Publications by authors named "Sheng Le"

35 Publications

Cytosporone B (Csn-B), an NR4A1 agonist, attenuates acute cardiac allograft rejection by inducing differential apoptosis of CD4+T cells.

Int Immunopharmacol 2022 Jan 10;104:108521. Epub 2022 Jan 10.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

CD4+T cell-mediated acute rejection remains a major factor that affects the early survival of transplanted organs post-transplantation. Here, we reveal that nuclear receptor subfamily 4 Group A member 1 (Nr4A1) was upregulated during cardiac allograft rejection and that the increased Nr4A1 was primarily localized in intragraft-infiltrating CD4+T cells. Nr4A1 acts as a transcription factor with an important role in CD4+T cell apoptosis, differentiation and T cell dysfunction, which indicates that Nr4A1 may play a critical role in transplant rejection. Cytosporone B (Csn-B) is a naturally occurring agonist of Nr4A1, and the role of Csn-B in the physiological process of cardiac rejection is poorly defined. This study constructed an acute rejection model of abdominal heterotopic cardiac transplantation in mice and investigated whether Csn-B could attenuate acute transplant rejection by modulating the CD4+T lymphocyte response. The results showed that Csn-B prolonged murine cardiac allograft survival and reduced inflammation in allografts. Subsequently, it was confirmed that Csn-B functions by inducing non-Treg apoptosis and promoting Treg cell differentiation. Finally, we also confirmed that Csn-B attenuates acute rejection by directly targeting Nr4A1 in CD4+T cells. Our data suggest that Csn-B is a promising novel therapeutic approach for acute cardiac allograft rejection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.intimp.2022.108521DOI Listing
January 2022

Incidence, Risk Factors and Outcomes of Postoperative Headache After Stanford Type a Acute Aortic Dissection Surgery.

Front Cardiovasc Med 2021 23;8:781137. Epub 2021 Dec 23.

Department of Cardiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Postoperative headache (POH) is common in clinical practice, however, no studies about POH after Stanford type A acute aortic dissection surgery (AADS) exist. This study aims to describe the incidence, risk factors and outcomes of POH after AADS, and to construct two prediction models. Adults who underwent AADS from 2016 to 2020 in four tertiary hospitals were enrolled. Training and validation sets were randomly assigned according to a 7:3 ratio. Risk factors were identified by univariate and multivariate logistic regression analysis. Nomograms were constructed and validated on the basis of independent predictors. POH developed in 380 of the 1,476 included patients (25.7%). Poorer outcomes were observed in patients with POH. Eight independent predictors for POH after AADS were identified when both preoperative and intraoperative variables were analyzed, including younger age, female sex, smoking history, chronic headache history, cerebrovascular disease, use of deep hypothermic circulatory arrest, more blood transfusion, and longer cardiopulmonary bypass time. White blood cell and platelet count were also identified as significant predictors when intraoperative variables were excluded from the multivariate analysis. A full nomogram and a preoperative nomogram were constructed based on these independent predictors, both demonstrating good discrimination, calibration, clinical usefulness, and were well validated. Risk stratification was performed and three risk intervals were defined based on the full nomogram and clinical practice. POH was common after AADS, portending poorer outcomes. Two nomograms predicting POH were developed and validated, which may have clinical utility in risk evaluation, early prevention, and doctor-patient communication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcvm.2021.781137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8733002PMC
December 2021

Nomogram Models to Predict Postoperative Hyperlactatemia in Patients Undergoing Elective Cardiac Surgery.

Front Med (Lausanne) 2021 2;8:763931. Epub 2021 Dec 2.

Department of Cardiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Postoperative hyperlactatemia (POHL) is common in patients undergoing cardiac surgery and is associated with poor outcomes. The purpose of this study was to develop and validate two predictive models for POHL in patients undergoing elective cardiac surgery (ECS). We conducted a multicenter retrospective study enrolling 13,454 adult patients who underwent ECS. All patients involved in the analysis were randomly assigned to a training set and a validation set. Univariate and multivariate analyses were performed to identify risk factors for POHL in the training cohort. Based on these independent predictors, the nomograms were constructed to predict the probability of POHL and were validated in the validation cohort. A total of 1,430 patients (10.6%) developed POHL after ECS. Age, preoperative left ventricular ejection fraction, renal insufficiency, cardiac surgery history, intraoperative red blood cell transfusion, and cardiopulmonary bypass time were independent predictors and were used to construct a full nomogram. The second nomogram was constructed comprising only the preoperative factors. Both models showed good predictive ability, calibration, and clinical utility. According to the predicted probabilities, four risk groups were defined as very low risk (<0.05), low risk (0.05-0.1), medium risk (0.1-0.3), and high risk groups (>0.3), corresponding to scores of ≤ 180 points, 181-202 points, 203-239 points, and >239 points on the full nomogram, respectively. We developed and validated two nomogram models to predict POHL in patients undergoing ECS. The nomograms may have clinical utility in risk estimation, risk stratification, and targeted interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmed.2021.763931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8674505PMC
December 2021

Development and Validation of Nomogram Models for Postoperative Pneumonia in Adult Patients Undergoing Elective Cardiac Surgery.

Front Cardiovasc Med 2021 11;8:750828. Epub 2021 Oct 11.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Postoperative pneumonia (POP) is a frequent complication following cardiac surgery, related to increased morbidity, mortality and healthcare costs. The objectives of this study were to investigate the risk factors associated with POP in adults undergoing elective cardiac surgery and to develop and validate nomogram models. We conducted a multicenter retrospective study in four cardiac centers in China. Adults operated with elective open-heart surgery from 2016 to 2020 were included. Patients were randomly allocated to training and validation sets by 7:3 ratio. Demographics, comorbidities, laboratory data, surgical factors, and postoperative outcomes were collected and analyzed. Risk factors for POP were identified by univariate and multivariate analysis. Nomograms were constructed based on the multivariate logistic regression models and were evaluated with calibration, discrimination and decision curve analysis. A total of 13,380 patients meeting the criteria were included and POP developed in 882 patients (6.6%). The mortality was 2.0%, but it increased significantly in patients with POP (25.1 vs. 0.4%, < 0.001). Using preoperative and intraoperative variables, we constructed a full nomogram model based on ten independent risk factors and a preoperative nomogram model based on eight preoperative factors. Both nomograms demonstrated good calibration, discrimination, and were well validated. The decision curves indicated significant clinical usefulness. Finally, four risk intervals were defined for better clinical application. We developed and validated two nomogram models for POP following elective cardiac surgery using preoperative and intraoperative factors, which may be helpful for individualized risk evaluation and prevention decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcvm.2021.750828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542719PMC
October 2021

Clinical risk score for postoperative pneumonia following heart valve surgery.

Chin Med J (Engl) 2021 Sep 15;134(20):2447-2456. Epub 2021 Sep 15.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.

Background: Postoperative pneumonia (POP) is one of the most common infections following heart valve surgery (HVS) and is associated with a significant increase in morbidity, mortality, and health care costs. This study aimed to identify the major risk factors associated with the occurrence of POP following HVS and to derive and validate a clinical risk score.

Methods: Adults undergoing open HVS between January 2016 and December 2019 at a single institution were enrolled in this study. Patients were randomly assigned to the derivation and validation sets at 1:1 ratio. A prediction model was developed with multivariable logistic regression analysis in the derivation set. Points were assigned to independent risk factors based on their regression coefficients.

Results: POP occurred in 316 of the 3853 patients (8.2%). Multivariable analysis identified ten significant predictors for POP in the derivation set, including older age, smoking history, chronic obstructive pulmonary disease, diabetes mellitus, renal insufficiency, poor cardiac function, heart surgery history, longer cardiopulmonary bypass, blood transfusion, and concomitant coronary and/or aortic surgery. A 22-point risk score based on the multivariable model was then generated, demonstrating good discrimination (C-statistic: 0.81), and calibration (Hosmer-Lemeshow χ2 = 8.234, P = 0.312). The prediction rule also showed adequate discriminative power (C-statistic: 0.83) and calibration (Hosmer-Lemeshow χ2 = 5.606, P = 0.691) in the validation set. Three risk intervals were defined as low-, medium-, and high-risk groups.

Conclusion: We derived and validated a 22-point risk score for POP following HVS, which may be useful in preventive interventions and risk management.

Trial Registration: Chictr.org, ChiCTR1900028127; http://www.chictr.org.cn/showproj.aspx?proj=46932.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CM9.0000000000001715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8654438PMC
September 2021

Development and validation of a nomogram model for early postoperative hyperlactatemia in patients undergoing cardiac surgery.

J Thorac Dis 2021 Sep;13(9):5395-5408

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: Postoperative hyperlactatemia (POHL) is common in patients undergoing cardiac surgery, associated with adverse outcomes. The aim of this study was to identify predictors for POHL after cardiac surgery and to develop and validate a predictive model.

Methods: Adult patients who underwent open heart surgery at our institution between 2016 and 2019 were retrospectively included. The patients were randomly divided into training and validation groups at a 2:1 ratio. Multivariate logistic regression was performed to identify independent predictors for POHL in the training set. A nomogram was then constructed and was validated in the validation set.

Results: POHL developed in 713 of the 5,323 patients (13.4%). The mortality rate was higher in patients with POHL compared with patients without that (9.5% 2.1%, P<0.001). Age, white blood cell (WBC) count, left ventricular ejection fraction, renal insufficiency, cardiac surgery history, red blood cell (RBC) transfusion, and cardiopulmonary bypass (CPB) time were identified as independent risk factors. The nomogram based on these predictors indicated good discrimination in both the training (c-index: 0.787) and validation (c-index: 0.820) sets. The calibration was reasonable by both visual inspection and goodness-of-fit test. The decision and clinical impact curves demonstrated good clinical utility.

Conclusions: We identified 7 independent risk factors and derived a prediction model for POHL in patients undergoing cardiac surgery. The model may contribute significantly to early risk assessment and clinical intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jtd-21-1004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482329PMC
September 2021

Risk factors and in-hospital mortality of postoperative hyperlactatemia in patients after acute type A aortic dissection surgery.

BMC Cardiovasc Disord 2021 09 11;21(1):431. Epub 2021 Sep 11.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

Background: Hyperlactatemia may be caused by increased production due to tissue hypoxia or non-hypoxia. The aim of this study was first to identify risk factors for postoperative hyperlactatemia (POHL) after Stanford type A acute aortic dissection surgery (AADS) and construct a predictive model, and second to evaluate the impact of POHL on prognosis.

Methods: This retrospective study involved patients undergoing AADS from January 2016 to December 2019 in Wuhan Union Hospital. Multivariate logistic regression analysis was performed to identify independent risk factors for POHL. A nomogram predicting POHL was established based on these factors and was validated in the original dataset. The receiver operating characteristic curve was drawn to assess the ability of postoperative lactate levels to predict the in-hospital mortality.

Results: A total of 188 patients developed POHL after AADS (38.6%). Male gender, surgery history, red blood cell transfusion and cardiopulmonary bypass time were identified as independent predictors. The C-index of the prediction model for POHL was 0.72, indicating reasonable discrimination. The model was well calibrated by visual inspection and goodness-of-fit test (Hosmer-Lemeshow χ = 10.25, P = 0.25). Decision and clinical impact curves of the model showed good clinical utility. The overall in-hospital mortality rate was 10.1%. Postoperative lactate levels showed a moderate predictive power for postoperative in-hospital mortality (C-index: 0.72).

Conclusion: We developed and validated a prediction model for POHL in patients undergoing AADS, which may have clinical utility in personal risk evaluation and preventive interventions. The POHL could be a good predictor for in-hospital mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12872-021-02244-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436469PMC
September 2021

Predictors and nomogram models for postoperative headache in patients undergoing heart valve surgery.

J Thorac Dis 2021 Jul;13(7):4236-4249

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: Headache is a frequent complication after cardiac surgery. However, studies on the risk factors of postoperative headache (POH) are rare. The purpose of this study was to identify independent risk factors for POH in patients undergoing heart valve surgery (HVS) and to develop and validate risk prediction models.

Methods: Consecutive patients undergoing open HVS from 2016 to 2019 were enrolled in this study. Patients were randomly assigned to training and validation sets at a 2:1 ratio. Univariate and multivariate analysis were applied to identify independent predictors for POH in the training set. A nomogram predicting POH was developed based on these factors, and was validated in the independent validation set.

Results: POH developed in 1,061 of the 3,853 patients (27.5%). The overall mortality was 2.9%, and it was significantly higher in patients with POH (4.3% versus 2.4%, P<0.001). In the training set, six independent predictors were identified by multivariate analysis, including female, smoking history, hypertension, headache history, left ventricular ejection fraction, and cardiopulmonary bypass time. The model demonstrated good discrimination in both the training (c-index: 0.811) and validation sets (c-index: 0.814), and calibration was assessed by visual inspection. A second nomogram was also constructed including only preoperative predictors, with good discrimination (c-index: 0.792) and calibration. The decision and clinical impact curves of the models showed good clinical utility.

Conclusions: We developed and validated two risk prediction models for POH in patients undergoing HVS. The models may have clinical utility in individualized risk assessment and preventive interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jtd-21-644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339753PMC
July 2021

Ablation of Survivin in T Cells Attenuates Acute Allograft Rejection after Murine Heterotopic Heart Transplantation by Inducing Apoptosis.

Front Immunol 2021 6;12:710904. Epub 2021 Aug 6.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Although studies in oncology have well explored the pharmacological effects of , little is known about its role in allogeneic T-cell responses. Therefore, the present study used a mouse model of acute heart allograft rejection to investigate the protective effect and mechanism of conditional knockout of in T cells. Survivin (encoded by ) was up-regulated in T cells activated and . Deletion of in T cells attenuated acute heart allograft rejection by reducing the ratio of effector to naive T cells and Th1 to Tregs. In addition, deletion of had no noticeable effect on proliferation but on apoptosis and the secretion of IFN-γ. The results revealed a significant increase in the percentage of Annexin V positive CD4 T cells in the group, compared to the WT. Moreover, there was significant increase in early apoptotic alloreactive T cells in mice and this was partly mediated by caspase-3. Furthermore, treatment with YM155 inhibited acute heart allograft rejection and increased T-cell apoptosis in healthy human PBMCs . The results highlight a potential therapeutic target for the prevention and treatment of acute transplant rejection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.710904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377163PMC
December 2021

Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis.

Eur J Neurosci 2021 09 26;54(6):6237-6255. Epub 2021 Aug 26.

Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonly treated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespan for people living with ALS, and its precise mechanisms of action remain unclear. Most ALS cases are characterised by accumulation of cytoplasmic TAR DNA binding protein of 43 kDa (TDP-43), and understanding the effects of riluzole in models that closely recapitulate TDP-43 pathology may provide insights for development of improved therapeutics. We therefore investigated the effects of riluzole in female transgenic mice that inducibly express nuclear localisation sequence (NLS)-deficient human TDP-43 in neurons (NEFH-tTA/tetO-hTDP-43ΔNLS, 'rNLS8', mice). Riluzole treatment from the first day of hTDP-43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did not alter TDP-43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS8 mice, riluzole did not ameliorate this disease-associated molecular phenotype. Likewise, riluzole did not alter the disease-associated atrophy of hindlimb muscle in rNLS8 mice. Finally, riluzole treatment beginning after disease onset in rNLS8 mice similarly had no effect on progression of late-stage disease or animal survival. Together, we demonstrate specific glutamatergic receptor alterations and muscle fibre-type changes reminiscent of ALS in female rNLS8 mice, but riluzole had no effect on these or any other disease phenotypes. Future targeting of pathways related to accumulation of TDP-43 pathology may be needed to develop better treatments for ALS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejn.15422DOI Listing
September 2021

Ufbp1, a Key Player of Ufm1 Conjugation System, Protects Against Ketosis-Induced Liver Injury via Suppressing Smad3 Activation.

Front Cell Dev Biol 2021 8;9:676789. Epub 2021 Jul 8.

College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China.

The dairy cattle suffer from severe liver dysfunction during the pathogenesis of ketosis. The Ufm1 conjugation system is crucial for liver development and homeostasis. Ufm1 binding protein (Ufbp1) is a putative Ufm1 target and an integral component, but its role in ketosis-induced liver injury is unclear so far. The purpose of this study is to explore the key role of Ufbp1 in liver fibrosis caused by ketosis and . Liver tissues were collected from ketotic cows and conditional knockout (CKO) mice . However, mouse embryonic fibroblast cells and Hela cells were used for validation. Subsequently, various assays were performed to reveal the underlying molecular mechanisms of the Ufbp1 protective effect. In this study, hepatic fibrosis, endoplasmic reticulum (ER) stress, and apoptosis were reported in the liver of ketotic cows, fibrotic markers (alpha-smooth muscle actin, Collagen1) and ER stress markers (glucose-regulated protein 78, CEBP homologous protein) were upregulated remarkably, and the apoptosis-related genes (Bcl2, Bax) were in line with expectations. Interestingly, Ufbp1 expression was almost disappeared, and Smad2/Smad3 protein was largely phosphorylated in the liver of ketotic cows, but Ufbp1 deletion caused Smad3 phosphorylation apparently, rather than Smad2, and elevated ER stress was observed in the CKO mice model. At the cellular level, Ufbp1 deficiency led to serious fibrotic and ER stress response, Smad3 was activated by phosphorylation significantly and then was translocated into the nucleus, whereas p-Smad2 was largely unaffected in embryonic fibroblast cells. Ufbp1 overexpression obviously suppressed Smad3 phosphorylation in Hela cells. Ufbp1 was found to be in full combination with Smad3 using endogenous immunoprecipitation. Taken together, our findings suggest that downregulation or ablation of Ufbp1 leads to Smad3 activation, elevated ER stress, and hepatocyte apoptosis, which in turn causes liver fibrosis. Ufbp1 plays a protective role in ketosis-induced liver injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2021.676789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297976PMC
July 2021

Dual-specificity Phosphatase 9 protects against Cardiac Hypertrophy by targeting ASK1.

Int J Biol Sci 2021 27;17(9):2193-2204. Epub 2021 May 27.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The functions of dual-specificity phosphatase 9 (DUSP9) in hepatic steatosis and metabolic disturbance during nonalcoholic fatty liver disease were discussed in our prior study. However, its roles in the pathophysiology of pressure overload-induced cardiac hypertrophy remain to be illustrated. This study attempted to uncover the potential contributions and underpinning mechanisms of DUSP9 in cardiac hypertrophy. Utilizing the gain-and-loss-of-functional approaches of DUSP9 the cardiac phenotypes arising from the pathological, echocardiographic, and molecular analysis were quantified. The results showed increased levels of DUSP9 in hypertrophic mice heart and angiotensin II treated cardiomyocytes. In accordance with the results of cellular hypertrophy in response to angiotensin II, cardiac hypertrophy exaggeration, fibrosis, and malfunction triggered by pressure overload was evident in the case of cardiac-specific conditional knockout of DUSP9. In contrast, transgenic mice hearts with DUSP9 overexpression portrayed restoration of the hypertrophic phenotypes. Further explorations of molecular mechanisms indicated the direct interaction of DUSP9 with ASK1, which further repressed p38 and JNK signaling pathways. Moreover, blocking ASK1 with ASK1-specific inhibitor compensated the pro-hypertrophic effects induced by DUSP9 deficiency in cardiomyocytes. The main findings of this study suggest the potential of DUSP9 in alleviating cardiac hypertrophy at least partially by repressing ASK1, thereby looks promising as a prospective target against cardiac hypertrophy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/ijbs.57130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241718PMC
May 2021

Risk factors for postoperative pneumonia after cardiac surgery: a prediction model.

J Thorac Dis 2021 Apr;13(4):2351-2362

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: Postoperative pneumonia is the main infectious complication following cardiac surgery and is associated with significant increases in morbidity, mortality and health care costs. The aim of this study was to identify potential risk factors related to the occurrence of postoperative pneumonia in adult patients undergoing cardiac surgery and to develop a predictive system.

Methods: Adult patients who underwent open heart surgery in our institution between 2016 and 2019 were enrolled in this study. Preoperative and intraoperative variables were collected and analyzed. A multivariate prediction model for evaluating the risk of postoperative pneumonia was established using logistic regression analysis via forward stepwise selection, and points were assigned to significant risk factors based on their regression coefficient values.

Results: Postoperative pneumonia occurred in 530 of the 5,323 patients (9.96%). Prolonged stays in the postoperative intensive care unit (ICU) and hospital, as well as higher mortality (25.66% versus 0.65%), were observed in patients with postoperative pneumonia. Multivariate analysis identified 13 independent risk factors including patient demographics, comorbidities, cardiac function, cardiopulmonary bypass (CPB) duration, and blood transfusion. The prediction model showed good discrimination (C-statistic: 0.80) and was well calibrated (Hosmer-Lemeshow χ=7.907, P value =0.443). A 32-point risk score was generated, and then three risk intervals were defined.

Conclusions: We derived and validated a prediction model for postoperative pneumonia after cardiac surgery incorporating 13 easily discernible risk factors. The scoring system may be helpful for individualized risk estimations and clinical decision-making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jtd-20-3586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107540PMC
April 2021

Selective recognition of a cyclic peptide hormone in human plasma by hydrazone bond-oriented surface imprinted nanoparticles.

Anal Chim Acta 2021 Apr 9;1154:338301. Epub 2021 Feb 9.

Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China; School of Chemistry, University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address:

As a kind of artificial recognition material, molecularly imprinted polymers (MIPs) offer a promising perspective to be developed as synthetic chemical binders capable of selectively recognize biomacromolecules. However, owing to the large size and conformational flexibility of proteins and peptides, imprinting of these biomacromolecules remains a challenge. Novel imprinting strategies still need exploration for the improvement of recognition performance of MIPs. Herein, we developed a hydrazone bond-oriented surface imprinting strategy for an endogenous peptide hormone, human atrial natriuretic peptide (ANP). Surface-oriented imprinting of peptide via reversible covalent bond anchoring approach increased the orientation homogeneity of imprinted cavities as well as the utility of templates. The prepared nanoparticles exhibited high selectivity and fast recognition kinetics for ANP epitope. The dissociation constant between ANP epitope and MIP was measured as 5.3 μM. The applicability of the material in real samples was verified by the selective magnetic extraction of ANP from human plasma samples. This hydrazone bond-oriented surface imprinting strategy provides an alternative approach for the separation of peptides or proteins in complex bio-samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.aca.2021.338301DOI Listing
April 2021

Autophagy-lysosome inhibitor chloroquine prevents CTLA-4 degradation of T cells and attenuates acute rejection in murine skin and heart transplantation.

Theranostics 2020 1;10(18):8051-8060. Epub 2020 Jul 1.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

: The immune checkpoint cytotoxic T lymphocyte antigen-4 (CTLA-4), induced upon T cell activation but degraded quickly, has been targeted in the clinical therapy of advanced cancers and autoimmune diseases. However, whether inhibiting CTLA-4 degradation ameliorates transplant rejection remains unknown. : The CTLA-4 expression in activated murine T cells treated with the inhibitors mediating protein degradation was detected by flow cytometry (FCM). CD45.1 mice, which received TEa T cells and underwent heart transplantation, were administrated with the inhibitor. Subsequently, CTLA-4 expression of TEa T cells was analyzed. Murine skin and heart transplantation models were built, then the survival and histopathology of the allografts, and T cell subsets in the spleens of each group were compared. : Chloroquine (CQ) was identified as an inhibitor of CTLA-4 degradation, which augmented both surface and total CTLA-4 expression in T cells. It considerably prolonged the skin and heart allograft survival time and reduced the infiltration of inflammatory cells in allografts. Besides decreasing the frequencies of the CD4 and CD8 effector T cells, especially IFN-γ producing T cells, CQ also increased the proportion of regulatory T cells in the spleen. The CTLA-4 blockade abrogated the benefits of CQ on the survival of heart allografts. Moreover, CQ enhanced CTLA-4 expression in activated human T cells and reduced the secretion of IFN-γ in human mixed lymphocyte reaction. : Targeting CTLA-4 degradation provides a novel means to prevent transplant rejection and induce transplant tolerance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.43507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381746PMC
May 2021

PLK1 Inhibition alleviates transplant-associated obliterative bronchiolitis by suppressing myofibroblast differentiation.

Aging (Albany NY) 2020 06 15;12(12):11636-11652. Epub 2020 Jun 15.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.

Chronic allograft dysfunction (CAD) resulting from fibrosis is the major limiting factor for long-term survival of lung transplant patients. Myofibroblasts promote fibrosis in multiple organs, including the lungs. In this study, we identified PLK1 as a promoter of myofibroblast differentiation and investigated the mechanism by which its inhibition alleviates transplant-associated obliterative bronchiolitis (OB) during CAD. High-throughput bioinformatic analyses and experiments using the murine heterotopic tracheal transplantation model revealed that PLK1 is upregulated in grafts undergoing CAD as compared with controls, and that inhibiting PLK1 alleviates OB . Inhibition of PLK1 reduced expression of the specific myofibroblast differentiation marker α-smooth muscle actin (α-SMA) and decreased phosphorylation of both MEK and ERK. Importantly, we observed a similar phenomenon in human primary fibroblasts. Our results thus highlight PLK1 as a promising therapeutic target for alleviating transplant-associated OB through suppression of TGF-β1-mediated myofibroblast differentiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.103330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343459PMC
June 2020

PreBötzinger complex neurons drive respiratory modulation of blood pressure and heart rate.

Elife 2020 06 15;9. Epub 2020 Jun 15.

Department of Physiology, University of Melbourne, Victoria, Australia.

Heart rate and blood pressure oscillate in phase with respiratory activity. A component of these oscillations is generated centrally, with respiratory neurons entraining the activity of pre-sympathetic and parasympathetic cardiovascular neurons. Using a combination of optogenetic inhibition and excitation in vivo and in situ in rats, as well as neuronal tracing, we demonstrate that preBötzinger Complex (preBötC) neurons, which form the kernel for inspiratory rhythm generation, directly modulate cardiovascular activity. Specifically, inhibitory preBötC neurons modulate cardiac parasympathetic neuron activity whilst excitatory preBötC neurons modulate sympathetic vasomotor neuron activity, generating heart rate and blood pressure oscillations in phase with respiration. Our data reveal yet more functions entrained to the activity of the preBötC, with a role in generating cardiorespiratory oscillations. The findings have implications for cardiovascular pathologies, such as hypertension and heart failure, where respiratory entrainment of heart rate is diminished and respiratory entrainment of blood pressure exaggerated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.57288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326498PMC
June 2020

PKM2 Activator TEPP-46 Attenuates Thoracic Aortic Aneurysm and Dissection by Inhibiting NLRP3 Inflammasome-Mediated IL-1β Secretion.

J Cardiovasc Pharmacol Ther 2020 07 23;25(4):364-376. Epub 2020 Apr 23.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: The development of thoracic aortic aneurysm and dissection (TAAD) is mediated by inflammasome activation, which exacerbates the secretion of pro-inflammatory cytokines, chemokines, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS). The glycolytic enzyme pyruvate kinase M2 (PKM2) has shown a protective role against various disorders with an inflammatory basis, such as sepsis, tumorigenesis, and diabetic nephropathy. However, its potential role in TAAD has not been investigated so far.

Approach And Results: We analyzed aortic tissues from TAAD patients and the β-aminopropionitrile fumarate (BAPN)-induced mouse model of TAAD and observed elevated levels of PKM2 in the aortic lesions of both. Treatment with the PKM2 activator TEPP-46 markedly attenuated the progression of TAAD in the mouse model as demonstrated by decreased morbidity and luminal diameter of the aorta. In addition, the thoracic aortas of the BAPN-induced mice showed reduced monocytes and macrophages infiltration and lower levels of IL-1β, MMPs, and ROS when treated with TEPP-46. Furthermore, TEPP-46 treatment also suppressed the activation of the NOD-like receptor (NLR) family and pyrin domain-containing protein 3 (NLRP3) inflammasome by downregulating p-STAT3 and HIF1-α.

Conclusion: Pyruvate kinase M2 plays a protective role in TAAD development, and its activation is a promising therapeutic strategy against the progression of TAAD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1074248420919966DOI Listing
July 2020

Corrigendum: A Student's Guide to Neural Circuit Tracing.

Front Neurosci 2020 10;14:177. Epub 2020 Mar 10.

Neurobiology of Vital Systems Node, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.

[This corrects the article DOI: 10.3389/fnins.2019.00897.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2020.00177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076267PMC
March 2020

Trametinib alleviates lipopolysaccharide-induced acute lung injury by inhibiting the MEK-ERK-Egr-1 pathway.

Int Immunopharmacol 2020 Mar 8;80:106152. Epub 2020 Jan 8.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address:

Acute lung injury (ALI) is a devastating clinical disorder with a high mortality rate and for which there is no effective treatment. The main characteristic of ALI is uncontrolled inflammation, and macrophages play a critical role in the development of this disorder. Trametinib, an inhibitor of MAPK/ERK kinase (MEK) activity that possesses anti-inflammatory properties, has been approved for clinical use. Herein, the influence of trametinib and its underlying mechanism were investigated using a lipopolysaccharide (LPS)-induced murine ALI model. We found that trametinib treatment prevented the LPS-facilitated expression of proinflammatory mediators in macrophages, and this anti-inflammatory action was closely correlated with suppression of the MEK-ERK-early growth response (Egr)-1 pathway. Furthermore, trametinib treatment alleviated LPS-induced ALI in mice, and attenuated edema, proinflammatory mediator production, and neutrophil infiltration. Trametinib pretreatment also attenuated the MEK-ERK-Egr-1 pathway in lung tissues. In conclusion, these data demonstrate that trametinib pretreatment suppresses inflammation in LPS-activated macrophages in vitro and protects against murine ALI established by LPS administration in vivo through inhibition of the MEK-ERK-Egr-1 pathway. Therefore, trametinib might have therapeutic potential for ALI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.intimp.2019.106152DOI Listing
March 2020

C. sakazakii activates AIM2 pathway accompanying with excessive ER stress response in mammalian mammary gland epithelium.

Cell Stress Chaperones 2020 03 10;25(2):223-233. Epub 2020 Jan 10.

College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.

Bovine mastitis is a common inflammatory disease caused by various factors. The main factor of mastitis is pathogenic microorganism infection, such as Staphylococcus aureus, Escherichia coli, and Streptococcus. Cronobacter sakazakii (C. sakazakii) is a newly discovered pathogenic bacteria in milk products, which seriously threat human health in recent years. At present, it has not been reported that the pathogenesis of mastitis is caused by C. sakazakii. This study investigated the inflammation of mammary gland epithelium, which was induced by C. sakazakii for the first time. We focused on bacterial isolation, histological observation, AIM2 inflammasome pathways, endoplasmic reticulum stress, and apoptosis. The results showed that C. sakazakii-induced inflammation caused damage of tissue, significantly increased the production of pro-inflammatory cytokines (including TNF-α, IL-1β, and IL-6), activated the AIM2 inflammasome pathway (increased the expression of AIM2 and cleaved IL-1β), and induced endoplasmic reticulum stress (increased the expression of ERdj4, Chop, Grp78) and apoptosis (increased the ratio of Bax/Bcl-2, a marker of apoptosis). In conclusion, it is suggested that it maybe inhibite AIM2 inflammasome pathways and alleviate endoplasmic reticulum stress (ER stress) against the C. sakazakii-induced inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12192-019-01065-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058749PMC
March 2020

Glibenclamide ameliorates transplant-induced arteriosclerosis and inhibits macrophage migration and MCP-1 expression.

Life Sci 2020 Jan 4;241:117141. Epub 2019 Dec 4.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China. Electronic address:

Aims: Glibenclamide, a diabetes mellitus type 2 medication, has anti-inflammatory and autoimmune properties. This study investigated the effects of glibenclamide on transplant-induced arteriosclerosis as well as the underlying molecular events.

Methods: Male C57Bl/6 (H-2b) and BALB/c (H-2d) mice were used for aorta transplantation. We used hematoxylin and eosin (HE) and Elastic Van Gieson (EVG) staining for histological assessment, and qRT-PCR and ELISA to measure mRNA and protein levels. Mouse peritoneal macrophages were isolated for lipopolysaccharide (LPS) stimulation and glibenclamide treatment followed by ELISA, Western blot, and Transwell assays.

Results: Glibenclamide inhibited transplant-induced arteriosclerosis in vivo. Morphologically, glibenclamide reduced inflammatory cell accumulation and collagen deposition in the aortas. At the gene level, glibenclamide suppressed aortic cytokine mRNA levels, including interleukin-1β (IL-1β; 10.64 ± 3.19 vs. 23.77 ± 5.72; P < .05), tumor necrosis factor-α (TNF-α; 4.59 ± 0.78 vs. 13.89 ± 5.42; P < .05), and monocyte chemoattractant protein-1 (MCP-1; 202.66 ± 23.44 vs. 1172.73 ± 208.80; P < .01), while IL-1β, TNF-α, and MCP-1 levels were also reduced in the mouse sera two weeks after glibenclamide treatment (IL-1β, 39.40 ± 13.56 ng/ml vs. 78.96 ± 9.39 ng/ml; P < .01; TNF-α, 52.60 ± 13.00 ng/ml vs. 159.73 ± 6.76 ng/ml; P < .01; and MCP-1, 56.60 ± 9.07 ng/ml vs. 223.07 ± 36.28 ng/ml; P < .001). Furthermore, glibenclamide inhibited macrophage expression and secretion of inflammatory factors in vitro through suppressing activation of the nuclear factor-κB (NF-κB) pathway and MCP-1 production.

Conclusion: Glibenclamide protected against aorta transplantation-induced arteriosclerosis by reducing inflammatory factors in vivo and inhibited macrophage migration and MCP-1 production in vitro.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2019.117141DOI Listing
January 2020

Neurons in the Intermediate Reticular Nucleus Coordinate Postinspiratory Activity, Swallowing, and Respiratory-Sympathetic Coupling in the Rat.

J Neurosci 2019 12 30;39(49):9757-9766. Epub 2019 Oct 30.

Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, 2109 New South Wales, Australia, and

Breathing results from sequential recruitment of muscles in the expiratory, inspiratory, and postinspiratory (post-I) phases of the respiratory cycle. Here we investigate whether neurons in the medullary intermediate reticular nucleus (IRt) are components of a central pattern generator (CPG) that generates post-I activity in laryngeal adductors and vasomotor sympathetic nerves and interacts with other members of the central respiratory network to terminate inspiration. We first identified the region of the (male) rat IRt that contains the highest density of lightly cholinergic neurons, many of which are glutamatergic, which aligns well with the putative postinspiratory complex in the mouse (Anderson et al., 2016). Acute bilateral inhibition of this region reduced the amplitudes of post-I vagal and sympathetic nerve activities. However, although associated with reduced expiratory duration and increased respiratory frequency, IRt inhibition did not affect inspiratory duration or abolish the recruitment of post-I activity during acute hypoxemia as predicted. Rather than representing an independent CPG for post-I activity, we hypothesized that IRt neurons may instead function as a relay that distributes post-I activity generated elsewhere, and wondered whether they could be a site of integration for para-respiratory CPGs that drive the same outputs. Consistent with this idea, IRt inhibition blocked rhythmic motor and autonomic components of fictive swallow but not swallow-related apnea. Our data support a role for IRt neurons in the transmission of post-I and swallowing activity to motor and sympathetic outputs, but suggest that other mechanisms also contribute to the generation of post-I activity. Interactions between multiple coupled oscillators underlie a three-part respiratory cycle composed from inspiratory, postinspiratory (post-I), and late-expiratory phases. Central post-I activity terminates inspiration and activates laryngeal motoneurons. We investigate whether neurons in the intermediate reticular nucleus (IRt) form the central pattern generator (CPG) responsible for post-I activity. We confirm that IRt activity contributes to post-I motor and autonomic outputs, and find that IRt neurons are necessary for activation of the same outputs during swallow, but that they are not required for termination of inspiration or recruitment of post-I activity during hypoxemia. We conclude that this population may not represent a distinct CPG, but instead may function as a premotor relay that integrates activity generated by diverse respiratory and nonrespiratory CPGs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.0502-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891060PMC
December 2019

A Student's Guide to Neural Circuit Tracing.

Front Neurosci 2019 27;13:897. Epub 2019 Aug 27.

Neurobiology of Vital Systems Node, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.

The mammalian nervous system is comprised of a seemingly infinitely complex network of specialized synaptic connections that coordinate the flow of information through it. The field of connectomics seeks to map the structure that underlies brain function at resolutions that range from the ultrastructural, which examines the organization of individual synapses that impinge upon a neuron, to the macroscopic, which examines gross connectivity between large brain regions. At the mesoscopic level, distant and local connections between neuronal populations are identified, providing insights into circuit-level architecture. Although neural tract tracing techniques have been available to experimental neuroscientists for many decades, considerable methodological advances have been made in the last 20 years due to synergies between the fields of molecular biology, virology, microscopy, computer science and genetics. As a consequence, investigators now enjoy an unprecedented toolbox of reagents that can be directed against selected subpopulations of neurons to identify their efferent and afferent connectomes. Unfortunately, the intersectional nature of this progress presents newcomers to the field with a daunting array of technologies that have emerged from disciplines they may not be familiar with. This review outlines the current state of mesoscale connectomic approaches, from data collection to analysis, written for the novice to this field. A brief history of neuroanatomy is followed by an assessment of the techniques used by contemporary neuroscientists to resolve mesoscale organization, such as conventional and viral tracers, and methods of selecting for sub-populations of neurons. We consider some weaknesses and bottlenecks of the most widely used approaches for the analysis and dissemination of tracing data and explore the trajectories that rapidly developing neuroanatomy technologies are likely to take.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2019.00897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718611PMC
August 2019

Network-based analysis reveals novel gene signatures in the peripheral blood of patients with sporadic nonsyndromic thoracic aortic aneurysm.

J Cell Physiol 2020 03 6;235(3):2478-2491. Epub 2019 Sep 6.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Thoracic aortic aneurysm (TAA), a serious cardiovascular disease that causes morbidity and mortality worldwide. At present, few biomarkers can accurately diagnose the appearance of TAA before dissection or rupture. Our research has the intention to investigate the developing applicable biomarkers for TAA promising clinically diagnostic biomarkers or probable regulatory targets for TAA. In our research, we built correlation networks utilizing the expression profile of peripheral blood mononuclear cell obtained from a public microarray data set (GSE9106). Furthermore, we chose the turquoise module, which has the strongest significance with TAA and was further analyzed. Fourteen genes that overlapped with differentially expressed proteins in the medial aortic layer were obtained. Subsequently, we verified the results applying quantitative polymerase chain reaction (Q-PCR) to our clinical specimen. In general, the Q-PCR results coincide with the majority of the expression profile. Fascinatingly, a notable change occurred in CLU, DES, MYH10, and FBLN5. In summary, using weighted gene coexpression analysis, our study indicates that CLU, DES, MYH10, and FBLN5 were identified and validated to be related to TAA and might be candidate biomarkers or therapeutic targets for TAA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcp.29152DOI Listing
March 2020

BCL6 inhibitor FX1 attenuates inflammatory responses in murine sepsis through strengthening BCL6 binding affinity to downstream target gene promoters.

Int Immunopharmacol 2019 Oct 8;75:105789. Epub 2019 Aug 8.

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Background: Sepsis occurs when an infection triggers deranged inflammatory responses. There exists no efficacious treatment for this condition. The transcriptional repressor B-cell Lymphoma 6 (BCL6) is known to act as an inhibitor of macrophage-mediated inflammatory responses. FX1, a novel specific BCL6 BTB inhibitor, is able to attenuate activity of B cell-like diffuse large B cell lymphoma (ABC-DLBCL). Nevertheless, the effect of FX1 in inflammatory responses and sepsis remains unknown.

Objectives: Here, we explored the effect and potential mechanisms of FX1 on the regulation of LPS-induced inflammatory responses in murine sepsis.

Method: Mice models of LPS-induced sepsis were monitored for survival rate following FX1 administration. ELISA was used to assess how FX1 administration affected pro-inflammatory cytokines present in macrophages exposed to LPS and in the serum of mice sepsis models. Flow cytometric analysis, Western blot and qRT-PCR were performed to evaluate differences in macrophages immune responses after FX1 pre-treatment. Finally, the affinity of BCL6 binding to downstream target genes was checked by ChIP.

Results: The survival rate of mice models of LPS-induced sepsis was improved in following FX1 administration. FX1 decreased the production of inflammatory cytokines, attenuated macrophage infiltration activities and reduced monocytes chemotaxis activities, all of which suggest that FX1 exert anti-inflammatory effects. Mechanistically, FX1 may enhance the affinity of BCL6 binding to downstream target pro-inflammatory genes.

Conclusions: These findings illustrated the anti-inflammatory properties and potential mechanisms of FX1 in sepsis caused by LPS. FX1 could potentially become a new immunosuppressive and anti-inflammatory drug candidate in sepsis therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.intimp.2019.105789DOI Listing
October 2019

Dual-Specificity Phosphatase 26 Protects Against Nonalcoholic Fatty Liver Disease in Mice Through Transforming Growth Factor Beta-Activated Kinase 1 Suppression.

Hepatology 2019 05;69(5):1946-1964

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Nonalcoholic fatty liver disease (NAFLD), which has a wide global distribution, includes different stages ranging from simple steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and liver cirrhosis according to the degree of severity. Chronic low-grade inflammation, insulin resistance, and lipid accumulation are the leading causes of NAFLD. To date, no effective medicine for NAFLD has been approved by governmental agencies. Our study demonstrated that the expression of dual-specificity phosphatase 26 (Dusp26), a member of the Dusp protein family, was decreased in the liver tissue of mice with hepatic steatosis and genetically obese (ob/ob) mice. In our study, hepatic steatosis, inflammatory responses, and insulin resistance were exacerbated in liver-specific Dusp26-knockout (KO) mice but ameliorated in liver-specific Dusp26-transgenic mice induced by a high-fat diet. In addition, the degree of liver fibrosis was aggravated in high-fat high-cholesterol diet-induced Dusp26-KO mice. We further found that the binding of Dusp26 to transforming growth factor beta-activated kinase 1 (TAK1) to block the phosphorylation of TAK1 regulated the TAK1-p38/c-Jun NH2-terminal kinase signaling axis to alleviate hepatic steatosis and metabolic disturbance. Conclusion: These findings suggest that Dusp26 is a good TAK1-dependent therapeutic target for NAFLD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.30485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594223PMC
May 2019

Well-defined magnetic surface imprinted nanoparticles for selective enrichment of 2,4-dichlorophenoxyacetic acid in real samples.

Talanta 2017 Nov 3;174:725-732. Epub 2017 Jul 3.

Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Superparamagnetic core-shell molecularly imprinted polymer nanoparticles (MIPs) were prepared via surface initiated reversible-addition fragmentation chain transfer (si-RAFT) polymerization for the selective recognition of 2,4-dichlorophenoxyacetic acid (2,4-D) in real samples. The construction of uniform core-shell structure with a 50nm MIP layer was successfully accomplished, which favored mass transfer and resulted in fast recognition kinetics. The static equilibrium experiments revealed the satisfied adsorption capacity and imprinting efficiency of [email protected] Moreover, the [email protected] exhibited high selectivity and affinity towards 2,4-D over structural analogues. The prepared [email protected] nanoparticles were used for the selective enrichment of 2,4-D in tap water and Chinese cabbage samples. Combined with RP-HPLC, the recoveries of 2,4-D were calculated from 93.1% to 103.3% with RSD of 1.7-5.4% (n = 3) in Chinese cabbage samples. This work provides a versatile approach for fabricating well-constructed core-shell MIP nanoparticles for rapid enrichment and highly selective separation of target molecules in real samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.talanta.2017.07.002DOI Listing
November 2017

Mapping and Analysis of the Connectome of Sympathetic Premotor Neurons in the Rostral Ventrolateral Medulla of the Rat Using a Volumetric Brain Atlas.

Front Neural Circuits 2017 1;11. Epub 2017 Mar 1.

Faculty of Medicine and Health Sciences, Neurobiology of Vital Systems, Macquarie University Sydney, NSW, Australia.

Spinally projecting neurons in the rostral ventrolateral medulla (RVLM) play a critical role in the generation of vasomotor sympathetic tone and are thought to receive convergent input from neurons at every level of the neuraxis; the factors that determine their ongoing activity remain unresolved. In this study we use a genetically restricted viral tracing strategy to definitively map their spatially diffuse connectome. We infected bulbospinal RVLM neurons with a recombinant rabies variant that drives reporter expression in monosynaptically connected input neurons and mapped their distribution using an MRI-based volumetric atlas and a novel image alignment and visualization tool that efficiently translates the positions of neurons captured in conventional photomicrographs to Cartesian coordinates. We identified prominent inputs from well-established neurohumoral and viscero-sympathetic sensory actuators, medullary autonomic and respiratory subnuclei, and supramedullary autonomic nuclei. The majority of inputs lay within the brainstem (88-94%), and included putative respiratory neurons in the pre-Bötzinger Complex and post-inspiratory complex that are therefore likely to underlie respiratory-sympathetic coupling. We also discovered a substantial and previously unrecognized input from the region immediately ventral to nucleus prepositus hypoglossi. In contrast, RVLM sympathetic premotor neurons were only sparsely innervated by suprapontine structures including the paraventricular nucleus, lateral hypothalamus, periaqueductal gray, and superior colliculus, and we found almost no evidence of direct inputs from the cortex or amygdala. Our approach can be used to quantify, standardize and share complete neuroanatomical datasets, and therefore provides researchers with a platform for presentation, analysis and independent reanalysis of connectomic data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fncir.2017.00009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331070PMC
October 2017

Neurochemistry of neurons in the ventrolateral medulla activated by hypotension: Are the same neurons activated by glucoprivation?

J Comp Neurol 2017 Jun 29;525(9):2249-2264. Epub 2017 Mar 29.

Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, NSW, 2109, Australia.

Previous studies have demonstrated that a range of stimuli activate neurons, including catecholaminergic neurons, in the ventrolateral medulla. Not all catecholaminergic neurons are activated and other neurochemical content is largely unknown hence whether stimulus specific populations exist is unclear. Here we determine the neurochemistry (using in situ hybridization) of catecholaminergic and noncatecholaminergic neurons which express c-Fos immunoreactivity throughout the rostrocaudal extent of the ventrolateral medulla, in Sprague Dawley rats treated with hydralazine or saline. Distinct neuronal populations containing PPCART, PPPACAP, and PPNPY mRNAs, which were largely catecholaminergic, were activated by hydralazine but not saline. Both catecholaminergic and noncatecholaminergic neurons containing preprotachykinin and prepro-enkephalin (PPE) mRNAs were also activated, with the noncatecholaminergic population located in the rostral C1 region. Few GlyT2 neurons were activated. A subset of these data was then used to compare the neuronal populations activated by 2-deoxyglucose evoked glucoprivation (Brain Structure and Function (2015) 220:117). Hydralazine activated more neurons than 2-deoxyglucose but similar numbers of catecholaminergic neurons. Commonly activated populations expressing PPNPY and PPE mRNAs were defined. These likely include PPNPY expressing catecholaminergic neurons projecting to vasopressinergic and corticotrophin releasing factor neurons in the paraventricular nucleus, which when activated result in elevated plasma vasopressin and corticosterone. Stimulus specific neurons included noncatecholaminergic neurons and a few PPE positive catecholaminergic neuron but neurochemical codes were largely unidentified. Reasons for the lack of identification of stimulus specific neurons, readily detectable using electrophysiology in anaesthetized preparations and for which neural circuits can be defined, are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cne.24203DOI Listing
June 2017
-->