Publications by authors named "Le Shen"

132 Publications

Argonaute (AGO) proteins play an essential role in mediating BMP9-induced osteogenic signaling in mesenchymal stem cells (MSCs).

Genes Dis 2021 Nov 13;8(6):918-930. Epub 2021 May 13.

Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA.

As multipotent progenitor cells, mesenchymal stem cells (MSCs) can renew themselves and give rise to multiple lineages including osteoblastic, chondrogenic and adipogenic lineages. It's previously shown that BMP9 is the most potent BMP and induces osteogenic and adipogenic differentiation of MSCs. However, the molecular mechanism through which BMP9 regulates MSC differentiation remains poorly understood. Emerging evidence indicates that noncoding RNAs, especially microRNAs, may play important roles in regulating MSC differentiation and bone formation. As highly conserved RNA binding proteins, Argonaute (AGO) proteins are essential components of the multi-protein RNA-induced silencing complexes (RISCs), which are critical for small RNA biogenesis. Here, we investigate possible roles of AGO proteins in BMP9-induced lineage-specific differentiation of MSCs. We first found that BMP9 up-regulated the expression of and in MSCs. By engineering multiplex siRNA vectors that express multiple siRNAs targeting individual genes or all four genes, we found that silencing individual expression led to a decrease in BMP9-induced early osteogenic marker alkaline phosphatase (ALP) activity in MSCs. Furthermore, we demonstrated that simultaneously silencing all four genes significantly diminished BMP9-induced osteogenic and adipogenic differentiation of MSCs and matrix mineralization and ectopic bone formation. Collectively, our findings strongly indicate that AGO proteins and associated small RNA biogenesis pathway play an essential role in mediating BMP9-induced osteogenic differentiation of MSCs.
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http://dx.doi.org/10.1016/j.gendis.2021.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427325PMC
November 2021

miR-135b-3p Promotes Cardiomyocyte Ferroptosis by Targeting GPX4 and Aggravates Myocardial Ischemia/Reperfusion Injury.

Front Cardiovasc Med 2021 13;8:663832. Epub 2021 Aug 13.

Department of Cardiology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.

Ferroptosis is a form of cell death induced by excess iron and accumulation of reactive oxygen species in cells. Recently, ferroptosis has been reported to be associated with cancer and ischemia/reperfusion (I/R) injury in multiple organs. However, the regulatory effects and underlying mechanisms of myocardial I/R injury are not well-understood. The role of miR-135b-3p as an oncogene that accelerates tumor development has been confirmed; however, its role in myocardial I/R is not fully understood. In this study, we established an myocardial I/R rat model and an hypoxia/reoxygenation (H/R)-induced H9C2 cardiomyocyte injury model and observed that ferroptosis occurred in tissues and cells during I/R myocardial injury. We used database analysis to find miR-135b-3p and validated its inhibitory effect on the ferroptosis-related gene glutathione peroxidase 4 (), using a luciferase reporter assay. Furthermore, miR-135b-3p was found to promote the myocardial I/R injury by downregulating GPX4 expression. The results of this study elucidate a novel function of miR-135b-3p in exacerbating cardiomyocyte ferroptosis, providing a new therapeutic target for improving I/R injury.
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http://dx.doi.org/10.3389/fcvm.2021.663832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414249PMC
August 2021

Doublecortin-Like Kinase 1 (DCLK1) Is a Novel NOTCH Pathway Signaling Regulator in Head and Neck Squamous Cell Carcinoma.

Front Oncol 2021 16;11:677051. Epub 2021 Jul 16.

Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, United States.

Despite recent advancements, the 5 year survival of head and neck squamous cell carcinoma (HNSCC) hovers at 60%. DCLK1 has been shown to regulate epithelial-to-mesenchymal transition as well as serving as a cancer stem cell marker in colon, pancreatic and renal cancer. Although it was reported that DCLK1 is associated with poor prognosis in oropharyngeal cancers, very little is known about the molecular characterization of DCLK1 in HNSCC. In this study, we performed a comprehensive transcriptome-based computational analysis on hundreds of HNSCC patients from TCGA and GEO databases, and found that DCLK1 expression positively correlates with NOTCH signaling pathway activation. Since NOTCH signaling has a recognized role in HNSCC tumorigenesis, we next performed a series of experiments in a collection of HNSCC cell lines to investigate the role of DCLK1 in NOTCH pathway regulation. Our analyses revealed that DCLK1 inhibition, using either a pharmacological inhibitor or siRNA, resulted in substantially decreased proliferation, invasion, migration, and colony formation. Furthermore, these effects paralleled downregulation of active NOTCH1, and its downstream effectors, HEY1, HES1 and HES5, whereas overexpression of DCLK1 in normal keratinocytes, lead to an upregulation of NOTCH signaling associated with increased proliferation. Analysis of 233 primary and 40 recurrent HNSCC cancer biopsies revealed that high DCLK1 expression was associated with poor prognosis and showed a trend towards higher active NOTCH1 expression in tumors with elevated DCLK1. Our results demonstrate the novel role of DCLK1 as a regulator of NOTCH signaling network and suggest its potential as a therapeutic target in HNSCC.
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http://dx.doi.org/10.3389/fonc.2021.677051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323482PMC
July 2021

Tracheal window resection and reconstruction via sternocleidomastoid flap for invasive thyroid carcinoma.

Interact Cardiovasc Thorac Surg 2021 Jul 19. Epub 2021 Jul 19.

Department of Otolaryngology-Head and Neck Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

Objectives: The aim of this study was to present surgical techniques and evaluate outcomes of a sternocleidomastoid muscle (SCM) myoperiosteal flap used for the reconstruction of tracheal or laryngotracheal defects after the radical resection of invasive thyroid carcinoma.

Methods: A retrospective study was performed for patients at Peking Union Medical College Hospital from January 2008 to December 2018 of papillary thyroid carcinoma with tracheal or laryngotracheal invasion. Patients were enrolled only when they received window resection and reconstruction via an SCM myoperiosteal flap. The primary outcome was a stable airway, and the secondary outcome was survival.

Results: A total of 15 invasive thyroid carcinoma patients were enrolled in this study. Laryngotracheal and tracheal reconstruction were performed in 11 and 4 patients respectively, with a median vertical defect of 3.5 cm (3.0, 4.5). A stable airway was achieved in 14 patients postoperatively. One patient experienced tracheal stenosis and received a second operation of tracheal sleeve resection and end-to-end anastomosis 105 days after the first operation. Tracheostomy was conducted in 5 out of 15 patients in whom the vertical defects were larger than 4 cm, and the tubes were extubated after a median time of 56 days (32, 84). The median observation time was 55 months (48, 86), and all 15 patients achieved a stable airway and showed no evidence of local recurrence at the end of follow-up.

Conclusions: For thyroid carcinoma with tracheal or laryngotracheal invasions, window resection with the SCM myoperiosteal flap reconstruction presented positive results in terms of a stable airway as well as oncological outcomes. The SCM myoperiosteal flap can be an appropriate reconstruction strategy, especially when the defects reach the thyroid cartilage.
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http://dx.doi.org/10.1093/icvts/ivab193DOI Listing
July 2021

Antiparasitic mebendazole (MBZ) effectively overcomes cisplatin resistance in human ovarian cancer cells by inhibiting multiple cancer-associated signaling pathways.

Aging (Albany NY) 2021 07 7;13(13):17407-17427. Epub 2021 Jul 7.

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Ovarian cancer is the third most common cancer and the second most common cause of gynecologic cancer death in women. Its routine clinical management includes surgical resection and systemic therapy with chemotherapeutics. While the first-line systemic therapy requires the combined use of platinum-based agents and paclitaxel, many ovarian cancer patients have recurrence and eventually succumb to chemoresistance. Thus, it is imperative to develop new strategies to overcome recurrence and chemoresistance of ovarian cancer. Repurposing previously-approved drugs is a cost-effective strategy for cancer drug discovery. The antiparasitic drug mebendazole (MBZ) is one of the most promising drugs with repurposing potential. Here, we investigate whether MBZ can overcome cisplatin resistance and sensitize chemoresistant ovarian cancer cells to cisplatin. We first established and characterized two stable and robust cisplatin-resistant (CR) human ovarian cancer lines and demonstrated that MBZ markedly inhibited cell proliferation, suppressed cell wounding healing/migration, and induced apoptosis in both parental and CR cells at low micromole range. Mechanistically, MBZ was revealed to inhibit multiple cancer-related signal pathways including ELK/SRF, NFKB, MYC/MAX, and E2F/DP1 in cisplatin-resistant ovarian cancer cells. We further showed that MBZ synergized with cisplatin to suppress cell proliferation, induce cell apoptosis, and blunt tumor growth in xenograft tumor model of human cisplatin-resistant ovarian cancer cells. Collectively, our findings suggest that MBZ may be repurposed as a synergistic sensitizer of cisplatin in treating chemoresistant human ovarian cancer, which warrants further clinical studies.
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http://dx.doi.org/10.18632/aging.203232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312413PMC
July 2021

Evaluation of Burnout Among Anesthesiologists Working in Tibet, China: Altitude and Attitude.

Chin Med Sci J 2021 Jun;36(2):97-102

Department of Anesthesiology,Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730 China.

Objective Burnout is a triad of emotional exhaustion, depersonalization, and reduced personal accomplishment resulting from job stress. Although with distinct regional and cultural characteristics, burnout among anesthesiologists in the Tibet has not been described. This study aimed to explore the prevalence of burnout among anesthesiologists in Tibet and its associated factors. Methods A cross-sectional survey was conducted in Tibet, China, with an anonymous questionnaire. Social-demographic characteristics, work status, three dimensions of burnout assessed by the Maslach Burnout Inventory-Human Service Survey were collected and analyzed. Results A total of 133 individuals from 17 hospitals completed the survey from March to June 2018. The prevalence of moderate- to high-level of emotional exhaustion, depersonalization, and burnout in personal accomplishment was 65.4% (95%, 57.0%-72.9%), 66.9% (95%, 58.5%-74.3%), and 83.5% (95%, 76.2%-88.8%), respectively. An annual caseload ≥500, frequent overtime work and fair to poor sleep quality were significantly associated with a higher level of emotional exhaustion ( <0.001,=0.001, and <0.0001, respectively). 5-9 years in anesthesiology experience was significantly associated with a high level of emotional exhaustion and depersonalization (=0.002 and =0.003, respectively). Conclusions More than half of anesthesiologists working in Tibet experience a moderate- to high- level of burnout in at least one dimensional scale. Anesthesiologists having 5-9 years of experience are more prone to emotional exhaustion and depersonalization. Efforts to decrease burnout through reducing the working load and raising the social recognition of anesthesiologists in Tibet should be considered.
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http://dx.doi.org/10.24920/003800DOI Listing
June 2021

Endothelial Aryl Hydrocarbon Receptor Nuclear Translocator Mediates the Angiogenic Response to Peripheral Ischemia in Mice With Type 2 Diabetes Mellitus.

Front Cell Dev Biol 2021 10;9:691801. Epub 2021 Jun 10.

Biological Sciences Division - Cardiology, Department of Medicine, University of Chicago, Chicago, IL, United States.

Hypoxia-inducible factors (HIFs) are the master regulators of angiogenesis, a process that is impaired in patients with diabetes mellitus (DM). The transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF1β) has been implicated in the development and progression of diabetes. Angiogenesis is driven primarily by endothelial cells (ECs), but both global and EC-specific loss of ARNT-cause are associated with embryonic lethality. Thus, we conducted experiments in a line of mice carrying an inducible, EC-specific ARNT-knockout mutation ( ) to determine whether aberrations in ARNT expression might contribute to the vascular deficiencies associated with diabetes. Mice were first fed with a high-fat diet to induce diabetes. mice were then adminstrated with oral tamoxifen to disrupt and peripheral angiogenesis was evaluated by using laser-Doppler perfusion imaging to monitor blood flow after hindlimb ischemia. The mice had impaired blood flow recovery under both non-diabetic and diabetic conditions, but the degree of impairment was greater in diabetic animals. In addition, siRNA-mediated knockdown of ARNT activity reduced measurements of tube formation, and cell viability in human umbilical vein endothelial cells (HUVECs) cultured under high-glucose conditions. The mutation also reduced measures of cell viability, while increasing the production of reactive oxygen species (ROS) in microvascular endothelial cells (MVECs) isolated from mouse skeletal muscle, and the viability of MVECs under high-glucose concentrations increased when the cells were treated with an ROS inhibitor. Collectively, these observations suggest that declines in endothelial ARNT expression contribute to the suppressed angiogenic phenotype in diabetic mice, and that the cytoprotective effect of ARNT expression in ECs is at least partially mediated by declines in ROS production.
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http://dx.doi.org/10.3389/fcell.2021.691801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222825PMC
June 2021

Solving, analyzing, manufacturing, and experimental testing of thickness distribution for a cycloid-like variable curvature mirror.

Opt Express 2021 Jun;29(12):18010-18025

A cycloid-like variable curvature mirror (VCM) for zoom-imaging systems was investigated. An analytical-deformation solution to a thin-elastic plate with a cycloid-like thickness distribution and simply supported boundary condition under uniform pressure was found using a small parameter method. The finite-element analysis of the thin-elastic plate and designed VCM showed a good correlation with the analytical solution. The VCM was manufactured and polished to the initial shape with a root mean square (RMS) of 1/80λ. Finally, with air-pressure-based actuation testing under 0.07 MPa, the VCM deforms approximately 36.89 µm and maintains the RMS surface performance of 1/10λ, 1/40λ with and without spherical aberrations, respectively.
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http://dx.doi.org/10.1364/OE.426989DOI Listing
June 2021

A functional autophagy pathway is essential for BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs).

Am J Transl Res 2021 15;13(5):4233-4250. Epub 2021 May 15.

Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University Qingdao 266061, China.

Mesenchymal stem cells (MSCs) are capable of differentiating into bone, cartilage and adipose tissues. We identified BMP9 as the most potent osteoinductive BMP although detailed mechanism underlying BMP9-regulated osteogenesis of MSCs is indeterminate. Emerging evidence indicates that autophagy plays a critical role in regulating bone homeostasis. We investigated the possible role of autophagy in osteogenic differentiation induced by BMP9. We showed that BMP9 upregulated the expression of multiple autophagy-related genes in MSCs. Autophagy inhibitor chloroquine (CQ) inhibited the osteogenic activity induced by BMP9 in MSCs. While overexpression of ATG5 or ATG7 did not enhance osteogenic activity induced by BMP9, silencing expression in MSCs effectively diminished BMP9 osteogenic signaling activity and blocked the expression of the osteogenic regulator Runx2 and the late marker osteopontin induced by BMP9. Stem cell implantation study revealed that silencing in MSCs profoundly inhibited ectopic bone regeneration and bone matrix mineralization induced by BMP9. Collectively, our results strongly suggest a functional autophagy pathway may play an essential role in regulating osteogenic differentiation induced by BMP9 in MSCs. Thus, restoration of dysregulated autophagic activity in MSCs may be exploited to treat fracture healing, bone defects or osteoporosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205769PMC
May 2021

miR-210-3p Promotes Lung Cancer Development and Progression by Modulating USF1 and PCGF3.

Onco Targets Ther 2021 9;14:3687-3700. Epub 2021 Jun 9.

Department of Respiratory Medicine, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, People's Republic of China.

Purpose: Lung cancer represents one of the most frequent solid tumors. Adenocarcinoma is a common type of tumor and a significant threat to individual health globally. MicroRNAs (miRNAs) are recognized as critical governors of gene expression during carcinogenesis, while their effects on lung cancer occurrence and development are required for further investigation. Herein, the functional role of miR-210-3p and its regulation mechanism were characterized in lung cancer.

Methods: A total of 50 pairs of tumor and tumor-free lung tissues were surgically resected from lung cancer patients. Dual-luciferase reporter assay and RNA immunoprecipitation assay were performed to examine USF1 binding with miR-210-3p and PCGF3. Cultured human lung cancer cells A549 were assayed for viability, apoptosis, migration, and invasion in vitro by CCK-8 test, flow cytometry, transwell chamber assays, tumorigenesis, and lymph node metastasis in vivo by mouse xenograft experiments.

Results: miR-210-3p was upregulated in lung cancer tissues. The inhibition of miR-210-3p by specific inhibitor tempered lung cancer development and metastasis in vitro and in vivo. miR-210-3p targeted USF1 and inhibited its expression. USF1 was bound with PCGF3, which increased its transcription. PCGF3-specific knockdown mimicked the effect of miR-210-3p on lung cancer development and metastasis in vitro and in vivo.

Conclusion: The current study demonstrated that miR-210-3p facilitates lung cancer development and metastasis by impairing USF1-mediated promotion of PCGF3, which provides a better understanding of the mechanism of lung cancer development and metastasis.
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http://dx.doi.org/10.2147/OTT.S288788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203303PMC
June 2021

Prediction of Anticancer Peptides with High Efficacy and Low Toxicity by Hybrid Model Based on 3D Structure of Peptides.

Int J Mol Sci 2021 May 26;22(11). Epub 2021 May 26.

State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.

Recently, anticancer peptides (ACPs) have emerged as unique and promising therapeutic agents for cancer treatment compared with antibody and small molecule drugs. In addition to experimental methods of ACPs discovery, it is also necessary to develop accurate machine learning models for ACP prediction. In this study, features were extracted from the three-dimensional (3D) structure of peptides to develop the model, compared to most of the previous computational models, which are based on sequence information. In order to develop ACPs with more potency, more selectivity and less toxicity, the model for predicting ACPs, hemolytic peptides and toxic peptides were established by peptides 3D structure separately. Multiple datasets were collected according to whether the peptide sequence was chemically modified. After feature extraction and screening, diverse algorithms were used to build the model. Twelve models with excellent performance (Acc > 90%) in the ACPs mixed datasets were used to form a hybrid model to predict the candidate ACPs, and then the optimal model of hemolytic peptides (Acc = 73.68%) and toxic peptides (Acc = 85.5%) was used for safety prediction. Novel ACPs were found by using those models, and five peptides were randomly selected to determine their anticancer activity and toxic side effects in vitro experiments.
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http://dx.doi.org/10.3390/ijms22115630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198792PMC
May 2021

Efficacy and Safety of Qishen Yiqi Dripping Pill for Heart Failure With Preserved Ejection Fraction: A Systematic Review and Meta-Analysis.

Front Pharmacol 2020 9;11:626375. Epub 2021 Feb 9.

Department of Cardiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.

The number of heart failure with preserved ejection fraction (HFpEF) patients is increasing year by year, yet all western medicines currently used for heart failure have been shown to be ineffective for HFpEF. Qishen Yiqi Dripping Pill is one of the commonly drugs for the treatment of heart failure in China. In recent years, some clinical studies found that it has curative effect on HFpEF. To evaluate the efficacy and safety of Qishen Yiqi Dripping Pill in treatment of HFpEF. Databases including CNKI, Wanfang, VIP, CBM, PubMed, Web of Science, The Cochrane Library and EMbase were searched from their inception to May 2020 to screen relevant randomized controlled trials. The "risk of bias" evaluation tool in the Cochrane Handbook was used to evaluate the quality of the included studies. RevMan 5.3 software was used for meta-analysis. Eight studies meeting the criteria were included, with a total of 895 patients. The results of meta-analysis showed that compared with western medicine alone, combination of western medicine and Qishen Yiqi Dripping Pill can further increase the quotient of early diastolic mitral inflow velocity and late diastolic mitral inflow velocity (E/A) in patients with HFpEF [mean difference (MD) = 0.20, 95% CI (0.14, 0.26), < 0.000 01], decrease the quotient of early diastolic mitral inflow velocity and mitral annular tissue velocity (E/e') [MD = -2.50, 95% CI (-3.18, -1.82), < 0.000 01], decrease brain natriuretic peptide (BNP) [MD = -151.83, 95% CI (-245.78, -57.89), = 0.002], increase cardiac function improvement rate [relative risk (RR) = 1.30, 95% CI (1.11, 1.52), = 0.001], and increase six-minutes walking distance (6-MWD) [MD = 64.75, 95% CI (22.65, 106.85), = 0.003]. Four studies reported the occurrence of adverse reactions, among which three studies reported no adverse reactions and one study reported three patients with mild adverse reactions in the intervention group. Current evidence suggests that Qishen Yiqi Dripping Pill may be effective in the treatment of HFpEF. However, due to the low quality of the included studies, lack of placebo control, large heterogeneity among different studies, and great possibility of publication bias, the results of our review should be evaluated with more prudence, more high-quality clinical studies are needed to verify the conclusion in the future. In addition, the safety of Qishen Yiqi Dripping Pill remains uncertain, further assessment is required in the future.
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http://dx.doi.org/10.3389/fphar.2020.626375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900630PMC
February 2021

Oxoeicosanoid receptor inhibition alleviates acute myocardial infarction through activation of BCAT1.

Basic Res Cardiol 2021 01 23;116(1). Epub 2021 Jan 23.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China.

5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is an arachidonic acid metabolite produced along with leukotrienes via the 5-lipoxygenase pathway. Metabolomics studies have shown that 5-oxo-ETE level is elevated in the serum in acute myocardial infarction (AMI). The actions of 5-oxo-ETE are mediated by the highly selective oxoeicosanoid receptor (OXE-R). Moreover, increased OXE-R content was verified in AMI patients and mice. However, the precise role of OXE-R in AMI is unclear. In the present study, we demonstrate that 5-oxo-ETE triggered myocardial injury in mice. Pathway enrichment analysis identified branched chain amino acid transaminase 1/2 (BCAT1/2) as potential mediators of this effect. Western blot and immunohistochemical analyses showed that BCAT1/BCAT2 expression was significantly reduced by AMI in vitro and in vivo, while pharmacologic inhibition of BCAT1/BCAT2 accelerated myocardial injury. Conversely, heart-specific overexpression of BCAT1/BCAT2 in mice protected against ischemic myocardial injury. Treatment with the selective OXE-R inhibitor Gue1654 alleviated coronary artery ligation-induced ischemic myocardial injury in mice and oxygen/glucose deprivation-induced injury in cardiomyocytes through activation of BCAT1, while inhibiting OXE-R suppressed protein kinase C-ε (PKC-ε)/nuclear factor κB (NF-κB) signaling and cardiomyocyte apoptosis. Overall, our study confirmed a novel target OXE-R for the treatment of AMI based on metabolomics, and targeting OXE-R may represent unrecognized therapeutic intervention for cardiovascular diseases through activation of BCAT1.
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http://dx.doi.org/10.1007/s00395-021-00844-0DOI Listing
January 2021

The inhibition of BRAF activity sensitizes chemoresistant human ovarian cancer cells to paclitaxel-induced cytotoxicity and tumor growth inhibition.

Am J Transl Res 2020 15;12(12):8084-8098. Epub 2020 Dec 15.

Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center Chicago, IL, USA.

Ovarian cancer is one of the most common cancers in women and the second most common cause of gynecologic cancer death in women worldwide. While ovarian cancer is highly heterogeneous in histological subtypes and molecular genetic makeup, epithelial ovarian cancer is the most common subtype. The clinical outcomes of ovarian cancer largely depend on early detection and access to appropriate surgery and systemic therapy. While combination therapy with platinum-based drugs and paclitaxel (PTX) remains the first-line systemic therapy for ovarian cancer, many patients experience recurrence and die of progressive chemoresistance. Thus, there is an unmet clinical need to overcome recurrent disease due to resistance to chemotherapies of ovarian cancer. Here, we investigated whether BRAF inhibitors (BRAFi) could sensitize PTX-resistant ovarian cancer cells to PTX, and thus would overcome the resistance to chemotherapies. We found that BRAF and several members of the RAS/MAPK pathways were upregulated upon PTX treatment in ovarian cancer cells, and that BRAF expression was significantly elevated in the PTX-resistant ovarian cancer cells. While the BRAFi vemurafenib (VEM) alone did not cause any significant cytotoxicity in PTX-resistant ovarian cancer cells, VEM significantly enhanced PTX-induced growth inhibition and apoptosis in a dose-dependent manner. Furthermore, VEM and PTX were shown to synergistically inhibit tumor growth and cell proliferation of PTX-resistant human ovarian cancer cells . Collectively, these findings strongly suggest that BRAFi may be exploited as synergistic sensitizers of paclitaxel in treating chemoresistant ovarian cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791515PMC
December 2020

Risk factors for unplanned reintubation caused by acute airway compromise after general anesthesia: a case-control study.

BMC Anesthesiol 2021 01 12;21(1):17. Epub 2021 Jan 12.

Department of Anesthesiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China.

Background: This study aimed to identify the risk factors and evaluate the prognosis of unplanned reintubation caused by acute airway compromise (AAC) after general anesthesia.

Methods: This case-control study included surgical patients who underwent unplanned reintubation in the operating room and postanesthesia care unit after general anesthesia between January 1, 2014, and December 31, 2018. Cases due to AAC were matched 1:4 with randomly selected controls.

Results: A total of 123,068 patients were included, and reintubation due to AAC was performed in 36 patients (approximate incidence 0.03%). Univariable analysis revealed that male sex, age > 65, ASA physical status 3, sepsis, heart disease history, cerebral infarction history, Cormack Lehane grade, surgery type, fresh frozen plasma infusion, increased intubation duration, white blood cell count, and creatinine clearance rate were related to AAC-caused unplanned reintubation. Multivariable analysis revealed that age > 65 (OR = 7.50, 95% CI 2.47-22.81, P < 0.001), ASA physical status 3 (OR = 6.51, 95% CI 1.18-35.92, P = 0.032), head-neck surgery (OR = 4.94, 95% CI 1.33-18.36, P = 0.017) or thoracic surgery (OR = 12.56, 95% CI 2.93-53.90, P < 0.001) and a high fluid load (OR = 3.04, 95% CI 1.16-7.99, P = 0.024) were associated with AAC-caused unplanned reintubation. AAC-caused unplanned reintubation patients had longer postoperative hospital (OR = 5.26, 95% CI 1.57-8.95, P < 0.001) and intensive care unit days (OR = 3.94, 95% CI 1.69-6.18, P < 0.001).

Conclusions: Age > 65, ASA physical status 3, head-neck or thoracic surgery and high fluid load were found to be associated with AAC-caused unplanned reintubation.
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http://dx.doi.org/10.1186/s12871-021-01238-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802267PMC
January 2021

Composition and risk assessment of perioperative patient safety incidents reported by anesthesiologists from 2009 to 2019: a single-center retrospective cohort study.

BMC Anesthesiol 2021 01 7;21(1). Epub 2021 Jan 7.

Department of Anesthesiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan 1#, Dongcheng District, 100730, Beijing, China.

Background: Patient safety incident (PSI) reporting has been an important means of improving patient safety and enhancing organizational quality control. Reports of anesthesia-related incidents are of great value for analysis to improve perioperative patient safety. However, the utilization of incident data is far from sufficient, especially in developing countries such as China.

Methods: All PSIs reported by anesthesiologists in a Chinese academic hospital between September 2009 and August 2019 were collected from the incident reporting system. We reviewed the freeform text reports, supplemented with information from the patient medical record system. Composition analysis and risk assessment were performed.

Results: In total, 847 PSIs were voluntarily reported by anesthesiologists during the study period among 452,974 anesthetic procedures, with a reported incidence of 0.17%. Patients with a worse ASA physical status were more likely to be involved in a PSI. The most common type of incident was related to the airway (N = 208, 27%), followed by the heart, brain and vascular system (N = 99, 13%) and pharmacological incidents (N = 79, 10%). Those preventable incidents with extreme or high risk were identified through risk assessment to serve as a reference for the implementation of more standard operating procedures by the department.

Conclusions: This study describes the characteristics of 847 PSIs voluntarily reported by anesthesiologists within eleven years in a Chinese academic hospital. Airway incidents constitute the majority of incidents reported by anesthesiologists. Underreporting is common in China, and the importance of summarizing and utilizing anesthesia incident data should be scrutinized.
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http://dx.doi.org/10.1186/s12871-020-01226-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789294PMC
January 2021

Perioperative Allogeneic Red Blood Cell Transfusion and Wound Infections: An Observational Study.

Anesth Analg 2020 11;131(5):1573-1581

From the Department of Anesthesiology and.

Background: It remains unclear whether the benefits of performing perioperative allogeneic red blood cell (RBC) transfusion outweigh the risks of postoperative wound infection. The aim of this study was to assess the impact of perioperative RBC transfusion as well as dose-response relationship on wound infections in surgical patients in a large cohort.

Methods: As a retrospective observational study, the national Hospital Quality Monitoring System database was used to retrieve information about in-hospital surgical patients without limitations on surgical types in the People's Republic of China between 2013 and 2018. Patients were divided into the perioperative RBC transfusion and non-RBC transfusion groups, and wound infection rates (the primary end point) were compared. Secondary end points included in-hospital mortality, nosocomial infections, and length of hospital stay. Furthermore, patients who underwent RBC transfusion were subdivided into 6 groups based on the volume of transfused RBCs to investigate the dose-response relationship between RBC transfusions and wound infections. The association between RBC transfusion and patient outcomes were analyzed using multivariable logistic regression models adjusted for potential confounders.

Results: A total of 1,896,584 patients from 29 provinces were included, among whom 76,078 (4.0%) underwent RBC transfusions; the overall wound infection rate was 0.7%. After adjusting for confounding factors, perioperative RBC transfusion was associated with higher odds of wound infection (odds ratio [OR] = 2.24, 95% confidence interval [CI], 2.09-2.40; P < .001). As the volume of transfused RBCs increased, so did the odds of wound infection with a clear dose-response relationship (OR of >0 and ≤1 U, >1 and ≤2 U, >2 and ≤4 U, >4 and ≤8 U, >8 U transfusion compared with no RBC transfusion were 1.20, 95% CI, 0.76-1.91; 1.27, 95% CI, 1.10-1.47; 1.70, 95% CI, 1.49-1.93; 2.12, 95% CI, 1.83-2.45 and 3.65, 95% CI, 3.13-4.25, respectively). RBC transfusion was also found to be associated with higher odds of in-hospital mortality, nosocomial infection, and longer hospital stay.

Conclusions: RBC transfusion was associated with an increased odd of postoperative wound infection in surgical patients, and a significant dose-related relationship was also observed. While there are still essential confounders not adjusted for and the results do not necessarily indicate a causal relationship, we still recommend to lessen perioperative blood loss and optimize blood conservation strategies.
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http://dx.doi.org/10.1213/ANE.0000000000005122DOI Listing
November 2020

Regulation of the Paneth cell niche by exogenous L-arginine couples the intestinal stem cell function.

FASEB J 2020 08 17;34(8):10299-10315. Epub 2020 Jun 17.

State Key Laboratory of Animal Nutrition, Department of Animal Nutrition & Feed Science, College of Animal Science & Technology, China Agricultural University, Beijing, China.

Although previous studies show that exogenous nutrients regulate the stem cell function, little is known about the effects of L-arginine on intestinal stem cells (ISCs). In this study, we utilize mice, small intestinal (SI) organoids, and ISC-Paneth cell co-cultured models to clarify the role of L-arginine in ISC function. We find that exogenous L-arginine is essential for ISCs proliferation and intestinal epithelial renewal. Our data show that Paneth cells, a critical component of the ISCs niche, augment the ISCs function in response to L-arginine. Moreover, enhanced the expression of Wnt3a in Paneth cells, which is a ligand of the Wnt/β-catenin signaling pathway, mediates the effects of L-arginine on ISCs function. Pre-treatment with L-arginine enhances the ISCs pool and protects the gut in response to injury provoked by murine tumor necrosis factor α (TNF-α) and 5-Fluorouracil (5-FU). Our findings establish that the regulation of Wnt3a in the Paneth cell niche by exogenous L-arginine couples ISCs function and favours a model in which the ISCs niche couples the nutrient levels to ISCs function.
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http://dx.doi.org/10.1096/fj.201902573RRDOI Listing
August 2020

Novel Murine Models of Cerebral Cavernous Malformations.

Angiogenesis 2020 11 24;23(4):651-666. Epub 2020 Jul 24.

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, 27705, USA.

Cerebral cavernous malformations (CCMs) are ectatic capillary-venous malformations that develop in approximately 0.5% of the population. Patients with CCMs may develop headaches, focal neurologic deficits, seizures, and hemorrhages. While symptomatic CCMs, depending upon the anatomic location, can be surgically removed, there is currently no pharmaceutical therapy to treat CCMs. Several mouse models have been developed to better understand CCM pathogenesis and test therapeutics. The most common mouse models induce a large CCM burden that is anatomically restricted to the cerebellum and contributes to lethality in the early days of life. These inducible models thus have a relatively short period for drug administration. We developed an inducible CCM3 mouse model that develops CCMs after weaning and provides a longer period for potential therapeutic intervention. Using this new model, three recently proposed CCM therapies, fasudil, tempol, vitamin D, and a combination of the three drugs, failed to substantially reduce CCM formation when treatment was administered for 5 weeks, from postnatal day 21 (P21) to P56. We next restricted Ccm3 deletion to the brain vasculature and provided greater time (121 days) for CCMs to develop chronic hemorrhage, recapitulating the human lesions. We also developed the first model of acute CCM hemorrhage by injecting mice harboring CCMs with lipopolysaccharide. These efficient models will enable future drug studies to more precisely target clinically relevant features of CCM disease: CCM formation, chronic hemorrhage, and acute hemorrhage.
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http://dx.doi.org/10.1007/s10456-020-09736-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530029PMC
November 2020

Anesthesia Considerations and Infection Precautions for Trauma and Acute Care Cases During the COVID-19 Pandemic: Recommendations From a Task Force of the Chinese Society of Anesthesiology.

Anesth Analg 2020 08;131(2):326-334

From the Department of Anesthesiology, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing, China.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide. During the ongoing COVID-19 epidemic, most hospitals have postponed elective surgeries. However, some emergency surgeries, especially for trauma patients, are inevitable. For patients with suspected or confirmed COVID-19, a standard protocol addressing preoperative preparation, intraoperative management, and postoperative surveillance should be implemented to avoid nosocomial infection and ensure the safety of patients and the health care workforce. With reference to the guidelines and recommendations issued by the National Health Commission and Chinese Society of Anesthesiology, this article provides recommendations for anesthesia management of trauma and emergency surgery cases during the COVID-19 pandemic.
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http://dx.doi.org/10.1213/ANE.0000000000004913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199776PMC
August 2020

Predictors of hemodynamic instability in patients with pheochromocytoma and paraganglioma.

J Surg Oncol 2020 Jun 20. Epub 2020 Jun 20.

Department of Anesthesiology, Peking Union Medical College Hospital, Beijing, China.

Background And Objectives: Intraoperative hemodynamic instability is common in patients with pheochromocytoma and paraganglioma. The aim of this study was to identify the predictive risk factors of intraoperative hemodynamic instability.

Methods: A total of 428 patients having elective resection of pheochromocytoma and/or paraganglioma at Peking Union Medical College Hospital between January 2014 and July 2019 were included. The association between preoperative parameters and the incidence of intraoperative hemodynamic instability were evaluated. Binary logistic regression was used to assess the predictive risk factors of hemodynamic instability.

Results: Patients with intraoperative hemodynamic instability were more prone to have elevated levels of norepinephrine and epinephrine. Binary Logistic regression showed the risk factors of hemodynamic instability were tumor size >5.0 cm (odds ratio [OR], 1.889; 95% confidence interval [CI], 1.243-2.870; P = .003) and five-fold increases of urine epinephrine (OR, 2.195; 95% CI, 1.242-3.880; P = .007).

Conclusions: Intraoperative hemodynamic instability is common despite adequate preoperative medical treatment. Tumor size and high level of urinary epinephrine are tumor-related factors for intraoperative hemodynamic instability. Identifying these factors can help clinicians to manage patients more effectively and improve patients' outcomes.
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http://dx.doi.org/10.1002/jso.26079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496938PMC
June 2020

Permissive microbiome characterizes human subjects with a neurovascular disease cavernous angioma.

Nat Commun 2020 05 27;11(1):2659. Epub 2020 May 27.

Section of Neurosurgery, Department of Surgery, The University of Chicago, 5841S. Maryland Avenue, Chicago, IL, 60637, USA.

Cavernous angiomas (CA) are common vascular anomalies causing brain hemorrhage. Based on mouse studies, roles of gram-negative bacteria and altered intestinal homeostasis have been implicated in CA pathogenesis, and pilot study had suggested potential microbiome differences between non-CA and CA individuals based on 16S rRNA gene sequencing. We here assess microbiome differences in a larger cohort of human subjects with and without CA, and among subjects with different clinical features, and conduct more definitive microbial analyses using metagenomic shotgun sequencing. Relative abundance of distinct bacterial species in CA patients is shown, consistent with postulated permissive microbiome driving CA lesion genesis via lipopolysaccharide signaling, in humans as in mice. Other microbiome differences are related to CA clinical behavior. Weighted combinations of microbiome signatures and plasma inflammatory biomarkers enhance associations with disease severity and hemorrhage. This is the first demonstration of a sensitive and specific diagnostic microbiome in a human neurovascular disease.
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http://dx.doi.org/10.1038/s41467-020-16436-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253448PMC
May 2020

Antibodies in cerebral cavernous malformations react with cytoskeleton autoantigens in the lesional milieu.

J Autoimmun 2020 09 30;113:102469. Epub 2020 Apr 30.

Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, 5842 S. Maryland Ave, Chicago, IL, 60637, United States. Electronic address:

Previous studies have reported robust inflammatory cell infiltration, synthesis of IgG, B-cell clonal expansion, deposition of immune complexes and complement within cerebral cavernous malformation (CCM) lesions. B-cell depletion has also been shown to reduce the maturation of CCM in murine models. We hypothesize that antigen(s) within the lesional milieu perpetuate the pathogenetic immune responses in CCMs. This study aims to identify those putative antigen(s) using monoclonal antibodies (mAbs) derived from plasma cells found in surgically removed human CCM lesions. We produced human mAbs from laser capture micro-dissected plasma cells from four CCM patients, and also germline-reverted versions. CCM mAbs were assayed using immunofluorescence on central nervous system (CNS) tissues and immunocytochemistry on human primary cell lines. Antigen characterization was performed using a combination of confocal microscopy, immunoprecipitation and mass spectrometry. Affinity was determined by enzyme-linked immunosorbent assay, and specificity by multi-color confocal microscopy and quantitative co-localization. CCM mAbs bound CNS tissue, especially endothelial cells and astrocytes. Non-muscle myosin heavy chain IIA (NMMHCIIA), vimentin and tubulin are three cytoskeleton proteins that were commonly targeted. Selection of cytoskeleton proteins by plasma cells was supported by a high frequency of immunoglobulin variable region somatic hypermutations, high affinity and selectivity of mAbs in their affinity matured forms, and profoundly reduced affinity and selectivity in the germline reverted forms. Antibodies produced by plasma cells in CCM lesions commonly target cytoplasmic and cytoskeletal autoantigens including NMMHCIIA, vimentin and tubulin that are abundant in endothelial cells and astrocytes. Binding to, and selection on autoantigen(s) in the lesional milieu likely perpetuates the pathogenetic immune response in CCMs. Blocking this in situ autoimmune response may yield a novel treatment for CCM.
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http://dx.doi.org/10.1016/j.jaut.2020.102469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483292PMC
September 2020

ZO-1 Regulates Intercalated Disc Composition and Atrioventricular Node Conduction.

Circ Res 2020 07 29;127(2):e28-e43. Epub 2020 Apr 29.

From the Departments of Pathology (W.D., H.L.S., Y.L., L.S., C.R.W.), The University of Chicago, IL.

Rationale: ZO-1 (Zona occludens 1), encoded by the tight junction protein 1 () gene, is a regulator of paracellular permeability in epithelia and endothelia. ZO-1 interacts with the actin cytoskeleton, gap, and adherens junction proteins and localizes to intercalated discs in cardiomyocytes. However, the contribution of ZO-1 to cardiac physiology remains poorly defined.

Objective: We aim to determine the role of ZO-1 in cardiac function.

Methods And Results: Inducible cardiomyocyte-specific deletion mice (; ) were generated by crossing the floxed mice and transgenic mice. Tamoxifen-induced loss of ZO-1 led to atrioventricular (AV) block without changes in heart rate, as measured by ECG and ex vivo optical mapping. Mice with tamoxifen-induced conduction system-specific deletion of () developed AV block while tamoxifen-induced conduction system deletion of distal to the AV node () did not demonstrate conduction defects. Western blot and immunostaining analyses of AV nodes showed that ZO-1 loss decreased Cx (connexin) 40 expression and intercalated disc localization. Consistent with the mouse model study, immunohistochemical staining showed that ZO-1 is abundantly expressed in the human AV node and colocalizes with Cx40. Ventricular conduction was not altered despite decreased localization of ZO-1 and Cx43 at the ventricular intercalated disc and modestly decreased left ventricular ejection fraction, suggesting ZO-1 is differentially required for AV node and ventricular conduction.

Conclusions: ZO-1 is a key protein responsible for maintaining appropriate AV node conduction through maintaining gap junction protein localization.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.316415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334106PMC
July 2020

Anaesthetic management of a large paraganglioma resection in a woman with isolated L-looped transposition of the great arteries: a case report.

BMC Anesthesiol 2020 04 6;20(1):79. Epub 2020 Apr 6.

Department of Anaesthesiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 100730, Beijing, P.R. China.

Background: Reports of anaesthetic management of paraganglioma resection in patients with isolated L-transposition of the great arteries (L-TGA) are rare. We focus on the preoperative evaluation, intraoperative management, and postoperative care of a frail patient with "physiologically corrected" L-TGA for paraganglioma resection.

Case Presentation: We performed general anaesthesia for a 46-year-old patient with "physiologically corrected" L-TGA undergoing open large retroperitoneal paraganglioma resection. Although the preoperative medical therapy had attained its goals, the patient went through three periods of severe episodic hypertension and tachycardia as tumour manipulation released catecholamines. Goal-directed fluid therapy based on pulse pressure variation (PPV) and point-of-care transesophageal echocardiography (TEE) imaging enabled anaesthesiologists to make rapid judgments and to regulate blood pressure in a timely manner, thereby reducing the risk of heart failure caused by massive rapid fluid bolus therapy. The patient was transferred to the intensive care unit because of intraoperative hemodynamic changes and significant blood loss. Despite transient myocardial injury (elevated troponin I), no lethal arrhythmia or complications occurred perioperatively, and the patient recovered well and was discharged 1 week later.

Conclusions: Goal-directed fluid therapy combined with the adoption of TEE could effectively guide fluid administration, which is helpful for anaesthesia management during operation. We recommend the routine use of TEE in such cases.
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http://dx.doi.org/10.1186/s12871-020-00998-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132883PMC
April 2020

Pyridoxamine alleviates mechanical allodynia by suppressing the spinal receptor for advanced glycation end product-nuclear factor-B/extracellular signal-regulated kinase signaling pathway in diabetic rats.

Mol Pain 2020 Jan-Dec;16:1744806920917251

Department of Anesthesiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, China.

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http://dx.doi.org/10.1177/1744806920917251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139183PMC
February 2021

Idiopathic pulmonary fibrosis is associated with tight junction protein alterations.

Biochim Biophys Acta Biomembr 2020 05 28;1862(5):183205. Epub 2020 Jan 28.

Department of Pathology, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, United States of America. Electronic address:

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by an abnormal healing response to injury of the alveolar epithelium. Tight junctions provide a physical barrier at the apical intercellular space between epithelial cells and regulate paracellular flux. While tight junction alterations are known to contribute to barrier dysfunction in a number of disease states, the role of tight junction proteins in IPF is poorly defined. To determine a potential role for tight junction protein alterations in IPF, we performed immunohistochemical staining for tight junction proteins ZO-1, occludin, claudin-2, claudin-3, claudin-4, claudin-5, and claudin-18. Staining intensity and localization were compared between IPF and control lung tissues. IPF was associated with type II pneumocyte hyperplasia and altered tight junction protein expression. While there was no difference in the expression of ZO-1, claudin-3, or claudin-5, between IPF and normal control, there was an overall increase in claudin-2 expression in bronchiolar and alveolar epithelium and a decrease in claudin-4 expression in type II pneumocytes. There was also increased occludin and decreased claudin-18 expression in pneumocytes overlying fibroblastic foci. These findings suggest that epithelial barrier alterations may be important to the pathogenesis of IPF.
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http://dx.doi.org/10.1016/j.bbamem.2020.183205DOI Listing
May 2020

Total Panax notoginseng saponin inhibits vascular smooth muscle cell proliferation and migration and intimal hyperplasia by regulating WTAP/p16 signals via mA modulation.

Biomed Pharmacother 2020 Apr 24;124:109935. Epub 2020 Jan 24.

Department of Cardiology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. Electronic address:

Intimal hyperplasia, the key event of arterial restenosis, is a result of vascular smooth muscle cell (VSMC) proliferation and migration. Previous studies have demonstrated that total Panax notoginseng saponin (TPNS) represses intimal hyperplasia and inhibits the proliferation of VSMCs following balloon injury. However, the underlying roles of TPNS in intimal hyperplasia remain unclear. In this study, we first found that TPNS inhibited the intimal hyperplasia and reversed the reduced mA quantity in balloon catheter-injured rat carotid artery. Then, we measured the expression profiles of mA "writers" (i.e., methyltransferase like 3 (METTL3), methyltransferase like 14 (METTL14), and WT1 associated protein (WTAP)) and "erasers" (i.e., FTO alpha-ketoglutarate dependent dioxygenase (FTO) and alkB homolog 5, RNA demethylase (ALKBH5)) in vivo and found that TPNS up-regulated the reduced the WTAP expression in balloon catheter-injured rat carotid artery. Furthermore, we illustrated that TPNS inhibited the viability, proliferation, and migration potential of VSMCs via promotion of WTAP expression and suppression of WTAP restored the TPNS-induced inhibition of cell viability, proliferation and migration potential of VSMCs. In addition, we found that p16 was up-regulated in VSMCs treated with TPNS and repression of p16 restored the TPNS-induced inhibition of cell viability, proliferation and migration potential of VSMCs. Finally, we elucidated that, mechanistically, WTAP exerted its role by regulating p16 via mA modification. Collectively, our results reveal the WTAP-p16 signaling axis and highlight the critical roles of m6A modification in intimal hyperplasia. Thus, this study provided a potential biomarker for the assessment of intimal hyperplasia risk following angioplasty as well as a novel therapeutic target for this disease.
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http://dx.doi.org/10.1016/j.biopha.2020.109935DOI Listing
April 2020

Computational Modeling of Claudin Structure and Function.

Int J Mol Sci 2020 Jan 23;21(3). Epub 2020 Jan 23.

Department of Physics, University of Illinois at Chicago, Chicago, IL 60607, USA.

Tight junctions form a barrier to control passive transport of ions and small molecules across epithelia and endothelia. In addition to forming a barrier, some of claudins control transport properties of tight junctions by forming charge- and size-selective ion channels. It has been suggested claudin monomers can form or incorporate into tight junction strands to form channels. Resolving the crystallographic structure of several claudins in recent years has provided an opportunity to examine structural basis of claudins in tight junctions. Computational and theoretical modeling relying on atomic description of the pore have contributed significantly to our understanding of claudin pores and paracellular transport. In this paper, we review recent computational and mathematical modeling of claudin barrier function. We focus on dynamic modeling of global epithelial barrier function as a function of claudin pores and molecular dynamics studies of claudins leading to a functional model of claudin channels.
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http://dx.doi.org/10.3390/ijms21030742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037046PMC
January 2020

The circular RNA hsa_circ_0007623 acts as a sponge of microRNA-297 and promotes cardiac repair.

Biochem Biophys Res Commun 2020 03 20;523(4):993-1000. Epub 2020 Jan 20.

Department of Cardiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 210029, China; Department of Cardiology, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China; First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China. Electronic address:

Circular RNAs (circRNAs) are a kind of closed loop endogenous non-coding RNAs have attracted increasing interest in recent years. However, the mechanism of circRNAs in the pathogenesis of multiple cardiovascular diseases, particularly myocardial ischemia, is rarely reported. In the present study, we examined a circular RNA, hsa_circ_0007623, which is highly expressed in hypoxia-induced human umbilical vein endothelial cells (HUVECs) and can act as a sponge for miR-297, which is involved in cardiac repair after acute myocardial ischemia. In hypoxia-stimulated HUVECs, the inhibition of hsa_circ_0007623 expression was found to reduce cell proliferation, migration, and angiogenesis. Further in vivo experiments confirmed the cardioprotective effect of hsa_circ_0007623 expression in isoproterenol-induced acute ischemia mice. Bioinformatics analysis predicted hsa_circ_0007623, sponge miR-297 and miR-297 directly target VEGFA, which was validated by dual-luciferase assay. Subsequently, functional experiments revealed hsa_circ_0007623 silencing could up-regulate miR-297 and down-regulate VEGFA expression, and reduce cell proliferation, migration, and angiogenesis. We concluded that hsa_circ_0007623 can bind to miR-297, promote cardiac repair after acute myocardial ischemia, and protect cardiac function.
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http://dx.doi.org/10.1016/j.bbrc.2019.12.116DOI Listing
March 2020
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