Publications by authors named "Jiahong Xia"

92 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.
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http://dx.doi.org/10.1016/j.intimp.2022.108521DOI Listing
January 2022

Long-Term Effects of COVID-19 on Health Care Workers 1-Year Post-Discharge in Wuhan.

Infect Dis Ther 2021 Oct 23. Epub 2021 Oct 23.

Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China.

Introduction: To assess the long-term consequences of coronavirus disease (COVID-19) among health care workers (HCWs) in China (hereafter surviving HCWs).

Methods: A total of 303 surviving HCWs were included. Lung (pulmonary function test, 6-min walk test [6MWT], chest CT), physical (St. George's Respiratory Questionnaire [SGRQ], Modified Medical Research Council dyspnea scale [mMRC], and Borg scale), and psychiatric functions (Essen Trauma Inventory) were evaluated during the 1-year follow-up.

Results: Surviving HCWs had an abnormal diffusion capacity 1 year post-discharge. Participants with a reduced carbon monoxide diffusing capacity (DLCO) comprised 43.48%. The proportion of HCWs with a median 6MWT distance below the lower limit of the normal was 19.4%. An abnormal CT pattern was observed in 37.5% of the HCWs. The SGRQ, mMRC, and Borg scores of surviving HCWs, especially those with critical/severe disease, were significantly higher than those in the normal population. Probable post-traumatic stress disorder (PTSD) was reported in 21.9% of the surviving HCWs. Diffusion capacity impairment was associated with women. Critical/severe illness and nurses were associated with impaired physical function.

Conclusions: Most surviving HCWs, especially female HCWs, still had an abnormal diffusion capacity at 1 year. The physical and psychiatric functions of surviving HCWs were significantly worse than those of the healthy population. Long-term follow-up of pulmonary, physical, and psychiatric functions for surviving HCWs is required.
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http://dx.doi.org/10.1007/s40121-021-00553-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8536919PMC
October 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.
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http://dx.doi.org/10.3389/fimmu.2021.710904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377163PMC
December 2021

Dynamic changes of functional fitness, antibodies to SARS-CoV-2 and immunological indicators within 1 year after discharge in Chinese health care workers with severe COVID-19: a cohort study.

BMC Med 2021 07 14;19(1):163. Epub 2021 Jul 14.

Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.

Background: Few studies had described the health consequences of patients with coronavirus disease 2019 (COVID-19) especially in those with severe infections after discharge from hospital. Moreover, no research had reported the health consequences in health care workers (HCWs) with COVID-19 after discharge. We aimed to investigate the health consequences in HCWs with severe COVID-19 after discharge from hospital in Hubei Province, China.

Methods: We conducted an ambidirectional cohort study in "Rehabilitation Care Project for Medical Staff Infected with COVID-19" in China. The participants were asked to complete three physical examinations (including the tests of functional fitness, antibodies to SARS-CoV-2 and immunological indicators) at 153.4 (143.3, 164.8), 244.3 (232.4, 259.1), and 329.4 (319.4, 339.3) days after discharge, respectively. Mann-Whitney U test, Kruskal-Wallis test, t test, one-way ANOVA, χ, and Fisher's exact test were used to assess the variance between two or more groups where appropriate.

Results: Of 333 HCWs with severe COVID-19, the HCWs' median age was 36.0 (31.0, 43.0) years, 257 (77%) were female, and 191 (57%) were nurses. Our research found that 70.4% (114/162), 48.9% (67/137), and 29.6% (37/125) of the HCWs with severe COVID-19 were considered to have not recovered their functional fitness in the first, second, and third functional fitness tests, respectively. The HCWs showed improvement in muscle strength, flexibility, and agility/dynamic balance after discharge in follow-up visits. The seropositivity of IgM (17.0% vs. 6.6%) and median titres of IgM (3.0 vs. 1.4) and IgG (60.3 vs. 45.3) in the third physical examination was higher than that in the first physical examination. In the third physical examination, there still were 42.1% and 45.9% of the HCWs had elevated levels of IL-6 and TNF-α, and 11.9% and 6.3% of the HCWs had decreased relative numbers of CD3 T cells and CD4 T cells.

Conclusion: The HCWs with severe COVID-19 showed improvement in functional fitness within 1 year after discharge, active intervention should be applied to help their recovery if necessary. It is of vital significance to continue monitoring the functional fitness, antibodies to SARS-CoV-2 and immunological indicators after 1 year of discharge from hospital in HCWs with severe COVID-19.
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http://dx.doi.org/10.1186/s12916-021-02042-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277525PMC
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.
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http://dx.doi.org/10.7150/ijbs.57130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241718PMC
May 2021

IL-4 inhibits regulatory T cells differentiation by HDAC9-mediated epigenetic regulation.

Cell Death Dis 2021 05 18;12(6):501. Epub 2021 May 18.

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

Regulatory T cells play a crucial role in orchestrating immune response and maintaining immune tolerance, and the expression of the Foxp3 gene is indispensable to the differentiation of regulatory T cells. IL-4 shows strong inhibitory effects on Foxp3 expression and regulatory T cells differentiation, but the detailed mechanisms are still unclear. Here, we revealed that epigenetic modulations are key to this process. Specifically, the inhibition was found to be STAT6 dependent, and HDAC9 was involved with the process of histone deacetylation at the Foxp3 locus, subsequently decreasing chromatin accessibility and Foxp3 gene transcription. Pan-histone deacetylation inhibitors, especially sodium butyrate, notably abolished the inhibitory effects of IL-4 and ameliorated allergic airway inflammation in mouse models. Our research provides important mechanistic insights into how IL-4 inhibits regulatory T cells differentiation and suggests the therapeutic potential of the sodium butyrate in allergic airway disease.
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http://dx.doi.org/10.1038/s41419-021-03769-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131756PMC
May 2021

A risk score based on baseline risk factors for predicting mortality in COVID-19 patients.

Curr Med Res Opin 2021 06 10;37(6):917-927. Epub 2021 Apr 10.

Department of Orthopedics, The First People's Hospital of Jingmen affiliated to Hubei Minzu University, Jingmen, China.

Background: To develop a sensitive and clinically applicable risk assessment tool identifying coronavirus disease 2019 (COVID-19) patients with a high risk of mortality at hospital admission. This model would assist frontline clinicians in optimizing medical treatment with limited resources.

Methods: 6415 patients from seven hospitals in Wuhan city were assigned to the training and testing cohorts. A total of 6351 patients from another three hospitals in Wuhan, 2169 patients from outside of Wuhan, and 553 patients from Milan, Italy were assigned to three independent validation cohorts. A total of 64 candidate clinical variables at hospital admission were analyzed by random forest and least absolute shrinkage and selection operator (LASSO) analyses.

Results: Eight factors, namely, xygen saturation, blood rea nitrogen, espiratory rate, admission before the date the national aximum number of daily new cases was reached, ge, rocalcitonin, -reactive protein (CRP), and absolute eutrophil counts, were identified as having significant associations with mortality in COVID-19 patients. A composite score based on these eight risk factors, termed the OURMAPCN-score, predicted the risk of mortality among the COVID-19 patients, with a C-statistic of 0.92 (95% confidence interval [CI] 0.90-0.93). The hazard ratio for all-cause mortality between patients with OURMAPCN-score >11 compared with those with scores ≤ 11 was 18.18 (95% CI 13.93-23.71;  < .0001). The predictive performance, specificity, and sensitivity of the score were validated in three independent cohorts.

Conclusions: The OURMAPCN score is a risk assessment tool to determine the mortality rate in COVID-19 patients based on a limited number of baseline parameters. This tool can assist physicians in optimizing the clinical management of COVID-19 patients with limited hospital resources.
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http://dx.doi.org/10.1080/03007995.2021.1904862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054492PMC
June 2021

Dual-Specificity Phosphatase 26 Protects Against Cardiac Hypertrophy Through TAK1.

J Am Heart Assoc 2021 02 30;10(4):e014311. Epub 2021 Jan 30.

Department of Cardiovascular Surgery Union Hospital Tongji Medical CollegeHuazhong University of Science and Technology Wuhan China.

Background Heart pathological hypertrophy has been recognized as a predisposing risk factor for heart failure and arrhythmia. DUSP (dual-specificity phosphatase) 26 is a member of the DUSP family of proteins, which has a significant effect on nonalcoholic fatty liver disease, neuroblastoma, glioma, and so on. However, the involvement of DUSP26 in cardiac hypertrophy remains unclear. Methods and Results Our study showed that DUSP26 expression was significantly increased in mouse hearts in response to pressure overload as well as in angiotensin II-treated cardiomyocytes. Cardiac-specific overexpression of DUSP26 mice showed attenuated cardiac hypertrophy and fibrosis, while deficiency of DUSP26 in mouse hearts resulted in increased cardiac hypertrophy and deteriorated cardiac function. Similar effects were also observed in cellular hypertrophy induced by angiotensin II. Importantly, we showed that DUSP26 bound to transforming growth factor-β activated kinase 1 and inhibited transforming growth factor-β activated kinase 1 phosphorylation, which led to suppression of the mitogen-activated protein kinase signaling pathway. In addition, transforming growth factor-β activated kinase 1-specific inhibitor inhibited cardiomyocyte hypertrophy induced by angiotensin II and attenuated the exaggerated hypertrophic response in DUSP26 conditional knockout mice. Conclusions Taken together, DUSP26 was induced in cardiac hypertrophy and protected against pressure overload induced cardiac hypertrophy by modulating transforming growth factor-β activated kinase 1-p38/ c-Jun N-terminal kinase-signaling axis. Therefore, DUSP26 may provide a therapeutic target for treatment of cardiac hypertrophy and heart failure.
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http://dx.doi.org/10.1161/JAHA.119.014311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955340PMC
February 2021

Development and validation of a risk score using complete blood count to predict in-hospital mortality in COVID-19 patients.

Med (N Y) 2021 Apr 8;2(4):435-447.e4. Epub 2021 Jan 8.

Humanitas Clinical and Research Hospital IRCCS, Rozzano-Milan, Italy.

Background: To develop a sensitive risk score predicting the risk of mortality in patients with coronavirus disease 2019 (COVID-19) using complete blood count (CBC).

Methods: We performed a retrospective cohort study from a total of 13,138 inpatients with COVID-19 in Hubei, China, and Milan, Italy. Among them, 9,810 patients with 2 CBC records from Hubei were assigned to the training cohort. CBC parameters were analyzed as potential predictors for all-cause mortality and were selected by the generalized linear mixed model (GLMM).

Findings: Five risk factors were derived to construct a composite score (PAWNN score) using the Cox regression model, including platelet counts, age, white blood cell counts, neutrophil counts, and neutrophil:lymphocyte ratio. The PAWNN score showed good accuracy for predicting mortality in 10-fold cross-validation (AUROCs 0.92-0.93) and subsets with different quartile intervals of follow-up and preexisting diseases. The performance of the score was further validated in 2,949 patients with only 1 CBC record from the Hubei cohort (AUROC 0.97) and 227 patients from the Italian cohort (AUROC 0.80). The latent Markov model (LMM) demonstrated that the PAWNN score has good prediction power for transition probabilities between different latent conditions.

Conclusions: The PAWNN score is a simple and accurate risk assessment tool that can predict the mortality for COVID-19 patients during their entire hospitalization. This tool can assist clinicians in prioritizing medical treatment of COVID-19 patients.

Funding: This work was supported by National Key R&D Program of China (2016YFF0101504, 2016YFF0101505, 2020YFC2004702, 2020YFC0845500), the Key R&D Program of Guangdong Province (2020B1111330003), and the medical flight plan of Wuhan University (TFJH2018006).
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http://dx.doi.org/10.1016/j.medj.2020.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831644PMC
April 2021

Multi-organ proteomic landscape of COVID-19 autopsies.

Cell 2021 02 9;184(3):775-791.e14. Epub 2021 Jan 9.

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

The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report a proteomic analysis of 144 autopsy samples from seven organs in 19 COVID-19 patients. We quantified 11,394 proteins in these samples, in which 5,336 were perturbed in the COVID-19 patients compared to controls. Our data showed that cathepsin L1, rather than ACE2, was significantly upregulated in the lung from the COVID-19 patients. Systemic hyperinflammation and dysregulation of glucose and fatty acid metabolism were detected in multiple organs. We also observed dysregulation of key factors involved in hypoxia, angiogenesis, blood coagulation, and fibrosis in multiple organs from the COVID-19 patients. Evidence for testicular injuries includes reduced Leydig cells, suppressed cholesterol biosynthesis, and sperm mobility. In summary, this study depicts a multi-organ proteomic landscape of COVID-19 autopsies that furthers our understanding of the biological basis of COVID-19 pathology.
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http://dx.doi.org/10.1016/j.cell.2021.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794601PMC
February 2021

The Neutrophil-to-Lymphocyte Ratio Determines Clinical Efficacy of Corticosteroid Therapy in Patients with COVID-19.

Cell Metab 2021 02 5;33(2):258-269.e3. Epub 2021 Jan 5.

Department of Neonatology, Renmin Hospital of Wuhan University, Wuhan, China.

Corticosteroid therapy is now recommended as a treatment in patients with severe COVID-19. But one key question is how to objectively identify severely ill patients who may benefit from such therapy. Here, we assigned 12,862 COVID-19 cases from 21 hospitals in Hubei Province equally to a training and a validation cohort. We found that a neutrophil-to-lymphocyte ratio (NLR) > 6.11 at admission discriminated a higher risk for mortality. Importantly, however, corticosteroid treatment in such individuals was associated with a lower risk of 60-day all-cause mortality. Conversely, in individuals with an NLR ≤ 6.11 or with type 2 diabetes, corticosteroid treatment was not associated with reduced mortality, but rather increased risks of hyperglycemia and infections. These results show that in the studied cohort corticosteroid treatment is associated with beneficial outcomes in a subset of COVID-19 patients who are non-diabetic and with severe symptoms as defined by NLR.
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http://dx.doi.org/10.1016/j.cmet.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832609PMC
February 2021

Managements of 13 emergency cardiac surgeries under COVID-19 pandemic in a Sentinel Hospital.

J Thorac Dis 2020 Nov;12(11):6663-6669

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

Background: The pneumonia outbreak caused by the 2019 novel coronavirus disease (COVID-19) creates many challenges for the healthcare sector. Currently, little is known of how the pandemic has impacted patients with cardiovascular disease. The primary focus of this study was to determine whether emergency cardiovascular surgeries can be carried out safely during the COVID-19 pandemic.

Methods: Between 17 January 2020 and 11 February 2020, 13 patients were admitted to Wuhan Union Hospital for emergency cardiovascular surgery. During this time, Wuhan was a COVID-19 epicenter, and Wuhan Union Hospital is a sentinel hospital located in this area. These patients' epidemiological histories, clinical records, laboratory assessments, imaging findings, and surgical outcomes were retrospectively reviewed. Throat swabs were collected from some patients preoperatively and all patients postoperatively for reverse transcription polymerase chain reaction (RT-PCR) testing to determine whether these patients had COVID-19.

Results: This cohort included 5 cases of acute aortic dissection, 3 cases of congenital heart disease, 2 cases of dilated cardiomyopathy with end-stage heart failure, 1 case of aortocoronary fistula that had undergone previous surgery, 1 case of subacute infective endocarditis with cerebral infarction, and 1 case of multivessel coronary disease. Six patients were suspected COVID-19 cases (46.2%). There were no confirmed COVID-19 cases in this cohort. None of the patients in this cohort died and none developed severe acute respiratory syndrome, renal failure, or septic shock after surgery. No cross-infection occurred with other patients or medical staff who came into close contact with this cohort.

Conclusions: Emergency surgery is crucial and unavoidable for many patients with acute and severe cardiovascular disease, regardless of the pandemic. Our study indicates that, with adequate preparation and the provision of appropriate treatment, satisfactory outcomes can be achieved for such patients.
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http://dx.doi.org/10.21037/jtd-20-1649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711366PMC
November 2020

Early outcomes of Stanford type A aortic dissection under the coronavirus disease 2019 (COVID-19) pandemic: a multicentre study from Hubei province.

Interact Cardiovasc Thorac Surg 2020 12;31(6):834-840

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

Objectives: Our goal was to compare the short-term outcomes of Stanford type A aortic dissection (TAAD), during the coronavirus disease 2019 (COVID-19) pandemic with those during normal times and summarize our perioperative management experience of patients with TAAD in the context of COVID-19.

Methods: From 17 January 2020 to 8 March 2020, a total of 27 patients with TAAD were operated on in 8 cardiovascular surgery centres in Hubei Province (COVID-19 group). The data from 91 patients with TAAD from the same centres during the same period last year were extracted from the Hubei Cardiac Surgery Registration System (control group). A propensity score matched subgroup of 26 pairs (1:2) was identified. Perioperative data and short-term outcomes were assessed.

Results: Nine patients in the COVID-19 group were categorized as suspicious for the disease (9/27, 33.3%), and others were excluded (18/27, 66.7%). No one was laboratory confirmed preoperatively. The average waiting, cross-clamp and circulatory arrest times were longer in the COVID-19 group (22.9 ± 8.3 vs 9.7 ± 4.0 h, P < 0.001; 135 ± 36 vs 103 ± 45 min, P = 0.003; 24 ± 9 vs 17 ± 8 min, P < 0.001, respectively). The 30-day or in-hospital deaths were 3.8% in both groups (P = 1.0). The COVID-19 group was associated with longer ventilation and intensive care unit times (81 ± 71 vs 45 ± 19 h, P < 0.001; 7.4 ± 3.8 vs 4.5 ± 2.7 days; P < 0.001, respectively). There were no statistical differences between the 2 groups in the incidence of complications such as stroke, neurological deficit, acute kidney injury, pulmonary infection and reoperation. Serum antibody tests for those patients showed 7 out of 9 suspected cases were Immunoglobulin G positive. No cross-infection occurred in other patients or associated medical staff.

Conclusions: With adequate preparation and appropriate protection, satisfactory early outcomes can be achieved after emergency operations for patients with TAAD during the COVID-19 pandemic.
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http://dx.doi.org/10.1093/icvts/ivaa209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665539PMC
December 2020

Metformin Is Associated with Higher Incidence of Acidosis, but Not Mortality, in Individuals with COVID-19 and Pre-existing Type 2 Diabetes.

Cell Metab 2020 10 20;32(4):537-547.e3. Epub 2020 Aug 20.

Department of Cardiology, Zhongnan Hospital, School of Basic Medical Science, Wuhan University, Wuhan, China.

The safety and efficacy of anti-diabetic drugs are critical for maximizing the beneficial impacts of well-controlled blood glucose on the prognosis of individuals with COVID-19 and pre-existing type 2 diabetes (T2D). Metformin is the most commonly prescribed first-line medication for T2D, but its impact on the outcomes of individuals with COVID-19 and T2D remains to be clarified. Our current retrospective study in a cohort of 1,213 hospitalized individuals with COVID-19 and pre-existing T2D indicated that metformin use was significantly associated with a higher incidence of acidosis, particularly in cases with severe COVID-19, but not with 28-day COVID-19-related mortality. Furthermore, metformin use was significantly associated with reduced heart failure and inflammation. Our findings provide clinical evidence in support of continuing metformin treatment in individuals with COVID-19 and pre-existing T2D, but acidosis and kidney function should be carefully monitored in individuals with severe COVID-19.
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http://dx.doi.org/10.1016/j.cmet.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439986PMC
October 2020

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

Haematological characteristics and risk factors in the classification and prognosis evaluation of COVID-19: a retrospective cohort study.

Lancet Haematol 2020 Sep 10;7(9):e671-e678. Epub 2020 Jul 10.

Institute of Haematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical and Research Centre of Thrombosis and Haemostasis, Wuhan, China. Electronic address:

Background: COVID-19 is an ongoing global pandemic. Changes in haematological characteristics in patients with COVID-19 are emerging as important features of the disease. We aimed to explore the haematological characteristics and related risk factors in patients with COVID-19.

Methods: This retrospective cohort study included patients with COVID-19 admitted to three designated sites of Wuhan Union Hospital (Wuhan, China). Demographic, clinical, laboratory, treatment, and outcome data were extracted from electronic medical records and compared between patients with moderate, severe, and critical disease (defined according to the diagnosis and treatment protocol for novel coronavirus pneumonia, trial version 7, published by the National Health Commission of China). We assessed the risk factors associated with critical illness and poor prognosis. Dynamic haematological and coagulation parameters were investigated with a linear mixed model, and coagulopathy screening with sepsis-induced coagulopathy and International Society of Thrombosis and Hemostasis overt disseminated intravascular coagulation scoring systems was applied.

Findings: Of 466 patients admitted to hospital from Jan 23 to Feb 23, 2020, 380 patients with COVID-19 were included in our study. The incidence of thrombocytopenia (platelet count <100 × 10 cells per L) in patients with critical disease (42 [49%] of 86) was significantly higher than in those with severe (20 [14%] of 145) or moderate (nine [6%] of 149) disease (p<0·0001). The numbers of lymphocytes and eosinophils were significantly lower in patients with critical disease than those with severe or moderate disease (p<0·0001), and prothrombin time, D-dimer, and fibrin degradation products significantly increased with increasing disease severity (p<0·0001). In multivariate analyses, death was associated with increased neutrophil to lymphocyte ratio (≥9·13; odds ratio [OR] 5·39 [95% CI 1·70-17·13], p=0·0042), thrombocytopenia (platelet count <100 × 10 per L; OR 8·33 [2·56-27·15], p=0·00045), prolonged prothrombin time (>16 s; OR 4·94 [1·50-16·25], p=0·0094), and increased D-dimer (>2 mg/L; OR 4·41 [1·06-18·30], p=0·041). Thrombotic and haemorrhagic events were common complications in patients who died (19 [35%] of 55). Sepsis-induced coagulopathy and International Society of Thrombosis and Hemostasis overt disseminated intravascular coagulation scores (assessed in 12 patients who survived and eight patients who died) increased over time in patients who died. The onset of sepsis-induced coagulopathy was typically before overt disseminated intravascular coagulation.

Interpretation: Rapid blood tests, including platelet count, prothrombin time, D-dimer, and neutrophil to lymphocyte ratio can help clinicians to assess severity and prognosis of patients with COVID-19. The sepsis-induced coagulopathy scoring system can be used for early assessment and management of patients with critical disease.

Funding: National Key Research and Development Program of China.
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http://dx.doi.org/10.1016/S2352-3026(20)30217-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351397PMC
September 2020

In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19.

Cell Metab 2020 08 24;32(2):176-187.e4. Epub 2020 Jun 24.

Department of Intensive Care Unit, Wuhan Third Hospital & Tongren Hospital of Wuhan University, Wuhan, China.

Statins are lipid-lowering therapeutics with favorable anti-inflammatory profiles and have been proposed as an adjunct therapy for COVID-19. However, statins may increase the risk of SARS-CoV-2 viral entry by inducing ACE2 expression. Here, we performed a retrospective study on 13,981 patients with COVID-19 in Hubei Province, China, among which 1,219 received statins. Based on a mixed-effect Cox model after propensity score-matching, we found that the risk for 28-day all-cause mortality was 5.2% and 9.4% in the matched statin and non-statin groups, respectively, with an adjusted hazard ratio of 0.58. The statin use-associated lower risk of mortality was also observed in the Cox time-varying model and marginal structural model analysis. These results give support for the completion of ongoing prospective studies and randomized controlled trials involving statin treatment for COVID-19, which are needed to further validate the utility of this class of drugs to combat the mortality of this pandemic.
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http://dx.doi.org/10.1016/j.cmet.2020.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311917PMC
August 2020

Low transmission risk of 9 asymptomatic carriers tested positive for both SARS-CoV-2 nucleic acid and serum IgG.

J Infect 2020 09 18;81(3):452-482. Epub 2020 Jun 18.

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

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http://dx.doi.org/10.1016/j.jinf.2020.06.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299860PMC
September 2020

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.
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http://dx.doi.org/10.18632/aging.103330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343459PMC
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.
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http://dx.doi.org/10.1177/1074248420919966DOI Listing
July 2020

Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19.

Circ Res 2020 06 17;126(12):1671-1681. Epub 2020 Apr 17.

General Surgery, Huanggang Central Hospital, Wuhan, China (W.M.).

Rationale: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension.

Objective: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19.

Methods And Results: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; =0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; =0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; =0.01) in patients with COVID-19 and coexisting hypertension.

Conclusions: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265882PMC
June 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.
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http://dx.doi.org/10.1016/j.intimp.2019.106152DOI Listing
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.
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http://dx.doi.org/10.1016/j.lfs.2019.117141DOI Listing
January 2020

PD-L1 regulation by SDH5 via β-catenin/ZEB1 signaling.

Oncoimmunology 2019;8(12):1655361. Epub 2019 Sep 17.

Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Programmed death-ligand 1 (PD-L1) is a crucial target for lung cancer immunotherapy. In lung cancer patients with high PD-L1 expression, blocking or reducing its expression can inhibit tumor growth. PD-L1 is regulated by signaling pathways, transcription factors and epigenetic factors, such as the GSK3β/β-catenin pathway, P53 protein and EMT. In our previous study, succinate dehydrogenase 5 () was reported to regulate ZEB1 expression, induce EMT and lead to lung cancer metastasis via the GSK3β/β-catenin pathway. It is possible that SDH5 is involved in the mechanisms of PD-L1 regulation.In the present study, we observed a negative correlation between the expression of PD-L1 and SDH5 in vivo and in vitro. The examination of patient tissues also confirmed our results. Furthermore, we also found that SDH5 could reverse PD-L1 expression by the GSK3β/β-catenin/ZEB1 pathways. All these results reveal that SDH5 regulates PD-L1 expression and suggest that SDH5 can be used as a marker to predict tumor immune micro-states and provide guidance for clinical immunotherapy.
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http://dx.doi.org/10.1080/2162402X.2019.1655361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844322PMC
September 2019

SDH5 Depletion Enhances Radiosensitivity by Regulating p53: A New Method for Noninvasive Prediction of Radiotherapy Response.

Theranostics 2019 14;9(22):6380-6395. Epub 2019 Aug 14.

Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

Radiotherapy is an effective treatment for lung cancer but lacks a reliable prediction method. Cell-free nucleic acids in plasma have been reported as a novel tumor marker. Here, we evaluate circulating succinate dehydrogenase 5 (SDH5) mRNA in plasma and SDH5 protein in tumors, assess their predictive value in lung cancer patients undergoing radiotherapy, and explore the underlying mechanisms. : SDH5 expression was measured in peripheral blood samples and fresh tumor specimens from 208 non-small cell lung cancer (NSCLC) patients and correlated with clinical outcomes. SDH5 knockout mice and human xenograft mice were used to evaluate radiosensitivity. Cell growth, apoptosis, and the DNA damage response were assessed. Relevant RNA and protein levels were analyzed by qRT-PCR and Western blotting. Immunoprecipitation and GST pulldown assays were performed to detect protein-protein interactions. Polyubiquitination of p53 was examined by an in vitro ubiquitination assay. : Plasma and tumor SDH5 mRNA levels were positively correlated (rho=0.894, P<0.001). Patients with relatively low SDH5 levels in plasma (0.47, 0.12-0.89) and tumors (3.85, 0.96-7.23) had a better prognosis after radiotherapy (median PFS: 30.0 versus 15.0 months, hazard ratio: 0.276, 95% CI: 0.201-0.379, P<0.001). In SDH5 knockout mice, the lung epithelial cells exhibited increased DNA damage after radiation. In human lung xenograft mice, SDH5-deficient tumors had a smaller volume after radiotherapy. Furthermore, SDH5 depletion inhibits p53 degradation via the ubiquitin/proteasome pathway, which promotes apoptosis and enhances radiosensitivity in NSCLC. : Our findings provide a novel noninvasive method for prediction of response to radiotherapy and may have significant implications for cancer radiotherapy.
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http://dx.doi.org/10.7150/thno.34443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771232PMC
October 2020

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

Cardiac rhabdomyomas with atrial septal defect and tricuspid insufficiency: A case report.

J Card Surg 2019 Oct 2;34(10):1123-1126. Epub 2019 Aug 2.

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

Primary cardiac tumors are very rare and generally benign. The most common type, cardiac rhabdomyoma, comprises 45% to 75% of primary cardiac tumors. Cardiac rhabdomyoma is a rare benign tumor that commonly presents with tuberous sclerosis. We present a case of an infant with multifocal cardiac rhabdomyomas with an atrial septal defect and tricuspid insufficiency and no sign of tuberous sclerosis. She was successfully treated with an operation, the treatment plan included mass resection, tricuspid annuloplasty, and closure of the patent foramen ovale. The right atrial lesion was resected entirely, while the lobulated lesion in the right ventricle was resected as two pieces. There was no evidence of recurrence 1 year after the surgery.
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http://dx.doi.org/10.1111/jocs.14191DOI Listing
October 2019

PDGFR-β Signaling Regulates Cardiomyocyte Proliferation and Myocardial Regeneration.

Cell Rep 2019 07;28(4):966-978.e4

State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. Electronic address:

Platelet-derived growth factor receptor (PDGFR) signaling is involved in proliferation and survival in a wide array of cell types. The role of PDGFR signaling in heart regeneration is still unknown. We find that PDGFR-β signaling decreases in myocardium with age and that conditional activation PDGFR-β in cardiomyocytes promotes heart regeneration. Employing RNA sequencing, we show that the enhancer of zeste homolog 2 (Ezh2) can be upregulated by PDGFR-β signaling in primary cardiomyocytes. Conditional knockout of Ezh2 blocks cardiomyocyte proliferation and H3K27me3 modification during neonatal heart regeneration with Ink4a/Arf upregulation, even in mice with myocyte-specific conditional activation of PDGFR-β. We also show that PDGFR-β controls EZH2 expression via the phosphatidylinositol 3-kinase (PI3K)/p-Akt pathway in cardiomyocytes. Gene therapy with adeno-associated virus serotype 9 (AAV9) encoding activated PDGFR-β enhances adult heart regeneration and systolic function. Our data demonstrate that the PDGFR-β/EZH2 pathway is critical for promoting cardiomyocyte proliferation and heart regeneration, providing a potential target for cardiac repair.
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http://dx.doi.org/10.1016/j.celrep.2019.06.065DOI Listing
July 2019
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