This study reports an innovative non-in situ HLTx performed in our center, preventing posterior mediastinal bleeding and phrenic nerve damage effectively.

Description: Between September 2015 and September 2020, twelve patients without previous heart surgery, underwent a traditional HLTx, were divided into a control group. Three patients underwent an innovative non-in situ HLTx. The operative time, cold ischemic time, intraoperative bleeding, intraoperative transfusion, and the length of intensive care unit (ICU) and hospital stay were assessed between traditional surgery and non-in situ HLTx.

Evaluation: The innovative non-in situ HLTx was successfully performed in the three cases. We found that the length of ICU and hospital stay, total surgical time, cold ischemic time, intraoperative bleeding, and intraoperative transfusion were decreased in the three cases compared with the traditional surgery.

Conclusion: Non-in situ HLTx may decrease posterior mediastinal bleeding and phrenic nerve damage effectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.athoracsur.2021.03.101DOI Listing
April 2021

Strategic infarct locations for post-stroke cognitive impairment: a pooled analysis of individual patient data from 12 acute ischaemic stroke cohorts.

Lancet Neurol 2021 Apr 23. Epub 2021 Apr 23.

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

Background: Post-stroke cognitive impairment (PSCI) occurs in approximately half of people in the first year after stroke. Infarct location is a potential determinant of PSCI, but a comprehensive map of strategic infarct locations predictive of PSCI is unavailable. We aimed to identify infarct locations most strongly predictive of PSCI after acute ischaemic stroke and use this information to develop a prediction model.

Methods: In this large-scale multicohort lesion-symptom mapping study, we pooled and harmonised individual patient data from 12 cohorts through the Meta-analyses on Strategic Lesion Locations for Vascular Cognitive Impairment using Lesion-Symptom Mapping (Meta VCI Map) consortium. The identified cohorts (as of Jan 1, 2019) comprised patients with acute symptomatic infarcts on CT or MRI (with available infarct segmentations) and a cognitive assessment up to 15 months after acute ischaemic stroke onset. PSCI was defined as performance lower than the fifth percentile of local normative data, on at least one cognitive domain on a multidomain neuropsychological assessment or on the Montreal Cognitive Assessment. Voxel-based lesion-symptom mapping (VLSM) was used to calculate voxel-wise odds ratios (ORs) for PSCI that were mapped onto a three-dimensional brain template to visualise PSCI risk per location. For the prediction model of PSCI risk, a location impact score on a 5-point scale was derived from the VLSM results on the basis of the mean voxel-wise coefficient (ln[OR]) within each patient's infarct. We did combined internal-external validation by leave-one-cohort-out cross-validation for all 12 cohorts using logistic regression. Predictive performance of a univariable model with only the location impact score was compared with a multivariable model with addition of other clinical PSCI predictors (age, sex, education, time interval between stroke onset and cognitive assessment, history of stroke, and total infarct volume). Testing of visual ratings was done by three clinicians, and accuracy, inter-rater reliability, and intra-rater reliability were assessed with Cohen's weighted kappa.

Findings: In our sample of 2950 patients (mean age 66·8 years [SD 11·6]; 1157 [39·2%] women), 1286 (43·6%) had PSCI. We achieved high lesion coverage of the brain in our analyses (86·9%). Infarcts in the left frontotemporal lobes, left thalamus, and right parietal lobe were strongly associated with PSCI (after false discovery rate correction, q<0·01; voxel-wise ORs >20). On cross-validation, the location impact score showed good correspondence, based on visual assessment of goodness of fit, between predicted and observed risk of PSCI across cohorts after adjusting for cohort-specific PSCI occurrence. Cross-validations showed that the location impact score by itself had similar performance to the combined model with other PSCI predictors, while allowing for easy visual assessment. Therefore the univariable model with only the location impact score was selected as the final model. Correspondence between visual ratings and actual location impact score (Cohen's weighted kappa: range 0·88-0·92), inter-rater agreement (0·85-0·87), and intra-rater agreement (for a single rater, 0·95) were all high.

Interpretation: To the best of our knowledge, this study provides the first comprehensive map of strategic infarct locations associated with risk of PSCI. A location impact score was derived from this map that robustly predicted PSCI across cohorts. Furthermore, we developed a quick and reliable visual rating scale that might in the future be applied by clinicians to identify individual patients at risk of PSCI.

Funding: The Netherlands Organisation for Health Research and Development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1474-4422(21)00060-0DOI Listing
April 2021

Endogenous glutamate determines ferroptosis sensitivity via ADCY10-dependent YAP suppression in lung adenocarcinoma.

Theranostics 2021 24;11(12):5650-5674. Epub 2021 Mar 24.

Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.

Ferroptosis, a newly identified form of regulated cell death, can be induced following the inhibition of cystine-glutamate antiporter system X because of the impaired uptake of cystine. However, the outcome following the accumulation of endogenous glutamate in lung adenocarcinoma (LUAD) has not yet been determined. Yes-associated protein (YAP) is sustained by the hexosamine biosynthesis pathway (HBP)-dependent O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation), and glutamine-fructose-6-phosphate transaminase (GFPT1), the rate-limiting enzyme of the HBP, can be phosphorylated and inhibited by adenylyl cyclase (ADCY)-mediated activation of protein kinase A (PKA). However, whether accumulated endogenous glutamate determines ferroptosis sensitivity by influencing the ADCY/PKA/HBP/YAP axis in LUAD cells is not understood. Cell viability, cell death and the generation of lipid reactive oxygen species (ROS) and malondialdehyde (MDA) were measured to evaluate the responses to the induction of ferroptosis following the inhibition of system X. Tandem mass tags (TMTs) were employed to explore potential factors critical for the ferroptosis sensitivity of LUAD cells. Immunoblotting (IB) and quantitative RT-PCR (qPCR) were used to analyze protein and mRNA expression. Co-immunoprecipitation (co-IP) assays were performed to identify protein-protein interactions and posttranslational modifications. Metabolite levels were measured using the appropriate kits. Transcriptional regulation was evaluated using a luciferase reporter assay, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA). Drug administration and limiting dilution cell transplantation were performed with cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. The associations among clinical outcome, drug efficacy and ADCY10 expression were determined based on data from patients who underwent curative surgery and evaluated with patient-derived primary LUAD cells and tissues. The accumulation of endogenous glutamate following system X inhibition has been shown to determine ferroptosis sensitivity by suppressing YAP in LUAD cells. YAP O-GlcNAcylation and expression cannot be sustained in LUAD cells upon impairment of GFPT1. Thus, Hippo pathway-like phosphorylation and ubiquitination of YAP are enhanced. ADCY10 acts as a key downstream target and diversifies the effects of glutamate on the PKA-dependent suppression of GFPT1. We also discovered that the protumorigenic and proferroptotic effects of ADCY10 are mediated separately. Advanced-stage LUADs with high ADCY10 expression are sensitive to ferroptosis. Moreover, LUAD cells with acquired therapy resistance are also prone to higher ADCY10 expression and are more likely to respond to ferroptosis. Finally, a varying degree of secondary labile iron increase is caused by the failure to sustain YAP-stimulated transcriptional compensation for ferritin at later stages further explains why ferroptosis sensitivity varies among LUAD cells. Endogenous glutamate is critical for ferroptosis sensitivity following the inhibition of system X in LUAD cells, and ferroptosis-based treatment is a good choice for LUAD patients with later-stage and/or therapy-resistant tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.55482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058707PMC
March 2021

Pulmonary fibrosis combined with lung cancer following lung transplantation: should we do more?

Transl Lung Cancer Res 2021 Mar;10(3):1588-1593

Department of Thoracic Surgery and Organ Transplantation, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Currently, lung transplantation is the standard of care for patients with end-stage lung disease, with interstitial lung disease (ILD) being the most common reason in the recent years In the other hand, in cases where stage II and III lung cancer have been identified following lung transplantation, long-term survival outcomes are poor when compared to lung cancer patients that have not received a lung transplant because the use of immunosuppressant and the problem of rejection and infection and the treatment of recurrence and so on. However, there is no statistical difference observed in stage I (pT1N0M0) patients. In this paper we report about a patient with ILD receiving left lung transplantation in the early time. A lesion of the right lung which was considered the normal ILD tissue and without enough attention. Post-transplant it showed progress and finally the whole right lung (native lung) was occupied by the tumor. Some ground glass changes could also be found in the transplanted lung several months later. A secondary lung transplant was performed for this patient, and there has been no postoperative recurrence thus far. For lung transplant patients with high-risk factors, effective surveillance methods are required for the early detection of lung cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/tlcr-21-46DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044479PMC
March 2021

Protective effect of scorpion venom heat-resistant synthetic peptide against PM-induced microglial polarization via TLR4-mediated autophagy activating PI3K/AKT/NF-κB signaling pathway.

J Neuroimmunol 2021 Jun 2;355:577567. Epub 2021 Apr 2.

College of Medical Laboratory, Dalian Medical University, Dalian 116044, Liaoning Province, China; National-Local Joint Engineering Research Center for Drug-Research and Development (R & D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, 116044, Liaoning Province, China. Electronic address:

There is growing evidence that fine particulate matter (PM) is a considerable risk factor for neurodegenerative diseases. Scorpion venom heat-resistant synthetic peptide (SVHRSP) plays a neuroprotective effect by promoting neurogenesis and neuron axon growth. In this study, SVHRSP inhibited the level of TLR4, autophagy and PM2.5-induced microglia M1 polarization, thereby promoting Phosphorylation of PI3K and AKT, inhibiting the expression of NF-κB. Moreover, SVHRSP suppressed the cytotoxic factors and increased the cytoprotective factor. This research demonstrates that SVHRSP relieves PM-induced microglial polarization via TLR4-mediated autophagy activating PI3K/AKT/NF-κB signaling pathway, which provides new insights for the treatment of PM-induced neurodegenerative diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jneuroim.2021.577567DOI Listing
June 2021

The microbiota-gut-bone axis and bone health.

J Leukoc Biol 2021 Apr 22. Epub 2021 Apr 22.

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, P.R. China.

The gastrointestinal tract is colonized by trillions of microorganisms, consisting of bacteria, fungi, and viruses, known as the "second gene pool" of the human body. In recent years, the microbiota-gut-bone axis has attracted increasing attention in the field of skeletal health/disorders. The involvement of gut microbial dysbiosis in multiple bone disorders has been recognized. The gut microbiota regulates skeletal homeostasis through its effects on host metabolism, immune function, and hormonal secretion. Owing to the essential role of the gut microbiota in skeletal homeostasis, novel gut microbiota-targeting therapeutics, such as probiotics and prebiotics, have been proven effective in preventing bone loss. However, more well-controlled clinical trials are still needed to evaluate the long-term efficacy and safety of these ecologic modulators in the treatment of bone disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/JLB.3MR0321-755RDOI Listing
April 2021

Effects of long noncoding RNA on prognosis of oral squamous cell carcinoma: A protocol for systematic review and meta analysis.

Medicine (Baltimore) 2021 Apr;100(16):e25507

Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Shandong University, Jinan.

Background: Long noncoding RNA (lncRNA) is reported to be upregulated in many tumors. Although the expression of lncRNA in oral squamous cell carcinoma has been assessed, the association between lncRNA expression and prognosis or clinicopathological feature still remains controversial. Therefore, we conducted a meta-analysis to verify whether lncRNA expression was related to prognosis or clinicopathological features in patients with oral squamous cell carcinoma.

Methods: We searched Embase, PubMed, Web of Science, Cochrane library, Chinese National Knowledge Infrastructure, and Wanfang databases from inception to February 2021. The language included Chinese and English. The published literature on lncRNA expression and prognosis or clinicopathological characteristics of patients with oral squamous cell carcinoma was statistically analyzed. The combination of hazard ratios (HRs), odds ratios (OR), and 95% confidence intervals (95% CIs) were applied to evaluate the effects of lncRNA on the prognosis and clinicopathological features of oral squamous cell carcinoma.

Results: This study could provide a comprehensive review of the available evidence of lncRNA on the prognosis and clinicopathological features of oral squamous cell carcinoma.

Conclusion: The conclusion of our study will provide the updated evidence to judge the lncRNA on the prognosis and clinicopathological features of oral squamous cell carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000025507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078265PMC
April 2021

Expression and functional characterization of INPP4B in gallbladder cancer patients and gallbladder cancer cells.

BMC Cancer 2021 Apr 20;21(1):433. Epub 2021 Apr 20.

Department of General Surgery, the Armed Police Corps Hospital of Anhui, Hefei, 230041, People's Republic of China.

Background: Inositol polyphosphate 4-phosphatase type II (INPP4B) is a negative regulator of the PI3K-Akt signalling pathway and plays a contradictory role in different types of cancers. However, the its biological role played by INPP4B in human gallbladder cancer (GBC) has not been elucidated. In this study, we investigated the expression, clinical significance and biological function of INPP4B in GBC patients and cell lines.

Methods: The INPP4B protein expression levels in gallbladder cancer tissues and normal gallbladder tissues were detected by immunohistochemistry, and the clinical significance of INPP4B was analysed. Knockdown and overexpression of INPP4B in GBC-SD and SGC-996 cells followed by cell proliferation, clonogenic, apoptosis detection, scratch wound-healing and transwell assays were used to identify INPP4B function in vitro.

Results: INPP4B was up-regulated in human GBC tissues compared with normal gallbladder tissues and was related to histopathological differentiation (p = 0.026). Here, we observed that INPP4B was highly expressed in high-moderately differentiated tumours compared with low-undifferentiated tumours (p = 0.022). Additionally, we found that INPP4B expression was not associated with overall survival of GBC patients (p = 0.071) and was not an independent prognostic factor. Furthermore, when we stratified the relationship between INPP4B expression and the prognosis of GBC based on histopathological differentiation, we found that INPP4B played a contradictory role in GBC progression depending on the degree of differentiation. In addition, INPP4B knockdown inhibited the proliferation, colony formation, migration and invasion in GBC cells, while INPP4B overexpression had the opposite effects in vitro, which indicates its role as an oncoprotein.

Conclusions: These findings suggested that INPP4B may play a dual role in the prognosis of GBC depending on the degree of differentiation and that INPP4B might act as an oncogene in gallbladder cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-021-08143-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056679PMC
April 2021

A neural network potential energy surface for the F + HO ↔ HF + OH reaction and quantum dynamics study of the isotopic effect.

Phys Chem Chem Phys 2021 Apr 31;23(14):8809-8816. Epub 2021 Mar 31.

State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, P. R. China.

A global potential energy surface for the F + HO ↔ HF + OH reaction has been constructed using the neural network method based on ∼24 000 ab initio energies calculated at the all-electron CCSD(T)-F12a/cc-pCVTZ-F12 level of theory. The correction term accounting for the influence of spin-orbit couplings has also been included with a hierarchical scheme. The isotopic effect on the total reaction probabilities of the reaction was investigated using the time-dependent wave packet method.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d1cp00641jDOI Listing
April 2021

Rhodium(III)-Catalyzed C-H Bond Functionalization of 2-Pyridones with Alkynes: Switchable Alkenylation, Alkenylation/Directing Group Migration and Rollover Annulation.

Chemistry 2021 Apr 19. Epub 2021 Apr 19.

Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania, 19104-6323, USA.

Cp*Rh(III)-catalyzed chelation-assisted direct C-H bond functionalization of 1-(2-pyridyl)-2-pyridones with internal alkynes that can be controlled to give three different products in good yields has been realized. Depending on the reaction conditions, solvents and additives, the reaction pathway can be switched between alkenylation, alkenylation/directing group migration and rollover annulation. These reaction manifolds allow divergent access to a variety of valuable C6-alkenylated 1-(2-pyridyl)-2-pyridones, (Z)-6-(1,2-diaryl-2-(pyridin-2-yl)vinyl)pyridin-2(1H)-ones and 10H-pyrido[1,2-a][1,8]naphthyridin-10-ones from the same starting materials. These protocols exhibit excellent regio- and stereoselectivity, broad substrate scope, and good tolerance of functional groups. A combination of experimental and computational approaches have been employed to uncover the key mechanistic features of these reactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/chem.202101074DOI Listing
April 2021

A Novel Small Molecule, LCG-N25, Inhibits Oral Streptococcal Biofilm.

Front Microbiol 2021 29;12:654692. Epub 2021 Mar 29.

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

Dental caries is a chronic oral infectious disease caused by cariogenic biofilm adhered on the tooth surface. Our previous study demonstrated that a repurposed natural compound napabucasin (NAP) showed good antimicrobial activity against oral streptococcal biofilms. The current study designed a novel small molecule, namely LCG-N25, using NAP as a lead compound, and aimed to investigate its potential as an antimicrobial agent in the control of dental caries. LCG-N25 was designed and synthesized with reference to the structure of NAP. The minimal inhibitory concentrations and the minimal bactericidal concentrations of LCG-N25 against , , and were evaluated by microdilution method. The antimicrobial activity of LCG-N25 was further evaluated by crystal violet staining, colony forming units counting, biofilm metabolism assay, dead/live fluorescent staining, and scanning electron microscopy. The effect of LCG-N25 on the extracellular polysaccharides of biofilms was determined by both anthrone-sulfuric acid method and fluorescent staining. The microbial composition of streptococcal biofilms after LCG-N25 treatment was further visualized and quantified by fluorescence hybridization. Besides, the cytotoxicity of LCG-N25 was evaluated by Cell Counting Kit-8 assay, and repeated exposure of to LCG-N25 treatment was performed to assess if this novel compound could induce drug resistance of this cariogenic bacterium. We found that LCG-N25 exhibited a good antibacterial activity, low-cytotoxicity, and did not induce drug resistance of cariogenic . These findings suggest that LCG-N25 may represent a promising antimicrobial agent that can be used as an adjuvant to the management of dental caries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmicb.2021.654692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044806PMC
March 2021

The Arachidonic Acid Metabolism Mechanism Based on UPLC-MS/MS Metabolomics in Recurrent Spontaneous Abortion Rats.

Front Endocrinol (Lausanne) 2021 2;12:652807. Epub 2021 Apr 2.

Department of Gynaecology, Beijing Traditional Chinese Medicine Hospital Affiliated to Capital Medical University, Beijing, China.

Recurrent spontaneous abortion (RSA) remains a critical and challenging problem in reproduction. To discover novel biomarkers for RSA, ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) metabolomics approach was applied to detect RSA serum metabolic profiles and explore its possible pathogenesis and mechanism. The abortion rat model was established, and a metabolomics analysis was performed to evaluate the differentially expressed metabolites between the control and model groups. Immunohistochemistry (IHC), qRT-PCR, and Western blot further examined the expression of Arachidonic acid metabolism-related genes in uterus tissues. To identify arachidonic acid metabolism-related changes in RSA, ELISA's potential mechanisms were further confirmed in serum. Ninety-one metabolites were significantly different between the two groups, as indicated by a VIP ≥1, fold change ≥1. The metabolic pathways involving arachidonic acid metabolism pathway ( = 0.00044) are related to RSA. Verification by experimental showed that compared with the control rats, the expression of the COX-1, COX-2, PTGFR, and TBXA2R genes associated with the arachidonic acid metabolism pathway has significantly increased the uterus and serum of RSA rats ( < 0.05). Regulation of the arachidonic acid metabolism pathway might serve as a promising therapeutic strategy for relieving RSA women's symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2021.652807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050334PMC
April 2021

Structure of Rad5 provides insights into its role in tolerance to replication stress.

Mol Cell Oncol 2021 4;8(2):1889348. Epub 2021 Mar 4.

Department of Biochemistry and Molecular Biology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, P. R. China.

The Rad5 family of proteins are critical genome maintenance factors, with helicase-like transcription factor (HLTF) and SNF2 histone linker PHD RING helicase (SHRPH) in humans implicated in several types of cancer. How their multiple activities coordinate has been unclear. Our recent study on Rad5 shed light on this question.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/23723556.2021.1889348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018420PMC
March 2021

Temporal transcriptome profiling of developing seeds reveals candidate genes involved in oil accumulation in safflower (Carthamus tinctorius L.).

BMC Plant Biol 2021 Apr 15;21(1):181. Epub 2021 Apr 15.

Agronomy College, Sichuan Agricultural University, Wenjiang, 611130, Chengdu, Sichuan, People's Republic of China.

Background: The investigation of molecular mechanisms involved in lipid metabolism plays a critical role for the genetic engineering of safflower (Carthamus tinctorius L.) to increase the oil accumulation level or to change the oil composition. Although transcript sequences are currently available for the leaves and flowers of safflower, a wide range scan of temporal transcripts at different stages of seed development has not been conducted for safflower.

Results: In this study, temporal transcriptome sequencing was executed at 10, 14, 18, and 22 days after flowering (DAF) to uncover the molecular networks concerned in the biosynthesis of unsaturated fatty acids (USFAs). The results revealed that the biosynthesis of fatty acids is a dominant cellular process from 10 to 14 DAF, while degradation mainly happens after 18 DAF. Significant expression changes of two genes, stearoyl-[acyl-carrier-protein] 9-desaturase gene (SAD) from 10 to 14 DAF and oleate desaturase (FAD2-1) from 14 to 18 DAF, were detected at the transcriptomic levels, and the temporal expression patterns revealed by the transcriptomic analysis were confirmed using quantitative real-time PCR experiments. In addition, 13 candidate transcription factors (TFs) involved in regulating the expression level of the FAD2-1 gene were identified.

Conclusions: These results create a link between fatty acid biosynthesis and gene expression at different developmental stages of the seeds, provide insight into the underlying lipid metabolism, and meanwhile lay an important foundation for the genetic engineering of safflower varieties. We have identified novel candidate genes, including TFs, that are worthy of further exploration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12870-021-02964-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051040PMC
April 2021

Effects of Infant Formula Supplemented With Prebiotics and OPO on Infancy Fecal Microbiota: A Pilot Randomized Clinical Trial.

Front Cell Infect Microbiol 2021 29;11:650407. Epub 2021 Mar 29.

Department of Child Health Care, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.

Several lines of evidence suggest that the intestinal microbiota plays crucial roles in infant development, and that it is highly influenced by extrinsic and intrinsic factors. Prebiotic-containing infant formula may increase gastrointestinal tolerance and improve commensal microbiota composition. However, it remains unknown whether supplementation of milk-formulas with prebiotics and 1,3-olein-2-palmitin (OPO) can achieve feeding outcomes similar to those of breastfeeding. In the present study, we investigated the effects of two kinds of infant formula with different additives on the overall diversity and composition of the fecal microbiota, to determine which was closer to breastfeeding. A total of 108 infants were enrolled, including breastfeeding (n=59) and formula feeding group (n=49). The formula feeding infants were prospectively randomly divided into a standard formula group (n=18), and a supplemented formula group(n=31). The fecal samples were collected at 4 months after intervention. Fecal microbiota analysis targeting the V4 region of the 16S rRNA gene was performed using MiSeq sequencing. The overall bacterial diversity and composition, key functional bacteria, and predictive functional profiles in the two different formula groups were compared with breastfeeding group. We found that the alpha diversity of the gut microbiota was not significantly different between the OPO and breastfeeding groups with Chaos 1 index (p=0.346). The relative abundances of and in the OPO group were more similar to those of the breastfeeding group than to those of the standard formula group. The gut microbiota metabolism function prediction analysis showed that the supplemented formula group was similar to the breastfeeding group in terms of ureolysis (p=0.297). These findings suggest that, when formula supplemented with prebiotics and OPO was given, the overall bacterial diversity and parts of the composition of the fecal microbiota would be similar to that of breastfeeding infants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcimb.2021.650407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039316PMC
March 2021

Antimicrobial activities of a small molecule compound II-6s against oral streptococci.

J Oral Microbiol 2021 Mar 30;13(1):1909917. Epub 2021 Mar 30.

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

: The side effects of present antimicrobials like chlorhexidine (CHX) and the emergence of drug resistance necessitate the development of alternative agents to control dental caries. : This study developed a novel small molecule, namely II-6s, and investigated its antimicrobial activities against common oral streptococci associated with dental caries. : The susceptibility of streptococci to II-6s was evaluated by the microdilution method, time-kill assay and scanning electron microscopy. The exopolysaccharides, dead/live bacteria and bacterial composition of the II-6s-treated // 3-species biofilms were analyzed by confocal laser scanning microscopy, fluorescent hybridization and quantitative PCR. The anti-demineralization effect and cytotoxicity of II-6s were evaluated by transverse microradiography and CCK-8 assay, respectively. Repeated exposure of to II-6s was performed to assess if II-6s could induce drug resistance. : II-6s exhibited antimicrobial activity similar to CHX against and and significantly inhibited exopolysaccharides production, live bacteria and the demineralizing capability of the 3-species streptococcal biofilms. Besides, II-6s showed reduced cytotoxicity relative to CHX and did not induce drug resistance in after 15 passages. : - II-6s may serve as a promising part of a successful caries management plan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/20002297.2021.1909917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018465PMC
March 2021

Herkinorin negatively regulates NLRP3 inflammasome to alleviate neuronal ischemic injury through activating Mu opioid receptor and inhibiting the NF-κB pathway.

J Cell Biochem 2021 Apr 9. Epub 2021 Apr 9.

Department of Neurobiology and Center of Stroke, School of Basic Medical Science, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.

Herkinorin is a novel opioid receptor agonist. Activation of opioid receptors, a member of G protein coupled receptors (GPCRs), may play an important role in Herkinorin neuroprotection. GPCRs may modulate NOD-like receptor protein 3 (NLRP3)-mediated inflammatory responses in the mechanisms of inflammation-associated disease and pathological processes. In this study, we investigated the effects of Herkinorin on NLRP3 and the underlying receptor and molecular mechanisms in oxygen-glucose deprivation/reperfusion (OGD/R)-treated rat cortex neurons. First, Western blot analysis showed that Herkinorin can inhibit the activation of NLRP3 and Caspase-1, decrease the expression of interleukin (IL)-1β, and decrease the secretion of IL-6 and tumour necrosis factor α detected by enzyme-linked immunosorbent assay in OGD/R-treated neurons. Then we found that Herkinorin downregulated NLRP3 levels by inhibiting the activation of nuclear factor kappa B (NF-κB) pathway, reducing the phosphorylation level of p65 and IκBα in OGD/R-treated neurons (p < .05 or .01, n = 3 per group). Instead, both the mu opioid receptor (MOR) inhibitor, β-funaltrexamine, and MOR knockdown reversed the effects of Herkinorin on NLRP3 (p < .05 or .01, n = 3 per group). Further, we found that the level of β-arrestin2 decreased in the cell membrane and increased in the cytoplasm after Herkinorin pretreatment in OGD/R-treated neurons. In co-immunoprecipitation experiments, Herkinorin increased the binding of IκBα with β-arrestin2, decreased the ubiquitination level of IκBα, and β-arrestin2 knockdown reversed the effects of Herkinorin on IκBα in OGD/R-treated neurons (p < .05 or .01, n = 3 per group). Our data demonstrated that Herkinorin negatively regulated NLRP3 inflammasome to alleviate neuronal ischemic injury through inhibiting NF-κB pathway mediated primarily by MOR activation. Inhibition of the NF-κB pathway by Herkinorin may be achieved by decreasing the ubiquitination level of IκBα, in which β-arrestin2 may play an important role.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcb.29929DOI Listing
April 2021

Early extubation in operating room after single-lung transplantation: a single institutional experience.

Ann Palliat Med 2021 Apr 23;10(4):4134-4142. Epub 2021 Mar 23.

Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China.

Background: Early endotracheal extubation in operating room (E-OR) after lung transplantation is rarely reported worldwide. Herein, we aim to explore the feasibility and safety of E-OR after lung transplantation and demonstrate its potential benefits.

Methods: This study is a single-center retrospective database analysis of 18 patients. All lung transplantation patients with E-OR attempted between June 2018 and September 2019 were included retrospectively. Perioperative variables, including ischemia time, total blood loss, blood lactic acid, the partial pressure of oxygen, partial pressure of oxygen/fraction of inspiration oxygen ratio, time of semi-open pulmonary artery occlusion clamp, extubation rate, and complications after E-OR, were analyzed. Data were compared using non-parametric tests and expressed as the median or number (percentage).

Results: Clinical data of 18 patients with E-OR attempted were collected. Overall, 15/18 (83.33%) patients successfully underwent E-OR without reintubation. Reintubation occurred in 3/18 (16.67%) patients; one patient presented with decreased blood oxygen saturation and unconsciousness, while two patients developed hypoxemia and respiratory failure after E-OR. Extracorporeal membrane oxygenation (ECMO) was not used postoperatively. No grade 3 primary graft dysfunction was observed and all eighteen patients were alive 1 year after the transplant. No postoperative hemodialysis and tracheotomy occurred. The median length of stay in the intensive care unit (ICU) for E-OR patients was 120 hours, the median length of postoperative hospital stay was 19 days, and the median hospitalization cost was 35,577 USD.

Conclusions: Early endotracheal extubation in operating room was feasible and did not delay postoperative recovery in these 18 lung transplantation recipients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/apm-20-1598DOI Listing
April 2021

A mechanism for matrikine regulation in acute inflammatory lung injury.

JCI Insight 2021 04 8;6(7). Epub 2021 Apr 8.

Department of Medicine, Division of Pulmonology, Allergy and Critical Care Medicine, and.

Proline-glycine-proline (PGP) and its acetylated form (Ac-PGP) are neutrophil chemoattractants generated by collagen degradation, and they have been shown to play a role in chronic inflammatory disease. However, the mechanism for matrikine regulation in acute inflammation has not been well established. Here, we show that these peptides are actively transported from the lung by the oligopeptide transporter, PEPT2. Following intratracheal instillation of Ac-PGP in a mouse model, there was a rapid decline in concentration of the labeled peptide in the bronchoalveolar lavage (BAL) over time and redistribution to extrapulmonary sites. In vitro knockdown of the PEPT2 transporter in airway epithelia or use of a competitive inhibitor of PEPT2, cefadroxil, significantly reduced uptake of Ac-PGP. Animals that received intratracheal Ac-PGP plus cefadroxil had higher levels of Ac-PGP in BAL and lung tissue. Utilizing an acute LPS-induced lung injury model, we demonstrate that PEPT2 blockade enhanced pulmonary Ac-PGP levels and lung inflammation. We further validated this effect using clinical samples from patients with acute lung injury in coculture with airway epithelia. This is the first study to our knowledge to determine the in vitro and in vivo significance of active matrikine transport as a mechanism of modulating acute inflammation and to demonstrate that it may serve as a potential therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.140750DOI Listing
April 2021