Publications by authors named "Jichen Yang"

20 Publications

  • Page 1 of 1

miR-30a-5p suppresses lung squamous cell carcinoma via ATG5 - mediated autophagy.

Aging (Albany NY) 2021 07 12;13(13):17462-17472. Epub 2021 Jul 12.

Department of Thoracic Surgery, Lung Cancer Research Center, Yunnan Institute of Oncology, the Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming Yunnan 650118, PR China.

Propose: Autophagy plays a complicated role in cancer progression. This study aims at assessing the function of ATG5-induced autophagy in progression of lung squamous cell carcinoma and its upstream mechanism.

Method: TCGA database of lung squamous cell carcinoma was analyzed to explore the differentially expressed miRNAs and mRNAs and relative prognosis. RT-PCR and Western blot were performed to evaluate autophagy relative gene expression level in human lung squamous cell carcinoma cell Lines. Autophagy flux was observed using transmission electron microscopy and immunofluorescence. Meanwhile, binding relationship of potential target miRNA and mRNAs were also confirmed using Dual-luciferase reporter gene assay. Lung metastatic model was established to evaluated the effect of targeting protein and miRNA.

Result: High level expression of ATG5 was detected in LUSC patients. Relative experiments confirmed that ATG5 silencing could decrease the autophagy flux in LUSC. In addition, our research revealed that there is a binding sites between hsa-mir-30a-5p and 3'-UTR of ATG5. Mimic miR-30a-5p suppresses ATG5-mediated autophagy in lung squamous cell carcinoma cells. The experiments confirmed that miR-30a-5p could attenuate lung squamous cell carcinoma progression through the autophagy pathway.

Conclusion: Accordingly, the and study in our research have demonstrated that miR-30a-5p inhibits lung squamous cell carcinoma progression via ATG5-mediated autophagy.
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http://dx.doi.org/10.18632/aging.203235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312466PMC
July 2021

Ang II Promotes Cardiac Autophagy and Hypertrophy via Orai1/STIM1.

Front Pharmacol 2021 17;12:622774. Epub 2021 May 17.

School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, China.

The pathophysiology of cardiac hypertrophy is complex and multifactorial. Both the store-operated Ca entry (SOCE) and excessive autophagy are the major causative factors for pathological cardiac hypertrophy. However, it is unclear whether these two causative factors are interdependent. In this study, we examined the functional role of SOCE and Orai1 in angiotensin II (Ang II)-induced autophagy and hypertrophy using neonatal rat cardiomyocytes (NRCMs) and mouse model, respectively. We show that YM-58483 or SKF-96365 mediated pharmacological inhibition of SOCE, or silencing of Orai1 with Orail-siRNA inhibited Ang II-induced cardiomyocyte autophagy both and . Also, the knockdown of Orai1 attenuated Ang II-induced pathological cardiac hypertrophy. Together, these data suggest that Ang II promotes excessive cardiomyocyte autophagy through SOCE/Orai1 which can be the prime contributing factors in cardiac hypertrophy.
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http://dx.doi.org/10.3389/fphar.2021.622774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165566PMC
May 2021

Deep learning-based algorithm for assessment of knee osteoarthritis severity in radiographs matches performance of radiologists.

Comput Biol Med 2021 06 23;133:104334. Epub 2021 Mar 23.

Department of Electrical and Computer Engineering, Duke University, Durham, USA; Department of Radiology, Duke University, Durham, USA.

A fully-automated deep learning algorithm matched performance of radiologists in assessment of knee osteoarthritis severity in radiographs using the Kellgren-Lawrence grading system.

Purpose: To develop an automated deep learning-based algorithm that jointly uses Posterior-Anterior (PA) and Lateral (LAT) views of knee radiographs to assess knee osteoarthritis severity according to the Kellgren-Lawrence grading system.

Materials And Methods: We used a dataset of 9739 exams from 2802 patients from Multicenter Osteoarthritis Study (MOST). The dataset was divided into a training set of 2040 patients, a validation set of 259 patients and a test set of 503 patients. A novel deep learning-based method was utilized for assessment of knee OA in two steps: (1) localization of knee joints in the images, (2) classification according to the KL grading system. Our method used both PA and LAT views as the input to the model. The scores generated by the algorithm were compared to the grades provided in the MOST dataset for the entire test set as well as grades provided by 5 radiologists at our institution for a subset of the test set.

Results: The model obtained a multi-class accuracy of 71.90% on the entire test set when compared to the ratings provided in the MOST dataset. The quadratic weighted Kappa coefficient for this set was 0.9066. The average quadratic weighted Kappa between all pairs of radiologists from our institution who took part in the study was 0.748. The average quadratic-weighted Kappa between the algorithm and the radiologists at our institution was 0.769.

Conclusion: The proposed model performed demonstrated equivalency of KL classification to MSK radiologists, but clearly superior reproducibility. Our model also agreed with radiologists at our institution to the same extent as the radiologists with each other. The algorithm could be used to provide reproducible assessment of knee osteoarthritis severity.
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http://dx.doi.org/10.1016/j.compbiomed.2021.104334DOI Listing
June 2021

Protective effects of three structurally similar polyphenolic compounds against oxidative damage and their binding properties to human serum albumin.

Food Chem 2021 Jul 14;349:129118. Epub 2021 Jan 14.

School of Life Sciences, Tianjin University, Tianjin 300072, PR China; Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Tianjin University, Tianjin 300072, PR China. Electronic address:

Brazilin (Bra), hematoxylin (Hto) and hematein (Hte) are structurally similar polyphenols having rich biological activities, but their antioxidant ability has not been well studied. Here, their protective ability against human serum albumin (HSA) oxidative degradation were investigated using 2,2'-Azobis (2-methylpropionamidine) dihydrochloride (AAPH), NaClO and Fenton like reactions methods. The results indicated that polyphenols inhibited the oxidative injuries of HSA in the order: Hto > Bra > Hte. Additionally, the biological effects of polyphenols were mostly influenced by their binding to protein. Therefore, the structure-affinity relationships of polyphenols binding to HSA were also explored. Fluorescence experiments indicated that polyphenols bound to HSA through static quenching mechanism. Furthermore, some conformational changes of HSA could be observed in the presence of polyphenols. Altogether, molecular structure of polyphenols played a significant role in their protective effect against HSA oxidative damage and binding ability, which provided fundamental insights into their application as health care foods.
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http://dx.doi.org/10.1016/j.foodchem.2021.129118DOI Listing
July 2021

Comparative study of inhibition mechanisms of structurally different flavonoid compounds on α-glucosidase and synergistic effect with acarbose.

Food Chem 2021 Jun 9;347:129056. Epub 2021 Jan 9.

School of Life Sciences, Tianjin University, Tianjin 300072, PR China; Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Tianjin University, Tianjin 300072, PR China. Electronic address:

Flavonoid compounds have anti-diabetic activity, which can control blood glucose levels by inhibiting α-glucosidase activity. In this paper, the inhibition mechanisms between four flavonoid compounds and α-glucosidase were studied by multispectroscopic methods and molecular docking. The results showed that the inhibitory activities of flavonoid compounds were higher than that of acarbose, and the sequence of inhibition effect was scutellarein > nepetin > apigenin > hispidulin > acarbose. Also, the synergistic effects of flavonoid compounds combined with acarbose on inhibiting α-glucosidase activity were observed. The fluorescence results showed that flavonoid compounds combined with α-glucosidase to form a stable complex. And the spectral analysis indicated that the microenvironmental and secondary structure of α-glucosidase were changed. The present study demonstrated that the molecular structure of flavonoid compounds played an important role in the inhibition process, namely, scutellarein with more hydroxyl groups on the A-ring might serve as the most effective α-glucosidase inhibitor.
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http://dx.doi.org/10.1016/j.foodchem.2021.129056DOI Listing
June 2021

[Progress in Survival Prognosis of Segmentectomy for 
Early-stage Non-small Cell Lung Cancer].

Zhongguo Fei Ai Za Zhi 2020 Sep;23(9):830-836

Department of Thoracic Surgery, the Third Affiliated Hospital of Kunming Medical University, Kunming 650105, China.

Surgery is currently the most appropriate treatment for early-stage non-small cell lung cancer (NSCLC). Increasing unilateral or bilateral multiple primary lung cancer being found, segmentectomy has attracted wide attention for its unique advantages in the treatment for such tumors. Ground glass opacity dominant early-stage NSCLC is associated with a good prognosis and can be cured by segmentectomy, however, the treatment of solid-dominant NSCLC remains controversial owing to the invasive nature. With the in-depth study on the lymph node metastasis pathway, radiological characteristics and molecular biology of NSCLC, a large part of solid nodules with certain characteristics can also be cured by segmentectomy. This paper reviews the research status and progress about the indication of segmentectomy.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2020.102.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519961PMC
September 2020

Both the presence of a micropapillary component and the micropapillary predominant subtype predict poor prognosis after lung adenocarcinoma resection: a meta-analysis.

J Cardiothorac Surg 2020 Jun 29;15(1):154. Epub 2020 Jun 29.

Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, No. 519 Kunzhou Road, Xishan District, Kunming City, Yunnan Province, China.

Objective: It has been confirmed that the micropapillary (MP) pattern is a poor prognostic factor after resection of lung adenocarcinoma (ADC), but the proportion of the MP component as a prognostic criterion is still controversial. Hence, a meta-analysis was performed to evaluate whether the presence of an MP component has equal prognostic power as the MP predominant subtype.

Methods: Literature retrieval was performed in the MEDLINE, EMBASE, and Cochrane databases until December 23, 2019. Eligible studies were selected based on the inclusion and exclusion criteria. The included studies were divided into two subgroups, the MP component subgroup and the MP predominant subgroup, according to the proportion of the MP pattern to analyse the effect of this pattern on disease-free survival (DFS) and overall survival (OS). The hazard ratio (HR) and 95% confidence interval (CI) were extracted from each study. Review Manager 5.3 was used for statistical analyses.

Results: Finally, 10 studies, including a total of 4934 lung ADC patients, were included in this meta-analysis. Our results indicated a significantly worse pooled DFS (HR 1.62, 95% CI 1.20-2.21) and OS (HR 1.53, 95% CI 1.19-1.96) in the subgroup of MP predominant subtype patients. The pooled DFS (HR 1.80, 95% CI 1.45-2.85) and OS (HR 2.26, 95% CI 1.46-3.52) were also poor in the subgroup of patients with the presence of an MP component.

Conclusions: Both the presence of an MP component and the MP predominant subtype are related to poor DFS and OS after lung ADC resection and represent adverse prognostic factor for lung ADC patients. However, there are some limitations in this meta-analysis, and quantitative stratification based on the proportion of the MP component is needed to explore its effect on prognosis of lung ADC patients in the future.
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http://dx.doi.org/10.1186/s13019-020-01199-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325156PMC
June 2020

Two-Way: A Novel Method for Identifying the Anatomy During Uniportal Thoracoscopic Segmentectomy.

Ann Thorac Surg 2020 11 31;110(5):e441-e443. Epub 2020 May 31.

Department of Thoracic Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, China.

Because the segmental bronchi and vessels are commonly variable and complicated, it is difficult to correctly identify them. Misidentification of the segmental anatomy could result in the failure of segmentectomy and conversion to other surgical procedures such as bisegmentectomy or lobectomy. We describe a novel method to identify the target segmental vessels and bronchi by exposing the adjacent segmental anatomy during uniportal video-assisted thoracoscopic segmentectomy, which could help to reduce the chance of misidentification.
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http://dx.doi.org/10.1016/j.athoracsur.2020.04.041DOI Listing
November 2020

Meta-analysis of segmentectomy versus lobectomy for radiologically pure solid or solid-dominant stage IA non-small cell lung cancer.

J Cardiothorac Surg 2019 Nov 13;14(1):197. Epub 2019 Nov 13.

Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, China.

Objective: Whether segmentectomy can be used to treat radiologically determined pure solid or solid-dominant lung cancer remains controversial owing to the invasive pathologic characteristics of these tumors despite their small size. This meta-analysis compared the oncologic outcomes after lobectomy and segmentectomy regarding relapse-free survival (RFS) and overall survival (OS) in patients with radiologically determined pure solid or solid-dominant clinical stage IA non-small cell lung cancer (NSCLC).

Methods: A literature search was performed in the MEDLINE, EMBASE, and Cochrane Central databases for information from the date of database inception to March 2019. Studies were selected according to predefined eligibility criteria. The hazard ratio (HR) and associated 95% confidence interval (CI) were extracted or calculated as the outcome measure for data combining.

Results: Seven eligible studies published between 2014 and 2018 enrolling 1428 patients were included in the current meta-analysis. Compared with lobectomy, segmentectomy had a significant benefit on the RFS of radiologically determined pure solid or solid-dominant clinical stage IA NSCLC patients (combined HR: 1.46; 95% CI, 1.05-2.03; P = 0.024) and there were no significant differences on the OS of these patients (HR: 1.52; 95% CI, 0.95-2.43; P = 0.08).

Conclusions: Segmentectomy leads to lower survival than lobectomy for clinical stage IA NSCLC patients with radiologically determined pure solid or solid-dominant tumors. Moreover, applying lobectomy to clinical stage IA NSCLC patients with radiologically determined pure solid or solid-dominant tumors (≤2 cm) could lead to an even bigger survival advantage. However, there are some limitations in the present study, and more evidence is needed to support the conclusion.
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http://dx.doi.org/10.1186/s13019-019-0996-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854787PMC
November 2019

[The inhibition of accessory gene regulator C specific binding peptides on biofilm formation of on the surface of polyvinyl chloride ].

Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2019 Mar;33(3):349-355

Department of Thoracic Surgery, the Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming Yunnan, 650118,

Objective: To investigate the effect of accessory gene regulator C (agr C) specific binding peptides (named N1) on the biofilm formation of on the surface of polyvinyl chloride (PVC) materials .

Methods: Firstly, the two strains (ATCC35984, ATCC12228) were cultured with N1 at concentrations of 100, 200, 400, 800, and 1 600 μg/mL, respectively. The control group was cultured with agrC specific binding unrelated peptides (named N0) at the same concentrations and the absorbance ( ) value was measured after 24 hours to determine the optimal bacteriostatic concentration of N1. The two strains were cultured with N1 and N0 of the optimal concentration, respectively. The values were measured at 6, 12, 18, 24, 30, and 48 hours to observe the effect of N1 on the biofilm formation ability of . On this basis, the surface structure of the biofilm on the surface of PVC material was observed by scanning electron microscopy after 6, 12, 18, 24, and 30 hours of incubation with PVC material sheet. The thickness of the biofilm was observed by laser confocal microscopy after 6, 12, 18, and 24 hours of incubation with ATCC35984 strain.

Results: The optimal bacteriostatic concentration of N1 was 800 μg/mL. ATCC 12228 strain did not form obvious biofilm after being cultured with N1 and N0. When ATCC35984 strain was cultured with N1 and N0 for 12 hours, the difference in biofilm formation ability between groups N1 and N0 was statistically significant ( <0.05), but there was no significant difference at 6, 18, 24, 30, and 48 hours ( >0.05). Scanning electron microscopy examination showed that mature biofilm structure was observed in ATCC35984 strain and was not observed in ATCC12228 strain. Laser confocal microscopy observation showed that the number of bacteria in the group N1 was significantly lower than that in the group N0 at 12 hours, and the most of bacteria were dead bacteria. There was no significant difference in the number of bacteria at 6, 18, and 24 hours, and the most of them were live bacteria. The biofilm thickness of group N1 was significantly lower than that of group N0 at 12 and 18 hours ( <0.05).

Conclusion: The intensity of N1 inhibiting the formation of biofilm is dose-dependent. During the aggregation period, N1 can inhibit the biofilm formation by hindering the bacterial growth and aggregation. The inhibition effect on mature biofilm is not obvious.
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http://dx.doi.org/10.7507/1002-1892.201806110DOI Listing
March 2019

Prediction of human population responses to toxic compounds by a collaborative competition.

Nat Biotechnol 2015 Sep 10;33(9):933-40. Epub 2015 Aug 10.

Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina, USA.

The ability to computationally predict the effects of toxic compounds on humans could help address the deficiencies of current chemical safety testing. Here, we report the results from a community-based DREAM challenge to predict toxicities of environmental compounds with potential adverse health effects for human populations. We measured the cytotoxicity of 156 compounds in 884 lymphoblastoid cell lines for which genotype and transcriptional data are available as part of the Tox21 1000 Genomes Project. The challenge participants developed algorithms to predict interindividual variability of toxic response from genomic profiles and population-level cytotoxicity data from structural attributes of the compounds. 179 submitted predictions were evaluated against an experimental data set to which participants were blinded. Individual cytotoxicity predictions were better than random, with modest correlations (Pearson's r < 0.28), consistent with complex trait genomic prediction. In contrast, predictions of population-level response to different compounds were higher (r < 0.66). The results highlight the possibility of predicting health risks associated with unknown compounds, although risk estimation accuracy remains suboptimal.
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http://dx.doi.org/10.1038/nbt.3299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568441PMC
September 2015

A DNA shape-based regulatory score improves position-weight matrix-based recognition of transcription factor binding sites.

Bioinformatics 2015 Nov 30;31(21):3445-50. Epub 2015 Jun 30.

Department of Biomedical Sciences and School of Electrical Engineering and Computer Science, Oregon State University, Corvallis, OR, USA.

Motivation: The position-weight matrix (PWM) is a useful representation of a transcription factor binding site (TFBS) sequence pattern because the PWM can be estimated from a small number of representative TFBS sequences. However, because the PWM probability model assumes independence between individual nucleotide positions, the PWMs for some TFs poorly discriminate binding sites from non-binding-sites that have similar sequence content. Since the local three-dimensional DNA structure ('shape') is a determinant of TF binding specificity and since DNA shape has a significant sequence-dependence, we combined DNA shape-derived features into a TF-generalized regulatory score and tested whether the score could improve PWM-based discrimination of TFBS from non-binding-sites.

Results: We compared a traditional PWM model to a model that combines the PWM with a DNA shape feature-based regulatory potential score, for accuracy in detecting binding sites for 75 vertebrate transcription factors. The PWM+shape model was more accurate than the PWM-only model, for 45% of TFs tested, with no significant loss of accuracy for the remaining TFs.

Availability And Implementation: The shape-based model is available as an open-source R package at that is archived on the GitHub software repository at https://github.com/ramseylab/regshape/.

Contact: [email protected]

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btv391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838056PMC
November 2015

A community computational challenge to predict the activity of pairs of compounds.

Nat Biotechnol 2014 Dec 17;32(12):1213-22. Epub 2014 Nov 17.

1] Department of Systems Biology, Columbia University, New York, New York, USA. [2] Center for Computational Biology and Bioinformatics, Columbia University, New York, New York, USA. [3] Department of Biomedical Informatics, Columbia University, New York, New York, USA. [4] Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA. [5] Institute for Cancer Genetics, Columbia University, New York, New York, USA. [6] Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.

Recent therapeutic successes have renewed interest in drug combinations, but experimental screening approaches are costly and often identify only small numbers of synergistic combinations. The DREAM consortium launched an open challenge to foster the development of in silico methods to computationally rank 91 compound pairs, from the most synergistic to the most antagonistic, based on gene-expression profiles of human B cells treated with individual compounds at multiple time points and concentrations. Using scoring metrics based on experimental dose-response curves, we assessed 32 methods (31 community-generated approaches and SynGen), four of which performed significantly better than random guessing. We highlight similarities between the methods. Although the accuracy of predictions was not optimal, we find that computational prediction of compound-pair activity is possible, and that community challenges can be useful to advance the field of in silico compound-synergy prediction.
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http://dx.doi.org/10.1038/nbt.3052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399794PMC
December 2014

Transcriptional interference by antisense RNA is required for circadian clock function.

Nature 2014 Oct 17;514(7524):650-3. Epub 2014 Aug 17.

Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.

Eukaryotic circadian oscillators consist of negative feedback loops that generate endogenous rhythmicities. Natural antisense RNAs are found in a wide range of eukaryotic organisms. Nevertheless, the physiological importance and mode of action of most antisense RNAs are not clear. frequency (frq) encodes a component of the Neurospora core circadian negative feedback loop, which was thought to generate sustained rhythmicity. Transcription of qrf, the long non-coding frq antisense RNA, is induced by light, and its level oscillates in antiphase to frq sense RNA. Here we show that qrf transcription is regulated by both light-dependent and light-independent mechanisms. Light-dependent qrf transcription represses frq expression and regulates clock resetting. Light-independent qrf expression, on the other hand, is required for circadian rhythmicity. frq transcription also inhibits qrf expression and drives the antiphasic rhythm of qrf transcripts. The mutual inhibition of frq and qrf transcription thus forms a double negative feedback loop that is interlocked with the core feedback loop. Genetic and mathematical modelling analyses indicate that such an arrangement is required for robust and sustained circadian rhythmicity. Moreover, our results suggest that antisense transcription inhibits sense expression by mediating chromatin modifications and premature termination of transcription. Taken together, our results establish antisense transcription as an essential feature in a circadian system and shed light on the importance and mechanism of antisense action.
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http://dx.doi.org/10.1038/nature13671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214883PMC
October 2014

Glutathione S-transferase Mu 2-transduced mesenchymal stem cells ameliorated anti-glomerular basement membrane antibody-induced glomerulonephritis by inhibiting oxidation and inflammation.

Stem Cell Res Ther 2014 Jan 30;5(1):19. Epub 2014 Jan 30.

Introduction: Oxidative stress is implicated in tissue inflammation, and plays an important role in the pathogenesis of immune-mediated nephritis. Using the anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM-GN) mouse model, we found that increased expression of glutathione S-transferase Mu 2 (GSTM2) was related to reduced renal damage caused by anti-GBM antibodies. Furthermore, mesenchymal stem cell (MSC)-based therapy has shed light on the treatment of immune-mediated kidney diseases. The aim of this study was to investigate if MSCs could be utilized as vehicles to deliver the GSTM2 gene product into the kidney and to evaluate its potential therapeutic effect on anti-GBM-GN.

Methods: The human GSTM2 gene (hGSTM2) was transduced into mouse bone marrow-derived MSCs via a lentivirus vector to create a stable cell line (hGSTM2-MSC). The cultured hGSTM2-MSCs were treated with 0.5 mM H2O2, and apoptotic cells were measured by terminal dUTP nick-end labeling (TUNEL) assay. The 129/svj mice, which were challenged with anti-GBM antibodies, were injected with 10⁶ hGSTM2-MSCs via the tail vein. Expression of hGSTM2 and inflammatory cytokines in the kidney was assayed by quantitative PCR and western blotting. Renal function of mice was evaluated by monitoring proteinuria and levels of blood urea nitrogen (BUN), and renal pathological changes were analyzed by histochemistry. Immunohistochemical analysis was performed to measure inflammatory cell infiltration and renal cell apoptosis.

Results: MSCs transduced with hGSTM2 exhibited similar growth and differentiation properties to MSCs. hGSTM2-MSCs persistently expressed hGSTM2 and resisted H2O2-induced apoptosis. Upon injection into 129/svj mice, hGSTM2-MSCs migrated to the kidney and expressed hGSTM2. The anti-GBM-GN mice treated with hGSTM2-MSCs exhibited reduced proteinuria and BUN (58% and 59% reduction, respectively) and ameliorated renal pathological damage, compared with control mice. Mice injected with hGSTM2-MSCs showed alleviated renal inflammatory cell infiltration and reduced expression of chemokine (C-C motif) ligand 2 (CCL2), interleukin (IL)-1β and IL-6 (53%, 46% and 52% reduction, respectively), compared with controls. Moreover, hGSTM2-MSCs increased expression of renal superoxide dismutase and catalase, which may associate with detoxifying reactive oxygen species to prevent oxidative renal damage.

Conclusions: Our data suggest that the enhanced protective effect of GSTM2-transduced MSCs against anti-GBM-GN might be associated with inhibition of oxidative stress-induced renal cell apoptosis and inflammation, through over-expression of hGSTM2 in mouse kidneys.
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http://dx.doi.org/10.1186/scrt408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055015PMC
January 2014

Detection of candidate tumor driver genes using a fully integrated Bayesian approach.

Stat Med 2014 May 18;33(10):1784-800. Epub 2013 Dec 18.

Quantitative Biomedical Research Center, Department of Clinical Sciences, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, U.S.A.

DNA copy number alterations (CNAs), including amplifications and deletions, can result in significant changes in gene expression and are closely related to the development and progression of many diseases, especially cancer. For example, CNA-associated expression changes in certain genes (called candidate tumor driver genes) can alter the expression levels of many downstream genes through transcription regulation and cause cancer. Identification of such candidate tumor driver genes leads to discovery of novel therapeutic targets for personalized treatment of cancers. Several approaches have been developed for this purpose by using both copy number and gene expression data. In this study, we propose a Bayesian approach to identify candidate tumor driver genes, in which the copy number and gene expression data are modeled together, and the dependency between the two data types is modeled through conditional probabilities. The proposed joint modeling approach can identify CNA and differentially expressed genes simultaneously, leading to improved detection of candidate tumor driver genes and comprehensive understanding of underlying biological processes. We evaluated the proposed method in simulation studies, and then applied to a head and neck squamous cell carcinoma data set. Both simulation studies and data application show that the joint modeling approach can significantly improve the performance in identifying candidate tumor driver genes, when compared with other existing approaches.
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http://dx.doi.org/10.1002/sim.6066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981913PMC
May 2014

A computational model of fibroblast and macrophage spatial/temporal dynamics in foreign body reactions.

J Immunol Methods 2013 Nov 31;397(1-2):37-46. Epub 2013 Aug 31.

Department of Mathematics, University of Texas at Arlington, Arlington, TX 76019, USA.

The implantation of medical devices often triggers several immune responses, one kind of which is categorized as foreign body reactions. It is well established that macrophages and many other cells participate in the complex processes of foreign body reactions, and cause severe inflammations and fibrotic capsule formation in surrounding tissues. However, the detailed mechanisms of macrophage responses, recruitment and activation, in foreign body reactions are not totally understood. In the meantime, mathematical models have been proposed to systematically decipher the behavior of this complex system of multiple cells, proteins and biochemical processes in wound healing responses. Based on these early works, this study introduces a mathematical model in two spatial dimensions to investigate the transient behavior of macrophages, fibroblasts and their interactions during the formation of fibrotic tissue. We find that the simulation results are consistent with the experimental observations. These findings support that the model can reveal quantitative insights for studying foreign body reaction processes.
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http://dx.doi.org/10.1016/j.jim.2013.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964857PMC
November 2013

Kallikrein transduced mesenchymal stem cells protect against anti-GBM disease and lupus nephritis by ameliorating inflammation and oxidative stress.

PLoS One 2013 23;8(7):e67790. Epub 2013 Jul 23.

Department of Immunology and Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.

Previously we have shown that kallikreins (klks) play a renoprotective role in nephrotoxic serum induced nephritis. In this study, we have used mesenchymal stem cells (MSCs) as vehicles to deliver klks into the injured kidneys and have measured their therapeutic effect on experimental antibody induced nephritis and lupus nephritis. Human KLK-1 (hKLK1) gene was transduced into murine MSCs using a retroviral vector to generate a stable cell line, hKLK1-MSC, expressing high levels of hKLK1. 129/svj mice subjected to anti-GBM induced nephritis were transplanted with 10(6) hKLK1-MSCs and hKLK1 expression was confirmed in the kidneys. Compared with vector-MSCs injected mice, the hKLK1-MSCs treated mice showed significantly reduced proteinuria, blood urea nitrogen (BUN) and ameliorated renal pathology. Using the same strategy, we treated lupus-prone B6.Sle1.Sle3 bicongenic mice with hKLK1-MSCs and demonstrated that hKLK1-MSCs delivery also attenuated lupus nephritis. Mechanistically, hKLK1-MSCs reduced macrophage and T-lymphocyte infiltration into the kidney by suppressing the expression of inflammation cytokines. Moreover, hKLK1 transduced MSCs were more resistant to oxidative stress-induced apoptosis. These findings advance genetically modified MSCs as potential gene delivery tools for targeting therapeutic agents to the kidneys in order to modulate inflammation and oxidative stress in lupus nephritis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067790PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720854PMC
March 2014

Influence of carbon monoxide on growth and apoptosis of human umbilical artery smooth muscle cells and vein endothelial cells.

Int J Biol Sci 2012 17;8(10):1431-46. Epub 2012 Nov 17.

Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.

Carbon monoxide (CO) is a vasoactive molecule that is generated by vascular cells as a byproduct of heme catabolism and it plays an important physiological role in circulation system. In order to investigate whether exogenous CO can mediate the growth and proliferation of vascular cells, in this study, we used 250 parts per million (ppm) of CO to treat human umbilical artery smooth muscle cell (hUASMC) and human umbilical vein endothelial cell (HuVEC) and further evaluated the growth and apoptosis status of SMC and HuVEC. After SMC and HuVEC were exposed to CO for 7-day, the growth of SMC and HuVEC was significantly inhibited by CO in vitro on day 5 of CO exposure. And CO blocked cell cycle progress of SMC and HuVEC, more SMC and HuVEC stagnated at G0/G1 phase by flow cytometric analysis. Moreover, CO treatment inhibited SMC and HuVEC apoptosis caused by hydrogen peroxide through decreasing caspase 3 and 9 activities. To confirm the molecular mechanism of CO effect on SMC and HuVEC growth, we compared the gene expression profile in SMC and CO-treated SMC, HuVEC and CO-treated HuVEC. By microarray analysis, we found the expression level of some genes which are related to cell cycle regulation, cell growth and proliferation, and apoptosis were changed during CO exposure. We further identified that the down-regulated CDK2 contributed to arresting cell growth and the down-regulated Caspase 3 (CASP3) and Caspase 9 (CASP9) were associated with the inhibition of cell apoptosis. Therefore, CO exerts a certain growth arrest on SMC and HuVEC by inhibiting cell cycle transition from G0/G1 phase to S phase and has regulatory effect on cell apoptosis by regulating the expression of apoptosis-associated genes.
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http://dx.doi.org/10.7150/ijbs.4664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509336PMC
May 2013
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