Publications by authors named "Zhipeng Wu"

119 Publications

Low Expression of RILPL2 Predicts Poor Prognosis and Correlates With Immune Infiltration in Endometrial Carcinoma.

Front Mol Biosci 2021 19;8:670893. Epub 2021 May 19.

Department of Oncology, Nantong Third People's Hospital Affiliated to Nantong University, Nantong, China.

Increasing numbers of biomarkers have been identified in various cancers. However, biomarkers associated with endometrial carcinoma (EC) remain largely to be explored. In the current research, we downloaded the RNA-seq data and corresponding clinicopathological features from the Cancer Genome Atlas (TCGA) database. We conducted an expression analysis, which resulted in RILPL2 as a novel diagnostic biomarker in EC. The dysregulation of RILPL2 in EC was also validated in multiple datasets. The correlations between clinical features and RILPL2 expression were assessed by logistic regression analysis. Then, Kaplan-Meier analysis, univariate and multivariate Cox regression analysis were performed to estimate prognostic values of RILPL2 in the TCGA cohort, which revealed that increased level of RILPL2 was remarkably associated with better prognosis and could act as an independent prognostic biomarker in patients with EC. Moreover, correlation analysis of RILPL2 and tumor-infiltrating immune cells (TIICs) indicated that RILPL2 might play a critical role in regulating immune cell infiltration in EC and is related to immune response. Besides, high methylation level was a significant cause of low RILPL2 expression in EC. Subsequently, weighted gene co-expression network analysis (WGCNA) and enrichment analysis were conducted to explore the RILPL2-involved underlying oncogenic mechanisms, and the results indicated that RILPL2 mainly regulated cell cycle. In conclusion, our findings provided evidence that downregulation of RILPL2 in EC is an indicator of adverse prognosis and RILPL2 may act as a promising target for the therapeutics of EC.
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http://dx.doi.org/10.3389/fmolb.2021.670893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171931PMC
May 2021

A Prognostic Ferroptosis-Related lncRNAs Signature Associated With Immune Landscape and Radiotherapy Response in Glioma.

Front Cell Dev Biol 2021 19;9:675555. Epub 2021 May 19.

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

Recent studies have demonstrated that long non-coding RNAs (lncRNAs) are implicated in the regulation of tumor cell ferroptosis. However, the prognostic value of ferroptosis-related lncRNAs has never been comprehensively explored in glioma. In this study, the transcriptomic data and clinical information of glioma patients were downloaded from TCGA, CGGA and Rembrandt databases. We identified 24 prognostic ferroptosis-related lncRNAs, 15 of which (SNAI3-AS1, GDNF-AS1, WDFY3-AS2, CPB2-AS1, WAC-AS1, SLC25A21-AS1, ARHGEF26-AS1, LINC00641, LINC00844, MIR155HG, MIR22HG, PVT1, SNHG18, PAXIP1-AS2, and SBF2-AS1) were used to construct a ferroptosis-related lncRNAs signature (FRLS) according to the least absolute shrinkage and selection operator (LASSO) regression. The validity of this FRLS was verified in training (TCGA) and validation (CGGA and Rembrandt) cohorts, respectively. The Kaplan-Meier curves revealed a significant distinction of overall survival (OS) between the high- and low-risk groups. The receiver operating characteristic (ROC) curves exhibited robust prognostic capacity of this FRLS. A nomogram with improved accuracy for predicting OS was established based on independent prognostic factors (FRLS, age, and WHO grade). Besides, patients in the high-risk group had higher immune, stroma, and ESTIMATE scores, lower tumor purity, higher infiltration of immunosuppressive cells, and higher expression of immune checkpoints. Patients in the low-risk group benefited significantly from radiotherapy, while no survival benefit of radiotherapy was observed for those in the high-risk group. In conclusion, we identified the prognostic ferroptosis-related lncRNAs in glioma, and constructed a prognostic signature which was associated with the immune landscape of glioma microenvironment and radiotherapy response.
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http://dx.doi.org/10.3389/fcell.2021.675555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170051PMC
May 2021

Childhood trauma is linked to decreased temporal stability of functional brain networks in young adults.

J Affect Disord 2021 May 2;290:23-30. Epub 2021 May 2.

Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Mental Health Institute of Central South University, Changsha, Hunan, China; China National Clinical Research Center on Mental Disorders, Changsha, Hunan, China. Electronic address:

Background: Both childhood trauma and disruptions in brain functional networks are implicated in the development of psychiatric disorders in early adulthood. However, the relationships between these two factors remain unclear. This study aimed to investigate whether and how childhood trauma would relate to changes of functional network dynamics in young adults.

Methods: Resting-state functional magnetic resonance imaging data were collected from 53 young healthy adults, whose childhood trauma histories were assessed by the Childhood Trauma Questionnaire (CTQ). Network switching rate, a measure of stability of dynamic brain networks over time, was calculated at both global and local levels for each participant. Switching rates at both levels were compared between participants with and without childhood trauma, and further correlated with CTQ total score.

Results: In the current sample, 19 (35.8%) participants reported a history of childhood trauma. At the global level, participants with childhood trauma showed significantly higher network switching rates than those without trauma (F = 10.021, p = 0.003). A significant positive correlation was found between network switching rates and CTQ scores in the entire sample (r = 0.378, p = 0.007). At the local level, these effects were mainly observed in the default-mode, fronto-parietal, cingulo-opercular, and occipital subnetworks.

Conclusions: Our study provides preliminary evidence for a possible long-term effect of childhood trauma on brain functional dynamism. These findings may have potential contributions to psychiatric disorders during adulthood.
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http://dx.doi.org/10.1016/j.jad.2021.04.061DOI Listing
May 2021

Robust Hierarchical Porous PTFE Film Fabricated via Femtosecond Laser for Self-Cleaning Passive Cooling.

Nano Lett 2021 May 10;21(10):4209-4216. Epub 2021 May 10.

The State Key Laboratory of High Performance and Complex Manufacturing, College of Mechanical and Electrical Engineering, Central South University, Changsha 410083, P.R. China.

Passive cooling materials that spontaneously cool an object are promising choices for mitigating the global energy crisis. However, these cooling effects are usually weakened or lost when dust contaminates the surface structure, greatly restricting their applications. In this work, a robust hierarchical porous polytetrafluoroethylene (PTFE) film with coral-like micro/nanostructures is generated by a facile and efficient femtosecond laser ablation technique. Owing to its unique micro/nanostructures, the as-prepared surface exhibits an outstanding self-cleaning function for various liquids with ultralow adhesion. This self-cleaning characteristic enhances the durability of its passive cooling effect. It is demonstrated that the titanium (Ti) sheet covered with laser-ablated PTFE film can realize a maximum temperature decrease of 4 and 10 °C compared to the Ti sheet covered with pristine PTFE film and uncovered, respectively. This study reveals that femtosecond laser micromachining is a facile and feasible avenue to produce robust self-cleaning passive cooling devices.
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http://dx.doi.org/10.1021/acs.nanolett.1c00038DOI Listing
May 2021

REGγ regulates hair cycle by activating Lgr5 positive hair follicle stem cells.

J Dermatol Sci 2021 May 18;102(2):101-108. Epub 2021 Apr 18.

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China. Electronic address:

Background: REGγ acts as a proteasome activating factor mediating proteasome degradation of substrate proteins in an ATP and ubiquitination independent manner and also as an important regulator of cell cycle, proliferation and apoptosis. Hair cycle involves dynamic, continuous morphological changes of three stages (anagen, catagen and telogen).

Objective: The function of REGγ in hair cycling is still unclear.

Methods: Here, we used REGγ knockout 293 T cells, inducible 293WT and 293N151Y cell, REGγ knockout mice to identify the novel molecular mechanism of REGγ in regulating hair follicle stem cells.

Results: In the present study, we found that REGγ deletion markedly delayed the transition of hair follicles from telogen to anagen and hair regeneration in mice. We also observed significant decrease of hair follicle stem cell number, stem-like property and proliferation ability. Interestingly, the results from real-time PCR, FACS, Western Blot and immunofluorescent analysis showed that REGγ deletion could greatly downregulate Lgr5 expression in the hair follicles. Meanwhile, REGγ was demonstrated to directly interact with LHX2 and promotes its degradation. Importantly, REGγ specific deletion in Lgr5 stem cells induced the marked delay of hair regeneration after depilation.

Conclusion: These data together indicate that REGγ was a new mediator of Lgr5 expression in hair follicle at least partly by promoting the degradation of its suppressive transcription factor LHX2. It seemed that REGγ regulated hair anagen entry and hair regrowth by activating Lgr5 positive hair follicle stem cells.
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http://dx.doi.org/10.1016/j.jdermsci.2021.04.002DOI Listing
May 2021

Reticulocalbin 3 deficiency in alveolar epithelium attenuated LPS-induced ALI via NF-κB signaling.

Am J Physiol Lung Cell Mol Physiol 2021 04 24;320(4):L627-L639. Epub 2021 Feb 24.

Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.

Acute respiratory distress syndrome (ARDS) is characterized by acute lung injury (ALI) secondary to an excessive alveolar inflammatory response. Reticulocalbin 3 (Rcn3) is an endoplasmic reticulum (ER) lumen protein in the secretory pathway. We previously reported the indispensable role of Rcn3 in type II alveolar epithelial cells (AECIIs) during lung development and the lung injury repair process. In the present study, we further observed a marked induction of Rcn3 in the alveolar epithelium during LPS-induced ALI. In vitro alveolar epithelial (MLE-12) cells consistently exhibited a significant induction of Rcn3 accompanied with NF-κB activation in response to LPS exposure. We examined the role of Rcn3 in the alveolar inflammatory response by using mice with a selective deletion of in alveolar epithelial cells upon doxycycline administration. The Rcn3 deficiency significantly blunted the ALI and alveolar inflammation induced by intratracheal LPS instillation but not that induced by an intraperitoneal LPS injection (secondary insult); the alleviated ALI was accompanied by decreases in NF-κB activation and NLRP3 levels but not in GRP78 and cleaved caspase-3 levels. The studies conducted in MLE-12 cells consistently showed that Rcn3 knockdown blunted the activations of NF-κB signaling and NLRP3-dependent inflammasome upon LPS exposure. Collectively, these findings suggest a novel role for Rcn3 in regulating the alveolar inflammatory response to pulmonary infection via the NF-κB/NLRP3/inflammasome axis and shed additional light on the mechanism of ARDS/ALI.
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http://dx.doi.org/10.1152/ajplung.00526.2020DOI Listing
April 2021

Salvia miltiorrhiza improves type 2 diabetes: A protocol for systematic review and meta-analysis.

Medicine (Baltimore) 2021 Feb;100(6):e23843

Hospital of Chengdu University of Traditional Chinese Medicine.

Background: Diabetes refers to any group of metabolic diseases characterized by high blood sugar and generally thought to be caused by insufficient production of insulin, impaired response to insulin. Globally, patients with type 2 diabetes account for more than 85% of the total diabetic patients, and due to factors, such as obesity, aging, environment and lifestyle, the incidence of diabetes is rising. Salvia miltiorrhiza (SM) is a medicine used to treat diabetes in China. In recent years, it has been reported that SM has the effect of improving type 2 diabetes. However, there is no systematic review of its efficacy and safety yet. Therefore, we propose a systematic review to evaluate the efficacy and safety of SM for T2D.

Methods: Six databases will be searched: China National Knowledge Infrastructure (CNKI), China Biological Medicine (CBM), China Scientific Journals Database (CSJD), Wanfang database, PubMed, and EMBASE. The information is searched from January 2010 to July 2020. Languages are limited to English and Chinese. The primary outcomes include 2 hour plasma glucose, fasting plasma glucose, hemoglobin A1c, homeostasis model assessment of insulin resistance, and fasting plasma insulin. The secondary outcomes include clinical efficacy and adverse events.

Results: This systematic review will evaluate the efficacy and safety of Salvia miltiorrhiza in the treatment of type 2 diabetes.

Conclusion: This systematic review provides evidence as to whether Salvia miltiorrhiza is effective and safe for type 2 diabetes.

Ethics: Ethical approval is not necessary as this protocol is only for systematic review and does not involve in privacy data or an animal experiment.

Systematic Review Registration: INPLASY2020110046.
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http://dx.doi.org/10.1097/MD.0000000000023843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886461PMC
February 2021

Red cell distribution width is associated with all-cause mortality in patients with acute stroke: a retrospective analysis of a large clinical database.

J Int Med Res 2021 Feb;49(2):300060520980587

Department of Neurology, Wenzhou Hospital of Traditional Chinese Medicine, Zhejiang, Wenzhou, China.

Objectives: This study aimed to evaluate the association between the red blood cell distribution width (RDW) and mortality in patients with stroke.

Methods: We conducted a retrospective cohort study on patients with stroke in the Medical Information Mart for Intensive Care Database III. Cox proportional hazards regression models were used to estimate hazard ratios of 30-day, 90-day, and 1-year mortality in relation to the RDW level.

Results: A total of 4134 patients were enrolled, including 2646 patients with ischemic stroke and 1668 with hemorrhagic stroke. After adjustment for potential confounders, the hazard ratio (95% confidence interval) of 30-day mortality for the second (RDW: 13.4%-14.3%) and third (>14.3%) tertiles was 1.15 (0.96, 1.37) and 1.40 (1.17, 1.68), respectively, compared with the reference group (<13.4%). A two-piecewise linear regression model was established and the inflection point of RDW was 16.7%. When RDW was >16.7%, an increase in RDW did not increase stroke mortality.

Conclusions: The RDW is a prognostic factor of patients with stroke. This finding needs to be confirmed in future prospective studies.
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http://dx.doi.org/10.1177/0300060520980587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871051PMC
February 2021

Recent advances in femtosecond laser-structured Janus membranes with asymmetric surface wettability.

Nanoscale 2021 Feb;13(4):2209-2226

Hunan Key Laboratory of Super Microstructure and Ultrafast Process, School of Physics and Electronics, Central South University, Changsha 410083, China.

Janus wettability membranes have received much attention because of their asymmetric surface wettability. On the basis of this distinctiveness from traditional symmetrical membranes, relevant scholars have been inspired to pursue many innovations utilizing such membranes. Femtosecond laser microfabrication shows many advantages, such as precision, short time, and environmental friendliness, over traditional fabrication methods. Now this has been applied in structuring Janus membranes by researchers. This review covers recent advances in femtosecond laser-structured Janus membranes with asymmetric surface wettability. The background in femtosecond laser-structured Janus membranes is first discussed, focusing on the Janus wettability membrane and femtosecond laser microfabrication. Then the applications of Janus membranes are introduced, which are divided into unidirectional fluid transport, oil-water separation, fog harvesting, and seawater desalination. Finally, based on femtosecond laser-structured Janus membranes, some existing problems are pointed out and future perspectives proposed.
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http://dx.doi.org/10.1039/d0nr06639gDOI Listing
February 2021

A combined experimental and molecular dynamics simulation study of an intrinsic self-healing polyurethane elastomer based on a dynamic non-covalent mechanism.

Soft Matter 2021 Mar;17(8):2191-2204

College of Science, Nanjing Forestry University, Nanjing 210037, China. and Institute of Polymer Materials, Nanjing Forestry University, Nanjing 210037, China.

An intrinsic self-healing polyurethane (PU) elastomer with excellent self-healing efficiency was prepared. The self-healing properties of this elastomer as well as the temperature dependence of self-healing can be tailored by regulating the molar ratio of hard to soft segments. The self-healing efficiency of 92.5% is the highest when the molar ratio of 4,4-methylenedicyclohexyl diisocyanate (HMDI) to polypropylene carbonate polyol (PPC) is 1.3 and the temperature is 25 °C. In situ temperature swing infrared spectra and low-field nuclear magnetic resonance reveal that the soft segment, PPC, endows PU with a dense dynamic hydrogen bond network, and the dissociation and reconstruction of the hydrogen bond network enable the PU to heal. To date, the exchange of hydrogen bonds has not been observed intuitively through experimental means. Therefore, the number, type, strength, lifetime, and the exchange of hydrogen bonds in the self-healing process at different temperatures were investigated by molecular dynamics (MD) simulation. The simulated results show that the type of hydrogen bond exchange between functional groups will be affected by temperature. The hydrogen bonds between urethane and urea groups play a leading role in the self-healing properties due to the high strength and a large number of hydrogen bonds at both 25 and 50 °C. The stronger strength, longer lifetime, and greater number of effective hydrogen bonds at 25 °C make the self-healing efficiency of PU higher than at 50 °C.
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http://dx.doi.org/10.1039/d0sm02085kDOI Listing
March 2021

MRI analysis and surgical treatment of Wassel Type IV duplicated thumbs.

J Hand Surg Eur Vol 2021 May 17;46(4):360-366. Epub 2021 Jan 17.

Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

We present the MRI findings for 39 Wassel Type IV duplicated thumbs in 38 patients. We found that MRI revealed the morphology of the cartilaginous connection between the thumb anlages and the location of the deviation corresponding to the classification of Horii, which allowed precise preoperative planning of corrective osteotomies. All 39 thumbs were available for follow-up after surgical reconstruction at a mean of 29 months (range 25 to 39). Four out of nine Horii Type A cases and all 12 Type B, as well as the six Type C and the six Type D cases, achieved good results according to the Tada scoring system. Five Type A cases achieved fair results with residual stiffness of the interphalangeal joint. No secondary operations were needed. We conclude that MRI proved useful in subclassifying Wassel Type IV duplicated thumbs and may aid in planning the osteotomies needed for their reconstruction. IV.
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http://dx.doi.org/10.1177/1753193420983213DOI Listing
May 2021

DUSP5 suppresses interleukin-1β-induced chondrocyte inflammation and ameliorates osteoarthritis in rats.

Aging (Albany NY) 2020 12 15;12(24):26029-26046. Epub 2020 Dec 15.

Department of Orthopaedics, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China.

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by deterioration of articular cartilage. Dual specificity phosphatase 5 (DUSP5), a member of the DUSP subfamily, is known to regulate cellular inflammation. Here, we studied the relationship between DUSP5 and OA by knockdown and overexpression DUSP5, respectively. Results from experiments demonstrated that the knockdown of DUSP5 increased interleukin-1β (IL-1β)-induced expression of inflammatory genes, such as inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), and matrix metalloproteinases (MMPs) in chondrocytes, whereas it decreased the expression of anti-inflammatory genes, such as tissue inhibitor of metalloproteinase 3 (TIMP3) and IL-10. Conversely, the overexpression of DUSP5 suppressed the IL-1β-induced expression of iNOS, COX-2, and MMPs, and upregulated the expression of TIMP3 and IL-10. Moreover, knockdown of DUSP5 enhanced the IL-1β-induced activation of NF-κB and ERK pathways, whereas its overexpression inhibited these pathways. DUSP5 overexpression prevented cartilage degeneration in a rat OA model, while its knockdown reversed that effect. Our findings reveal that DUSP5 suppresses IL-1β-induced chondrocyte inflammation by inhibiting the NF-κB and ERK signaling pathways and ameliorates OA.
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http://dx.doi.org/10.18632/aging.202252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803505PMC
December 2020

A novel prognostic model based on immunogenomics for clear cell renal cell carcinoma.

Int Immunopharmacol 2021 Jan 24;90:107119. Epub 2020 Nov 24.

Department of Urology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing 211100, Jiangsu Province, China. Electronic address:

Background: Immune cell infiltration into tumor tissue is closely related to the clinical outcomes of patients with clear cell renal cell carcinoma (ccRCC). This study aimed to screen out potential immune genes associated with ccRCC, analyze their relationships with clinical outcomes, and construct a signature to predict ccRCC.

Methods: The transcriptome RNA-sequencing data in 539 ccRCC and 72 adjacent normal tissues were obtained from TCGA database. Biomedical computational algorithms were conducted to identify immune-related differential expressed genes (IRDGs) and enriched pathways. Then, LASSO Cox and multivariate Cox analyses were performed to screen out genes that were then used to construct the prognostic model.

Results: A total of 116 down-regulated and 565 up-regulated IRDGs were identified. Pathway enrichment analysis suggested that IRDGs was mainly enriched in the pathway of "cytokines and cytokine receptors". The entire data of ccRCC were randomly divided into the training set and the test set with a ratio of 1:1. A 4-gene signature was then constructed using LASSO Cox analysis and multivariate Cox analysis in the training set. This prognostic signature could stratify patients into high- and low-risk groups successfully, and serve as an independent predictor when adjusted with clinical factors by univariate and multivariate Cox regression analysis. These results were verified in the test set and the entire set. Besides, the abundance of CD4 + T cells and dendritic cells increased in the high-risk group. Finally, we built a nomogram incorporating risk score and clinical factors to predict the overall survival of ccRCC patients.

Conclusions: These findings may contribute to the research of ccRCC in immunization part.
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http://dx.doi.org/10.1016/j.intimp.2020.107119DOI Listing
January 2021

Prognostic Significance of a Novel Score Model Based on Preoperative Indicators in Patients with Breast Cancer Spine Metastases (BCSM).

Cancer Manag Res 2020 10;12:11501-11513. Epub 2020 Nov 10.

Spine Tumor Center, Department of Orthopedic Oncology, Changzheng Hospital, Navy Medical University, Shanghai, People's Republic of China.

Background: Surgery remains the mainstay of treatment for breast cancer spinal metastasis (BCSM) to relieve symptoms and improve the quality of life of BCSM patients. Therefore, it is important to effectively predict the prognosis of patients to determine whether they can undergo surgical operation. However, the prevalent methods for prognosis evaluation lack specificity and sensitivity for indicated malignancies like breast cancer because they are built on a relatively small number of heterogeneous types of primary tumors. The aim of the present study was to explore a novel predictive model based on the clinical, pathological and blood parameters obtained from BCSM patients before they received surgical intervention.

Methods: Altogether, 144 patients were included in this study. Univariate and multivariate analyses were performed to investigate the significance of preoperative parameters and identify independent factors for prognostic prediction of BCSM. A nomogram for survival prediction was then established and validated. Time-dependent ROC (TDROC) curves were graphed to evaluate the accuracy of the novel model vs other scoring systems including Tomita Score, revised Tokuhashi Score, modified Bauer Score and New England Spinal Metastasis Score. values <0.05 were considered statistically significant.

Results: Independent factors, including preoperative postmenopausal (=0.034), visceral metastasIs (=0.021), preoperative Frankel Score (=0.001), estrogen receptor status (=0.014), platelet-to-lymphocyte ratio (=0.012), lymphocyte-monocyte ratio (<0.001) and albumin-globulin ratio (=0.017), were selected into the nomogram model with the C-index of 0.834 (95% CI, 0.789-0.890). TDROC curves showed that the Changzheng Hospital (CZ) Score system had the best performance and exhibited the largest IAUC value in comparison with the other scoring systems.

Conclusion: We constructed a nomogram model known as CZ Score based on the significant factors to predict the prognosis for BCSM patients. The result showed that CZ Score had a better value for prognostic evaluation and surgical decision-making as compared with the other scoring systems.
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http://dx.doi.org/10.2147/CMAR.S273785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667004PMC
November 2020

Tectorigenin Alleviates Inflammation, Apoptosis, and Ossification in Rat Tendon-Derived Stem Cells Modulating NF-Kappa B and MAPK Pathways.

Front Cell Dev Biol 2020 22;8:568894. Epub 2020 Oct 22.

Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Tendinopathy is a common musculoskeletal disorder that mainly affects athletes and people of older age. Tumor necrosis factor-α (TNF-α) plays an important role in initiating tendinopathy. Tectorigenin, an extract component of , possesses anti-inflammatory and anti-apoptosis activity. The present study was established to investigate the role of tectorigenin against the pathogenetic effects of TNF-α on tendon-derived stem cells (TDSCs) and . The findings indicated that TNF-α is able to induce TDSC inflammation, apoptosis, and ossification, as well as activate nuclear factor-kappa B and mitogen-activated protein kinase (MAPK). Furthermore, the results confirmed that tectorigenin is able to inhibit the TNF-α-induced inflammation, apoptosis, and ossification. Tectorigenin treatment decreases activation of NF-kappa B and MAPK signaling in TDSCs. Tectorigenin ameliorates tendinopathy in the rat model. Thus, these data reveal that tectorigenin can serve as a potential treatment for tendinopathy.
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http://dx.doi.org/10.3389/fcell.2020.568894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642480PMC
October 2020

The HDL from septic-ARDS patients with composition changes exacerbates pulmonary endothelial dysfunction and acute lung injury induced by cecal ligation and puncture (CLP) in mice.

Respir Res 2020 Nov 4;21(1):293. Epub 2020 Nov 4.

Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, No. 5 Jingyuan road, Beijing Chaoyang Hospital Jingxi Branch, Beijing, China.

Background: Septic-acute respiratory distress syndrome (ARDS), characterized by the acute lung injury (ALI) secondary to aberrant systemic inflammatory response, has high morbidity and mortality. Despite increased understanding of ALI pathogenesis, the therapies to prevent lung dysfunction underlying systemic inflammatory disorder remain elusive. The high density lipoprotein (HDL) has critical protective effects in sepsis and its dysfunction has a manifested contribution to septic organ failure. However, the adverse changes in HDL composition and function in septic-ARDS patients are large unknown.

Methods: To investigate HDL remodeling in septic-ARDS, we analyzed the changes of HDL composition from 40 patients with septic-ARDS (A-HDL) and 40 matched normal controls (N-HDL). To determine the deleterious functional remodeling of HDL, A-HDL or N-HDL was administrated to C57BL/6 and apoA-I knock-out (KO) mice after cecal ligation and puncture (CLP) procedure. Mouse lung microvascular endothelial cells (MLECs) were further treated by these HDLs to investigate whether the adverse effects of A-HDL were associated with endothelial dysfunction.

Results: Septic-ARDS patients showed significant changes of HDL composition, accompanied with significantly decreased HDL-C. We further indicated that A-HDL treatment aggravated CLP induced ALI. Intriguingly, these deleterious effects of A-HDL were associated with pulmonary endothelial dysfunction, rather than the increased plasma lipopolysaccharide (LPS). Further in vitro results demonstrated the direct effects of A-HDL on MLECs, including increased endothelial permeability, enhanced expressions of adhesion proteins and pro-inflammatory cytokines via activating NF-κB signaling and decreased junction protein expression.

Conclusions: Our results depicted the remodeling of HDL composition in sepsis, which predisposes lung to ARDS via inducing ECs dysfunction. These results also demonstrated the importance of circulating HDL in regulating alveolar homeostasis.
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http://dx.doi.org/10.1186/s12931-020-01553-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640393PMC
November 2020

Sorption mechanisms of lead on soil-derived black carbon formed under varying cultivation systems.

Chemosphere 2020 Dec 3;261:128220. Epub 2020 Sep 3.

College of Tropical Crops, Hainan University, Haikou, 570228, China. Electronic address:

The knowledge about lead (Pb) sorption on soil-derived black carbons (SBCs) under different cultivation intensities of soils is limited. In this study, chemical and spectroscopic methods were applied to investigate the Pb sorption mechanisms on SBCs in soils from a forest land, a rubber plantation area, and a vegetable farm with none, less and highly intensive cultivation, respectively, that are located in the Hainan Island of China. Results showed that the specific surface area and cation exchange capacity of the SBCs from the less and highly intensive cultivation soils were 4.5- and 2.7-fold, and 1.3- and 1.8-fold higher compared to that of SBC from the no-cultivation soil, which subsequently enhanced the Pb sorption capacities of SBCs in iron exchange fraction. Ion exchange and hydrogen bonded Pb fractions together accounted for about 80% of total Pb sorbed on all SBCs at an externally added 1000 mg L Pb solution concentration. The OC-O groups also played key roles in Pb sorption by forming complexes of OC-O-Pb-O and/or OC-O-Pb. Overall, SBCs in soils under all studied cultivation intensities showed high potential to sorb Pb (with the maximum absorbed Pb amount of 46.0-91.3 mg g), and increased Pb sorption capacities of the studied soils by 18.7-21.1 mg kg in the stable fraction (complexation). Therefore, SBC might be a potential environment-friendly material to enhance the Pb immobilization capacity of soil.
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http://dx.doi.org/10.1016/j.chemosphere.2020.128220DOI Listing
December 2020

Author Correction: The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells.

Nat Commun 2020 Sep 23;11(1):4888. Epub 2020 Sep 23.

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-18767-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511305PMC
September 2020

NAT1 promotes osteolytic metastasis in luminal breast cancer by regulating the bone metastatic niche via NF-κB/IL-1B signaling pathway.

Am J Cancer Res 2020 1;10(8):2464-2479. Epub 2020 Aug 1.

Spine Tumor Center, Department of Orthopedic Oncology, Changzheng Hospital, Navy Medical University (Second Military Medical University) Shanghai, China.

Breast cancer is a molecularly heterogeneous disease that can be subdivided into different subtypes. Compared with the other subtypes, luminal breast cancer (LBC) is considered more susceptible to bone metastasis. However, the intrinsic mechanisms remain elusive. Bioinformatics analysis of the preset study showed that N-acetyltransferase 1 (NAT1) was specifically expressed in LBC and closely correlated with bone metastasis. In addition, NAT1 could promote LBC cell migration and clonal formation, induce osteoclast differentiation and raise the Rankl/Opg ratio in osteoblasts. Our in vivo experiment demonstrated that NAT1 promoted LBC bone metastasis and bone destruction, which could be reversed by NAT1 inhibitor treatment. The result of cytokine array showed that NAT1 could significantly over activate the NF-κB signaling pathway and up-regulate the expression of IL-1B, which further worked as downstream factors in these processes. All these results demonstrated NAT1 was up-regulated in LBC and promoted the formation of bone metastatic niche and osteolytic bone metastasis through the NAT1/NF-κB/IL-1B axis. This finding may provide a new pathway to help understand the mechanisms of LBC bone metastasis and suggest a novel therapeutic and diagnostic target for its treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471372PMC
August 2020

Apatinib in patients with advanced chordoma: a single-arm, single-centre, phase 2 study.

Lancet Oncol 2020 09;21(9):1244-1252

Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China. Electronic address:

Background: No standard treatment exists for advanced chordoma. Apatinib has been found to have promising efficacy and manageable adverse effects for the treatment of solid tumours. We aimed to investigate the safety and antitumour activity of apatinib in patients with advanced chordoma.

Methods: We did a single-arm, phase 2 study at one tertiary hospital in Shanghai, China. Eligible patients were aged 18-75 years, with histologically confirmed advanced chordoma that was unresectable or resectable only through demolitive surgery, who had previously received surgical treatment, with at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, evidence of tumour progression on enhanced CT or MRI in the previous 6 months, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients received oral 500 mg apatinib once daily until disease progression or unacceptable toxicity. The co-primary endpoints were progression-free survival and objective response rate according to RECIST 1.1 and Choi criteria by investigator assessment. Progression-free survival was assessed in the intention-to-treat population. Objective response rate was assessed in the per-protocol population, which included all enrolled patients who were compliant with the protocol and had at least one post-baseline assessment. Safety was analysed in all patients with complete safety data. This study is ongoing, but recruitment is complete. This study is registered with Chictr.org.cn, ChiCTR-OIC-17013586.

Findings: Between Aug 21, 2017, and May 31, 2019, we screened 32 patients, of whom 30 were enrolled. Median follow-up was 14·2 months (IQR 9·4-19·7). Of the 27 patients included in the per-protocol population, one patient (3·7%; 95% CI 0-11·3) achieved an objective response according to RECIST, and seven patients (25·9%; 8·3-43·6) achieved an objective response according to Choi criteria. Median progression-free survival was 18 months (95% CI 3-34) according to RECIST and 18 months (3-33) according to Choi criteria. The most common treatment-related grade 3 adverse events were hypertension (seven [24%] of 29 patients) and proteinuria (two [7%]). No treatment-related grade 4 adverse events or treatment-related deaths were observed.

Interpretation: To our knowledge, this is the first trial of apatinib for the treatment of advanced chordoma. Apatinib shows promising activity and manageable toxicity and thus might be an option for the treatment of advanced chordoma.

Funding: None.
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http://dx.doi.org/10.1016/S1470-2045(20)30466-6DOI Listing
September 2020

A prognostic signature based on immune-related genes for cervical squamous cell carcinoma and endocervical adenocarcinoma.

Int Immunopharmacol 2020 Nov 11;88:106884. Epub 2020 Aug 11.

Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China. Electronic address:

Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) is the fourth commonest female malignancy worldwide. CESC progresses in immune-microenvironment mainly composed of infiltrating immune and stromal cells. Here, we performed an integrated analysis incorporating the expression profiles from the Cancer Genome Atlas (TCGA) database and scores of immune and stromal cells calculated by Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm. A two-gene signature (CD1C and CD6 genes) was established to predict the prognosis of CESC. Based on this signature, patients were divided into the high- and low-risk groups, and this signature showed good prognostic performance according to the results of Kaplan-Meier analysis and receiver operating characteristic (ROC) analysis in train set and two validation sets. A nomogram was built for evaluating the clinical applicability of this signature. In addition, based on Tumor Immune Estimation Resource (TIMER) database, 2 hub genes showed negative correlations with tumor purity and positive correlations with infiltrating levels of immune filtrating cells. What's more, we propose new treatment strategies for the two prognostic subtypes. Low- risk patients were found presenting with a higher level of immune checkpoint molecules and showing higher immunogenicity in immunophenoscore (IPS) analysis, which indicated a better response for immunotherapy. Meanwhile, estimated by Genomics of Drug Sensitivity in Cancer (GDSC) database, the high-risk patients showed sensitive responses to five chemotherapy drugs. Finally, 10 candidate small-molecule drugs for CESC were defined. In summary, the CD1C-CD6 signature can accurately predict the prognosis of CESC.
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http://dx.doi.org/10.1016/j.intimp.2020.106884DOI Listing
November 2020

Using mRNAsi to identify prognostic-related genes in endometrial carcinoma based on WGCNA.

Life Sci 2020 Oct 10;258:118231. Epub 2020 Aug 10.

Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China. Electronic address:

Aims: Cancer Stem Cells (CSCs) refers to heterogeneous tumor cells retaining the abilities of self-renewal and differentiation. This study used mRNAsi, which is an index to describe the similarity between tumor cells and CSCs, to define genes involved in endometrial carcinoma.

Materials And Methods: The mRNA expression profiles of 552 tumor samples and 23 non-tumor samples were calculated for differentially expressed genes. WGCNA was utilized to construct gene co-expression networks and classify screened genes into different modules. Univariate and multivariate Cox regression models were performed to identify and construct the prognostic model. Time-dependent receiver operating characteristic (ROC), Kaplan-Meier curve, multivariate Cox regression analysis, and nomogram were used to assess the prognostic capacity of the six-gene signature. The screened genes were further validated by GEO (GSE17025) and qRT-PCR in EC tissues.

Key Findings: 2573 upregulated and 1890 downregulated genes were identified. A total of 35 genes in the turquoise module were identified as key genes. With multivariate analysis, six genes (DEPDC1, FAM83D, NCAPH, SPC25, TPX2, and TTK) up-regulated in endometrial carcinoma were identified, and their higher expression was associated with a higher stage/age/grade. Moreover, ROC and Kaplan-Meier plots indicated these genes had a high prognostic value for EC. A nomogram was constructed for clinical use. In addition, we explored the pathogenesis involving six genes. The results showed that these genes may become pathogenic as their copy numbers changes and methylation level reduces. Finally, GSEA revealed these genes had a close association with cell cycle, etc. SIGNIFICANCE: These findings may provide new insights into the treatment of diseases.
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http://dx.doi.org/10.1016/j.lfs.2020.118231DOI Listing
October 2020

The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells.

Nat Commun 2020 08 6;11(1):3904. Epub 2020 Aug 6.

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, 200241, Shanghai, China.

A major challenge in chemotherapy is chemotherapy resistance in cells lacking p53. Here we demonstrate that NIP30, an inhibitor of the oncogenic REGγ-proteasome, attenuates cancer cell growth and sensitizes p53-compromised cells to chemotherapeutic agents. NIP30 acts by binding to REGγ via an evolutionarily-conserved serine-rich domain with 4-serine phosphorylation. We find the cyclin-dependent phosphatase CDC25A is a key regulator for NIP30 phosphorylation and modulation of REGγ activity during the cell cycle or after DNA damage. We validate CDC25A-NIP30-REGγ mediated regulation of the REGγ target protein p21 in vivo using p53-/- and p53/REGγ double-deficient mice. Moreover, Phosphor-NIP30 mimetics significantly increase the growth inhibitory effect of chemotherapeutic agents in vitro and in vivo. Given that NIP30 is frequently mutated in the TCGA cancer database, our results provide insight into the regulatory pathway controlling the REGγ-proteasome in carcinogenesis and offer a novel approach to drug-resistant cancer therapy.
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http://dx.doi.org/10.1038/s41467-020-17667-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413384PMC
August 2020

Surface-Mediated Interconnections of Nanoparticles in Cellulosic Fibrous Materials toward 3D Sensors.

Adv Mater 2020 Sep 23;32(36):e2002171. Epub 2020 Jul 23.

Department of Chemistry, and System Science and Industrial Engineering State University of New York at Binghamton, Binghamton, NY, 13902, USA.

Fibrous materials serve as an intriguing class of 3D materials to meet the growing demands for flexible, foldable, biocompatible, biodegradable, disposable, inexpensive, and wearable sensors and the rising desires for higher sensitivity, greater miniaturization, lower cost, and better wearability. The use of such materials for the creation of a fibrous sensor substrate that interfaces with a sensing film in 3D with the transducing electronics is however difficult by conventional photolithographic methods. Here, a highly effective pathway featuring surface-mediated interconnection (SMI) of metal nanoclusters (NCs) and nanoparticles (NPs) in fibrous materials at ambient conditions is demonstrated for fabricating fibrous sensor substrates or platforms. Bimodally distributed gold-copper alloy NCs and NPs are used as a model system to demonstrate the semiconductive-to-metallic conductivity transition, quantized capacitive charging, and anisotropic conductivity characteristics. Upon coupling SMI of NCs/NPs as electrically conductive microelectrodes and surface-mediated assembly (SMA) of the NCs/NPs as chemically sensitive interfaces, the resulting fibrous chemiresistors function as sensitive and selective sensors for gaseous and vaporous analytes. This new SMI-SMA strategy has significant implications for manufacturing high-performance fibrous platforms to meet the growing demands of the advanced multifunctional sensors and biosensors.
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http://dx.doi.org/10.1002/adma.202002171DOI Listing
September 2020

Establishment of a novel cell cycle-related prognostic signature predicting prognosis in patients with endometrial cancer.

Cancer Cell Int 2020 20;20:329. Epub 2020 Jul 20.

Department of Gynecology and Obstetrics, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, No. 48, Huaishu Road, Wuxi, 214000 Jiangsu China.

Background: Endometrial cancer (EnCa) ranks fourth in menace within women's malignant tumors. Large numbers of studies have proven that functional genes can change the process of tumors by regulating the cell cycle, thereby achieving the goal of targeted therapy.

Methods: The transcriptional data of EnCa samples obtained from the TCGA database was analyzed. A battery of bioinformatics strategies, which included GSEA, Cox and LASSO regression analysis, establishment of a prognostic signature and a nomogram for overall survival (OS) assessment. The GEPIA and CPTAC analysis were applied to validate the dysregulation of hub genes. For mutation analysis, the "maftools" package was used.

Results: GSEA identified that cell cycle was the most associated pathway to EnCa. Five cell cycle-related genes including HMGB3, EZH2, NOTCH2, UCK2 and ODF2 were identified as prognosis-related genes to build a prognostic signature. Based on this model, the EnCa patients could be divided into low- and high-risk groups, and patients with high-risk score exhibited poorer OS. Time-dependent ROC and Cox regression analyses revealed that the 5-gene signature could predict EnCa prognosis exactly and independently. GEPIA and CPTAC validation exhibited that these genes were notably dysregulated between EnCa and normal tissues. Lower mutation rates of PTEN, TTN, ARID1A, and etc. were found in samples with high-risk score compared with that with low-risk score. GSEA analysis suggested that the samples of the low- and high-risk groups were concentrated on various pathways, which accounted for the different oncogenic mechanisms in patients in two groups.

Conclusion: The current research construct a 5-gene signature to evaluate prognosis of EnCa patients, which may innovative clinical application of prognostic assessment.
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http://dx.doi.org/10.1186/s12935-020-01428-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372883PMC
July 2020

Lead and copper-induced hormetic effect and toxicity mechanisms in lettuce (Lactuca sativa L.) grown in a contaminated soil.

Sci Total Environ 2020 Nov 23;741:140440. Epub 2020 Jun 23.

College of Tropical Crops, Hainan University, Haikou, Hainan 570228, China. Electronic address:

Lead (Pb) and copper (Cu) contamination seriously threatens agricultural production and food safety. This study aims to investigate Pb and Cu induced hormetic effect and toxicity mechanisms in lettuce (Lactuca sativa L.) and establish reliable empirical models of potentially toxic elements (PTEs) transfer in the soil-plant system. The content and distribution of Pb and Cu at subcellular levels in lettuce plants were examined using inductively coupled plasma-mass spectrometry, differential centrifugation and micro-X-ray fluorescence spectroscopy. The PTE-loaded capacity of Pb that ensures food safety was lower than that of Cu in the studied soil, but the PTE-loaded capacity of Pb that limits yield was higher than that of Cu. Lead in lettuce roots mainly accumulated in the cell wall (41%), while Cu mainly accumulated in the vacuoles (46%). The Pb and Cu were primarily distributed in the radicle of lettuce seeds under severe PTE stress, resulting in no seed development. Iron plaque formed on the root surface of lettuce seedlings and sequestered Pb and Cu via chelation. At the same concentration, lettuce was less tolerant to Cu in contaminated soil than Pb due to the higher activity of Cu ions in the soil. Lead was more phytotoxic to lettuce than Cu, however, since the radicle emerged from the seed under severe Cu levels, while it did not protrude under severe Pb levels. The potentially damaging effect of Pb in the visually healthy lettuce appeared to be higher than that of Cu under the same soil contamination level.
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http://dx.doi.org/10.1016/j.scitotenv.2020.140440DOI Listing
November 2020

Exploration of a novel prognostic risk signatures and immune checkpoint molecules in endometrial carcinoma microenvironment.

Genomics 2020 09 29;112(5):3117-3134. Epub 2020 May 29.

Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China. Electronic address:

In this study, we devoted to investigate immune-related genes and tumor microenvironment (TME) in EC based on The Cancer Genome Atlas (TCGA) database. In total 799 up-regulated and 139 down-regulated immune-related and differentially expressed genes in EC were investigated for functional annotations and prognosis. By a conjoint Cox regression analysis, we built two risk models for OS and DFS, as well as the consistent nomograms. Immune-related pathways were revealed mostly enriched in the low-risk group. By further analyzing TME based on the risk signatures, the higher immune cell infiltration and activation, lower tumor purity and higher tumor mutational burden were found in low-risk group, which presented a better prognosis. Both the expression and immunophenoscore of immune checkpoints PD-1, CTLA4, PD-L1 and PD-L2 increased significantly in low-risk group. These findings may provide new ideas for novel biomarkers and immunotherapy targets in EC.
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http://dx.doi.org/10.1016/j.ygeno.2020.05.022DOI Listing
September 2020

The role of SIRT3-mediated mitochondrial homeostasis in osteoarthritis.

Cell Mol Life Sci 2020 Oct 28;77(19):3729-3743. Epub 2020 May 28.

Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Osteoarthritis is the most common degenerative joint disease and causes major pain and disability in adults. It has been reported that mitochondrial dysfunction in chondrocytes is associated with osteoarthritis. Sirtuins are a family of nicotinamide adenine dinucleotide-dependent histone deacetylases that have the ability to deacetylate protein targets and play an important role in the regulation of cell physiological and pathological processes. Among sirtuin family members, sirtuin 3, which is mainly located in mitochondria, can exert its deacetylation activity to regulate mitochondrial function, regeneration, and dynamics; these processes are presently recognized to maintain redox homeostasis to prevent oxidative stress in cell metabolism. In this review, we provide present opinions on the effect of mitochondrial dysfunction in osteoarthritis. Furthermore, the potential protective mechanism of SIRT3-mediated mitochondrial homeostasis in the progression of osteoarthritis is discussed.
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http://dx.doi.org/10.1007/s00018-020-03497-9DOI Listing
October 2020

Reactivation of NR4A1 Restrains Chondrocyte Inflammation and Ameliorates Osteoarthritis in Rats.

Front Cell Dev Biol 2020 17;8:158. Epub 2020 Mar 17.

Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Osteoarthritis (OA) is the most prevalent joint disease and uncontrolled inflammation is now recognized to play vital roles in OA development. Targeting the endogenous counterpart of inflammation may develop new therapeutic approaches in resolving inflammation persistence and treating inflammatory disease including OA. The orphan nuclear receptor 4A1 (NR4A1) is a key negative regulator of inflammatory responses but its role in osteoarthritis remains unclear. In the present study, we found that the NR4A1 expression was elevated in human osteoarthritis cartilage and OA model, which could be blocked by NF-κB signal inhibitor JSH23. The overexpression of NR4A1 inhibited, whereas knockdown of NR4A1 enhanced IL-1β induced COX-2, iNOS, MMP3, MMP9 and MMP13 expression, and luciferase reporter activity of NF-κB response element. Though NR4A1 was upregulated in inflammatory stimulation and creates a negative feedback loop, persistent inflammatory stimulation inhibited NR4A1 expression and activation. The expression of NR4A1 declined rapidly after an initial peak in conditions of chronic IL-1β stimulation, which could be partially restored by HDACs inhibitor SAHA. The phosphorylation of NR4A1 was increased in human osteoarthritis cartilage, and p38 inhibitor SB203580, JNK inhibitor SP600125 and ERK inhibitor FR180204 could significantly inhibited IL-1β induced NR4A1 phosphorylation. Reactivation of NR4A1 by its agonist cytosporone B could inhibit IL-1β induced chondrocyte inflammation and expression of COX-2, iNOS, MMP3, MMP9, and MMP13. In rat OA model, intra-articular injection of cytosporone B protected cartilage damage and ameliorated osteoarthritis. Thus, our study demonstrated that the NR4A1 is a key endogenous inhibitor of chondrocyte inflammation, which was relatively inactivated under chronic inflammatory stimulation through HDACs mediated transcriptional suppression and MAKP dependent phosphorylation in osteoarthritis. NR4A1 agonist cytosporone B could reactivate and restore the inhibitory regulatory ability of NR4A1, prevent excessive inflammation, and ameliorates osteoarthritis.
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http://dx.doi.org/10.3389/fcell.2020.00158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090231PMC
March 2020

A Novel Prognostic Index Based on Alternative Splicing in Papillary Renal Cell Carcinoma.

Front Genet 2019 29;10:1333. Epub 2020 Jan 29.

Department of Urology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.

Background: Papillary renal cell carcinoma (pRCC) is a heterogeneous multifocal or isolated tumor with an invasive phenotype. Previous studies presented that alternative splicing, as a crucial posttranscriptional regulator in gene expression, is associated with tumorigenesis. However, the association between alternative splicing and pRCC has not been clarified.

Methods: The RNA sequencing data and clinical information were downloaded from The Cancer Genome Atlas database and mRNA splicing profiles from TCGASpliceSeq. The percent spliced in data of alternative splicing merged with survival information was firstly calculated by univariate Cox regression analysis to screen for survival-associated alternative splicing events, and survival-associated alternative splicing events were then analyzed by Gene Ontology categories using Kyoto Encyclopedia of Genes and Genomes. Meanwhile, the least absolute shrinkage and selection operator Cox analysis and multivariate Cox analysis were performed to calculate the prognostic index for each alternative splicing type. In addition, clinical factors were introduced to assess the performance of prognostic index.

Results: A total of 4,084 candidate survival-associated alternative splicing events in 2,558 genes were screened out. Patients were divided into the low-risk group and the high-risk group based on the median prognostic index value. The Kaplan-Meier survival analysis (p < 0.05) and receiver operating characteristics curves (AUC>0.9) indicated that prognostic index was effective and stable for predicting the prognosis of pRCC patients. Furthermore, a regulatory network was constructed incorporating alternative splicing events and survival-associated splicing factors.

Conclusion: Our study provides new insights into the mechanism of alternative splicing events in tumorigenesis and their clinical potential for pRCC.
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http://dx.doi.org/10.3389/fgene.2019.01333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999693PMC
January 2020